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Health Technology Assessment 2010; Vol. 14: No. 47
Intensity-modulated radiotherapy
for the treatment of prostate cancer:
a systematic review and economic
evaluation
S Hummel, EL Simpson, P Hemingway,
MD Stevenson and A Rees
October 2010
10.3310/hta14470
Health Technology Assessment
NIHR HTA programme
www.hta.ac.uk
HTA
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Intensity-modulated radiotherapy
for the treatment of prostate cancer:
a systematic review and economic
evaluation
S Hummel,* EL Simpson, P Hemingway,
MD Stevenson and A Rees
School of Health and Related Research (ScHARR), The University of
Sheffield, Sheffield, UK
*Corresponding author
Declared competing interests of authors: none
Published October 2010
DOI: 10.3310/hta14470
This report should be referenced as follows:
Hummel S, Simpson EL, Hemingway P, Stevenson MD, Rees A. Intensity-modulated
radiotherapy for the treatment of prostate cancer: a systematic review and economic
evaluation. Health Technol Assess 2010;14(47).
Health Technology Assessment is indexed and abstracted in Index Medicus/MEDLINE,
Excerpta Medica/EMBASE, Science Citation Index Expanded (SciSearch) and Current
Contents /Clinical Medicine.
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T
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G
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Abstract
Intensity-modulated radiotherapy for the treatment
of prostate cancer: a systematic review and economic
evaluation
S Hummel,* EL Simpson, P Hemingway, MD Stevenson and A Rees
School of Health and Related Research (ScHARR), The University of Sheffield, Sheffield, UK
*Corresponding author
Background: Prostate cancer (PC) is the most
common cancer in men in the UK. Radiotherapy
(RT) is a recognised treatment for PC and high-dose
conformal radiotherapy (CRT) is the recommended
standard of care for localised or locally advanced
tumours. Intensity-modulated radiotherapy (IMRT)
allows better dose distributions in RT.
Objective: This report evaluates the clinical
effectiveness and cost-effectiveness of IMRT for the
radical treatment of PC.
Data sources: The following databases were
searched: MEDLINE (1950–present), EMBASE (1980–
present), Cumulative Index to Nursing and Allied
Health Literature (CINAHL) (1982–present), BIOSIS
(1985–present), the Cochrane Database of Systematic
Reviews (1991–present), the Cochrane Controlled
Trials Register (1991–present), the Science Citation
Index (1900–present) and the NHS Centre for Reviews
and Dissemination databases (Database of Abstracts
of Reviews of Effects, NHS Economic Evaluation
Database, Health Technology Assessment) (1991–
present). MEDLINE In-Process & Other Non-Indexed
Citations was searched to identify any studies not yet
indexed on MEDLINE. Current research was identified
through searching the UK Clinical Research Network,
National Research Register archive, the Current
Controlled Trials register and the Medical Research
Council Clinical Trials Register. In addition, abstracts
of the American Society of Clinical Oncology, the
American Society for Therapeutic Radiology and
Oncology, and European Society for Therapeutic
Radiology and Oncology conferences were browsed.
Review methods: A systematic literature review
of the clinical effectiveness and cost-effectiveness
of IMRT in PC was conducted. Comparators were
three-dimensional conformal radiotherapy (3DCRT)
or radical prostatectomy. Outcomes sought were
overall survival, biochemical [prostate-specific antigen
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
(PSA)] relapse-free survival, toxicity and health-related
quality of life (HRQoL). Fifteen electronic bibliographic
databases were searched in January 2009 and updated
in May 2009, and the reference lists of relevant articles
were checked. Studies only published in languages
other than English were excluded. An economic model
was developed to examine the cost-effectiveness of
IMRT in comparison to 3DCRT. Four scenarios were
modelled based on the studies which reported both
PSA survival and late gastrointestinal (GI) toxicity.
In two scenarios equal PSA survival was assumed
for IMRT and 3DCRT, the other two having greater
PSA survival for the IMRT cohort. As there was very
limited data on clinical outcomes, the model estimates
progression to clinical failure and PC death from the
surrogate outcome of PSA failure.
Results: No randomised controlled trials (RCTs)
of IMRT versus 3DCRT in PC were available, but
13 non-randomised studies comparing IMRT with
3DCRT were found, of which five were available only
as abstracts. One abstract reported overall survival.
Biochemical relapse-free survival was not affected
by treatment group, except where there was a dose
difference between groups, in which case higher dose
IMRT was favoured over lower dose 3DCRT. Most
studies reported an advantage for IMRT in GI toxicity,
attributed to increased conformality of treatment
compared with 3DCRT, particularly with regard to
volume of rectum treated. There was some indication
that genitourinary toxicity was worse for patients
treated with dose escalated IMRT, although most
studies did not find a significant treatment effect.
HRQoL improved for both treatment groups following
radiotherapy, with any group difference resolved by
6 months after treatment. No comparative studies
of IMRT versus prostatectomy were identified. No
comparative studies of IMRT in PC patients with bone
metastasis were identified.
iii
Abstract
Limitations: The strength of the conclusions of
this review are limited by the lack of RCTs, and any
comparative studies for some patient groups.
Conclusions: The comparative data of IMRT versus
3DCRT seem to support the theory that higher
doses, up to 81 Gy, can improve biochemical survival
for patients with localised PC, concurring with data
on CRT. The data also suggest that toxicity can be
iv
reduced by increasing conformality of treatment,
particularly with regard to GI toxicity, which can
be more easily achieved with IMRT than 3DCRT.
Whether differences in GI toxicity between IMRT and
3DCRT are sufficient for IMRT to be cost-effective is
uncertain, depending on the difference in incidence
of GI toxicity, its duration and the cost difference
between IMRT and 3DCRT.
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Contents
Glossary and list of abbreviations ........... vii
Appendix 3 Quality assessment of the
eight studies fully reported in peerreviewed publications ............................... 85
Executive summary .................................. xi
1Background ............................................... 1
Description of health problem ................. 1
Current service provision ......................... 9
Description of technology under
assessment ............................................ 11
Appendix 4 Quality assessment for the
five included abstracts .............................. 89
Appendix 5 Table of key excluded
studies with rationale ............................... 91
2 Definition of the decision problem ......... 15
Decision problem ..................................... 15
Overall aims and objectives of
assessment ............................................ 15
Appendix 6 Resource use and cost
assumptions for IMRT and 3DCRT ......... 93
Appendix 7 Critical appraisal checklist
for the economic evaluations using key
components of the British Medical Journal
checklist for economic evaluations
together with the Eddy checklist on
mathematical models employed in
technology assessments ............................ 95
Appendix 8 Example search for
cost and cost-effectiveness evidence
(MEDLINE) .............................................. 97
Appendix 9 Summary study survival
and toxicity data by dose .......................... 99
3 Assessment of clinical effectiveness ....... 17
Methods for reviewing effectiveness ......... 17
Results ...................................................... 18
4 Assessment of cost-effectiveness ........... 33
Systematic review of existing costeffectiveness evidence .......................... 33
Independent economic assessment .......... 34
5 Assessment of factors relevant to the
NHS and other parties ............................. 53
Factors relevant to the NHS ..................... 53
Factors relevant to other parties .............. 53
6Discussion .................................................. 55
Statement of principal findings ................ 55
Strengths and limitations of the
assessment ............................................ 56
Uncertainties ............................................ 56
Appendix 10 Biological equivalent
radiotherapy doses ................................... 101
Appendix 11 Example search for utility
values in prostate cancer (MEDLINE) ..... 103
7Conclusions ............................................... 57
Implications for service provision ............ 57
Suggested research priorities ................... 57
Appendix 12 Unit cost ............................ 105
Appendix 13 Prostate-specific antigen
variable distribution parameters .............. 107
Acknowledgements ................................ 59
Health Technology Assessment
reports published to date ........................ 109
Health Technology Assessment
programme ............................................... 133
References ................................................. 61
Appendix 1 Literature search strategies ... 73
Appendix 2 Data abstraction tables ........ 75
v
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Glossary and list of abbreviations
Glossary
Adjuvant radiotherapy Radiotherapy
supplementary to the main treatment (usually
surgery, chemotherapy), given after main
treatment.
Androgen deprivation A form of hormonal
therapy, given to suppress or block the
production or action of male sex hormones
(androgens).
Chemotherapy Treatment with cytotoxic drugs
that kill cancer cells, or prevent or slow their
growth.
clinical target volume Clinically defined
target volume, containing tumour, unless
surgically excised, and microscopic invisible
tumour; to be treated with the prescribed
radiation dose.
Compensators/dose compensators Method of
dose modulation.
Computed tomography An X-ray technique
using a scanner to take a series of images across
the body.
Conformal radiotherapy Radiotherapy
delivered by non-modulated beams, which can
be shaped geometrically to avoid irradiating
normal surrounding tissue.
Distant recurrence Recurrence of cancer at
distant sites.
Dose escalation Increasing the total
radiotherapy dose.
Dose–volume histogram Histogram showing
the dose distribution within an outlined
structure, often presented as cumulative plotvolume of organ plotted against dose.
Dosimetrist Specialist radiotherapy planning
staff, also known as clinical technologist.
Forward planned intensity-modulated
radiotherapy (IMRT) The planner modifies a
provisional plan (based on the treatment beam
arrangements that are likely to be used) until
the dose distribution is improved.
Fraction A unit of radiotherapy treatment.
Fractionation Schedule of treatment sessions
required for a course of radiotherapy treatment.
Gross tumour volume The gross palpable or
visible/demonstrable extent and location of the
malignant growth.
Gy A unit of radiation (Gray) used to measure
radiation dose.
Histological grade Measure of the malignancy
of a tumour.
Hypofractionated The radiotherapy dose per
fraction is greater than standard care, requiring
fewer total fractions to achieve the same
biological equivalent dose (BED) as for standard
fractionation (see Appendix 9).
Immobilisation Techniques designed to reduce
patient movement during radiotherapy.
Incremental cost-effectiveness ratio
(ICER) The ratio of the incremental cost of
the new treatment compared with the existing
treatment to the incremental effectiveness,
the latter usually being expressed in qualityadjusted life-years (QALYs).
Intensity-modulated radiotherapy The beam
of radiation is not uniform across the field to be
irradiated, but consists of beamlets of varying
intensity. Combinations of several intensitymodulated fields coming from different beam
directions are used to create a highly conformal
dose distribution.
vii
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Glossary and list of abbreviations
Inverse planned IMRT Utilises computers,
manipulating many hundreds of treatment
beamlets, in order to produce highly complex
treatment plans. The computer iteratively
attempts to fulfil the planner’s defined dose
target and normal tissue constraints.
Linear accelerator Machine that generates and
delivers radiation.
Locoregional recurrence Recurrence of cancer
at local or regional sites, e.g. within lymph
nodes.
Lymph nodes Small structures that act as filters
in the lymphatic system.
Metastases/metastatic cancer Cancer which has
spread to distant sites from the primary tumour.
Multileaf collimator Device attached to or
inherent within to linear accelerator to allow
beam modulation, uses a number of leaves to
create an irregular shaped radiation beam.
Neoadjuvant Treatment given prior to surgery,
chemotherapy or radiotherapy.
Overall survival Outcome measure defined as
the hazard of death from any cause after a given
follow-up period, or time from randomisation to
death from any cause.
Planned dose inhomogeneity Planning higher
doses to regions of high risk and lower doses
to regions of low risk, usually termed with
treatment delivered with a single treatment
plan.
Planning target volume Geometrical concept
defined to ensure that appropriate beam sizes
and arrangements are chosen so that the
viii
prescribed dose is directed to the clinical target
volume, taking into account setup and delivery
errors and physiological changes such as motion
and changes in tumour volume.
Progression-free survival Outcome measure
defined as the hazard of disease progression
or death from any cause after a given follow-up
period, or time from randomisation to first of
these events.
Prostatectomy Surgery to remove all of the
prostate gland and some of the tissue around it,
to treat prostate cancer.
Quality-adjusted life-years (QALYs) The
number of life-years adjusted for population
preferences for different health states. A lifeyear in perfect health is 1 QALY.
Quality assurance Procedures that ensure
consistency of the prescription and safe delivery
of prescription dose to the target volume.
Radiotherapy/radiation therapy Radiation
delivered locally to affected site to kill cancer
cells, or to stop cancer cells from dividing and
growing.
Short Form questionnaire-36 items A healthrelated quality of life scale.
Staging/stage of cancer An internationally
recognised system for defining a tumour in
terms of its size and degree of spread through
the body.
Toxicity grade A measure of the severity of
adverse events, either during radiotherapy
(acute) or long-term toxicity (chronic).
Wedges Method of dose modulation.
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
List of abbreviations
3DCRT
three-dimensional conformal
radiotherapy
AE
adverse event
ASCO
American Society of Clinical
Oncology
ASTRO
GTV
gross tumour volume
GU
genitourinary
HR
hazard ratio
HRQoL
health-related quality of life
American Society of Therapeutic
Radiology and Oncology
ICER
incremental cost-effectiveness
ratio
BED
biological equivalent dose
ICRU
BPE
benign prostatic enlargement
International Commission
on Radiation Units and
Measurements
CHHiP
Conventional or
Hypofractionated High
dose Intensity-modulated
radiotherapy for Prostate cancer
IGRT
image-guided radiotherapy
IMRT
intensity-modulated
radiotherapy
CI
confidence interval
IPEM
CRT
conformal radiotherapy
Institute of Physics and
Engineering in Medicine
CT
computed tomographic
LUTS
lower urinary tract symptoms
CTV
clinical target volume
MAICER
maximum incremental costeffectiveness ratio
DRE
digital rectal examination
MLC
multileaf collimator
EORTC
European Organisation for
Research and Treatment of
Cancer
MRC
Medical Research Council
MRI
magnetic resonance imaging
European Organisation for
Research and Treatment of
Cancer Prostate Cancer-specific
Questionnaire
NCCN
National Comprehensive Cancer
Network
NCI
National Cancer Institute
EPIC
Expanded Prostate Cancer
Index Composite
NCI-CTC
National Cancer Institute–
Common Toxicity Criteria
EQ-5D
European Quality of Life-5
Dimensions
NICE
National Institute for Health and
Clinical Excellence
ESTRO
European Society for
Therapeutic Radiology and
Oncology
NRAG
National Radiotherapy Advisory
Group
GI
gastrointestinal
PC
prostate cancer
GP
general practitioner
PSA
prostate-specific antigen
EORTC
QLQ-PR25
ix
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Glossary and list of abbreviations
PTV
planning target volume
SD
standard deviation
QA
quality assurance
SF-36
QALY
quality-adjusted life-year
Short Form questionnaire-36
items
RCR
Royal College of Radiologists
SV
seminal vesicle
RCT
randomised controlled trial
TNM
tumour node metastasis
RT
radiotherapy
TRUS
trans-rectal ultrasonography
RTOG
Radiation Therapy Oncology
Group
UCLA PCI
University of California Los
Angeles Prostate Cancer Index
SCOR
Society and College of
Radiographers
WP
whole pelvis
All abbreviations that have been used in this report are listed here unless the abbreviation is well
known (e.g. NHS), or it has been used only once, or it is a non-standard abbreviation used only in
figures/tables/appendices, in which case the abbreviation is defined in the figure legend or in the
notes at the end of the table.
x
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Executive summary
Background
Results
Prostate cancer (PC) is the most common cancer in
men in the UK. Radiotherapy (RT) is a recognised
treatment for PC and high-dose conformal
radiotherapy (CRT) is the recommended standard
of care for localised or locally advanced tumours.
Intensity-modulated radiotherapy (IMRT) allows
better dose distributions in RT.
No randomised controlled trials (RCTs) of IMRT
versus 3DCRT in PC were available, but 13 nonrandomised studies comparing IMRT with 3DCRT
were found, of which five were only available as
abstracts. One abstract reported overall survival.
Biochemical relapse-free survival was not affected
by treatment group, except where there was a dose
difference between groups, in which case higher
dose IMRT was favoured over lower dose 3DCRT.
Most studies reported an advantage for IMRT in
GI toxicity, attributed to increased conformality
of treatment compared with 3DCRT, particularly
with regard to volume of rectum treated. There
was some indication that genitourinary (GU)
toxicity was worse for patients treated with doseescalated IMRT, although most studies did not find
a significant treatment effect. HRQoL improved
for both treatment groups following RT, with
any group difference resolved by 6 months after
treatment. No comparative studies of IMRT versus
prostatectomy were identified. No comparative
studies of IMRT in PC patients with bone
metastasis were identified.
Objectives
This report evaluates the clinical effectiveness
and cost-effectiveness of IMRT for the radical
treatment of PC.
Methods
A systematic literature review of the clinical
effectiveness and cost-effectiveness of IMRT in
PC was conducted. Comparators were threedimensional conformal radiotherapy (3DCRT)
or radical prostatectomy. Outcomes sought were
overall survival, biochemical [prostate-specific
antigen (PSA)] relapse-free survival, toxicity and
health-related quality of life (HRQoL). Fifteen
electronic bibliographic databases were searched
(including MEDLINE, EMBASE, Cumulative
Index to Nursing and Allied Health Literature
(CINAHL), MEDLINE In-Process & Other NonIndexed Citations, etc.) in January 2009 and
updated in May 2009, and the reference lists
of relevant articles were checked. Studies only
published in languages other than English were
excluded.
An economic model was developed to examine
the cost-effectiveness of IMRT in comparison to
3DCRT. Four scenarios were modelled based on
the studies which reported both PSA survival and
late gastrointestinal (GI) toxicity. In two scenarios
equal PSA survival was assumed for IMRT and
3DCRT, the other two having greater PSA survival
for the IMRT cohort. As there was very limited
data on clinical outcomes, the model estimates
progression to clinical failure and PC death from
the surrogate outcome of PSA failure.
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Summary of costs
The additional cost of IMRT compared with
3DCRT was estimated to be £1100, arising from
additional medical, radiographer and physics staff
time.
Summary of cost-effectiveness
For the scenarios with greater survival for IMRT
than 3DCRT-treated patients the results are
unambiguous. IMRT either dominates 3DCRT
[that is results in more quality-adjusted life-years
(QALYs) for lower total costs], or the incremental
cost-effectiveness ratio (ICER) is relatively modest
(£5000), results which are robust to variation in
other key parameters.
The two scenarios where equivalent survival
is assumed for IMRT and 3DCRT, and QALY
differences between the two cohorts are derived
solely from differences in late GI toxicity alone,
show IMRT to be borderline cost-effective
xi
Executive summary
depending on the difference in GI toxicity,
duration of GI toxicity and the cost difference
between IMRT and 3DCRT. At baseline parameter
values the scenario with a difference in late
GI toxicity of 5% (scenario 1) gave an ICER of
£104,000, but scenario 2 with a difference in
GI toxicity of 15% gave an ICER of £31,000.
The probabilistic analysis of the latter scenario
showed that only with a maximum incremental
cost-effectiveness ratio (MAICER) of ≥ £30,000
was it probable that IMRT was more costeffective than 3DCRT. These results are highly
sensitive to two very uncertain parameters: the
incremental cost of IMRT and the duration of late
GI toxicity. Variation of these parameters within
plausible bounds can reduce the ICER of IMRT
in comparison to 3DCRT to below a threshold
of £20,000, or equally push it clearly beyond a
threshold of £30,000. The scenarios modelled
were all based on studies where both PSA survival
and toxicity were reported. To put the values of
incidence of late GI toxicity from the modelled
studies in context the results of other studies
included in the review were considered. These
suggest model scenario 2 is more representative of
the literature than scenario 1.
For RT to the whole pelvis (usually only considered
for men with a > 15% risk of pelvic lymph node
involvement) IMRT may be more cost-effective
than for treatment of the prostate (and seminal
vesicles) alone. A previous report published
by Sanguineti et al. (Sanguineti G, Cavey ML,
Endres EJ, Franzone P, Barra S, Parker BC, et al.
Does treatment of the pelvic nodes with IMRT
increase late rectal toxicity over conformal prostate
only radiotherapy to 76 Gy? Strahlenther Onkol
2006;182:543–9) reports a difference of 15% in
late GI toxicity at only two years, despite the IMRT
group receiving whole pelvis RT in comparison to
treatment of the prostate only in the comparator
(3DCRT) group.
xii
Discussion
A comprehensive, systematic literature review was
undertaken, but the strength of the conclusions
of this review are limited by the lack of RCTs, and
any comparative studies for some patient groups.
The comparative data of IMRT versus 3DCRT
seem to support the theory that higher doses, up
to 81 Gy, can improve biochemical survival for
patients with localised PC, concurring with data
on CRT. The data also suggest that toxicity can be
reduced by increasing conformality of treatment,
particularly with regard to GI toxicity, which can
be more easily achieved with IMRT than 3DCRT.
Whether differences in GI toxicity between IMRT
and 3DCRT are sufficient for IMRT to be costeffective is uncertain, depending on the difference
in incidence of GI toxicity, its duration and the cost
difference between IMRT and 3DCRT.
Conclusions
Implications for service
provision
Clinical advice suggests that most RT centres
already possess the equipment required to
deliver IMRT, but that lack of available staff such
as medical physicists hinders implementation.
3DCRT may be safely delivered at the currently
recommended total dose of 74 Gy, and there is no
evidence that PSA survival is improved by giving
IMRT at the same dose as 3DCRT. However,
there is evidence that IMRT reduces toxicity,
in particular late GI toxicity. The magnitude
of the difference is uncertain, which, together
with uncertainties in other variables such as the
difference in cost between IMRT and 3DCRT,
in turn makes the cost-effectiveness of IMRT in
comparison to 3DCRT uncertain. If a difference in
late GI toxicity of 15% is assumed the probability
of IMRT being more cost-effective than 3DCRT is
only true for a MAICER of ≥ £30,000.
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Chapter 1
Background
Description of health
problem
Prostate cancer (PC) is the most common cancer
in men in England and Wales and constitutes
approximately 25% of the new diagnoses of
malignant cancer in men in England and Wales.1
The incidence appears to be rising.1 It is also
considered to be the most common malignant
disease in males in Western Europe and North
America.2 The focus of this systematic review will
be to address the question ‘what is the clinical
and cost-effectiveness of intensity-modulated
radiotherapy (IMRT) for the radical treatment of
PC compared with three-dimensional radiotherapy
(3DCRT) and radical prostatectomy?’.
Aetiology, pathology and
prognosis
The specific causes of PC remain unknown.2 Hsing
and Chokkalingam provided a comprehensive
review of PC epidemiology3 and reported that the
risk of developing PC was related to: age, genetics,
and family history of PC. It was reported that
putative risk factors include: obesity, hormones,
smoking, dietary factors, physical inactivity,
occupation, vasectomy, genetic susceptibility, and
sexual factors have also been implicated.
Localised PC (confined within the prostatic
capsule) is usually asymptomatic in the early
stage.4 However, with regard to locally advanced
PC it is because it is frequently asymptomatic in
the early stage that it often presents at a more
advanced stage. Lower urinary tract symptoms
(LUTS) of frequency, urgency, hesitancy, terminal
dribbling and/or overactive bladder can be related
to benign prostatic enlargement (BPE) alone,
but can also present in early PC and in locally
advanced PC cases.5 The LUTS often present in
a similar way to symptoms of benign prostatic
hyperplasia within locally advanced PC.5 However,
by the time PC itself causes LUTS, it may have
reached an advanced and incurable stage.4 Garrick
suggests that a new onset of impotence should
also be recognised.6 PC frequently develops into
bone metastases which causes pain. An abnormal
or rising prostate-specific antigen (PSA) level is
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
the most common indication of PC in the UK
health-care system. In the UK, a diagnosis of PC
is typically prompted by urological symptoms
and biochemical information (particularly PSA).7
Collin et al. conclude in a case-control study nested
within the UK population-based Prostate testing
for cancer and Treatment (ProtecT) study, that a
history of LUTS before PSA testing marginally
improves the prediction of an individual’s risk
of PC.8 The PSA test and other ways to measure
PC are described in more detail in Subgroups of
patients with PC for whom radiotherapy (RT) may
be indicated.
Prostate cancer is no longer seen as solely an
indolent disease that rarely results in mortality for
PC patients.9 Johansson et al. examined the natural
course of early localised PC in a consecutive
sample of 223 initially untreated patients observed
over 21 years and found that although most PCs
diagnosed at an early stage have an indolent
course, local tumour progression and aggressive
metastatic disease may develop in the long term.9
The findings support early radical treatment
notably among patients with an estimated life
expectancy exceeding 15 years.9 Furthermore,
as men’s life expectancy increases, the effect
of untreated PC may need to be re-evaluated.
A recent study by Widmark et al.10 showed that
in patients with locally advanced or high-risk
localised PC, addition of local RT to endocrine
treatment halved the 10-year PC-specific mortality
(23.9% in the endocrine alone group and 11.9% in
the endocrine plus RT group), and substantially
decreased overall mortality with fully acceptable
risk of side-effects compared with endocrine
treatment alone. In the light of these data
endocrine treatment plus RT may be regarded as
the new standard.10
Ongoing research may clarify how best to treat
men with PC. With regard to early PC, the
ProtecT randomised controlled trial (RCT)
aims to evaluate the clinical effectiveness, costeffectiveness and acceptability of active monitoring,
radical prostatectomy and radical conformal
radiotherapy (CRT) for men with localised PC.8
In addition, the ProSTART study, a pilot study for
an international phase III randomised parallel
1
Background
group trial in patients with favourable risk PC (as
defined as clinical stage T1b, T1c, T2a or T2b at
time of diagnosis), is comparing active surveillance
therapy against radical treatment (prostatectomy
or RT).11 With regard to more advanced PC, the
Medical Research Council (MRC) PR07 study,12 is
investigating the role of RT in locally advanced
PC. In this trial, men with locally advanced nonmetastatic PC are randomised between hormone
therapy alone and hormone therapy plus RT.
However, it is noted that if the subjects are
allocated RT [given to the prostate and pelvis (or
prostate alone if necessary)] in doses up to 69 Gy
this is below the usual IMRT dose level.12
Incidence and prevalence
The incidence of PC in the UK, in common with
many other countries, has been rising.13 In 2006,
there were 35,515 new cases of PC diagnosed in the
UK.14 Despite the large increase in incidence, the
mortality rate has been relatively stable.14
Prostate cancer frequently progresses slowly
and men with less aggressive disease rarely die
of their cancer, but this is not the case for those
men with the most aggressive tumours (poorly
differentiated).2 Table 1 shows the percentage of
men in whom PC was detected at autopsy in the
USA.4,15 Burford et al. reported that 93% of PC
deaths occur in the 65 and over age group.4 By the
age of 80 years, approximately 80% of men will
have some cancer cells in their prostate. Table 1
indicates that prevalence of PC increases with age,
but is not insignificant at younger ages.4,15
However, the extent of age-adjusted PC incidence
rates varies considerably throughout the world.
Between 1996 and 2006 the age-standardised (to
the world standard population) rate in the UK
increased by nearly 38%.16 The lifetime risk of PC
diagnosis has been estimated at 10%.14 Further
statistics concerning the incidence rates of PC in
the UK during 2006 are reported in Table 2. The
majority of cases are in England; however, in terms
of the crude rate per 100,000 population, Wales
has the highest rate and Scotland has the lowest
rate.
Prostate cancer risk is strongly related to age;
very few diagnosed cases are registered in men
under 50 years and three-quarters of cases occur
in men over 65 years. The largest number of cases
is diagnosed in those aged 70–74 years.14 Figure 1
reports the age-specific incidence rates for PC in
the UK during 2006.
Impact of health problem
Prostate cancer is a major health problem and
is a significant burden to patients and the NHS
in England and Wales.13 Sutcliffe et al.2 reported
that PC is a primary reason for consultation
with general practitioners (GPs) among men
with cancer. It has been estimated that PC in
England and Wales costs the health service at
least £45M per year.17 This is likely to be increased
TABLE 1 Percentage of men with prostate cancer at autopsy in the USA4,15
Age (years)
20–29
30–39
40–49
50–59
60–69
70–79
Percentage of men in whom PC was detected at autopsy
8
28
39
53
66
80
TABLE 2 Number of new cases and rates of prostate cancer in the UK during 200614
England
Wales
Scotland
Northern
Ireland
UK
30,024
2164
2,506
821
35,515
149.8
101.5
96.2
119.6
Cases
Male
Crude rate per 100,000 population
Male
120.5
Age-standardised rate (European) per 100,000 population
2
Male
98.1
108.2
81.6
92.1
97.1
95% CI
97.0 to 99.2
103.7 to 112.8
78.4 to 84.8
85.8 to 98.4
96.1 to 98.1
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
8000
1000
Male cases
800
Number of cases
6000
5000
600
4000
400
3000
2000
200
Rate per 100,000 population
7000
Male rates
1000
0
85+
80–84
75–79
70–74
65–69
60–64
55–59
50–54
45–49
40–44
35–39
30–34
25–29
20–24
15–19
5–9
10–14
0–4
0
Age at diagnosis (years)
FIGURE 1 Numbers of new cases and age-specific incidence rates of male prostate cancer in the UK during 2006.14
by the burden of disease from bone metastasis
(and prolonged palliative care) and this has
repercussions in terms of cost to society, decreased
quality of life and decreased survival.17 In addition
there is a significant patient burden of stress and
anxiety, sexual function, urinary function, bowel
function18 and potential loss of earnings.
Subgroups of patients with
prostate cancer for whom
radiotherapy may be indicated
Several patient subgroups exist where RT may be
used:
• primary radical treatment of localised cancers
• primary radical treatment of locally advanced
cancers (prostate or whole pelvis)
• adjuvant RT treatment for high risk radical
prostatectomy patients (prostate or whole
pelvis)
• salvage treatment (prostate or whole pelvis)
• palliation of bone metastases.
The latest National Institute for Health and
Clinical Excellence (NICE) clinical guideline
20081 states that several factors have been shown
to predict the risk of recurrence after treatment
of localised PC. These include the Gleason
score, the serum PSA level, and the clinical T
stage [according to the tumour node metastasis
(TNM) staging system]. Table 3 provides a fuller
description of the TNM staging system. These
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
predictive factors have been used to classify
localised PC into recurrence risk groups,
specifically:
• low-risk: PSA < 10 ng/ml and Gleason score ≤ 6
and clinical stage T1–T2a
• intermediate-risk: PSA 10–20 ng/ml or Gleason
score 7 or clinical stage T2b–T2c
• high-risk: PSA > 20 ng/ml or Gleason score
8–10 or clinical stage T3–T4.1
Adjuvant and salvage radiotherapy
Adjuvant RT is an additional treatment given to
patients with PC after localised therapy, such as
surgery, which ‘assists’ the primary treatment.
Adjuvant RT may be offered to some patients
in the UK, but until recently was not standard
treatment. The NICE PC guideline1 advised
that immediate post-operative RT after radical
prostatectomy is not routinely recommended,
even in men with margin-positive disease, other
than in the context of a clinical trial. However,
recent trial data appears to supersede the NICE
guideline. Cozzarini et al.19 conducted a phase I to
II trial with 50 patients; they found excellent acute
and early late toxicity outcomes of a moderately
hypofractionated regimen with post-operative early
adjuvant RT delivered by helical tomotherapy,
which is a form of adaptive IMRT technology.
In addition, Wiegel et al.20 examined 192 men
assigned to a wait-and-see policy compared with
193 men assigned to immediate post-operative RT.
These authors examined the primary end point
3
Background
of biochemical progression-free survival. Wiegel et
al. concluded that adjuvant RT for T3 PC patients
with postoperatively undetectable PSA significantly
reduces the risk of biochemical progression;
however, further follow-up is needed to assess the
effect on metastases-free and overall survival.
Further recent evidence by Thompson et al.21
from the South West Oncology Group supports
that adjuvant RT after radical prostatectomy for
men with PC graded as T3N0M0 using the TNM
classification system significantly reduces the risk
of metastasis and increases survival.
Salvage RT is performed after surgery to help
eliminate any remaining cancerous cells in patients
with biochemical relapse. Salvage treatment in
the form of radical RT treatment to the prostatic
bed should be offered to patients after radical
prostatectomy treatment if they have PSA failure,
but there is no evidence of metastases. It is
uncertain whether adjuvant hormonal therapy
should also be given.
Whole pelvis radiotherapy
The role of whole pelvis RT (to include the
treatment of pelvic lymph nodes) for primary or
salvage treatment is controversial. The treatment
may result in an increased risk of adverse effects
and these patients have a relatively poor longterm survival (< 10 years). However, the use of
IMRT could potentially reduce the toxic effects
of treatment due to a more focused delivery of
RT. The 2008 PC guideline1 recommends that
treatment to the prostate alone is currently the
standard approach to radical RT for PC in the
UK. In common with other cancer sites (e.g.
breast), there may be a benefit from treating
regional lymph nodes as well. However NICE
also recommends that clinical oncologists should
consider pelvic RT in men with locally advanced
PC who have a > 15% risk of pelvic lymph node
involvement, who are to receive neoadjuvant
hormonal therapy and radical RT.
Measurement of disease
Several methods of measurement of PC currently
exist. The following section presents the most
common measurement methods (which are
predictive parameters of disease) seen in studies of
IMRT.
4
Gleason grading system
The initial diagnosis of PC requires confirmation
and is performed via histological examination of
prostate tissue from trans-rectal ultrasonography
(TRUS) biopsy samples.4 A TRUS biopsy involves
taking 10–12 cores of prostatic tissue through
the rectum under ultrasound guidance and the
result reveals the level of tumour differentiation.4
The predominant histological system for tumour
differentiation is the Gleason grading system via
analysing the most common tumour patterns.
Each tumour pattern is assigned a grade (1 to 5)
and these grades are combined to produce the
Gleason score of 2–10.4 Burford et al.4 indicate that
the lower the score, the more well differentiated
the tumour, the less likely the tumour is to
progress and the better the prognosis. Tumours
can be classified into low grade (≤ 6), intermediate
grade (= 7) and high grade (8–10). Berney et al.22
reassigned Gleason grades to 1789 localised PC
patients in the UK between 1991 and 1996 and
found that there was significant reassignment
in the Gleason score with increases of Gleason
score across a wide spectrum of patients (the same
data were reclassified as far as it is possible to
determine). A drift in Gleason score over the past
decade has also been reported by Veldeman et al.23
This relates to the observation that PCs are now
commonly graded higher than in previous decades
due to diagnostic improvements, resulting in a
greater percentage of higher-grade PCs.
TNM staging system and ABCD system
Developed in France in the 1940s by Pierre
Denoix, the TNM classification has become
the accepted basis of cancer staging24 and has
undergone several revisions. Table 3 shows the
2002 version (Sixth Edition),25 as, where stated,
the studies included in this review use either the
1992 or 2002 version. However, a later version
(Seventh Edition) was published in 2009.25 In
Europe, the TNM staging system has been most
commonly used to establish how far the disease
has progressed.26 The letter T refers to the size
of the primary tumour, N describes the extent
of lymph node involvement and M refers to the
presence or absence of metastases.27 T1 and T2
are considered to be localised PC and both T3
and T4 are often referred to as locally advanced
disease. However, some studies include patients
classified as stages T1, T2 and T3 in the study of
localised PC.28,29 There are two key changes to the
2002 TNM classification system compared with the
older versions, these being: (1) subdivision of the
T2 disease into three clinical substages, and (2)
recommendation that the Gleason scoring system
is used for grading.2
The clinical stage is based on information obtained
before surgery to remove the tumour and can
DOI: 10.3310/hta14470
be limited since the information is obtained by
making indirect assessment of the tumour while it
is still in the patient.2 Pathologic staging provides
Health Technology Assessment 2010; Vol. 14: No. 47
additional information from the microscopic
examination of the tumour2 and provides a direct
examination of the tumour and its spread.
TABLE 3 Tumour node metastasis staging system (2002)25
Primary tumour, clinical (T)
TX
Primary tumour cannot be assessed
T0
No evidence of primary tumour
T1
Clinically unapparent tumour not palpable or visible by imaging
T1a
Tumour incidental histologic finding in ≤ 5% of tissue resected
T1b
Tumour incidental histologic finding in > 5% of tissue resected
T1c
Tumour identified by needle biopsy (because of elevated PSA level); tumours found in one or both lobes by
needle biopsy but not palpable or reliably visible by imaging
T2
Tumour confined within prostate
T2a
Tumour involving less than or equal to half a lobe
T2b
Tumour involving more than half a lobe but not more than one lobe
T2c
Tumour involving both lobes
T3
Tumour extending through the prostatic capsule; no invasion into the prostatic apex or into, but not
beyond, the prostatic capsule
T3a
Extracapsular extension (unilateral or bilateral)
T3b
Tumour invading seminal vesicle(s)
T4
Tumour fixed to or invading adjacent structures other than seminal vesicles (e.g. bladder neck, external
sphincter, rectum, levator muscles, pelvic wall)
Primary tumour, pathological (PT)
PT2
Organ-confined
PT2a
Tumour involves one half of one lobe, but not both lobes
PT2b
Tumour involves more than one half of one lobe, but not both lobes
PT2c
Tumour involves both lobes
PT3
Extraprostatic extension
PT3a
Extraprostatic extension
PT3b
Seminal vesicle invasion
PT4
Invasion of bladder, rectum
Regional lymph nodes (N)
NX
Regional lymph nodes (cannot be assessed)
N0
No regional lymph node metastasis
N1
Metastasis in regional lymph node or nodes
Distant metastasis (M)
PM1c
More than one site of metastasis present
MX
Distant metastasis cannot be assessed
M0
No distant metastasis
M1
Distant metastasis
M1a
Non-regional lymph node(s)
M1b
Bone(s)
M1c
Other site(s)
continued
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
5
Background
TABLE 3 Tumour node metastasis staging system (2002)25 (continued)
Stage grouping
Stage I
T1a
NO
MO
G1 (Gleason Score 2–4)
Stage II
T1a
NO
MO
G2, 3–4(Gleason Score 5–10)
T1b
NO
MO
Any G
T1c
NO
MO
Any G
T1
NO
MO
Any G
T2
NO
MO
Any G
Stage III
T3
NO
MO
Any G
Stage IV
T4
NO
MO
Any G
Any T
N1
MO
Any G
Any T
Any N
M1
Any G
A second staging method called the ABCD
(modified Whitmore-Jewett) system is often used
in the USA. It has been indicated that a weakness
of the ABCD system is its inability to characterise
regional lymph nodes (N+) or distant metastases
(M+) relative to the category of the lesion and
that N+ or M+ lesions are categorised as stage.30
Table 4 shows the ABCD grading system.
Table 5 is cited as Jewett31 within Sutcliffe.2
Table 5 shows a comparison between the TNM
classification and the Whitmore-Jewett system
which was presented in Selley et al.30
6
Serum prostate-specific antigen level
A further method for measuring and assisting the
diagnosis of PC and assessing the risk of disease
burden is the PSA level. PSA is a glycoprotein,
almost exclusively produced by the epithelium
of the prostate gland, responsible for liquefying
semen and allowing sperm to swim freely.4,13
Burford et al. report that due to an alteration in
the architecture of the prostate in conditions such
as prostatitis and BPE as well as PC, PSA leaks out,
leading to increased levels in the bloodstream.4
Collin et al. describe the test’s limited sensitivity
and specificity which may lead to false reassurance
or false alarm followed by invasive investigations.8
The PSA test remains an imperfect predictor
of PC, but remains a useful tool that is widely
used in clinical practice.32 However, until a more
superior diagnostic blood test becomes widely
available, screening for PC will continue to
comprise PSA testing in conjunction with digital
rectal examination (DRE) and fine-core biopsies
of the prostate when indicated by an abnormal
PSA and/or DRE.33 Rosario et al.34 (the ProtecT
trial) indicate that the exact level at which to
recommend biopsy is controversial and may start
as low as 2.5 ng/ml; however, they conclude that
following an initial PSA of 3.0–19.99 ng/ml in men
aged 50–70 years, a repeat PSA within 7 weeks
allows more accurate risk prediction that may assist
in the decision-making as to whether or not to
proceed with prostate biopsy.
Risk of recurrence
The latest NICE clinical guideline 20081 discusses
predictive factors which have been used to
classify localised PC into recurrence risk groups
specifically:
• low-risk PSA < 10 ng/ml and Gleason score ≤ 6
and clinical stage T1–T2a
• intermediate-risk PSA 10–20 ng/ml or Gleason
score 7 or clinical stage T2b–T2c
• high-risk PSA > 20 ng/ml or Gleason score 8–10
or clinical stage T3–T4.
The above risk categories closely resemble the
recurrence risk groups of PC for clinically localised
PC stated by the National Comprehensive Cancer
Network (NCCN) in their Clinical Practice Guidelines
in Oncology.35 All NCCN recurrence risk groups are
presented below:
• Clinically localised:
–– low-risk PSA < 10 ng/ml and Gleason score
2–6 and clinical stage T1–T2a
–– ‌intermediate-risk PSA 10–20 ng/ml or
Gleason score 7 or clinical stage T2b–T2c
–– ‌high-risk PSA > 20 ng/ml or Gleason score
8–10 or clinical stage T3a
• locally advanced:
–– very high risk T3b–T4
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
TABLE 4 ABCD grading system31
Stage A
Very early and without symptoms; cancer cells confined to the prostate
A1 Well differentiated and slightly abnormal cancer cells
A2 Moderately or poorly differentiated and abnormal cancer cells in several locations within the prostate
Stage B
Confined to the prostate, but palpable (detectable by DRE) and/or detectable by elevated PSA
B0 Confined to the prostate, non-palpable; PSA elevated
B1 Single cancerous nodule in one lobe of the prostate
B2 Extensive, involvement in one or both prostate lobes
Stage C
Cancer cells found outside the prostate capsule (membrane covering the prostate); spread confined to surrounding
tissues and/or seminal vesicles
C1 Extends outside the prostate capsule
C2 Bladder or urethral obstruction
Stage D
Metastasis (spread) to regional lymph nodes, or to distant bones, organs (e.g. liver, lungs), and/or other tissues
D0 Metastatic, clinically localised, and showing elevated blood prostatic acid phosphatase levels
D1 Regional lymph nodes involved
D2 Distant lymph nodes, bones, or organs involve
D3 Metastatic disease after treatment
TABLE 5 Comparison of TNM and Whitmore-Jewett classifications for staging prostate cancer adapted from Selley et al. 30
TNM classification
Whitmore-Jewett
T1
A
T1,T2
A1
T2,T3
A2
T2
B
T2a,T2b
B1
T2c
B2
T3
C
T3a,T3b
C1
T3c
C2
M1 and N1
D
• metastatic:
–– any T, N1
–– any T, any N, M1
–– patients with multiple adverse factors
may be shifted into the next highest risk
group.35
Key measurement systems for adverse
events
The most common measurement systems of
adverse events (AE) is published by the Radiation
Therapy Oncology Group (RTOG) based in
Philadelphia, PA, USA. The RTOG is a national
clinical cooperative group funded by the National
Cancer Institute (NCI) since 1968 to increase the
survival and improve the quality of life of patients
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
diagnosed with cancer.36 The RTOG grades are
embedded within the system of AE measurement
called the NCI–Common Toxicity Criteria, often
abbreviated to NCI-CTC. The AEs are graded
from 0 to 4 for many different types of cancer.37
However, from January 2009 the Cancer Therapy
Evaluation Program at the NCI recommends the
use of the Active Common Terminology Criteria
for Adverse Events (CTCAE), Version 4.0 (http://
evs.nci.nih.gov/ftp1/CTCAE/About.html). The
RTOG grades range from 1 to 5, grade 1 meaning
a mild AE to grade 5 meaning death; the CTCAE
lists many disorders such as gastrointestinal (GI)
disorders and then lists subcategories such as rectal
haemorrhage together with the definitions of
grades 1–5.
7
Background
Neoadjuvant/adjuvant hormone therapy
Studies also differentiate between patients who
have, or have not, received adjuvant hormone
treatment at baseline. As PC is driven in part
by male sex hormones, the use of hormonal
treatment to reduce the level of circulating male
hormones is a potentially very useful method of
treating all stages of this disease.38 This technique
is also sometimes called androgen deprivation or
suppression. Neoadjuvant hormone therapy in the
management of PC translates into administering
hormone treatment before the primary therapy to
assist in reducing tumour burden. Reviews suggest
that adjuvant hormone therapy combined with
either prostatectomy or RT can improve diseasefree survival in patients with local or locally
advanced PC.38,39 Significant local control may
be achieved when given prior to prostatectomy
or RT, which may improve the patient’s quality of
life. Neoadjuvant hormone therapy is associated
with significant clinical benefit when given with
RT and improves pathological outcome prior to
prostatectomy, but is of minimal value prior to
radical prostatectomy.40 Neoadjuvant hormones
also have an important role in reducing tumour
volume and therefore potentially reducing dose to
the rectum and hence toxicity.
8
Key health-related quality of life
measures
Health-related quality of life (HRQoL) is also
measured in relation to PC patients receiving
IMRT. HRQoL may play a crucial role in
determining treatment modality as it is likely
that patients with localised PC will live for a
long time.41 However, despite improvement
in survival, many survivors are at risk of posttreatment psychological and physical sequelae
which may reduce their quality of life.42 HRQoL
measures for PC in relation to IMRT include the
following: Lips et al.43 used the RAND-36 generic
health survey, a cancer-specific QoL measure by
the European Organisation for Research and
Treatment of Cancer (EORTC) core questionnaire
[QLQ-C30(+3)] and the Prostate Tumour-Specific
Questionnaire by the EORTC PC module(QLCPR25). Lips et al. found that IMRT and accurate
position verification seem to provide a possibility
to increase the radiation dose for PC without
deterioration in HRQoL. In addition, within PC
the well validated Medical Outcomes Survey Short
Form questionnaire-36 items (SF-36) has been used
to measure physical and mental components of
HRQoL and the 20-item University of California
Los Angeles Prostate Cancer Index (UCLA PCI)
has been used to measure treatment-specific
function and bother (bowel, urinary, sexual).
Higher scores represented better function for both
SF-36 and the PCI.42
Definitions of biochemical failure
As an alternative to the clinical measurement of
disease-free survival (local disease recurrence, or
the development of metastatic disease, or both),
PSA testing has largely replaced clinical failure
as a measure of treatment efficacy as it is easier to
perform on a routine basis than serial bone scans
and computed tomographic (CT) scans.44 The PSA
level has been used as a surrogate endpoint in
trials of PC. The American Society for Therapeutic
Radiology and Oncology (ASTRO) Consensus
Panel44 state that ‘biochemical’ failure has come
to be widely used in the absence of clinical or
histopathology evidence of local persistence or
recurrence or demonstrable distant metastasis. An
ASTRO consensus panel in 1996 agreed on four
guidelines:
1. Biochemical failure is not justification per
se to initiate additional treatment. It is not
equivalent to clinical failure; it is, however, an
appropriate early end point for clinical trials.
2. Three consecutive increases in PSA is a
reasonable definition of biochemical failure
after RT. For clinical trials, the date of
failure should be the midpoint between postirradiation nadir PSA and the first of the three
consecutive rises.
3. No definition of PSA failure has as yet
been shown to be a surrogate for clinical
progression or survival.
4. Nadir PSA is a strong prognostic factor.44
However, these guidelines have been criticised
as this definition was not linked to clinical
progression or survival; it performed poorly
in patients undergoing hormonal therapy, and
backdating biased the Kaplan–Meier estimates of
event-free survival.45 Consequently, as reported in
Roach et al.45 a second consensus panel convened in
2005 and revised the ASTRO definition. The panel
recommended:45
1. A rise by 2 ng/ml or more above the nadir
PSA be considered the standard definition for
biochemical failure after external beam RT
with or without hormonal therapy.
2. The date of failure be determined ‘at call’
(not backdated). They recommended that
investigators be allowed to use the ASTRO
consensus definition after external beam
RT alone (no hormonal therapy) with strict
DOI: 10.3310/hta14470
adherence to guidelines as to ‘adequate followup’. To avoid the artefacts resulting from short
follow-up, the reported date of control should
be listed as 2 years short of the median followup. For example, if the median follow-up is
5 years, control rates at 3 years should be cited.
Retaining a strict version of the ASTRO definition
would allow comparisons with a large existing
body of literature.45 The current review reports,
where available and appropriate, the definition of
biochemical failure, as used in the studies to allow
full comparison.
Kupelian et al.46 reported that the length of
the natural history of localised PC makes the
relationship between the biochemical failure and
overall survival difficult to establish for patients
diagnosed in the PSA era and that biochemical
failure after definitive RT for localised PC is not
associated with increased mortality within the first
10 years after initial therapy, although a trend
toward worse outcome was observed at 10 years.
With longer follow-up from initial therapy,
significant differences may be observed at 15 or
20 years after therapy and may assist our full
understanding of the impact of biochemical failure
on overall survival.46
Current service provision
Management of disease
For men with disease localised to the prostate,
the 2008 NICE PC guidelines recommend active
surveillance as the first choice of treatment for
low-risk localised disease.1 Radical treatment, that
is either external beam CRT or prostatectomy,
is recommended for those with intermediate
risk localised disease.1 Other treatment options
for localised disease are watchful waiting or
brachytherapy (internal seed RT).1 RT is also
offered to patients with locally advanced disease
(tumours which have spread no further than the
pelvic region).1 There are other treatment options
for PC, not recommended in the UK except as part
of research, such as the radical treatment options
cryotherapy or high-intensity focused ultrasound,
and the non-radical treatment option hormone
therapy alone.1
Radiotherapy, including 3DCRT and IMRT,
stops cancer cells from dividing and growing,
thus slowing tumour growth. 3DCRT is a form of
external beam RT that allows better targeting of
Health Technology Assessment 2010; Vol. 14: No. 47
RT than two-dimensional or conventional RT, by
using three-dimensional imaging to define the
target volume and critical organs at risk (OAR),
computerised 3D planning utilising multiple beams
to conform to the 3D shape of the tumour and
maximally avoid the OAR.47 NICE recommends
that patients receiving radical external beam RT
for localised PC should be given a minimum dose
of 74 Gy to the prostate at no more than 2 Gy per
fraction.1 Whole pelvis radiation may be considered
in men with locally advanced PC who have more
than 15% risk of pelvic lymph node involvement,
{by Roach formula 2 3 PSA + [(GS−6) × 10]}, who
are to receive neoadjuvant hormonal therapy and
radical RT.1
Patients receiving RT may also be treated with
neoadjuvant and/or adjuvant hormone therapy.
NICE recommends adjuvant hormonal therapy
for a minimum of 2 years in men receiving radical
RT for localised PC who have a Gleason score of
8 or more.1 Adjuvant chemotherapy is not usual
UK practice. Chemotherapy may be given in
metastatic, hormone-refractory disease.1
Toxicity can cause side effects during or
immediately after RT treatment (acute effects)
or many months or years after completion of
treatment (late effects). Degree of toxicity can be
related to irradiated dose volumes for organs at
risk. In PC, acute effects include genitourinary
(GU) symptoms (frequency, urgency, urinary
retention, bladder spasms, urinary incontinence,
haematuria, dysuria) and GI symptoms (proctitis,
rectal or perirectal pain, rectal bleeding,
diarrhoea).23,48,49 Late effects include similar
urinary symptoms, sexual dysfunction and GI
symptoms; these late effects may permanently
affect quality of life.23 Management of side effects
may include referral to specialist gastroenterology
or urology services.1
Current service cost
The costing report50 that accompanied the recent
NICE guideline for PC1 reported the costs of RT
for PC. The cost of an RT fraction was assumed
to be £135, from the National Tariff price 2008–9
(inflated by the national average market forces
factor) for ‘complex teletherapy with imaging’.
The authors estimated the number of fractions
provided for radical RT of PC to be 117,000 per
year, based on activity data from the RT equipment
survey 2007. From these figures the estimated
2008 cost was calculated as £15.8M.50
9
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Background
The 2008 PC guideline1 recommended that
men having external beam RT for localised
PC should have a total dose of at least 74 Gy to
the prostate at no more than 2 Gy per fraction.
Thus the total number of fractions required is
37. In the costing report it was estimated that
an additional 43,000 fractions were required to
meet this recommendation, based on an analysis
of Radiotherapy Episode Statistics data from
24 centres in the UK for the period 2000–5.
The additional cost is £5.8M. Thus the total
cost of radical RT, once the national guideline
is implemented is estimated to be £21.6M
(£15.8M + £5.8M).50
These figures, however, appear to omit the costs
of planning RT. These costs are reported in the
NHS reference costs 2007–8.51 Those shown in Table
6 are for an outpatient service, which is the most
common mode.
The reported costs are not entirely consistent,
with some more complex planning procedures
apparently costing less than simpler ones. However
they indicate that RT planning for radical RT for
PC costs at least £200 per patient.
It should be noted, however, that the national
guideline also recommended the option of active
surveillance of low-risk localised PCs.1 If more
men choose this option the demand for radical RT
may be reduced, although this recommendation is
controversial. Such a reduction was not quantified
in the national costing report, although a 10%
reduction in radical prostatectomy was estimated.50
Variation in services and/or
uncertainty about best practice
The needs assessment report,52 that accompanied
the recent NICE guideline for PC,1 shows RT data
for PC (2003–4) for a sample of five NHS Trusts
in the South West government office region. The
total dose and number of fractions per course is
reported, showing clear differences between the
Trusts. For example, in two of the five Trusts no
courses of RT were given with a total dose of 40 Gy
or more, whereas in one Trust 47% of courses were
at a dose of 40 Gy or more.
Relevant national guidelines,
including National Service
Frameworks
The 2008 NICE PC guidelines give detailed
recommendations for the management of PC, and
cover a range of treatments including external
beam CRT.1 External beam CRT may be given to
men with intermediate risk localised disease or
with locally advanced disease.1 NICE recommends
that patients should be given a minimum dose
of 74 Gy to the prostate at no more than 2 Gy per
fraction.1 Whole pelvis radiation may be considered
for men with locally advanced PC who have more
than 15% risk of pelvic lymph node involvement
and who are to receive neoadjuvant hormonal
therapy and radical RT.1
The Royal College of Radiologists (RCR), the
Institute of Physics and Engineering in Medicine
(IPEM), The Society and College of Radiographers
(SCOR) and The National Radiotherapy
Advisory Group (NRAG) recommend the use
TABLE 6 NHS reference costs 2007–8 for RT planning
Description
Activity
National
average
unit cost
SC01Z
Define volume for SXR, DXR, electron or megavoltage RT without imaging
and with simple calculation
11,595
£121
SC02Z
Define volume for simple RT with imaging (simulator, CT scanner, etc.) but
with simple calculation and without dosimetry
21,644
£219
SC03Z
Define volume for simple RT with imaging and dosimetry
17,601
£388
SC04Z
Define volume for multiple phases of complex RT with imaging and
dosimetry
37,500
£209
SC05Z
Define volume for RT with imaging, dosimetry and technical support, e.g.
mould room
18,554
£317
SC06Z
Define volume for RT with imaging and IMRT dosimetry or equivalent
18,530
£194
HRG
code
10
DXR, deep energy photons; HRG, Health Resource Group; SXR, superficial energy photons.
DOI: 10.3310/hta14470
of magnetic resonance imaging (MRI) for
imaging the tumour.53,54 To reduce the random
and systematiceffects of organ motion, patient
interventional techniques such as drugs are used
to stimulate bowel emptying to stabilise the rectal
volume; alternatively rectal balloons have been
suggested, although these are not in widespread
use.54 NRAG suggest image-guided RT (IGRT)
may be useful in tumours that have unpredictable
daily movement, and explain that changing RT
across time is a technology called four-dimensional
adaptive RT.54 RCR, in a 2002 policy statement
on conformal RT, recommend effective patient
immobilisation techniques are used as these can
reduce random and systematic errors.53
The RCR, IPEM and SCOR53 recommend
specialised training for all staff involved in
planning RT, and suggest close collaboration
between a skills mix of staff groups, which may
include clinical radiologists, clinical oncologists,
RT physicists, planning radiographers, therapy
radiographers, dosimetrists and clinical
technologists. They also recommended that IMRT
should be developed and introduced across the UK
with research in the form of controlled studies.53
The International Commission on Radiation
Units and Measurements (ICRU) have produced
guidelines on prescribing, recording and reporting
RT. They indicate that the method used for
delineation of gross tumour volume (GTV), that is
gross palpable or demonstrable extent and location
of the malignant growth, should be detailed.
Around the GTV, ICRU describe two safety
margins. The clinical target volume (CTV) takes
into account subclinical malignant involvement.
The planning target volume (PTV) compensates
for the variations in size, shape, and position of
the CTV, and for uncertainties in patient–beam
positioning.55,56
Description of technology
under assessment
Summary of intervention
Concepts of IMRT were developed by Brahme57
and Webb58 and is a technological advance leading
on from 3DCRT. The principle behind IMRT
is the use of intensity-modulated beams, which
are defined as beams that deliver more than two
intensity levels for a single beam direction and
a single source position in space.23 Both 3DCRT
and IMRT deliver beams that are geometrically
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Health Technology Assessment 2010; Vol. 14: No. 47
shaped, but IMRT also modulates the intensities of
constituent beams.53
Increasing the dose of RT can increase the
effectiveness in terms of biochemical relapsefree survival. There is evidence from RCTs that
dose escalation to 74–79 Gy provides superior
biochemical relapse-free survival compared with
lower doses of approximately 64–70 Gy.59–63 There
are no convincing data supporting superior
biochemical outcomes at radiation doses above
81 Gy.64 A meta-analysis of studies comparing
doses of conformal RT showed an advantage for
high-dose RT over lower dose RT for biochemical
failure, but not for overall survival, nor for PC
specific survival.65
However, increased dose can increase toxicity, as
has been shown in RCTs of dose escalation.66,67
Doses upward of 78–80 Gy are difficult to achieve
when using 3DCRT, due to the unacceptable risk
of side effects.68 The benefit of IMRT is largely
related to the avoidance of side effects of radiation.
IMRT can sculpt the radiation to the target area
of the PC more precisely than 3DCRT, by allowing
further conformation to the PTV compared with
3DCRT, so toxicity to the surrounding normal
tissues (bladder, rectum, urethral bulb and small
bowel) may be reduced, or could allow dose
escalation.54 Unlike 3DCRT or earlier forms of
RT, IMRT can deliver non-uniform RT, producing
concave shapes that spare critical structures that
surround or push into the tumour.47,53 IMRT allows
delivery of complex dose distributions.54 RCTs
of IMRT in breast cancer, and head and neck
cancer, compared with two-dimensional conformal
radiotherapy or conventional RT, have shown
reduced side effects or improved quality of life.69–73
Planning of therapy identifies a PTV which
incorporates the tumour, sites of suspected
microscopic malignancy, and an extended volume
to take into account uncertainty in the position of
the target, and set-up and delivery uncertainties.54
There are two different methods of planning:
inverse or forward. Inverse-planned IMRT utilises
software algorithms, manipulating many hundreds
of treatment beamlets, in order to produce highly
complex treatment plans which would be beyond
the scope of a treatment planner. The computer
iteratively attempts to achieve the planner’s defined
dose target and normal tissue constraints. This
complex planning process is time consuming
and requires considerable quality assurance
(QA) per patient. There are inherent constraints
still applied to inverse planned IMRT, such as
11
Background
number of beams, and advances are occurring to
overcome this, such as rotational therapy. Forwardplanned IMRT involves the planner modifying
a provisional plan, based on the treatment beam
arrangements that are likely to be used, until the
dose distribution is improved. Planning studies
have shown that IMRT improves upon 3DCRT with
respect to conformality to, and dose homogeneity
within, the target.64
Radiotherapy is delivered by linear accelerators,
and IMRT methods of delivery comprise static
compensators, step and shoot by multiple static
field multileaf collimator (MLC), dynamic MLC or
sliding window technique, tomotherapy, scanned
photon beams, or moving attenuating bar.53
Quality assurance is an important component of
IMRT. QA consists of ensuring that the treatment
plan is correctly delivered. It involves verifying
that the linear accelerator is optimally set up
by making direct measurements. IMRT QA can
be individualised by patient or adopted as a
standardised departmental QA procedure.
Radiotherapy may be given to patients with low- or
intermediate-risk localised disease who are not
undergoing surgery (prostatectomy), or patients
with locally advanced disease.1 Patients are usually
treated on an outpatient basis, once a day, 5 days
a week, over 6 or 7 weeks.74 For localised PC, the
recommended minimum dose is 74 Gy to the
prostate at no more than 2 Gy per fraction.1 Followup is required for assessing disease status and
management of toxicity.1 A range of personnel is
required including clinical radiologists, clinical
oncologists, RT physicists, planning radiographers,
therapy radiographers, dosimetrists and clinical
technologists.53
Current usage in the NHS
The use of IMRT has been growing in the UK over
the last few years. A survey of UK RT departments
in 2003 identified nine of the total of 66 (14%)
departments routinely offering IMRT.75 Of these,
six were using IMRT for PC. A survey in 2007
found 46% of centres using IMRT.76 However, only
27% were using IMRT for the routine management
of patients. Of the centres that were not using
IMRT, 38% were planning to implement it in the
next year. If their plans were realised this would
mean that two-thirds of RT centres were now able
to provide IMRT, although not necessarily in the
routine management of patients.
The same 2007 survey76 indicated that 8% of
centres routinely used IGRT, and a further
13% used it in research studies. A quarter of
departments were planning on introducing it in
the next year, potentially meaning 42% of centres
now have some capacity for IGRT. PC was the most
common tumour for the use of IGRT.
Anticipated costs associated
with intervention
No published costs for the provision of IMRT in
the UK were identified. International studies which
report costs of IMRT and 3DCRT for the treatment
of PC are shown in Table 7.
The estimates from Europe and the USA are very
different. The relatively generous reimbursement
of IMRT in comparison to 3DCRT by Medicare
in the USA has been commented on by other
authors.47 Note the cost difference between IMRT
and 3DCRT reported by Marchal77 arose almost
entirely from differences in equipment and
maintenance costs, assuming only 30 patients
are treated a year, and therefore are likely also to
represent an overestimate of current UK costs.
TABLE 7 Published costs of IMRT and 3DCRT for prostate cancer
Study
12
Cost
year
Costs included
Cost source
Currency
IMRT
cost
3DCRT
cost
Additional
cost IMRT
€
4911
2357
2554
Marchal
et al.
200177
2002
RT (staff, capital
and maintenance
costs)
Prospective study
Konski et
al. 200678
2004
RT
Billing units with expected US$
Medicare reimbursement
38,000
9900
28,100
Pearson
et al.
200764
2005
RT
Medicare reimbursement
2005 (constituent codes
as Konski 2006)
42,450
10,900
31,550
US$
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
St. Bartholemew’s Hospital, London, UK, had
developed costs for IMRT and 3DCRT, initially
for ear, nose and throat cancers. These were
adapted for PC by removing items not relevant
to PC (such as dental care), and amending others
(e.g. planning time, frequency of treatment review,
number of fractions). The time required for
delivery of each fraction was assumed to be the
same as for head and neck. The costs for IMRT
and 3DCRT are shown in Table 8 (Nuala Close,
St. Bartholomew’s Hospital, London, UK, 2009,
personal communication). Tasks included within
the radiographer category are simulator set-up
and verification, CT scan, image referencing, and
pre-treatment data input and checks. Physics time
includes treatment planning and verification,
as well as QA. The treatment times assumed
per fraction are 18.0 minutes for 3DCRT and
20.6 minutes for IMRT, representing a 14.4%
increase for IMRT. The absolute difference in
time between IMRT and 3DCRT of 2.6 minutes is
similar to that reported by Van de Werf et al.79 of
2.8 minutes for a mixture of prostate, and head
and neck cancer patients, although Van der Werf
et al. reported lower treatment times per fraction
for both IMRT and 3DCRT, so the difference of
2.8 minutes represents a 27% increase in treatment
time for IMRT. Miles et al.80 also report shorter
treatment times, with a median of 12 minutes for
a fraction of IMRT for PC patients, but reports
times between 15 and 28 minutes from other
published studies. No comparative data for 3DCRT
is reported. For incremental cost-effectiveness it
is only the additional time taken for IMRT that
is important, and in this regard the information
from St. Bartholomew’s Hospital is consistent with
Van de Werf et al.79
The category ‘equipment support’ comprises
an allocation of capital costs for the linacs and
the building used to house them, as well as
maintenance costs. The calculation assumes two
linacs will deliver a total of 24,000 fractions per
year for 10 years.
The costs are based on the current fractionation
schedule for both 3DCRT and IMRT, which
is 37 fractions. Both 3DCRT and IMRT may
be delivered with hypofractionated schedules
(fewer fractions delivering the same biologically
equivalent dose), but the potential reduction in
toxicity from IMRT compared to 3DCRT may
mean that hypofractionation may be more viable
for IMRT than for 3DCRT. The Conventional or
Hypofractionated High dose Intensity modulated
radiotherapy for Prostate cancer (CHHiP) study,
which is currently in progress, is studying the
effects of hypofractionated IMRT on PSA survival
and toxicity. Hypofractionated regimes are likely
to cost less as fewer sessions are required to
deliver the RT, and therefore may affect the cost
difference between IMRT and 3DCRT.
TABLE 8 Costs of IMRT and 3DCRT for prostate cancer 2008
Cost item
Cost IMRT
Cost 3DCRT
Difference
Pay
Medical
£219.13
£141.61
£77.52
£1709.00
£1409.16
£299.84
Physics
£960.00
£474.57
£485.43
Admin
£327.78
£327.78
£0.00
£16.49
£16.49
£0.00
£3232.40
£2369.61
£862.79
£25.00
£25.00
£0.00
£91.90
£91.90
£0.00
£705.26
£705.26
£0.00
Radiographers
Support
Total pay
Non pay
Drugs
Consumables
Equipment support
Diagnostics
Total non pay
Total direct costs
Indirect costs (overheads 30%)
Total cost of treatment
£500.00
£500.00
£0.00
£1322.16
£1322.16
£0.00
£4554.56
£3691.77
£862.79
£1366.37
£1107.53
£258.84
£5920.93
£4799.31
£1121.62
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
13
Background
The full assumptions on which the costs shown in
Table 8 are based are shown in Appendix 6.
Note both clinical experience and evidence from
the literature for head and neck cancers indicate
that the time taken to deliver IMRT varies
considerably according to the experience of a unit
in providing the treatment. Bonastre et al.81 studied
resource use and costs for the provision of IMRT
for head and neck cancer patients across nine
centres in France. The mean treatment cost per
patient at experienced centres was €6332 compared
to €14,192 at centres initiating IMRT treatment.
This demonstrates that the introduction of IMRT
is likely to cause short-term staff and machine
capacity issues.
14
The costs shown in Table 8 and used in the
economic analysis are from an institution which is
at a relatively early stage of IMRT implementation.
The difference in treatment time between IMRT
and 3DCRT assumed is consistent with that
reported in the literature, but the study does
not report the experience of the institution with
IMRT.82 It is possible that the cost differential
between IMRT and 3DCRT will be less at
institutions with more experience of IMRT. The
difference in treatment time assumed contributes
only £157 (or 14%) to the total difference in cost
assumed between IMRT and 3DCRT and so is not
critical in the cost comparison.
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Chapter 2
Definition of the decision problem
Decision problem
This assessment report addressed the question
‘What is the clinical and cost-effectiveness of
intensity-modulated radiotherapy for the radical
treatment of prostate cancer?’.
Intervention
The included intervention was IMRT. This
included systems that either do or do not combine
the ability to simultaneously image (IGRT). IMRT
using either forward planning or inverse planning
was included.
Population including subgroups
Adult men with PC for whom RT is appropriate.
Subgroups principally included localised PC and
locally advanced PC.
Relevant comparators
Current standard therapy: 3DCRT or radical
prostatectomy.
Outcomes
Outcomes sought were survival (overall and
disease-specific), progression-free survival [clinical
or biochemical (PSA) relapse free], adverse effects
of treatment and HRQoL.
Overall aims and objectives
of assessment
The review addressed the following issues:
1. To evaluate the clinical effectiveness of IMRT
in terms of overall or progression-free survival
[clinical and biochemical (PSA) relapse free]
compared with 3DCRT (current standard
therapy).
2. To evaluate the side effect profile of IMRT
compared with 3DCRT (current standard
therapy).
3. To estimate the incremental cost-effectiveness
of IMRT compared with 3DCRT (current
standard therapy).
The review did not attempt to address IMRT
in comparison with other radical treatment
options such as internal seed RT (brachytherapy,
cryotherapy, etc.) or the non-radical treatment
options watchful waiting, active monitoring, or
hormone therapy alone.
Although sought, no data were available directly
comparing IMRT with prostatectomy. No data
were available to compare post-operative 3DCRT
with post-operative IMRT. No data were available
to evaluate IMRT in patients with bone metastasis.
15
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Chapter 3
Assessment of clinical effectiveness
Methods for reviewing
effectiveness
All searches were conducted in January 2009 and
were updated for recent publications in May 2009.
Search strategy
Inclusion and exclusion criteria
A comprehensive search was undertaken to
systematically identify clinical effectiveness and
cost-effectiveness literature concerning IMRT in
men with PC. The search strategy comprised the
following main elements: searching of electronic
databases; contact with experts in the field; and
scrutiny of bibliographies of retrieved papers.
Study design
According to the accepted hierarchy of evidence,
RCTs and meta-analyses from systematic reviews
were searched initially, as they provide the most
authoritative forms of evidence. As no relevant
RCTs were identified, other comparative studies
were included. Systematic reviews were not
included in the analysis but were used to identify
relevant comparative studies.
The following databases were searched: MEDLINE
(1950–present), EMBASE (1980–present),
Cumulative Index to Nursing and Allied Health
Literature (CINAHL) (1982–present), BIOSIS
(1985–present), the Cochrane Database of
Systematic Reviews (CDSR) (1991–present), the
Cochrane Controlled Trials Register (CCTR)
(1991–present), the Science Citation Index (1900–
present) and the NHS Centre for Reviews and
Dissemination databases [Database of Abstracts
of Reviews of Effects (DARE), NHS Economic
Evaluation Database (EED), Health Technology
Assessment (HTA)] (1991–present). MEDLINE
In-Process & Other Non-Indexed Citations was
searched to identify any studies not yet indexed
on MEDLINE. Current research was identified
through searching the UK Clinical Research
Network, National Research Register archive, the
Current Controlled Trials register and the MRC
Clinical Trials Register. In addition, abstracts
of the American Society of Clinical Oncology
(ASCO), ASTRO and European Society for
Therapeutic Radiology and Oncology (ESTRO)
conferences were browsed. Systematic reviews
which incorporated evidence relating to the
inclusion criteria were hand-searched in order to
identify any further clinical trials. Searches were
not restricted by date or publication type. Studies
only published in languages other than English
were excluded. The MEDLINE search strategy for
randomised clinical trials is presented in Appendix
1. Searches targeted the comparators of 3DCRT
and radical prostatectomy as well as 11 other
comparators to capture potential data meeting
the inclusion criteria hidden within other studies.
Case-control and cohort studies were also sought.
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Intervention
Intensity-modulated radiotherapy with systems
that either do or do not combine the ability to
simultaneously image (IGRT), whether delivered
using forward planning or inverse planning.
Comparators
Three-dimensional conformal radiotherapy or
radical prostatectomy.
Population
The population comprised men with PC for whom
radical RT was appropriate. Data were considered
separately for localised PC and locally advanced
PC, where available.
Outcomes
Outcomes sought were survival (overall and
disease-specific), progression-free survival [clinical
or biochemical (PSA) relapse free], adverse effects
of treatment and HRQoL.
Exclusion criteria
Studies only published in languages other than
English were excluded. Other less common
treatment options such as internal seed RT
(brachytherapy, cryotherapy, etc.) and non-radical
treatment options such as watchful waiting, active
monitoring and hormone therapy alone were
outside the scope of the assessment. Studies which
focused solely on planning, organ motion, proton
therapy, positioning, localisation, verification,
contouring, target volume definition, alignment
methods, gene therapy, optimisation, dose–volume
17
Assessment of clinical effectiveness
histogram and dosimetric analysis were also
excluded unless data meeting the inclusion criteria
were also available.
Based on the above inclusion/exclusion criteria,
study selection was made by one reviewer, with
involvement of a second reviewer when necessary.
Data abstraction strategy
Data were extracted with no blinding to authors or
journal. Data were extracted by one reviewer using
a standardised form. Data extraction forms are
available in Appendix 2.
Critical appraisal strategy
As no RCTs were found, the quality of studies
was assessed according to accepted criteria for
randomised and non-randomised studies by Downs
and Black83 which was adapted for the purposes
of this review. The Downs and Black checklist is
a structured checklist originally comprising of 27
items. Checklist items relate to the appropriateness
and adequate description of the hypotheses, study
design, intervention, main outcomes and methods
of analysis. The checklist demonstrated good interrater reliability, although further development
and testing of the tool was recommended.83 After
minimal adaptation the checklist comprised of 29
items with the addition of items regarding study
group comparison, data collection methods and
treatment group comparison. The item regarding
power calculation was removed. Additional
guidance regarding multivariate analysis to
examine group differences was added to item 21.
The answers are recorded as ‘yes/no’ for items
1–13 (also ‘partial’ for item 7) and ‘yes/no/unable
to determine’ for items 14–30 in accordance with
the original paper.83 The evaluation of quality was
conducted according to the checklist guidance
for cohort and non-randomised studies.83 One
reviewer rated the quality of studies using the
adapted Downs and Black checklist. The purpose
of quality assessment was to provide a narrative
summary of trial quality which can be found in
Quality of included studies. The quality assessment
checklist for the eight studies can be seen in
Appendix 3. The quality assessment checklist for
the five included abstracts can also be seen later in
Appendix 3. The response ‘unable to determine’
was used throughout the checklist in Appendix 3.
Methods of data synthesis
Pre-specified outcomes were tabulated and
discussed within a descriptive synthesis. Metaanalysis was precluded due to heterogeneity,
18
mainly in the intervention and comparator
treatments given. Treatments differed in PTV,
dose constraints, dose delivered, fractionation and
patient positioning. There were also differences
between studies in population, length of follow-up
and definitions of outcome measures.
Results
Quantity and quality of research
available
Number of studies identified
A flow chart describing the process of identifying
relevant literature can be found in Figure 2.
Following the removal of duplicates our searches
identified 1060 potentially relevant papers. A
total of 896 papers not meeting our inclusion
criteria were removed at title sift, leaving a total
of 164 papers to be screened at abstract sifting
stage. Of these, eight studies and five abstracts (in
total 13 studies described in 27 publications) were
concerned with IMRT compared with 3DCRT and
no studies were identified comparing IMRT with
radical prostatectomy.
Number and type of studies excluded
In total 83 publications were excluded from those
retrieved and inspected. A list of the 83 excluded
papers at full paper sift with reasons for specific
exclusions are provided in Appendix 5.
Number and type of studies included
There were eight studies meeting inclusion
criteria for this review that were published in peerreviewed journals, six of which were of localised
PC, and two on locally advanced PC (see Included
studies). In addition, five conference abstracts
were considered to meet the inclusion criteria,
but are considered separately as localisation of
cancer is unclear, as abstracts necessarily provide
less information about the studies (see Included
conference abstracts).
Included studies
There were eight included comparative studies
published as full reports in peer-reviewed journals:
Kupelian;28,84–87 Sanguineti et al.;88 Shu et al.;29
Vora et al.;89,90 Yoshimura et al.;41 Zelefsky;91–99
Ashman et al.100 (this was part of the Zelefsky study,
but is classified here as a different study as it has
distinct treatment and population characteristics,
suggesting that the patients do not overlap with
those from the other Zelefsky publications); and
Lips et al.43
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
The population for six included studies was
patients with localised PC.28,29,41,88,89,91 For two
included studies the population was patients with
locally advanced PC.43,100
(30%) patients were given chemotherapy, and in
the Lips et al.43 study for which some (26%) of the
3DCRT group were given hyperthermia treatment
(see Appendix 2).
Four of the studies were retrospective patient
records studies.28,29,88,89 Three studies were
prospective comparisons of case series,41,43,91 and
one study100 retrospectively selected patients from
one of these prospective studies.91 Two of the
studies compared contemporary series of patients
from the same hospital,28,29 four used historical
controls from the same centre,43,89,91,100 one study
used both contemporary and historical controls
from the same centre,41 while the other used
historical controls from a different hospital.88
For most studies, patients were assessed at 3 to
6 month intervals,28,29,88,91,100 with one study setting
patient assessments at 6 to 12 month intervals.89
The two studies with primary outcome HRQoL set
data collection for 12 months41 or 6 months43 after
RT.
Four studies had a primary outcome measure of
toxicity,29,88,91,100 while for two studies the primary
outcome was biochemical relapse-free survival,28,89
and for two studies the primary outcome was
HRQoL.41,43 None of the studies reported overall
survival.
Five of the studies were set in the USA,28,29,89,91,100
one was set in both Italy and the USA,88 one was
set in Japan41 and one was set in the Netherlands.43
None of the studies were set in the UK, but patients
and treatments in the studies were of relevance to
UK practice. There was some difference from UK
practice in the Ashman et al.100 study in that some
Two relevant systematic reviews of IMRT for PC
were identified: Pearson et al.;64 and Mast et al.101,102
In addition two relevant systematic reviews of
IMRT, which included PC, were identified via web
searches: Van den Steen et al.;47 and Veldeman et
al.23 These were searched for relevant comparative
studies. No meta-analyses were presented in these
reviews.
Study details for the included comparative studies
are shown in Table 9.
Within studies, treatment groups differed in more
than just IMRT versus 3DCRT. Dose was higher
in the IMRT group than the 3DCRT group for
the studies of Vora et al.,89 Yoshimura et al.,41
Zelefsky et al.,91 Ashman et al.100 and Lips et al.43
Dose was similar between treatment groups for
the studies of Kupelian et al.28 (doses between two
Potentially relevant citations
identified through electronic
searches: N = 1060
Papers rejected at the title stage:
n = 896
Abstracts screened and
inspected: n = 164
Papers rejected at the abstract
stage: n = 54
Publications retrieved and
inspected: n = 110
Publications excluded: n = 83
Publications meeting inclusion
criteria: 27 publications
describing 13 studies
FIGURE 2 QUOROM (quality of reporting of meta-analyses) flow chart of study selection for the review of clinical effectiveness.
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
19
Assessment of clinical effectiveness
groups were reported as equivalent, 70 Gy in 28
fractions vs 78 Gy in 39 fractions), Sanguineti et
al.88 and Shu et al.29 In the Sanguineti et al.88 study,
treatments differed in that IMRT involved treating
the whole pelvis, whereas 3DCRT was restricted
to the prostate. There was higher proportion of
the IMRT group that had the whole pelvis treated
than in the 3DCRT group of the Shu et al.29 study.
In the Lips et al.43 study there was more accurate
positioning of the prostate for IMRT than 3DCRT.
Yoshimura et al.41 and Zelefsky et al.91 had two
comparator groups with different doses of 3DCRT
(see Appendix 2). Some studies had longer followup for IMRT than 3DCRT (see Appendix 2).
Between studies treatments differed in terms of
PTV, dose, dose constraints, fractionation and
patient positioning. More details about RT are in
Appendix 2.
Included conference abstracts
Five conference abstracts of comparative studies
of IMRT versus 3DCRT in PC were identified
(Table 10). Three abstracts were from the same
single centre study from the USA, Kirichenko et
al.,105 Sharma et al.,106 and Morgan et al.,107 which
compared a case series of IMRT with a historical
case series of 3DCRT. One of these three abstracts
described a subset of patients treated with
hormonal therapy,106 and one described a subset of
patients with intermediate to high risk disease.107
One abstract,108 also available as a poster,109 was
from a single centre in Germany which evaluated
contemporary IMRT and 3DCRT patients in a
matched pair analysis. One abstract110 from a single
centre in the USA studied IMRT versus 3DCRT,
with both treatments utilising adaptive image
guided RT. None of the abstracts specified whether
the population was localised or locally advanced
PC.
Quality of included studies
Quality assessment was undertaken for the
eight studies which were fully reported using an
adapted Downs and Black checklist83 according
to the guidance within the checklist on nonrandomised studies. A summary of the quality
of the eight studies can be seen in Appendix 3.
A table is presented in Appendix 3 for relevant
quality headings in the Downs and Black checklist
(reporting, internal validity, external validity-bias
and external validity-confounding). A narrative
summary of the key aspects of the Downs and
Black checklist follows.
20
Reporting
All studies clearly reported an aim or hypothesis.
Seven out of eight studies clearly described the
main outcomes. Seven studies clearly described
patient characteristics, but Ashman et al.100
did not present population characteristics per
group. Seven out of eight studies did not have
similar study groups on the basis of population
characteristics, but one study did have groups with
similar population characteristics.91 One study88
did not have the same data collection methods
owing to the treatments being delivered in
different countries, whereas the other seven studies
appeared to have the same data collection methods
per group. All eight studies clearly described the
interventions. Four studies did not clearly describe
potential confounders, two studies did clearly
describe confounders88,91 and two studies partially
described confounders.43,84 Six studies did not have
similar treatment groups displaying differences
in treatment years and areas to be irradiated,
one study had aspects which were similar but the
treatment groups were not identical, and one
study91 had similar treatment groups. Findings
were clearly reported in six studies, but two
studies41,100 did not clearly report their findings.
Ashman et al.100 reported incorrect numbers of
patients with grade 2 GU events (of 11 patients with
GU events, Ashman et al.100 state that eight were
treated with 3DCRT and four patients were treated
with IMRT which is clearly incorrect). Related
papers by Ashman et al. were not available to
clarify this point. Estimates of random variability
were present in all but one study.29 Seven studies
fully addressed adverse events but one study did
not88 but focused on late rectal toxicity. Loss to
follow-up was not described in seven studies and
was unable to be determined in one study.43 All
eight studies reported actual probability values.
External validity
It was not possible to determine from the reporting
whether or not those subjects who did participate
were representative of the entire population from
which they were recruited, although this may be
presumed. Seven studies had a location/setting
which was representative of the treatment that
the majority of patients receive as far as this was
possible to determine and for one study it was not
possible to determine this aspect.84
Internal validity-bias
The eight studies were not single- or doubleblinded trials and all showed clarity regarding data
dredging if this occurred. Five studies adjusted for
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Localised PC
Localised PC
Localised PC
Locally advanced
PC
Locally advanced
PC
Vora et al. 89 2007
USA
Yoshimura et al.41
2007 Japan
Zelefsky et al.91
2008 USA
Ashman et al.100
2005 USA
Lips et al.43 2007
The Netherlands
SVs, seminal vesicles.
Localised PC
Shu et al.29 2001
USA
Localised PC
Localised PC
84
Population
Sanguineti et al. 88
2006 USA/Italy
Kupelian et al.
2002 USA
Study
Prostate and
SVs103
Whole pelvis
Prostate and
SVs97
Prostate only or
prostate and SVs
Prostate and SVs
Prostate only
(28% patients),
whole pelvis
(72%)
Whole pelvis
Prostate only or
prostate and SVs
76 Gy
81 Gy
81 Gy
76.5 Gy
75.6 Gy
85 Gy
76 Gy
70 Gy (hypofractionated)
84 Gy
76 Gy
78 Gy
Approximate dose
Prostate and
SVs104
whole pelvis
Prostate and
SVs96
Prostate only or
prostate and SVs
70 Gy
75.6 Gy
75.6 Gy or
66–70.2 Gy
70 or 73.5 Gy
Prostate and SVs 68.4 Gy
Prostate only
(96% patients),
whole pelvis
(4%)
Prostate only
Prostate only or
prostate and SVs
Whole pelvis
or prostate
only
Whole pelvis
or prostate
only
Approximate dose
Comparator
3DCRT
Intervention
IMRT
TABLE 9 Summary of included published studies
170
27
1571
144
416
44
113
282
Number of
patients
HRQoL
Toxicity
Toxicity
HRQoL
Biochemical
relapse-free
survival
Toxicity
Toxicity
Toxicity
Biochemical
relapse-free
survival
Toxicity
Outcomes
6 months
Median
30 months
Median
96 months
12 months
Median
60 months
Median
23.1 months
Mean
25.9 months
Median
25 months
Follow-up
DOI: 10.3310/hta14470
Health Technology Assessment 2010; Vol. 14: No. 47
21
Assessment of clinical effectiveness
TABLE 10 Summary of included conference abstracts
Study
Intervention
IMRT
Comparator
3DCRT
Whole pelvis
or prostate
Approximate
only
dose
Whole
pelvis or
prostate
only
Number
Approximate of
dose
patients Follow-up
Outcome(s)
Total
1417;
IMRT
489;
3DCRT
928
Median
Toxicity
IMRT
29.9 months;
3DCRT
63.3 months
NR
Mean 76 Gy
(presume
(73–80)
same as
Kirichenko
et al.)105
Total 293;
IMRT
123;
3DCRT
170
Median
IMRT
41 months;
3DCRT
62 months
NR
Median 80 Gy
(presume
(range 76–82)
same as
Kirichenko
et al.)105
Total 376; Median
IMRT
35 months
188;
3DCRT
188
Toxicity,
biochemical
failure, distant
metastasis,
cause specific
mortality
72.2 Gy (70.2–
73.8)
Total 187; Median
IMRT 96; 20 months
3DCRT
91
Toxicity
Adaptive
image-guided,
median
isocentre dose
79.7 Gy
Total
728;
IMRT
172;
3DCRT
556
Kirichenko Prostate only,
et al.105
or prostate
2006 USA and PNs
Prescription
dose 74–78 Gy,
95% PTV
received 100%
dose
Prostate
only, or
whole
pelvis
Sharma et
al.106 2007
USA
NR (presume
same as
Kirichenko et
al.)105
Mean 76 Gy
(74–76)
Morgan et
al.107 2007
USA
NR (presume
same as
Kirichenko et
al.)105
Median 81 Gy
(range 77–85)
Boehmer
et al.108
2006
Germany
NR
79.7 Gy (78–82), NR
simultaneous
integrated boost
2 Gy
Martinez
et al.110
2007 USA
Prostate only
or prostate
and SVs (60%)
Adaptive imageguided, median
isocentre dose
79.7 Gy
Prostate
only or
prostate
and SVs
(51%)
Median
peripheral
CTV dose
72 Gy (range
70–79 Gy)
prescribed to
95% isodose
line
Median
IMRT
2.2 years;
3DCRT
4.3 years
Toxicity
Toxicity
PNs, pelvic nodes; NR, not reported; SVs, seminal vesicles.
different follow-up lengths, two studies did not,89,91
and it was not possible to determine this item
in one study. All eight studies used appropriate
statistical testing. It was not possible to determine
if compliance with the intervention(s) were reliable
for all eight studies. All eight studies described
valid and reliable outcome measure(s).
22
Internal validity-confounding
Seven studies individually used comparison groups
selected from the same institution, apart from
one study which had comparison groups from
two separate institutions.88 Only two studies29,91
sampled in the same time period for each group,
and the other six studies sampled during different
treatment periods/years per group. Kupelian et
al. (2005)111 suggests that independent of tumour
stage, radiation dose, failure definition and follow-
up parameters, the year in which RT is performed
is an independent predictor of outcomes. Three
studies are worst affected as they have historical
controls in the previous decade29,88,89 and these
studies may overestimate biochemical control
in the IMRT group.23 None of the comparative
studies were randomised, so concealment of
randomisation was not an issue. Three studies
made adequate adjustment for confounders84,88,91
but five studies did not. It was not possible to
determine if the studies accounted for losses of
patients to follow-up.
Overall most of the information from all the
eight studies has a medium- to high-risk of bias;
sufficient to affect the interpretation of results (i.e.
weakens confidence in the results). Therefore, the
results should be interpreted with caution.
DOI: 10.3310/hta14470
Quality of included conference abstracts
Quality assessment was undertaken for all
five105–108,110 included conference abstracts using the
adapted Downs and Black checklist.83 A summary
of the quality of the five abstracts can be seen later
in Appendix 4. A table is presented in Appendix
4 for key quality headings in the Downs and Black
checklist (reporting, internal validity, external
validity-bias, external validity-confounding) with
regard to the five abstracts. However, it was not
possible to perform a full quality assessment using
the Downs and Black checklist83 as the information
within the abstracts was necessarily limited. None
of the studies were identified as having later been
published in full.
Within the limits of the abstract reporting
level, it was not possible to determine the main
outcomes or patient characteristics clearly for all
five abstracts. However, the limited findings were
largely clear; an attempt to cover the key adverse
events was made, but losses to follow-up were not
described in all five abstracts. Two abstracts105,110
were marginally more clearly reported than the
other abstracts. It was not possible to determine
the items regarding external validity for all five
abstracts. It was largely not possible to determine
items regarding internal validity-bias for all five
abstracts; with the exception of two studies106,107
which mentioned that adjustment was made for
different lengths of follow-up, one abstract108
gave information about a reliable and valid
outcome measure and two abstracts105,107 indicated
appropriate statistical testing. With regard to
internal validity, only one abstract108 sampled
within the same time period for both groups,
otherwise it was not possible to determine many of
the items for the five abstracts.
Health Technology Assessment 2010; Vol. 14: No. 47
rise. No significant difference between treatment
groups was found (p = 0.084) (Table 11). When the
Kupelian et al. study applied a stricter definition of
biochemical relapse-free survival, that is reaching
and maintaining a follow-up PSA level at less
than or equal to 0.5 ng/ml, there remained no
significant difference between treatment groups
(p = 0.24). By multivariate Cox proportional
hazards analysis, taking into account age, race,
stage, pre-treatment PSA, biopsy Gleason score
and neoadjuvant androgen deprivation, treatment
group showed a non-significant trend favouring
IMRT (p = 0.058).
The Kupelian et al. study85 reported 5-year
biochemical survival data for the IMRT group
only (n = 100) at median 5.5 years follow-up. The
five-year biochemical relapse-free survival using
the ASTRO consensus definition was 85% [95%
confidence interval (CI) 78 to 93%], and using their
stricter definition was 88% (95% CI 82 to 95%).
Survival data by risk groups were 97% for low-risk
disease, 88% for intermediate risk, and 70% for
high-risk disease. Using an expanded comparison
group treated with 3DCRT (n = 310, median followup 71 months) 5-year biochemical relapse-free
survival using the ASTRO consensus definition
was 78%. A later report of this study,86 when 770
IMRT patients had been recruited with a median
follow-up of 45 months, reported that the 5-year
biochemical relapse-free survival using the ASTRO
consensus definition was 82% (95% CI 79 to 85%).
None of the studies reported overall survival or
clinically measured disease-free survival. One
conference abstract107 reported, at 4 years, no
significant difference between treatment groups
in distant metastasis (from n = 88 in both groups,
those developing distant metastasis IMRT 4%,
3DCRT 3%, p = 0.36), or in cause-specific mortality
(IMRT 1%, 3DCRT 0%, p = 0.32).107
The Vora et al. study89 using the ASTRO consensus
definition, found a significant difference between
treatment groups (p < 0.0001) by either univariate
or multivariate analysis (Table 11). Multivariate Cox
proportional hazards analysis took into account
stage, perineural invasion, PSA, Gleason score,
hormonal therapy and percentage positive biopsies
in addition to treatment group, and found all
factors except hormonal therapy and percentage
positive biopsies were significantly associated with
biochemical failure. The Vora et al. study also
used the ASTRO Phoenix definition45 rise in PSA
level of 2 ng/ml or more above the nadir with no
backdating. There was a significant difference
between treatment groups by either univariate
(p < 0.0326) or multivariate analysis (p < 0.0359).
Biochemical relapse-free survival
The Kupelian et al.84 study used the ASTRO
consensus definition44 of biochemical failure,
that is three consecutive rising PSA levels after
reaching a nadir, and calculated the time to failure
as midway between time of nadir and first PSA
The Vora et al. study89 investigated biochemical
survival by the NCCN defined risk group, that is
risk group decided by PSA ≤ 10 ng/ml, stage T1–T2,
Gleason score ≤ 6; if patient meets all three criteria
they are considered to have low-risk disease, an
increase in one indicator translates as intermediate
Assessment of effectiveness
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
23
Assessment of clinical effectiveness
TABLE 11 Biochemical relapse-free survival
Study
Follow-up
Definition of
failure
Number
of
patients
IMRT
Kupelian et
al. 84
30 months
ASTRO consensus
166
Kupelian et
al. 84
30 months
PSA level reaching
and maintaining
0.5 ng/mL or over
Vora et al. 89
36 months
Vora et al.
89
Vora et al.
89
Vora et al. 89
Survival
IMRT%
Survival
3DCRT%
116
94 (95% CI
91 to 98)
88 (95% CI
82 to 94)
166
116
87% (95%
80% (95%
CI 81 to 93) CI 72 to
88)
ASTRO consensus
145
271
95.2
71.1
36 months
ASTRO Phoenix
145
271
93.8
89.8
60 months
ASTRO consensus
145
271
74.1
60.4
p < 0.0001
60 months
ASTRO Phoenix
145
271
84.6
74.4
p < 0.0326
risk, and an increase in two or three indicators is
classed as high risk.91 Using the ASTRO consensus
definition, Vora et al. found 5-year survival for
IMRT patients was 87.5% for low-risk patients,
72.6% for intermediate risk, and 60.2% for highrisk patients. For 3DCRT the survival data by risk
group were 76.2%, 50.1%, and 35.0% respectively.
IMRT significantly improved biochemical survival
for intermediate- (p < 0.0001) and high-risk
(p = 0.0188) patients, but for low-risk patients there
was no significant difference between treatment
groups (p = 0.181).
The Zelefsky study does not report comparative
data, but reports data from IMRT patients using
the ASTRO consensus definition. There was no
dose effect on PSA relapse-free survival for IMRT
dose of 81 Gy or 86.4 Gy.92 There was no difference
in results according to whether or not patients
had neoadjuvant androgen deprivation.92 For
IMRT patients aged ≤ 60 years, a dose < 75.6 Gy
was the most important predictor of biochemical
relapse in younger patients.94 The 3-year actuarial
PSA relapse-free survival rates by NCCN defined
risk group: low risk (n = 275) 92%, intermediate
(n = 322) 86%, and high (n = 175) 81%.92 The 8-year
actuarial PSA relapse-free survival rates by risk
group for IMRT patients were for low risk (n = 203)
85%, intermediate (n = 255) 76%, and high
(n = 103) 69%.
The Morgan et al.107 abstract reported biochemical
failure using the ASTRO Phoenix definition in
patients with intermediate to high-risk PC. At
4 years there was no significant difference between
treatment groups, with a biochemical failure rate
of 18% for the IMRT group (PSA survival 82%),
24
Number
of
patients
3DCRT
Comparison
p = 0.084
p = 0.24
and 19% (PSA survival 81%) for the 3DCRT group
(p = 0.675).
For the studies Kupelian et al.28 and Vora et al.89
that reported comparative statistics, Kupelian et
al.28 did not report a difference between treatment
groups, whereas Vora et al.89 found a significant
biochemical survival advantage for IMRT. The
different results cannot be explained by definition
of biochemical failure, as both studies used the
ASTRO consensus definition. Across the two
studies at 30 or 36 months, biochemical survival
data appear similar for IMRT groups (see Table
8); however, for the 3DCRT groups Vora et al.89
reported lower survival than Kupelian et al.28 This
might be explained by dose. The 3DCRT dose
in the Vora et al.89 study was lower than in the
Kupelian et al.28 study. The Vora et al.89 study had
a lower dose in 3DCRT than in the IMRT group,
and the Kupelian et al.28 study had an equivalent
dose between treatment groups. The Morgan et
al.107 abstract, which did not find a treatment group
difference in biochemical failure, had similar
dose for both treatment groups. The 3DCRT dose
in the Vora et al.89 study was lower than in other
studies, and was approximately 68.4 Gy. There is
evidence from RCTs that in CRT 68 Gy leads to
lower biochemical survival than for CRT at 78 Gy.59
The lack of dose effect on PSA relapse-free survival
for IMRT dose of 81 Gy or 86.4 Gy in the Zelefsky
study92 is consistent with the lack of evidence
of benefit for increasing dose of 3DCRT above
81 Gy.64
It is unlikely that the difference between Kupelian
et al.28 and Vora et al.89 study results could be
explained by risk group. Although the Vora et al.89
study found that low-risk disease did not benefit
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
significantly from IMRT over 3DCRT, they found
intermediate and high-risk patients did differ
significantly between treatment groups, and the
Kupelian et al.28 study had 70% high-risk tumours.
It is unlikely that the difference between study
results could be explained by their difference in
hormonal therapy between treatment groups,
as neither study found an association between
hormonal therapy and biochemical survival,
Kupelian et al.28 (p = 0.66) and Vora et al.89
(p = 0.08), which agrees with the Zelefsky et al.91
study. However, the focus of this review was not
hormonal therapy, and these limited data are not
presented as conclusive evidence on the effect of
hormonal therapy.
durations were not long enough. It may be that
follow-up in excess of 10 years, and a larger sample
size, would be needed to detect group differences
in secondary malignancies.64 There is a lack of
comparative data on sexual dysfunction as an AE,
but sexual function is measured as part of HRQoL.
Toxicity
For defining AEs, five of the studies (Kupelian et
al.,28 Sanguineti et al.,88 Shu et al.,29 Vora et al.,89
Ashman et al.100) used RTOG and the other study
(Zelefsky et al.91) used NCICTC for AEs.
By univariate analysis, the Shu et al. study found
an advantage for 3DCRT.29 However, this might
be attributed to the lower proportion of 3DCRT
patients treated with whole pelvis (WP) radiation.
As well as treatment group effect, the Shu et al.
study found that WP radiation was significantly
correlated with the incidence of acute GI toxicity
(p = 0.001).29 In the IMRT group, 9 (69%) of 13
patients receiving pelvic irradiation had acute GI
toxicity versus 2 (40%) of 5 patients not receiving
pelvic irradiation (both cases were grade 1). The
Zelefsky et al. study91 did not find any demonstrable
influence of age, radiation dose or hormonal
therapy on incidence of acute rectal symptoms.
For patients treated with IMRT, Zelefsky found no
difference in GI toxicity between doses 86.4 Gy and
81 Gy.92
Among all studies, there are no mentions of
treatment-related deaths, with the possible
exception of one patient from the Kupelian et al.28
study. However, although one patient treated with
IMRT died in this study it was unclear if the death
could be attributed to treatment-related late rectal
toxicity or if it was due to the patient’s underlying
medical condition.
None of the studies report secondary
malignancies, probably because the follow-up
The studies concentrate on GI and GU AEs. These
are considered separately for acute and late effects.
Acute gastrointestinal toxicity
Kupelian et al.84 and Zelefsky et al.91 found a
significant advantage for IMRT over 3DCRT (Table
12). Vora et al.89 did not find a significant difference
between treatment groups.
TABLE 12 Acute gastrointestinal toxicity in localised prostate cancer
Study
Follow-up/
definition
Definition
Number of
patients
IMRT
Number of
patients
3DCRT
Acute GI
toxicity
IMRT
Acute GI
toxicity
3DCRT
Comparison
Kupelian et
al. 84
Acute
RTOG rectal
166
toxicity scores
116
Score 0
30%, score
1 55%, and
score 2
15%
Score 0
p = 0.002
12%, score
1 70%, and
score 2
18%
Shu et al.29
Within
6 months
RTOG grades
1–3
18
26
NR
NR
Vora et al. 89
Acute
RTOG grade
145
271
Grade 0
16%, grade
1 34%,
grade 2
49%, grade
3 1%
p = 0.83
Grade 0
27%, grade
1 20%,
grade 2
54%, grade
3 0%
Zelefsky et
al.91
During or
NCI-CTC
within 3 months
472
358
3%
1%
NR, not reported.
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
p = 0.003
higher in IMRT
group
p = 0.04
25
Assessment of clinical effectiveness
Across studies, toxicity grades were generally low.
Only one (IMRT) patient in the Shu et al. study
developed grade 3 toxicity.29 In the Vora et al. study
no grade 4 or 5 toxicity was found.89
The only study looking at toxicity specifically in
locally advanced PC, Ashman et al. (Table 13),
found no grade 3 or higher acute GI toxicities
developed in any of the patients; however, the
sample size was small.100 As five of the six patients
in the 3DCRT group who had grade 2 diarrhoea
were additionally treated with chemotherapy, it
is difficult to attribute the results to treatment
difference between groups.
Three of the studies106,107,110 published as conference
abstracts favoured IMRT for acute GI toxicity. The
Sharma et al. abstract106 on hormonally treated
PC patients found significantly [hazard ratio
(HR) = 4.39, p = 0.003] lower acute GI toxicity
in the IMRT group than in the 3DCRT group.
The Morgan et al. abstract107 on patients with
intermediate- to high-risk PC found significantly
less (p = 0.015) grade 2 or higher acute GI toxicity
in the IMRT group (4%) than the 3DCRT group
(10%). The Martinez et al. abstract110 on adaptive
IGRT found a significantly (p < 0.01) lower rate of
grade 2 or higher rectal pain or tenesmus in the
IMRT group (5%) than the 3DCRT group (19%).
The Kirichenko et al. abstract105 did not report a
treatment group difference in acute toxicity, but
did find that patients with WP treatment involving
lymph nodes were more likely to have acute
toxicity than patients with smaller treatment fields
(HR = 2.1, p < 0.0001).
The Boehmer et al. abstract found no treatment
group differences were found for rectal pain,
bleeding, urgency or incontinence. However, they
did report significantly (p = 0.002) more proctitis
(common toxicity criteria) in the IMRT group than
in the 3DCRT group. Most toxicities were grade
1.109 Unlike the Shu et al. study,29 the treatment
108
group difference does not appear to be explained
by difference between WP or prostate only
radiation. There was a higher dose in the IMRT
group, but this was also the case for the Vora et al.89
and Zelefsky et al.91 studies which did not show the
same pattern of treatment group effect.
Acute GU toxicity
There was no significant treatment group effect
for acute GU toxicity in the Kupelian et al.,85 Shu
et al.,29 or Vora et al.89 studies, although in the Vora
et al. study there was a trend for IMRT to have
higher acute GU toxicity (Table 14). The Zelefsky
et al. study results significantly favoured 3DCRT
(p = 0.001).91 Zelefsky attributes this to the urethral
dose not being constrained in the IMRT group.92
For patients treated with IMRT, Zelefsky found a
non-significant trend for higher toxicity at 86.4 Gy
than for 81 Gy.92
The Shu et al. study found that WP radiation
correlated with the incidence of acute GU toxicity
(p = 0.021).29
Toxicity was generally low grade; in the Shu et al.
study no patients developed grade 3 toxicity,29 and
in the Vora et al. study no grade 4 or 5 toxicity was
found.
The Ashman et al. study of locally advanced PC
had slightly higher incidence of acute GU toxicity
in the IMRT group than the 3DCRT group
[7 or 8 (reporting unclear in publication) out of 13
patients, vs 3 or 4 out of 14 patients]; however, this
was based on a small sample size.100
Three of the conference abstracts106–108 on PC did
not find treatment group effects. The Sharma et
al. abstract106 on hormonally treated PC patients
found no significant treatment group difference
in acute GU toxicity. They did find that hormonal
treatment of 6 months or longer duration was
associated with increased acute GU toxicity
(p = 0.045). The authors gave no explanation for
TABLE 13 Acute gastrointestinal toxicity in locally advanced prostate cancer
Follow-up/
definition
Study
Ashman et al.
26
Definition
Number of Number of
patients
patients
IMRT
3DCRT
Acute GI
toxicity
IMRT
Acute GI
toxicity
3DCRT
100
During or within
3 months of
treatment
RTOG grade 2
diarrhoea
13
14
0%
43% (n = 6)
Ashman et al.100
During or within
3 months of
treatment
RTOG grade 2
proctitis
13
14
7% (n = 1)
36% (n = 5)
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
TABLE 14 Acute GU toxicity in localised prostate cancer
Number
of
patients
IMRT
Study
Follow-up
Definition
Kupelian
et al. 84
Acute
Urinary toxicity 166
RTOG scores
Number
of
patients
3DCRT
Acute GU
toxicity
IMRT
Acute GU
toxicity
3DCRT
116
Score 0
15%, score
1 62%,
score 2
22%, score
3 1%
Score 0
19%, score
1 63%,
score 2
17%, score
3 1%
p = 0.64
Comparison
Shu et al.29 Within 6 months RTOG grade
1–2
18
26
NR
NR
p = 0.535
Vora et
al. 89
Acute
RTOG grade
145
271
Grade 0
28%, grade
1 23%,
grade 2
46%, grade
3 5%
Grade 0
38%, grade
1 21%,
grade 2
40%, grade
3 1%
p = 0.094
Zelefsky
et al.91
During or within
3 months of
treatment
NCI-CTC
grade 1 or
higher GU
symptoms
472
358
37%
22%
p = 0.001
NR, not reported.
this, and no definitive conclusions about duration
are drawn from one small study. The Morgan et al.
abstract107 on patients with intermediate to high
risk PC did not find a treatment group difference
(p = 0.116) grade 2 or higher acute GU toxicity
between the IMRT (10%) and 3DCRT (5%) groups.
The Boehmer et al. abstract108 did not find any
treatment group difference for acute GU toxicity.
The Martinez et al. abstract110 on adaptive IGRT
found a significantly (p = 0.03) lower rate of grade
2 or higher urinary retention in the IMRT group
(2%) than the 3DCRT group (7%). Other acute
GU symptoms are not mentioned. This pattern
of results is unlike the other studies, and cannot
be explained by dose as treatment groups had
equivalent doses. This study did differ from the
others in that IGRT was used.
Late GI toxicity
The Zelefsky et al. study91 favoured IMRT in terms
of late GI toxicity (Table 15), as did the Kupelian et
al. study84 when considering only grade 3 toxicity.
The Shu et al. study29 did not find significant
treatment effects. The Vora et al. study89 did
not find significant treatment effect despite the
higher dose in the IMRT group. In the Sanguineti
et al. study, the difference between groups was
non-significant by univariate analysis (Table 15),
but multivariate analysis significantly favoured
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
IMRT, with adjusted HR = 0.1 (95% CI 0.0 to
0.06) p = 0.01.88 The analysis adjusted for dose to
most anterior and posterior rectal points along
the central axis, age, race, hypertension, diabetes,
vascular comorbidity, GI comorbidity, any other
comorbidity, transurethral resection of prostate,
androgen deprivation, acute toxicity and T-stage.
Sanguineti et al. dosimetric comparison found
that although IMRT had higher average dose
to anterior rectum, the percentage of rectum
receiving a given dose was significantly (p < 0.05)
lower with IMRT than the 3DCRT group.
Sanguineti et al. reported that for 22% of 3DCRT
patients, and 0% IMRT patients, treatment failed
to meet dose–volume constraints.88 A multivariate
analysis of AEs from the Kupelian et al.28 study
found the only factor that significantly predicted
grade 2–3 late rectal toxicity was the volume of
rectum receiving the prescription dose (p = 0.006).
Zelefsky et al.91 found a higher incidence of late GI
toxicity in those patients who experienced acute GI
toxicity (p < 0.0001).
For patients with locally advanced PC, Ashman et
al.100 reported that none of the patients developed
grade 3 or higher toxicity. Both patients with grade
2 late rectal bleeding were in the 3DCRT group,
but sample size was too small to draw conclusions
about significance. The two patients who got
27
Assessment of clinical effectiveness
TABLE 15 Late GI toxicity in localised prostate cancer
Number
of
patients
IMRT
Number
of
patients
3DCRT
Late GI
toxicity
IMRT
Late GI
toxicity
3DCRT
Comparison
Study
Follow-up
Definition
Kupelian et
al. 84
30 months
Actuarial
combined
grade 2 and
3 late rectal
toxicity
166
116
5%
12%
p = 0.24
Kupelian et
al. 84
30 months
Grade 3
late rectal
toxicity
166
116
2%
8%
p = 0.059
Sanguineti
et al. 88
Complications
developing
> 90 days after
treatment and
those starting
prior to and
persisting for
> 90 days after
completion of
treatment, 2 years
follow-up
Estimated
45
cumulative
incidence
grade 2 rectal
toxicity
68
6% ± 4%
21.2% ± 6% HR
(unadjusted) = 0.2,
95% CI 0.1 to 1.1;
p = 0.06
Shu et al. 29
Minimum
10 months
RTOG grade
1–3
18
26
NR
NR
p = 0.163
Vora et
al. 89
60 months
RTOG grade
145
271
Grade
0 56%,
grade
1 20%,
grade
2 23%,
grade 3
1%
Grade
0 57%,
grade
1 26%,
grade
2 14%,
grade 3
2%
p = 0.24
Zelefsky et
al. 91
10 years
NCI-CTC
grade 2 or
higher
472
358
5%
13%
p < 0.001
NR, not reported.
grade 2 rectal bleeding (Table 16) did not receive
chemotherapy.
28
Four105–107,110 of the five105–108,110 conference
abstracts favoured IMRT in terms of late GI
toxicity. The Kirichenko et al. abstract105 found a
significantly (univariate p = 0.009, multivariate
HR = 0.6, p = 0.0499) lower rate of late grade 2
or higher GI toxicity in the IMRT group (6.2%)
at 3-year follow-up compared with the 3DRCT
group (10.4%). In addition, treatment to the WP
or lymph nodes was associated with higher late
GI toxicity (HR, p = 0.003). The Sharma et al.
abstract106 on hormonally treated PC patients
found significantly lower (HR = 2.45, p = 0.02) late
grade 2 or higher GI toxicity in the IMRT group
(9%) than in the 3DCRT group (22%), based on
5-year estimates. The Morgan et al. abstract107 on
patients with intermediate to high-risk PC found
a non-significant trend for less (p = 0.061) grade
2 or higher late GI toxicity in the IMRT group
(4%) than the 3DCRT group (9%) at 4 years. The
Martinez et al. abstract110 on adaptive IGRT found
a significantly (p < 0.01) lower rate of late grade 2
or 3 rectal bleeding in the IMRT group (4%) than
the 3DCRT group (16%). There was no treatment
group difference for late grade 2 or 3 rectal pain,
tenesmus or diarrhoea. Median time to rectal
bleeding was 11 months for IMRT and 12 months
for 3DCRT.
The Boehmer et al. abstract108 did not find any
treatment group difference (p = 0.23) for late GI
toxicity. This was despite acute GI toxicity results
showing more proctitis in the IMRT group than in
the 3DCRT group.
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
TABLE 16 Late GI toxicity in locally advanced prostate cancer
Study
Follow-up/definition
Ashman et More than 3 months after
al. 100
treatment (minimum
follow-up 10 months)
Definition
RTOG grade 2
rectal bleeding
Number of Number of
patients
patients
IMRT
3DCRT
Late GI
toxicity
IMRT
Late GI
toxicity
3DCRT
12
0%
15% (n = 2)
13
Late GU toxicity
Health-related quality of life
The Zelefsky et al.91 and Shu et al.31 studies favoured
3DCRT for late GU toxicity (Table 17). There was
no significant treatment effect in the Vora et al.89
study, and the Kupelian et al.84 study reported they
had too few events to determine significance. Shu
et al. found late GU toxicity was related to maximal
tumour dose (p = 0.019), and WP radiation
(p = 0.016).29 Both Shu et al.29 and Zelefsky et al.91
found a higher incidence of late GU toxicity in
those patients who had experienced acute GU
toxicity (p = 0.025 and p < 0.001 respectively).
Yoshimura et al.41 assessed HRQoL in localised
PC at three time points; before RT, immediately
after RT, and 12 months after RT ended. On the
eight domains in SF-36 there were no significant
differences between treatment groups. There were
also no significant differences across the three time
points. On the UCLA PCI there were no significant
differences between groups. Although there was
a significant interaction between group and time
point on the sexual function domain (p < 0.05),
this was seemingly due to difference between
groups at baseline. There was a non-significantly
higher pre-RT sexual function score in the lowdose 3DCRT group, than in the other two groups.
The low-dose 3DCRT group deteriorated between
pre-RT and immediately post-RT then improved
at 12 months, whereas the IMRT and high-dose
3DCRT groups improved between pre-RT and
immediately post-RT as well as improving between
immediately post-RT and 12 months. All three
groups improved significantly between pre-RT and
12 months, though this was greater in the IMRT
and high-dose 3DCRT groups (p < 0.001) than the
low-dose 3DCRT group (p < 0.01). For all groups
there was significant deterioration (p < 0.05) in
urinary bother, bowel function and bowel bother
domains during RT, but these were restored at
12 months.
For locally advanced PC, Ashman et al. found none
of the 12 IMRT patients, but four of 13 3DCRT
patients with late GU toxicities (Table 18).100 All
of the patients with late GU toxicity were treated
with chemotherapy as well as 3DCRT, making it
difficult to attribute the group difference to type of
RT delivered.
Three105,107,108 conference abstracts reported
no treatment group effect on late GU toxicity.
The Kirichenko et al. abstract105 did not find a
significant treatment group difference in late GU
toxicity, although there was a trend (univariate
p = 0.06, multivariate p = 0.11) for more toxicity in
the IMRT group (8.4%) than the 3DCRT group
(5.7%) at 3 years. The Morgan et al. abstract107 on
patients with intermediate to high risk PC did not
find a treatment group difference (p = 0.661) grade
2 or higher late GU toxicity between the IMRT
(2%) and 3DCRT (1%) groups. The Boehmer et
al. abstract108 did not find any treatment group
difference (p = 0.42) for late GU toxicity.
The Martinez et al. abstract110 on adaptive IGRT
found no treatment group difference for late grade
2 or 3 frequency, urgency, haematuria or urethral
stricture. However, they did report a significantly
(p < 0.05) lower rate of late grade 2 or 3 urinary
retention in the IMRT group (0.5%) than the
3DCRT group (3%). This pattern of results is
unlike the other studies, and cannot be explained
by dose as treatment groups had equivalent doses.
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Lips et al.43 assessed HRQoL in locally advanced
PC at three time points; before treatment,
1 month after treatment, and 6 months after
treatment. Considering the time points baseline
and 1 month post-RT, for six of the 29 items there
was a significant interaction between treatment
group and time, with the 3DCRT group showing
more deterioration than the IMRT group. These
items were RAND-36 (RAND-36 item health
survey, that uses the same items as SF-36 but with
different scoring) social functioning (p = 0.006),
pain (p = 0.01) and change in health (p < 0.0001);
EORTC QLQ-C30(+3) physical functioning
(p = 0.006) and role functioning (p = 0.006);
EORTC QLQ-PR25 urinary symptoms/function
(p < 0.0001). For baseline and 6 months post-RT,
29
Assessment of clinical effectiveness
TABLE 17 Late GU toxicity in localised prostate cancer
Number
of
patients
IMRT
Number
of
patients
3DCRT
Late GU
toxicity
IMRT
Late GU
toxicity
3DCRT
Study
Follow-up
Definition
Comparison
Kupelian
et al. 84
30 months
RTOG urinary
toxicity
166
116
Grade
2 n = 2,
grade 3
n = 0
Grade
2 n = 2,
Grade 3
n = 0
NA
Shu29
Minimum 10
months
RTOG grade 1–3
18
26
NR
NR
p = 0.025
Vora 89
60 months
RTOG grade
145
271
Grade 0
45%, grade
1 27%,
grade 2
23%, grade
3 6%
Grade 0
66%, grade
1 13%,
grade 2
17%, grade
3 5%
p = 0.33
Zelefsky 91
10 years
NCICTC grade 2
or higher
472
358
20%
12%
p = 0.01
TABLE 18 Late GU toxicity in locally advanced prostate cancer
Study
Ashman
100
Follow-up/definition
Definition
Number of Number of
patients
patients
IMRT
3DCRT
More than 3 months after
treatment (minimum
follow-up 10 months)
RTOG grade 1–3
12
there were no significant differences between
groups on any of the items measured. For the
other 23 items there were no significant differences
between groups and no significant interaction
between treatment group and time. These
included items relating to emotional, cognitive,
social and sexual functioning, and GI symptoms.
Kupelian et al.84 assessed HRQoL in localised PC,
but only after treatment, no baseline data were
reported. Two years after treatment 77 patients
(IMRT n = 38, 3DCRT n = 39) completed the
Expanded Prostate Cancer Index Composite
(EPIC) questionnaire. The groups did not differ
in urinary (p = 0.85), bowel (p = 0.12) or hormonal
(p = 0.38) scores, but the IMRT group scored better
on the sexual summary score (p = 0.003). There
was no difference between treatment groups on
the SF-12, either on physical (p = 0.11) or mental
(p = 0.81) QoL scores.
30
Discussion
No comparative studies of IMRT versus
prostatectomy were identified. No RCTs were
available of IMRT versus 3DCRT in PC. Eight
13
Late GU
toxicity
IMRT
Late GU
toxicity
3DCRT
0%
31% (n = 4)
studies29,41,43,84,88,89,91,100 comparing IMRT and
3DCRT were found that were published in
full, and an additional five studies105–108,110
published as conference abstracts only were
identified. None of the studies investigated
overall survival. Comparative evidence on
biochemical relapse-free survival was available
from two studies84,89 published in full and one
abstract.107 Toxicity data were available from
six studies29,84,88,89,91,100 published in full and
five abstracts.105–108,110 Comparative evidence on
HRQoL with baseline and follow-up data were
available from two studies41,43 published in full.
Of the studies published in full, six were studies
of clinically localised PC,29,41,84,88,89,91 and two of
locally advanced PC.43,100 The five conference
abstracts105–108,110 did not specify whether patients
had localised or locally advanced PC. The only
study reporting toxicity data for locally advanced
PC had a sample size of only 27, precluding
significance testing.100
With regard to overall quality of the eight studies
included in the review,29,41,43,84,88,89,91,100 the studies
displayed weaknesses which included differences
DOI: 10.3310/hta14470
between the treatment and comparator groups
on population differences. Two studies involved
populations which had higher biopsy Gleason
scores in the IMRT group compared with one
study which had higher biopsy Gleason scores
in the 3DCRT group. Two studies had higher
clinical T stages in the 3DCRT group and one
study had higher PSA scores in the IMRT group.
One study had higher numbers of patients with
androgen deprivation therapy in the IMRT
group compared with one study which had higher
numbers of patients with androgen deprivation
therapy in the 3DCRT group. The direction of bias
differs between the studies on these population
characteristics making it difficult to assess the
impact on the treatment effect of the IMRT
group. Some studies adjusted for such differences
with multivariate analysis, but not all studies did.
Overall the disease severity of the IMRT group
patients may be higher than in the 3DCRT group
patients, which may indicate that the results are
biased against IMRT.23
Half of the studies used historical controls and
many of the studies sampled different treatment
years per group. With regard to the latter point,
many of the studies were conducted within the
last decade. However, the studies with historical
controls in the previous decade and thus most
affected were Vora et al.,89 Sanguineti et al.88 and
Shu et al.29 so their results may be potentially
biased.23 Studies had longer follow-up periods
for the 3DCRT groups compared with the IMRT
groups, as the 3DCRT groups tended to be the
historical controls being sampled first. This may
have introduced potential bias towards more
toxicity, although in some studies the IMRT followup may have been long enough to capture late
toxicity.
There were differences in the details of oncological
management between studies and within studies
including the use of hormonal therapy (which
may affect PSA control, overall survival, acute
toxicity, late toxicity and HRQoL). One might
assume that use of this therapy suggests more
advanced disease, but it might easily just represent
change in standard practice. It is unlikely that
the difference between study results could be
explained by differences in hormonal therapy
between treatment groups, as two studies did not
find an association between hormonal therapy and
biochemical survival,84,89 which also agrees with the
Zelefsky et al. study.91
Health Technology Assessment 2010; Vol. 14: No. 47
There were differences between studies use of
pelvic nodal RT (which may also affect PSA
control, overall survival, acute toxicity, late toxicity
and HRQoL) and regarding the use of doseescalated RT (which may also affect PSA control,
overall survival, acute toxicity, late toxicity and
HRQoL). The use of dose escalation may indicate
a change in standard practice, but it might also
represent more advanced disease.
There were inter- and intra-study differences with
regard to the definition of biochemical failure;
however, studies such as Vora et al.89 presented
treatment group data for both the ASTRO
consensus and the ASTRO Phoenix definition of
biochemical failure, therefore limiting potential
bias.
The reliability of results presented in abstract
form may be questionable. Abstracts may present
preliminary results of an ongoing study and may
differ from those eventually published in full.2,112
For biochemical relapse-free survival, two studies
did not report a difference between treatment
groups. One study found a significant biochemical
survival advantage for IMRT. This difference
between studies is probably explained by dose.
The study finding an advantage for IMRT had
higher dose than in the 3DCRT group, unlike the
other studies that had equivalent doses between
treatment groups.
Most of the studies reported an advantage for
IMRT in acute and late GI toxicity, either in
reducing toxicity or producing similar toxicity to
lower dose 3DCRT. GI toxicity was associated with
larger treatment field, as WP versus prostate only,
or as volume of rectum treated. Late GI toxicity
was associated with acute GI toxicity.
Most of the studies found no treatment group
effect for acute and late GU toxicity, although one
study favoured 3DCRT. Adaptive IGRT favoured
IMRT for GU toxicity, however this was only
from one study abstract,110 and so does not allow
firm conclusions to be drawn. Acute GU toxicity
was found to be associated with WP radiation
or hormonal treatment of 6 months or longer
duration, although this may be due to baseline
differences in symptoms, with higher risk disease
patients being prescribed these treatments. Late
GU toxicity was associated with acute GU toxicity.
31
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Assessment of clinical effectiveness
In localised PC, for both IMRT and 3DCRT there
was a decrease in HRQoL during treatment,
but this was restored by 12 months after RT. For
patients treated with higher dose RT (IMRT or
3DCRT), HRQoL improved to a greater extent
than for lower dose RT. In locally advanced
PC, there was no treatment group difference by
6 months after treatment, although 1 month after
RT the 3DCRT group showed more deterioration
in pain, functioning and urinary symptoms. It may
be that follow-up was not long enough in these
32
studies to provide meaningful HRQoL data ‘as late
adverse effects frequently do not manifest until
after two years of treatment completion’.62
Although studies had methodological flaws, taken
together they seem to support the theory that
higher dose up to 81 Gy can improve biochemical
survival, and that restricting treatment field,
particularly with regard to constraining volume of
rectal wall receiving prescription dose, can lessen
toxicity.
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Chapter 4
Assessment of cost-effectiveness
Systematic review of
existing cost-effectiveness
evidence
A systematic literature search was undertaken for
previous economic studies of IMRT for PC. An
example search strategy for MEDLINE is shown in
Appendix 8. A total of 587 studies were identified.
Of these, three report a cost–utility analysis78,113,114
and two report costs of IMRT compared with
3DCRT.77,115 A further search for grey literature
in the CRD databases (DARE, NHS EED and
HTA) identified 15 records. One study64 had a full
report available in the English language and had
relevant economic content. Pearson et al. is a review
of IMRT for PC including a cost–utility study
comparing IMRT with 3DCRT.64
Cost–utility studies
The results of the four cost–utility studies are
summarised in Table 19. Of the three Konski
studies,64,78,114 the latest78 is the most complete
report so this was used for the quality assessment
(see Appendix 7). It appears that the same model
was used for all studies, although the first report
(2004)113 is an abstract only, so it is not clear. The
varying results reported in the different Konski
studies may be principally due to the differing time
horizons of the models. The 2006 study78 reports
the incremental cost-effectiveness ratio (ICER)
varying from US$57,794 at 5 years to US$28,132
at 15 years.78 A limitation of the Konski studies are
that key parameters (such as disease progression
and utility values for patients following RT) are not
based on a review of the literature. Data are taken
from different studies for IMRT and 3DCRT, so
their comparability is questionable. Utility values
were taken from studies which used different
methods of measurement. Reasons for the choice
of data sources were not explained.
Pearson et al.64 reports a very different ICER
(US$706,000) to Konski et al. (US$40,100)78
for IMRT compared with 3DCRT. The unit
treatment costs in Pearson et al.64 are based on
the resource use items used by Konski et al. The
key difference between the ICER estimates lies in
different assumptions regarding the effectiveness
of IMRT compared with 3DCRT. After reviewing
the evidence, Pearson et al. concluded that there
was no evidence of difference in progression-free
survival or survival. The difference in qualityadjusted life-years (QALYs) in the model arises
solely from a difference in rectal toxicity, with a
median duration of 1 year.64 Konski et al., however,
based on one case series for each of IMRT and
3DCRT, assumes a 14% difference in progressionfree survival between the two treatments at 5 years,
and also a relatively large difference in utility
following the two treatments (0.09), which endures
until patients progress. Actual differences in toxic
effects are not considered. This compares with the
difference in utility between those with best and
worst urinary and bowel function of 0.1 reported
by Shimizu et al.116 (see Utility values). Thus the
difference in utility post-IMRT and 3DCRT used
by Konski et al. is tantamount to assuming no
IMRT patients and all 3DCRT patients suffer from
late toxic GI effects until disease progression,
i.e. for several years. Although data is limited,
the results of Zelefsky et al.91 suggests that, for
the majority of men, such effects are limited to
2–3 years. Thus there appears to be bias in the
assumptions made by Konski, favouring IMRT.78
The Pearson et al. model is clearly limited as it
only considers adverse effects of RT, and not
survival.64 As well as the previously discussed
data limitations of the Konski et al.78 model, the
assumption that PSA failure is synonymous with
the start of hormone treatment is likely to lead
to the costs of PSA failure being exaggerated in a
UK setting, where hormone therapy is normally
commenced only after symptomatic disease
progression, proven metastases or a PSA doubling
time of less than 3 months.1 The Konski et al.78
model also does not explicitly include the costs and
effects on HRQoL of toxic effects of treatment. A
new economic model was therefore developed, as
described in Methods. The modelled disease states
are the same as those used by Konski et al.,78 but
with the addition of a state for PSA failure (prior to
hormone therapy) and also late toxic effects.
33
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Assessment of cost-effectiveness
TABLE 19 Cost-effectiveness studies of IMRT compared with 3DCRT
Time
horizon
(years)
Cost
year
IMRT
cost
US$(£) a
3DCRT
cost
US$(£) a
IMRT
QALYs
3DCRT
QALYs
ICER
US$(£) a
$27,357
(£17,098)
7.62
6.65
$25,580
(£15,988)
$33,837
(£21,148)
$21,377
(£13,361)
6.29
5.52
$16,182
(£10,114)
2004
$47,931
(£29,957)
$21,865
(£13,666)
6.27
5.52
$40,101
(£25,063)
2005
$42,450 b
(£26,531)
$10,900 b
(£6813)
NR
NR
$706,000
(£441,000)
Study
Patient group
Konski
et al.
2004113
Age 70 years,
intermediate risk
15
Not
reported
$52,170
(£32,606)
Konski
et al.
2005114
Age 70 years,
intermediate risk
10
2004
Konski et Age 70 years,
al. 200678 intermediate risk
NR
Pearson
et al.
200764
Lifetime
Age 69 years, low
to intermediate
risk (Stage T1/2,
PSA ≤ 20, any
Gleason)
NR, not reported.
a Assuming an exchange rate of US$1.6 to £1.
b Costs of treatment only.
Cost studies
Remonnay et al.115 and Marchal et al.77 report
costs of IMRT in a prospective comparative (nonrandomised) study of the costs of IMRT and
3DCRT in France. The data from Remonnay et al.
is likely to be a subset of that used in the analysis
of Marchal et al., is reported in abstract only, and
is not specific to PC. In both studies the time
taken by medical personnel (physicists, physicians,
dosimetrists and radiotherapists) to give either
IMRT or 3DCRT to patients with PC or head and
neck cancer is reported. Capital and maintenance
costs for equipment were also included. Remonnay
et al. only reports the difference in cost between
IMRT and 3DCRT, which was €1780, assuming 30
patients a year, or €1172 if 60 patients are treated
per year (2002–3).
34
Marchal et al. reports an average cost of €2357 per
patient for 3DCRT for PC, compared to €4911 for
IMRT, a difference of €2554 (2002). Although an
additional 335 minutes of staff time was required
on average for IMRT, mainly for preparation and
quality control, this costs only an additional €36.
The additional time relates to routine use of IMRT,
after a run-in period. The total number of patients
treated with IMRT was 86, of which 48 had PC.
The number of patients in the training and routine
phase are not specified. The greatest difference
in cost arose from equipment and maintenance
costs, which were an additional €2706 per patient,
assuming 30 patients are treated per year (note this
is greater than the overall difference in costs as
there was a small cost saving for IMRT in the use
of consumables).77
Independent economic
assessment
Methods
Model structure
A discrete event simulation model was developed in
simul8® for patients undergoing radical treatment
for PC with either IMRT or 3DCRT. There
were no data to model other patient groups. All
studies that reported clinical effectiveness did so
in terms of PSA failure. The PSA failure hazard
was not constant with time (i.e. not exponentially
distributed), and the literature indicated that the
hazards of clinical failure or death from the time
of PSA failure is also not necessarily constant
with time, which would make a Markov model
formulation complex.
In a discrete event simulation individual patients
are followed, with the time of events (such as
transition to another state) sampled from a
relevant statistical distribution. The simulation
time-clock moves immediately to the time of the
next event. This contrasts with a state transition
model that uses fixed time cycles which is less
efficient in periods of no state change, and
requires numerous states when patient history
affects future transition rates. The time to PSA
failure was sampled for each patient and compared
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
with the expected time of all-cause death, taken
from life tables. If the expected time of death
from other causes was less than the time to PSA
failure, then the patient died from other causes,
without experiencing PSA progression. Similarly
time to clinical progression and PC death are
sampled and compared to time to death from
other causes, to determine whether the patient
dies of other causes or progresses through to more
advanced PC disease states. Note the distributions
from time from PSA failure to clinical failure and
time from PSA failure to PC death were sampled
independently, so there is a possibility of patients
dying of PC without incurring the costs associated
with the more advanced disease states, but they
do incur terminal care costs. Distributions for
the incidence and timing of late adverse events
following RT were also sampled. The model has a
lifetime perspective.
by definition of short duration, it has a negligible
effect on QALYs, especially as the difference in
rates of grade 2 or more adverse effects between
IMRT and 3D are small (see Chapter 3, Toxicity).
Ten thousand individual patients were simulated
for each model run. This number was chosen as
the mean results had clearly stabilised with this
number of patients.
Other model outputs include the proportion of
patients who progress to each PC disease state and
death from other causes. The perspective of the
analysis is England and Wales 2008–9.
The model structure is shown in Figure 3.
Model scenarios
The rationale for IMRT is that higher doses of RT
may be given, with the intention of improving PSA
survival (and hence disease-specific survival), while
limiting additional radiation toxicity to organs
close to the prostate. Ideally different scenarios
would be modelled with varying doses of IMRT
and 3DCRT to investigate the relationship between
survival, late toxic effects of RT and treatment
costs.
Patients with localised PC enter the model at the
time of treatment (IMRT or 3DCRT). At some time
later they may experience PSA failure, then clinical
failure and death from PC. Due to the distributions
for time from PSA failure to clinical failure and
PSA failure and PC death some patients may
progress directly from PSA failure to PC death.
Death from other causes and late AEs of treatment
may occur in any state (with the obvious exception
of death). A fixed loss in QALYs is attributed to
a patient suffering a late AE at the time that the
AE occurs. Acute toxicity is not included, as being
Progression
free from PSA
failure
PSA
fail
Post-PSA
fail
Clinical
failure
It is assumed that patients with clinical failure
are on hormone therapy and hormone-refractory
patients have a course of chemotherapy, as well as
palliative care.
Model outputs:
The primary model outputs are:
• total costs for each treatment (IMRT/3DCRT)
• total QALYs for each treatment
(IMRT/3DCRT).
From the above the ICERs were calculated for each
scenario.
The clinical studies included in the review varied
as to whether the IMRT and 3DCRT cohorts
received similar total doses of radiation, or
Clinically
progressed
disease
(hormone therapy)
Hormonerefractory
metastic
disease
Prostate
cancer
death
All-cause
death
FIGURE 3 Diagram of model structure.
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
35
Assessment of cost-effectiveness
whether the dose in the IMRT cohort was higher.
In some studies 3DCRT was given at relatively
high total doses (≥ 80 Gy).29,107,110 However, there
is considerable heterogeneity between studies in
patient disease states, adjuvant hormone therapy
and RT techniques. Appendix 9 shows for the
included studies a summary of PSA survival
and toxicity for IMRT and 3DCRT ordered by
RT dose. It can be seen that the results are too
heterogeneous for dose effects to be apparent.
Thus the studies are too heterogenous both for
meta-analysis and to attempt to identify variation
in effects by dose.
There is evidence from RCTs of dose escalation
for 3DCRT that show that PSA survival improves
with increasing dose.59–62 A recent meta-regression
shows the relationship to be linear across a range
of doses between 64 Gy and 79.2 Gy, with a 1.8%
increase in biochemical control at 5 years for
each 1 Gy increase in total RT dose.65 The results
of these studies are relevant to IMRT. There is
also evidence from 3DCRT studies of variation
in toxicity with increasing dose. An RCT of dose
escalation of 3DCRT from 64 Gy to 74 Gy showed
an increase in late grade 2+ GI toxicity of 9% at
5 years.62 The results of a meta-regression of cohort
studies show that the incidence of late GI toxicity
of grade 2 or more increases by 12% to 16% when
the RT dose is increased from 70 Gy to 80 Gy.117
However, the toxicity results of the 3DCRT studies
are not applicable to IMRT as IMRT allows the
radiation to be sculpted to the target area of the
PC more precisely than 3DCRT, thus reducing
toxicity to the surrounding normal tissues at
similar doses. Thus there is no data on the effects
of dose escalation on adverse effects for IMRT.
The effect of dose escalation on late GI toxicity for
IMRT might be ascertained indirectly using the
results of an analysis of the correlation of rectal
toxicity with the volume of the rectum receiving
different RT doses.118 For example, for every 5%
increase in rectal volume receiving 30 Gy the
odds ratio of grade 2 rectal bleeding was 1.14
(p = 0.006), and for every 5% increase in dose of
70 Gy the similar odds ratio was 1.41 (p = 0.001). To
use these results to compare toxic effects between
IMRT and 3DCRT or for dose escalation of IMRT
would require a review of dosimetric studies, which
is beyond the scope of this review.
36
Given the limitations described it was deemed
most appropriate to treat each study as a different
scenario. Only three included studies reported
PSA survival,84,89,107 of which one is reported in
abstract only.107 Patients in all of these studies
had localised PC and were treated with radiation
to the prostate and seminal vesicles (SVs) only.
In two studies where similar radiation doses
were given to IMRT and 3DCRT patients there
was no statistically significant difference in PSA
survival,84,107 although Kupelian et al.85 did report
an absolute difference of 7% at 5 years. In both
studies relatively high doses of RT were given. Note
that although the 3DCRT patients in the Kupelian
et al.84,85 study received 78 Gy compared to 70 Gy
for IMRT the doses are considered biologically
equivalent as the IMRT was given in fractions of
2.5 Gy (hypofractionated) compared to the more
usual schedule of 2 Gy fractions for 3DCRT. In
comparison to the total doses reported by other
studies both arms in Kupelian et al.84,85 may be
considered to have received RT doses equivalent
to 78 Gy. See Appendix 10 for details of the
estimation of biologically equivalent doses. Morgan
et al. reports a median dose of 80 Gy and 81 Gy for
3DCRT and IMRT respectively.107
The model scenarios are thus as follows:
1. Morgan et al.107 IMRT and 3D high dose
(80/81 Gy) – no PSA survival difference.
2. Kupelian et al.84,85 IMRT and 3D high dose
(78 Gy) – no PSA survival difference.
3. Kupelian et al.85 IMRT and 3D high dose
(78 Gy) – PSA survival difference as reported.
4. Vora et al.89 IMRT 75.6 Gy, 3DCRT 68 Gy –
PSA survival difference.
Note the total RT dose given to 3DCRT patients
in the Vora et al.89 study is low compared to the
current NICE guideline recommendation of at
least 74 Gy. The scenario will illustrate however
how cost-effective IMRT may be in comparison to
3DCRT if higher doses may be given with IMRT
than for 3DCRT.
A baseline age of 70 years is used, the approximate
age at which PC incidence peaks. A sensitivity
analysis was run on each of the four scenarios with
age at 60 and 80 years,
Model distributions
Disease progression: overview
None of the studies included in the clinical
effectiveness review report time to progression to
the clinical outcomes of clinical progression or
PC death. They do, however, report time to PSA
failure. In order to estimate the effect of IMRT
on clinical outcomes it is therefore necessary to
estimate the time from PSA failure to clinical
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
disease occurrence and also to PC death. Death
from other causes also needs to be considered.
Thus the disease progression model requires three
distributions:
The mean of a Weibull (γ,λ) distribution is:
• [A] time from treatment (IMRT/3DCRT) to
PSA failure
• [B] time from PSA failure to clinical failure
• [C] time from PSA failure to PC death.
where Γ(x) is the gamma function.
 1
 λ
 
1
γ

1
Γ 1 + 
 γ
Morgan et al.107
The Morgan et al. study is reported in abstract
only, but a small figure was published showing
actuarial time to PSA failure. At 4 years there was
only 1% difference in failure rates between the
IMRT and 3DCRT cohorts, which was statistically
non-significant. The two failure curves cross, and
are in effect indistinguishable from each other.
Points were read from both lines and the results
averaged at each time point to give a single curve
for both IMRT and 3DCRT. The resulting survival
curve is shown in Figure 4, together with the fitted
Weibull curve.
The method used to estimate these distributions
are described in the following paragraphs.
A Effectiveness of IMRT and 3DCRT:
time from treatment (IMRT/3DCRT) to
PSA failure
Three studies included in the effectiveness review
report time to PSA failure, all showing either
a survival or time to failure curve.84,89,107 The
published graphs were scanned and imported into
techdig software so that points could be read more
efficiently and accurately off the curves. Weibull
distributions were then fitted to the data points
obtained. Particular issues in fitting curves to the
data are discussed for each of the studies below.
The two-parameter Weibull distribution was used
with shape parameter γ, and scale parameter
λ.The form used is shown below, and the Weibull
parameters used and resulting mean PSA survival
are shown in Table 20.
Kupelian et al. 84,85
The length of follow-up in the Kupelian et al.84
study is relatively short: median 21 and 32 months
respectively for IMRT and 3DCRT. The number
of patients with PSA failure was small in both
cohorts, so the PSA survival curves are relatively
flat. Curves fitted to this data reflected this, and
gave implausibly long mean survival. Some PSA
survival curves in other studies, for example Vora
et al.89 (see below) are also relatively flat (low rate of
PSA failure) in the first few months, with the rate
of failure increasing with time, suggesting that the
length of follow-up in the Kupelian et al.84 study is
insufficiently long to base projections beyond the
The survivor function is:
S( t) = exp(− λ tγ )
0.8
Weibull
0.6
Pooled
0.4
4.00
3.50
3.00
2.50
2.00
1.50
1.00
0
0.50
0.2
0.00
Survival from PSA failure
1
Time (years)
FIGURE 4 Actual and fitted PSA survival curves: data from Morgan et al.107 IMRT/3DCRT.
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
37
Assessment of cost-effectiveness
duration of the study. A later publication85 shows
more mature data, albeit for a smaller cohort,
but only shows a PSA survival curve for the IMRT
group. The study reports an absolute difference
in PSA survival of 7% at 5 years, but this was not
statistically significant. The IMRT PSA survival
curve was used for both 3DCRT and IMRT in
the scenario which assumes no difference in PSA
survival between the two treatment methods
(Figure 5).
scenario the Weibull 3DCRT shape parameter was
assumed to be the same as for the IMRT curve,
with the scale parameter adjusted to reflect the
proportional difference in survival (85% IMRT,
78% 3DCRT) reported by Kupelian et al.85 [i.e.
(78/85) × (shape parameter IMRT)].
A second scenario was modelled to reflect the
difference in survival reported in the study,
although it was statistically non-significant. For this
Vora et al. 89
The Weibull curves were fitted from 20 months
onwards for both IMRT and 3DCRT curves to
give a better fit to the later data, as the plot of
ln(−ln(survival)) with ln(time) was not linear in the
first few months. The plots of the original data and
Survival from PSA failure
1
0.8
Data
0.6
Weibull Fit
0.4
0.2
5.5
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
0
Time (years)
FIGURE 5 Actual and fitted PSA survival curves: data from Kupelian et al. 85 IMRT.
1
Survival from PSA failure
0.9
0.8
0.7
Data
0.6
Weibull Fit
0.5
0.4
0.3
0.2
0.1
Time (years)
38
FIGURE 6 Actual and fitted PSA survival curves: data from Vora et al. 89 IMRT.
5.0
4.6
4.2
3.8
3.3
2.9
2.5
2.1
1.7
1.3
0.8
0.4
0.0
0
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Survival from PSA failure
1
0.8
Data
0.6
Weibull Fit
0.4
0.2
5.0
4.6
4.2
3.8
3.3
2.9
2.5
2.1
1.7
1.3
0.8
0.4
0.0
0
Time (years)
FIGURE 7 Actual and fitted PSA survival curves: data from Vora et al. 89 3DCRT.
TABLE 20 Summary of Weibull parameters and estimated mean survival for different scenarios
Study
Group
Scale
Shape
Mean survival to PSA fail (years)
Vora et al. 200789
IMRT
0.0082
1.755
13.7
3DCRT
0.0064
2.437
7.1
Kupelian et al.
2002/200584,85
IMRT
0.0171
1.370
17.8
3DCRT
0.0239
1.370
14.0
Morgan et al. 2007107
IMRT/3DCRT
0.0227
1.463
12.0
fitted curves are shown in Figures 6 and 7 for IMRT
and 3DCRT respectively.
definitions from which outcomes could be inferred
for these.
B/C Time from PSA failure to clinical
failure/prostate cancer death
In 2005 a Consensus conference, jointly sponsored
by ASTRO and RTOG, was held to consider
evidence for a revised definition of PSA failure.
At the conference several researchers presented
data showing the association between varying
definitions of PSA failure and clinical outcomes.
This evidence is summarised in a paper by Roach
et al.45 As well as potentially relevant references in
Roach et al. a MEDLINE search was undertaken
on the names of the researchers named in the
Roach et al. study. By this means one study by
Kestin et al.119 was identified which showed survival
data from PSA failure to clinical failure and PC
death, using relevant definitions of PSA failure.
Relevant definitions were defined as either the
ASTRO consensus or Phoenix definitions, or other
Kestin et al.119 explored the association of various
biochemical failure definitions with clinical
outcomes, including clinical failure and PC death.
The analysis is based on 727 men at a single
institution in the USA with clinically localised
(T1–T3, N0, M0) PC treated with radical externalbeam RT alone (no hormone therapy prior to
clinical failure) between 1987 and 1997, and
with at least five post-RT PSA measurements.
Thus the data is a good match to the population
being considered in the model, although the
dates of the collection period might lead to
slight underestimation of current PC survival as
more recent treatments for advanced PC such as
docetaxel chemotherapy would be expected to
affect this.120
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Summary results relevant to the model are shown
in Table 21. It can be seen that the actual results
39
Assessment of cost-effectiveness
required (rates of clinical failure and PC death
with time) are not reported for the ASTRO
Phoenix definition of PSA failure (a rise ≥ 2 ng/ml
above nadir PSA). However, they are reported for
similar definitions: a rise of ≥ 1ng/ml above nadir
PSA and a rise of ≥ 3ng/ml above nadir PSA.
The rates of clinical failure and PC death at
10 years after RT for all three definitions (a rise
≥ 1, 2 or 3 ng/ml above nadir PSA) are shown in
Table 22. It appears that the relationship is linear,
with the results for a rise ≥ 2 ng/ml above nadir
PSA midway between those for 1 and 3 ng/ml. It
therefore is reasonable to assume that the rate of
clinical failure or PC death can be estimated as
the mid-points for those for 1 and 3 ng/ml. These
estimated values are shown in Table 21.
Weibull curves were fitted to these data points.
The data and fitted curves for clinical survival and
PC death from the time of PSA failure (ASTRO
Phoenix) are shown in Figures 8 and 9 respectively.
The fitted Weibull curves result in mean estimated
time from PSA failure to clinical failure and PC
death of 3.1 and 7.8 years respectively.
It was originally anticipated that clinical outcomes
following PSA failure as defined by both ASTRO
consensus and Phoenix PSA definitions would
be required as Kupelian et al.84 reported PSA fail
with the former definition. In fact, the results
of Kupelian et al.84 proved to be unusable as
the data was insufficiently mature, and those
of Kupelian et al.85 were used in their place,
which were reported using the ASTRO Phoenix
definition. This had the advantage that all
scenarios are equivalent in this respect.
Other clinical parameters
These include duration of hormone-refractory
disease, time to all-cause death and adverse effects
of treatment.
Duration of hormone-refractory disease
It is assumed that the time with hormonerefractory disease is independent of the time
from clinical failure to death from PC. The
time in this state was taken from a review of
the treatment of hormone-refractory metastatic
PC with docetaxel.120 Median survival from the
TAX327 trial was 18.9 months. By fitting a Weibull
distribution to the data Collins et al. estimated
the mean survival time to be 22.4 months or
1.9 years.120 Thus in the model it is assumed that a
patient has hormone-refractory metastatic PC for
the final 22 months prior to PC death.
Time from treatment to all-cause death
Mean survival death from all causes for the
different age scenarios modelled was taken from
UK National Statistics.121 It was assumed that all
patients survived to this time unless they had
previously died from PC.
Adverse effects of treatment
The only adverse effect of treatment
operationalised in the model is late GI toxicity.
TABLE 21 Rates of clinical failure and PC death after biochemical failure (from date of failure)
Rates of clinical failure (%)
with time (years)
Definition
Years 0.5
Rates of PC death (%) with
time (years)
2
5
0.5
2
5
Rise of ≥ 1 ng/ml above nadir PSA
11
31
70
0.3
4
24
Rise of ≥ 3 ng/ml above nadir PSA
23
54
96
1.1
9
38
Estimated ASTRO Phoenix (rise of ≥ 2ng/ml
above nadir PSA) – see text
17
43
83
0.7
6.5
31
TABLE 22 Ten-year clinical failure and PC death from time of RT for various definitions of PSA failure
40
Definition
Clinical failure (%)
PC death (%)
Rise of ≥ 1 ng/ml above nadir PSA
64
40
Rise of ≥ 2 ng/ml above nadir PSA (ASTRO Phoenix)
73
45
Rise of ≥ 3 ng/ml above nadir PSA
82
50
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Survival from clinical failure
1
0.8
Data
0.6
Weibull Fit
0.4
0.2
0
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
Time (years)
FIGURE 8 Clinical survival from the time of PSA failure (ASTRO Phoenix).
Survival from prostate cancer death
1
0.8
Data
0.6
Weibull Fit
0.4
0.2
0
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
Time (years)
FIGURE 9 PC survival from the time of PSA failure (ASTRO Phoenix).
Most studies did not find a difference in GU
toxicity between IMRT and 3DCRT (see Toxicity).
None of the included studies report changes in
sexual function following RT, and therefore it is
unknown if there is any difference between the
treatment modes.
studies, and the values shown in Table 23. Only
grade 2 and 3 effects are considered. Grade
1 effects were seldom reported in the clinical
effectiveness studies (see Tables 15, 17) as they are
of limited clinical significance, and thus unlikely to
have important economic consequences either.
Studies which showed actuarial curves for late
GI toxicity indicate that incident cases with time
could be approximated by a straight line, starting
at 6 months after RT, and plateauing (no further
incident cases) by 5 years. The data used in the
model are derived from the clinical effectiveness
Note that Kupelian et al.85 only reports adverse
effects of treatment for IMRT patients. In order
to estimate their incidence for 3DCRT at 5 years
the ratio of late GI toxicity for IMRT at 5 years85 to
that at 2.5 years84 was applied to that for 3DCRT at
2.5 years.84
41
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Assessment of cost-effectiveness
TABLE 23 Incidence of late GI toxicity with time in modelled studies
Study
Vora et al. 2007
Start of late GI toxic
effects (years)
Finish time at which
no further incidence
Proportion of
of late GI toxic effects patients affected
IMRT
3D
IMRT
3D
IMRT
3D
0.5
0.5
5
5
0.24
0.16
Kupelian et al.
2002/200584,85
0.5
0.5
5
5
0.11
0.264
Morgan et al.
2007107
0.5
0.5
3.5
3.5
0.04
0.09
89
Not actuarial
Estimated – see
text
Note it has been assumed that the two different
AE reporting systems (RTOG, NCI-CTC) are
equivalent for GI incidence.
methods guide is the European Quality of Life-5
Dimensions (EQ-5D),122 a measure based on public
preferences.
Duration of gastrointestinal toxicity
Only one included clinical effectiveness study91
reports the duration for GU and GI toxicity. For
GI it is reported that 91% of cases were resolved,
with a median time to resolution of 26 months.
An estimate was made of the lower bound of mean
duration assuming:
In order to identify utility values for the patient
states in the model a systematic search of the
following databases was undertaken: MEDLINE,
EMBASE, CDSR, DARE, CCTR, HTA and NHS
EED. An example search strategy is shown in
Appendix 11.
• 91% of patients have a mean duration of
26 months
• the remaining 9% unresolved have a mean
duration estimated as the difference in
median follow-up time and median time to
incidence, giving 79 months (median time to
development 17 months and median follow-up
96 months – difference 79 months).
This results in an overall estimate of 2.6 months.
As this is likely to be an underestimate, with some
patients’ symptoms unresolved at the end of followup, the number was rounded up to 36 months
(3 years). Evidence from a 3DCRT dose escalation
trial also shows a proportion of patients whose
late GI toxicity symptoms take several months to
resolve.62 The RT01 trial showed prevalence of late
GI toxicity peaking at 18 months after RT, then
declining, with prevalence at 5 years approximately
30–40% of the peak value (estimated from curve).
Sensitivity analysis of the duration of late toxicity
was undertaken, with values of 2.5 and 4 years.
42
Comment
Utility values
For cost-effectiveness analysis the value of health
effects are measured in terms of QALYs. QALYs
are calculated by weighting life-years with utility
values, to reflect patients’ HRQoL. There are
different methods of determining utility values.
The recommended tool for use in the NICE
A total of 101 unique references were identified.
Of these 40 were selected on title and abstract
for potential inclusion as reporting utility values
(ascertained by any method). An iterative method
of study selection was planned to identify the best
evidence on utility values:
1. values obtained using the EQ-5D
2. values obtained using other public preferencebased weights of patient HRQoL scores (e.g.
the Health Utilities Index)
3. other studies.
Four studies report EQ-5D utilities for PC.116,123–125
Of these, two report utilities for states relevant to
the model.116,125 The results of Korfage et al. are
of interest only in terms of a global comparison
as utility values are reported for all patients who
had primary treatment of RT.123 Pickard et al.
was excluded as only a single utility value for PC
patients of undefined disease status is reported.124
As EQ-5D utility values were identified for all
model states, utility studies using alternative
measurement methods were not considered.
The key characteristics of the three studies
reporting relevant EQ-5D PC utilities are shown in
Table 24, and their results in Table 25.
It is assumed that following RT for localised PC
men not suffering adverse effects of treatment
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
TABLE 24 Studies reporting EQ-5D utility values for prostate cancer
Subjects
Mean age
(years)
Korfage et The Netherlands
al. 2005123
Localised PC RT (or radical prostatectomy), prior to
treatment and to 52 months post-treatment
RT patients
68
RT 187
Shimizu et
al. 2008116
Japan
Patients receiving RP, RT, brachytherapy, WW, or
combination for localised PC, and patients with
hormone-refractory PC
NR
323
Sullivan et
al. 2007125
Europe, North
America and
Australia
Symptomatic metastatic cancer
72
280
Study
Country
n
NR, not reported; RP, radical prostatectomy; WW, watchful waiting
TABLE 25 Summary results of EQ-5D studies
Utility
score
Comments
Pre-treatment
0.81
Decrease with age was probably the result
of ageing
After 6 months
0.83
After 12 months
0.82
After 52 months
0.76
Study
Patient group
Korfage et al.
2005123
RT
Shimizu et al.
2008116
Sexual function: EPIC score
16–85 (best)
0.93
0 (worst)
0.90
Urinary function: EPIC score
100 (best)
0.94
11–74 (worst)
0.84
Apparently some double measurement of
urinary symptoms, although both measures
(urinary function, LUTS) significant in
multivariate analysis of predictors of score,
as was bowel and hormone function. Sexual
function not significant
Bowel problem: EPIC score
100 (best)
0.94
0–80 (worst)
0.84
Hormonal function: EPIC score
100 (best)
0.93
35–80 (worst)
0.84
LUTS: IPSS
EPIC score
Sullivan et al.
2007125
0–7 (best)
0.93
20–35 (worst)
0.83
Symptomatic metastatic hormone-refractory 0.635
cancer
have the same mean utility as similarly aged men.
Ara and Brazier show how utility values vary with
age in UK adults.126 For men aged 60, 70 and
80 years their mean utility was 0.850, 0.813 and
0.771 respectively. These values were used for the
baseline utility values in the first year of the model
for the different age scenarios. These values were
also assumed to apply to patients who had PSA
failure, but not clinical progression. The baseline
utility values for men were assumed to decline with
age as the men progress through time in the model
according to the Ara and Brazier formula.126
43
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Assessment of cost-effectiveness
The utility values reported by Shimizu et al.116 (see
Table 25) are higher in general than those reported
by Ara and Brazier,126 even for men suffering
adverse effects of RT. They may be from a younger
population of PC patients (age not reported), and
they are not UK values. In order to estimate the
utility of men suffering adverse effects of treatment
in a UK population the ratio of utility values for
full function and poor function was applied to the
unaffected126 utility value. This resulting utility
values for men aged 70 years are shown in Table 26.
For example, for men who progress to clinical
failure, who are assumed to be on hormone
treatment, their utility is calculated as the ratio of
utility score worst hormone function to utility score
best hormone function (from Shimizu et al.116),
applied to the Ara and Brazier126 age-related utility.
Thus for a man aged 70 years with clinical failure
their utility is (0.84/0.93) × 0.813 = 0.734.
Similarly an adjustment to age-related utility was
calculated for hormone-refractory cancer from the
utility value reported by Sullivan et al.125 for men of
mean aged 72 years as a ratio of the mean utility
for men aged 72 years which is 0.805.126
Cost of IMRT/3DCRT
The costs reported in Description of technology
under assessment, show an additional cost of £1122
for IMRT compared to 3DCRT. As the objective
of the analysis is to determine incremental costeffectiveness it is sufficient to assume zero cost for
3DCRT and £1122 for IMRT.
Monitoring of patients post-RT (prePSA fail)
Initial monitoring of patients for the acute effects
of RT is assumed the same for both IMRT and
3DCRT and is included in the costs of treatment
shown in Table 8. The NICE guideline1 indicates
that patients should have two PSA tests a year for
the first 2 years following RT. These normally take
place at the oncology centre. It is assumed that
this cost is the same for both IMRT and 3DCRT
patients as very few patients progress in this time,
and is therefore not included in the model.
There is some variation in practice in subsequent
monitoring. Some patients may continue to be
monitored by an oncology centre up to twice a
year. The costs shown below, and used in the
model, are based on the recommendation in the
NICE guideline that after the first 2 years patients
may be monitored by their GP, with one PSA test
per year.1 The costs are shown in Table 27.
Resource use/costs
All unit costs used, together with their source, are
shown in Appendix 12. Most costs were sourced
from NHS reference costs 2007–8,51 Unit costs of
health and social care127 and the British National
Formulary.128 Where costs were not 2008–9 they
were inflated by the Hospital and Community
Health Sector (HCHS) inflation index.127
Monitoring of patients post-PSA failure
It is assumed that these patients are monitored
as hospital outpatients, with the cost of the PSA
tests absorbed into the cost of the outpatient
TABLE 26 Utility values used in the model, men aged 70 years
State
Utility value
Source
Post-RT, no AE
0.813
Ara and Brazier126
Post-RT, GI toxicity (bowel problem)
0.727
Ara and Brazier,126 Shimizu et al.116 (see
text)
Clinical failure (on hormone treatment)
0.734
Ara and Brazier,126 Shimizu et al.116 (see
text)
Hormone-refractory cancer
0.641
Ara and Brazier,126 Sullivan et al.125 (see
text)
TABLE 27 Annual cost of patient monitoring from 2 years post-RT
44
Item
Cost 2008–9
Number/year
Annual cost
PSA test
£10.19
1
£10.19
GP attendance
£36.97
1
£36.97
Total
–
–
£47.16
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
consultations. They have a CT scan and bone scan
every 2 years. The costs are shown in Table 28.
and a terminal care cost of £4007. The latter is
implemented in the model at PC death.
Monitoring of patients post-clinical
failure
It is assumed that these patients are on hormone
therapy. While patients may go through a sequence
of different hormone treatment strategies it has
been assumed for simplicity that these patients are
treated with the gonadorelin analogue goserelin,
by injection every 3 months. The annual resources
and costs for treating patients on hormone therapy
are shown in Table 29.
Cost of treating late gastrointestinal
toxicity
It has been assumed that all patients with grade
2 and 3 toxicities will be monitored in a hospital
outpatient setting, with the frequency depending
on severity (see Table 30). There is no standard
treatment for late GI toxicity. Most are likely to
be investigated with flexible sigmoidoscopy, and
possibly biopsy. The majority will be treated with
low-cost items such as laxatives, the cost of which
have not been considered. Some patients with more
severe cases may need procedures such as laser
treatment.
Hormone refractory/metastatic
The costs of treatment of hormone-refractory
metastatic cancer are taken from an analysis of the
cost-effectiveness of docetaxel chemotherapy in
these patients in comparison to other therapies.120
Docetaxel with prednisolone is the only
chemotherapy regime licensed for use in hormonerefractory PC.129 While not all men will receive
chemotherapy, the majority do, and the costs are
likely to be a reasonable representation of the costs
of care in the final months of life.
In the economic analysis by Collins et al.,120 as well
as the costs of chemotherapy costs of palliative and
terminal care were included, all based on resource
use in the TAX327 trial. The total cost of care in
2003–4 (with mean survival 1.9 years) was £15,833,
including a cost for terminal care of £3528. These
costs, inflated by the HCHS inflation index127 to
2008–9 costs, gives an annual cost of care of £7385
The average monitoring and treatment costs for
the treatment of all late GI toxic effects has been
calculated by estimating the proportion of patients
with grade 3 toxic effects. Table 31 shows the data
available from the included studies. The weighted
proportion of grade 3 toxic effects of all grade 2
and 3 effects is 26%, as shown in Table 31.
All costs and QALYs are discounted at 3.5% per
year.122
Sensitivity analysis
A key parameter in the analysis is the cost
difference between IMRT and 3DCRT. The costs
were obtained from a single institution only, and
therefore subject to some uncertainty as to their
TABLE 28 Annual cost of patient monitoring patients who have experienced PSA failure
Item
Oncology outpatient
Cost 2008–9
£88.33
Number/year
Annual cost
6
£529.96
CT scan (one area)
£112.98
0.5
£56.49
Bone scan
£168.44
0.5
£84.22
Total
£670.67
TABLE 29 Treatment costs for patients on hormone therapy
Item
Nurse (GP practice)
Cost 2008–9
Number/year
Annual cost
£10.27
4
£41.08
£267.48
4
£1069.92
Oncology outpatient
£88.33
2
£176.65
Dexa scan
£72.92
0.5
Goserelin (Zoladex LA) 10.8-mg syringe
Total
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
£36.46
£1324.12
45
Assessment of cost-effectiveness
TABLE 30 The costs of treating late gastrointestinal toxic effects of RT treatment
Annual monitoring cost
Cost 2008–9
Number/year
Annual cost
£88
3
£265
£88
6
£530
Grade 2
Oncology outpatient
Grade 3
Oncology outpatient
Mean cost (based on 26% grade 3)
£335
Treatment costs per patient
Cost 2008–9
Number/patient
Total cost
Flexible sigmoidoscopy ± colonoscopy, biopsy
£497
1
£497
Laser therapy
£1201
0.25
£300
Enemas (2/day for 2 weeks, community nurse)
£26
28
£728
Flexible sigmoidoscopy ± colonoscopy, biopsy
£497
2
£993
Laser therapy
£1201
2
£2403
Blood transfusion
£462
1
£462
Grade 2
Grade 3
Mean cost (based on 26% grade 3)
£2139
TABLE 31 Proportion of patients with grade 2 or 3 adverse effects who have grade 3 effects
Study
Kupelian et al. 2002
Vora et al. 200789
84
Treatment group
Number of patients
Proportion grade 3
IMRT
166
0.40
3DCRT
116
0.67
IMRT
145
0.04
3DCRT
271
0.13
698
0.26
Total
generalisability. A one-way sensitivity analysis was
undertaken on this key parameter.
The mean duration of late GI toxicity is also an
important parameter in some scenarios, where the
difference in QALYs between IMRT and 3DCRT
depends only on the difference between incidence
of late GI toxicity. For these scenarios (one and
two) a sensitivity analysis was undertaken, varying
the baseline value of 3 years to 2.5 and 4 years.
The effect of the age of men at the time of
treatment on the results was tested by running the
model with starting ages of 60 and 80 years.
46
A probabilistic sensitivity analysis was undertaken.
The purpose of a probabilistic sensitivity analysis is
to show the effect of the uncertainty in individual
model parameters on the uncertainty in the model
results. In a probabilistic sensitivity analysis, rather
than using the expected value of variables, values
are sampled from a distribution. The distributions
used for each parameter are shown in Appendix
13. For each scenario (e.g. Morgan et al.107 IMRT)
1000 model runs were made, as this was assumed
to adequately reflect the joint uncertainty between
parameters within the model.
Results
Baseline scenarios
Table 32 shows the estimated total life-years and
proportions of patients who progress to more
advanced stages of PC disease for men aged
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
TABLE 32 Modelled clinical results for men aged 70 years
Scenario
number
Scenario
Total
lifeyears
Discounted
life-years
PSA failure
Clinical
failure
Hormonerefractory
metastatic
disease
PC
death
1
Morgan et al. 2007107
IMRT/3DCRT
11.3
8.9
56%
40%
26%
29%
2
Kupelian et al. 2002/200584,85
IRMT/3DCRT (equal survival
scenario)
11.8
9.2
42%
29%
19%
21%
3
Kupelian et al. 2002/200584,85
IRMT
11.8
9.2
42%
29%
19%
21%
Kupelian et al. 2002/200584,85
3D
11.4
8.9
53%
37%
26%
28%
Vora et al. 200789 IMRT
11.8
9.2
49%
34%
22%
24%
Vora et al. 2007 3D
10.5
8.4
76%
55%
38%
42%
4
89
TABLE 33 Total costs, QALYS and ICERs for IMRT and 3DCRT scenarios for men aged 70 years
Scenario
number
1
2
3
4
Total
discounted
costs
Total
discounted
QALYs
Additional
cost IMRT
QALY gain
IMRT
Incremental
cost/QALY of
IMRT
Morgan et al. 2007107
IMRT
£6173
6.802
£989
0.010
£104,066
Morgan et al. 2007107
3DCRT
£5184
6.792
Kupelian et al.
2002/200584,85 IMRT
£4946
7.070
£732
0.023
£31,162
£4214
Kupelian et al.
2002/200584,85 3DCRT
(survival equal to IMRT)
7.046
Kupelian et al.
2002/200584,85 IMRT
£4946
7.070
£40
0.087
£5295
Kupelian et al.
2002/200584,85 3DCRT
£4486
6.983
Vora et al. 200789 IMRT
£5687
7.015
–£1802
0.613
Dominates
Vora et al. 200789
3DCRT
£7489
6.402
Scenario
70 years, for the four modelled scenarios. There
is some variation between the scenarios in the
proportion of men estimated to die from PC: 42%
for Vora et al.89 (3DCRT) and 21% for Kupelian
et al.84,85 (IMRT). This reflects differences in the
study results themselves.
The total discounted costs and QALYs for each
scenario for men aged 70 years is shown in Table
33, as well as the resulting ICER. In scenario 1,
based on Morgan et al.,107 IMRT is not cost-effective
judged by the maximum NICE threshold of an
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
ICER of £30,000.122 In this scenario equal doses of
RT were given to both IMRT and 3DCRT patients,
resulting in the same PSA progression rates for
both cohorts. The incidence of late GI toxicity
was low in both cohorts compared to other studies
(IMRT 4%, 3DCRT 9%), but the difference yields
the small 0.01 difference in QALYs (see Table 33)
between IMRT and 3DCRT.
In scenario 2, based on Kupelian et al.,84,85 survival
is also assumed to be the same for the IMRT and
3DCRT groups, but the estimated difference in
47
Assessment of cost-effectiveness
late GI toxicity was 15%, giving a total difference
in QALYs between the two groups of 0.023.
Although IMRT treatment itself is assumed to cost
£1122 more than 3DCRT, the additional costs of
treating a greater proportion of 3DCRT patients
for late GI toxicity reduces the additional total
cost of IMRT to £732. The ICER falls at the upper
NICE threshold of £30,000. Between £20,000
and £30,000 NICE takes into consideration
other factors such as the strength of evidence.1
In scenario 4 (Vora et al.89), where a difference
between IMRT and 3DCRT in mean survival to
PSA failure of 6.6 years has been assumed, IMRT is
actually cost-saving, owing to the reduced costs of
treating advanced PC. There is also a much greater
QALY gain for IMRT compared to 3DCRT, due to
the increased survival for IMRT. Thus IMRT yields
greater QALYs at lower cost than 3DCRT and is
therefore said to dominate 3DCRT.
For scenario 3, where a smaller difference between
IMRT and 3DCRT in mean survival to PSA failure
of 3.8 years has been assumed, the ICER is small
but positive, at £5300.
Sensitivity analyses
Age of men at the time of treatment with
RT
Clearly the age of men at the time of RT has an
effect on the proportion of men estimated to
die of PC as older men are more likely to die of
other causes before their PC progresses. Table 34
illustrates the effect for scenario 2 (Kupelian et
al.,84,85 equal survival for IMRT and 3DCRT).
TABLE 34 Proportion of men who have clinical disease
progression and die of PC according to age at time of RT
(Kupelian et al., 84,85 equal survival for IMRT and 3DCRT)
Age (years)
Clinical
progression
PC death
60
45%
41%
70
29%
21%
80
23%
7%
Table 35 shows the variation in ICER with age. It
shows that although there is some variation in the
TABLE 35 Variation in ICER with age
Age at RT (years)
Scenario
number
Scenario
1
2
60
70
80
Morgan et al. 2007
£92,788
£104,066
£133,832
Kupelian et al. 2002/200584,85 (equal survival
IMRT/3DCRT)
£31,181
£31,162
£38,211
3
Kupelian et al. 2002/200584,85 (greater survival IMRT)
£1762
£5295
£16,914
4
Vora et al. 2007
Dominates
Dominates
Dominates
107
89
TABLE 36 Sensitivity analysis on the additional costs of IMRT compared to 3DCRT
Additional cost IMRT compared to 3DCRT
Scenario
number
48
Scenario
Baseline
–40%
Baseline
–20% (£900)
Baseline
(£1120)
Baseline
+20% (£1350)
Baseline
+40% (£1570)
1
Morgan et al.
2007107
£56,832
£80,449
£104,066
£127,683
£151,301
2
Kupelian et al.
2002/200584,85
(equal survival
IMRT/3DCRT)
£12,063
£21,612
£31,162
£40,711
£50,260
3
Kupelian et al.
2002/200584,85
(greater
survival IMRT)
£125
£2710
£5295
£5295
£10,464
4
Vora et al.
200789
Dominates
Dominates
Dominates
Dominates
Dominates
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
ICER by age, the conclusions are unaffected by
the age group modelled. The ICER is generally
lower for younger men, as they have more years to
benefit.
Relative cost of IMRT compared to
3DCRT
The costs of IMRT and 3DCRT were obtained
from a single institution. The relative cost of
IMRT compared to 3DCRT may vary according
to the equipment used for planning and delivery
of RT, and experience of staff with the different
techniques. The results of a sensitivity analysis on
the additional costs of IMRT compared to 3DCRT
are shown in Table 36. The cost difference was
varied by plus and minus 20% and 40% of the
baseline value at £1122.
Although the ICERs vary quite considerably with
the variation in mean cost difference between
IMRT and 3DCRT explored in Table 36, in fact
the results of the sensitivity analysis show that
only scenario 2 is sensitive to the variation. In
the first scenario (Morgan et al.107), where late
GI toxicity is low in both cohorts and there is no
survival difference the ICER remains above the
maximum NICE threshold of £30,000. In scenario
4 IMRT dominates 3DCRT (is less costly and more
effective) even if the mean additional cost of IMRT
was 40% more (a cost difference of £1570) than the
baseline estimate. In scenario 3 the ICER remains
well within the £20,000 threshold for the modelled
cost differentials. For scenario 2, however, the
additional cost of IMRT over 3DCRT is critical to
cost-effectiveness. If the baseline additional cost is
overestimated the ICER for IMRT in comparison
to 3DCRT falls within a threshold of £20,000, but
if the additional cost is greater than the baseline
(cost difference greater than £1350) it falls beyond
the maximum threshold of acceptability to NICE
of £30,000.
Duration of late GI toxicity
The duration of late GI toxicity was reported in
just one study.91 Given the variability between
studies in other parameters, there is considerable
uncertainty around the estimate of 3 years which
was used in the model. For scenarios 3 and 4
(Kupelian et al.84,85 – survival difference, Vora et
al.89) the duration of toxicity is not important,
as the far greater difference in QALYs arises
principally from the difference in survival. For
scenarios 1 and 2 (Morgan et al.,107 Kupelian
et al.84,85 – equal survival), where no survival
difference is assumed between the IMRT and
3DCRT cohorts, the ICERs are sensitive to this
parameter, as shown in Table 37.
However, it is only for scenario 2 (equal survival
IMRT and 3D, 15% difference in late GI toxicity)
that the duration of late GI toxicity is critical to
cost-effectiveness.
Probabilistic sensitivity analysis
The mean cost per QALY calculated from a
probabilistic sensitivity analysis is preferable to an
answer from a deterministic analysis as it explicitly
incorporates the uncertainty surrounding each
parameter and can take non-linearities and
interacting parameters into account. It is of
particular use when events which are associated
with high costs and high utility losses but occur
with low probability exist within the model or
skewed distributions such as Weibull are used.122,130
In fact the results of the probabilistic sensitivity
analysis are similar to the results of the
deterministic analysis. For scenario 1 (Morgan
et al.107), the expected value of ICER is £104,000
in the deterministic analysis and £120,000 in
the stochastic. For this scenario, with no survival
difference and little difference in GI toxicity,
there is only a 29% probability of IMRT being
TABLE 37 Variation in ICER by mean duration of late GI toxicity
Mean duration late GI toxicity
Scenario
number
Scenario
1
Morgan et al. 2007107
2
Kupelian et al. 2002/2005
IMRT/3DCRT)
3
4
2.5 years
3 years (baseline)
4 years
£131,231
£104,066
£73,107
£42,138
£31,162
£19,842
Kupelian et al. 2002/200584,85 (greater survival
IMRT)
£5929
£5295
£4244
Vora et al. 200789
Dominates
Dominates
Dominates
84,85
(equal survival
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
49
Assessment of cost-effectiveness
1
0.9
Probability cost-effective
0.8
0.7
0.6
0.5
0.4
IMRT
0.3
3DCRT
0.2
0.1
100
95
90
85
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
0
0
MAICER (£000)
FIGURE 10 Cost-effectiveness acceptability curve scenario 1 (Morgan et al.107).
1
0.9
Probability cost-effective
0.8
0.7
0.6
0.5
0.4
IMRT
0.3
3DCRT
0.2
0.1
50
45
40
35
30
25
20
15
10
5
0
0
MAICER (£000)
FIGURE 11 Cost-effectiveness acceptability curve scenario 2 (Kupelian et al. 84,85 – equal survival IMRT/3DCRT).
cost-effective in comparison with 3DCRT with a
maximum incremental cost-effectiveness ratio
(MAICER) of £30,000 (see Figure 10). Even
with a MAICER of £100,000 there is less than
50% probability of IMRT being cost-effective in
comparison with 3DCRT.
50
Given the similarity of the stochastic and
deterministic analyses the stochastic analysis
was not run for all scenarios. For scenario 2
(Kupelian et al.84,85 – equal survival IMRT/3DCRT)
it is of particular interest as IMRT is borderline
cost-effective according to NICE thresholds.
The expected value for the ICER of IMRT in
comparison to 3DCRT for the probabilistic analysis
is £34,781, in comparison to £31,162 from the
deterministic analysis. At a MAICER of £20,000
there is only a 20% probability that IMRT is costeffective, but this rises to 48% for a MAICER
of £30,000, as shown in the cost-effectiveness
acceptability curve (Figure 11).
Discussion
A limitation of all economic studies comparing
IMRT with 3DCRT, including this one, is the
DOI: 10.3310/hta14470
limited clinical data comparing the two treatment
modes. There are no RCTs and the comparative
studies have weaknesses such as differences
between the patient groups. Only three studies (all
localised cancer) were identified which reported
PSA survival (Morgan et al.,107 Kupelian et al.,84 and
Vora et al.89). Of the three studies, one was reported
as an abstract only, and this was the only study to
report survival (Morgan107).
Based on these three studies four scenarios were
modelled. The heterogeneity of the clinical studies
is reflected in the results of economic analysis,
which, depending on the scenario modelled, range
from IMRT dominating 3DCRT (i.e. is both more
effective and less costly) to having an ICER of
£104,000.
The additional cost of IMRT compared to 3DCRT
is relatively modest at £1120, so for scenarios where
it is assumed that IMRT can improve freedom
from PSA failure and hence survival (likely by dose
escalation), IMRT is cost-effective, a result which
is robust to variation in other key parameters.
The baseline scenarios where equivalent survival
is assumed for IMRT and 3DCRT, and QALY
differences between the two cohorts are derived
from differences in GI toxicity alone, show IMRT
to be borderline cost-effective depending on
the difference in late GI toxicity, duration of GI
toxicity and the cost difference between IMRT and
3DCRT.
At baseline parameter values the scenario with
a difference in late GI toxicity of 5% (Morgan et
al.107 – scenario 1) gave an ICER of £104,000, but
scenario 2 (Kupelian et al.84,85 – equal survival)
with a difference in GI toxicity of 15% gave an
ICER of £31,000. The probabilistic analysis of the
latter scenario showed that only with a MAICER
of £30,000 or more was it probable that IMRT was
cost-effective in comparison to 3DCRT. This is at
the upper NICE threshold, where other factors
such as the strength of evidence are taken into
consideration. The results for this scenario are
very sensitive to the incremental cost of IMRT
in comparison to 3DCRT, as well as the mean
duration of late GI toxicity, both very uncertain
parameters. If the incremental cost of IMRT is
£860, or around 20% less than the baseline value
used, the ICER falls to £20,000. Similarly if the
mean duration of late GI toxicity is 4 years rather
than 3 years the ICER falls to £20,000. Of course,
if these parameters are varied in the opposite
direction the ICER of IMRT in comparison with
3DCRT increases, and then clearly falls beyond a
threshold of £30,000.
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Health Technology Assessment 2010; Vol. 14: No. 47
The scenarios modelled were all based on studies
where both PSA survival and toxicity were
reported. To put the values of incidence of late
GI toxicity from the modelled studies in context
the results of other studies were considered. Of
those where the same RT dose was given to both
IMRT and 3DCRT patients with localised cancers
(Martinez et al.,110 Sharma et al.106), both report
a 13% difference in late GI toxicity at 5 years.
Sanguineti et al.88 reports a difference of 15% at
2 years, despite the IMRT group receiving WP RT
in comparison to treatment of the prostate only in
the comparator group. Both the Martinez et al.110
and Sharma et al.106 studies are reported in abstract
only, but, with Sanguineti et al.,88 suggest model
scenario 2 (Kupelian et al.84,85 – equal survival)
is more representative than scenario 1 (Morgan
et al.,107 also reported in abstract only). Reduced
toxicity from IMRT in comparison to 3DCRT may
be greater in patients requiring WP RT, making
it more cost-effective than for treatment of the
prostate and seminal vesicles alone.
Previous economic analyses of IMRT in
comparison with 3DCRT have shown very different
results. Pearson et al.64 assumed no difference in
survival, and so in common with some scenarios
modelled in this study (1 and 2), relies only
on differences in GI toxicity to yield QALY
differences between IMRT and 3DCRT treated
patients. He reports an ICER of US$706,000.
This is considerably greater than the results of
our analysis, but the cost differential between
IMRT and 3DCRT in the Pearson et al. analysis
was estimated to be US$31,500 (approximately
£19,000),64 very different from our estimate of
£1120.
Konski et al.131 found IMRT to be cost-effective in
comparison to 3DCRT, despite a cost differential
almost as great as that of Pearson et al.64 However,
a large difference between IMRT and 3DCRT
in PSA survival at 5 years was assumed (16%),
derived from PSA survival in two different cohort
studies. The greatest PSA survival difference
reported in the studies included in this review was
14% (ASTRO consensus definition), but this was
reduced to 11% when PSA failure was defined by
the ASTRO Phoenix definition.89 Konski et al. also
assumed a long-term higher utility for all IMRT
patients compared to those who had had 3DCRT,
independent of adverse effects of treatment, the
utility values used being derived from two separate
studies using different methods of determining
utility values.131
51
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Chapter 5
Assessment of factors relevant to
the NHS and other parties
Factors relevant to the
NHS
Both IMRT and 3DCRT require a range of trained
staff, including therapeutic radiographers, nurses,
RT physics staff and clinical oncologists.132 Both
require equipment including a linear accelerator to
deliver radiation. Changes in skills mix would be
needed for widespread implementation of IMRT,
such as IMRT planning and QA requiring more
treatment planning, oncologist and medical physics
support.53,54 There is currently a shortage of RT
physicists, which means that greater use of IMRT
is likely to have implications on the provision
of other services, at least in the short term. The
Royal College of Radiologists is developing an
e-learning programme to support the training
of clinical oncologists to further enhance the
UKs ability to deliver IMRT to a uniform high
standard. Image-guided IMRT takes more staff
time.54 Enhanced immobilisation may be needed in
IMRT for precise patient positioning.53 Verification
of IMRT delivery (QA) is time consuming.54 The
National Radiotherapy Advisory Group suggest
that although new techniques increase time
taken for planning and delivery, processes will
become more efficient with practice.54 IMRT
requires extra equipment, such as a multi-leaf
collimator able to be driven in at least ‘step-and-
shoot’ mode; a 3D planning system capable of
importing at least CT data and preferably MRI
data; tools to experimentally validate dosimetry
and methods to verify the patient position; and
inverse planning requires computer software.53,54
This equipment, though, is now standard. IGRT
requires imaging equipment which is attached to
the linear accelerator.54 If toxicity can be reduced,
this may reduce the burden on gastroenterology
and urology services.
Factors relevant to other
parties
Intensity-modulated RT may involve a small
increase in treatment time of a few minutes per
fraction, especially in centres new to delivering
IMRT, potentially affecting carers as well as
patients. However the additional time is negligible
in relation to the total time required for travel
to the centre and the treatment itself. Current
research into hypofractionated schedules
(delivering fewer fractions at higher dose) of both
3DCRT and
IMRT may potentially lead to patients having to
attend the treatment centre less often for their
course of RT.
53
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Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Chapter 6
Discussion
Statement of principal
findings
No RCTs were identified, only comparative
studies, and all of these compared treatment with
IMRT to 3DCRT for localised or locally advanced
PC. There were no studies comparing IMRT
with radical prostatectomy, and there were no
comparative studies for adjuvant RT for high-risk
radical prostatectomy patients, salvage treatment,
or palliation of bone metastases. One study,
reported in abstract form only, reports disease
specific survival107 and only three (of which one
is reported in abstract only107) report biochemical
survival,46,89,107 all for the treatment of localised
cancers.
The only study included in this review to show a
statistically significant difference in biochemical
survival between IMRT and 3DCRT gave a higher
dose (75.6 Gy) of IMRT than 3DCRT (68.4 Gy).89
The theory that dose, rather than RT technique,
explains survival difference is supported by a
published meta-analysis of 3DCRT dose escalation
studies, which shows improved biochemical
survival with increasing RT doses up to 79.2 Gy.65
Although studies had methodological flaws, taken
together they seem to support the theory that
restricting treatment field, particularly with regard
to constraining volume of rectal wall receiving
prescription dose, can lessen toxicity. This can
be more easily achieved with IMRT than 3DCRT.
Again, more systematic evidence is available from
analysis of 3DCRT RCT data.118 Some studies have
given 3DCRT at doses > 80 Gy, with reported late
GI toxicity rates similar to those reported at lower
doses.107,110 However, these studies are reported in
abstract only, so the strength of their conclusions
is uncertain, and other variations in technique
(such as planning, imaging, margins treated) may
account for the limitation of toxic effects. The
effect of these other variables on survival and costs
are unknown.
Two previous economic studies (one reported
in different forms in three papers) of IMRT in
comparison with 3DCRT for the treatment of
localised PCs were identified.64,113,114,131 One study,78
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
which found IMRT to be cost-effective, is flawed
by the biased use of data to populate the economic
model. The other, which reported an ICER of
over £400,000 for IMRT compared to 3DCRT,
is limited in scope as it only considers toxicity.64
Both studies are from the USA and report a much
greater difference in RT costs for IMRT compared
to 3DCRT (over £16,000) than was identified in
this study (£1100), so the results are unlikely to be
applicable to the UK. A difference between the
US costs and those for the UK is that the costs
from the USA actually reflect reimbursement, and
therefore do not necessarily represent real cost
differences in the provision of the different therapy
modes.
An economic model was developed to examine
the cost-effectiveness of IMRT in comparison
to 3DCRT. Four scenarios were modelled based
on the three studies which reported both PSA
survival and late GI toxicity.84,85,89,107 In two
scenarios equal survival was assumed for IMRT
and 3DCRT, the other two having greater survival
for the IMRT cohort. For the latter scenarios,
with greater survival for IMRT than 3DCRTtreated patients the results are unambiguous.
IMRT either dominates 3DCRT (that is results in
more QALYs for lower total costs), or the ICER is
relatively modest (£5000), results which are robust
to variation in other key parameters.
The two scenarios where equivalent survival
is assumed for IMRT and 3DCRT, and QALY
differences between the two cohorts are derived
solely from differences in late GI toxicity alone,
show IMRT to be borderline cost-effective
depending on the difference in GI toxicity,
duration of GI toxicity and the cost difference
between IMRT and 3DCRT. At baseline parameter
values the scenario with a difference in late
GI toxicity of 5% (scenario 1) gave an ICER of
£104,000, but scenario 2 with a difference in
GI toxicity of 15% gave an ICER of £31,000.
The probabilistic analysis of the latter scenario
showed that only with a MAICER of £30,000 or
more was it probable that IMRT was more costeffective than 3DCRT. These results are highly
sensitive to two very uncertain parameters: the
incremental cost of IMRT and the duration of late
55
Discussion
GI toxicity. Variation of these parameters within
plausible bounds can reduce the ICER of IMRT
in comparison to 3DCRT to below a threshold
of £20,000, or equally push it clearly beyond a
threshold of £30,000. The scenarios modelled
were all based on studies where both PSA survival
and toxicity were reported. To put the values of
incidence of late GI toxicity from the modelled
studies in context the results of other studies
included in the review were considered. These
suggest model scenario 2 is more representative of
the literature than scenario 1.
For RT to the WP (usually only considered for
men with a greater than 15% risk of pelvic lymph
node involvement)1 IMRT may be more costeffective than for treatment of the prostate (and
seminal vesicles) alone. Sanguineti et al.88 reports a
difference of 15% in late GI toxicity at only 2 years,
despite the IMRT group receiving WP RT in
comparison to treatment of the prostate only in the
comparator (3DCRT) group.
Strengths and limitations of
the assessment
The strengths of the assessment were that
the literature search was comprehensive and
the included studies were of relevance to UK
practice in terms of populations and treatments.
Populations from US studies may have earlier
stage disease than UK populations due to the USA
practice of screening. It is unclear if this would
limit generalisability of results to UK populations.
Limitations of the assessment were that there was a
lack of data comparing IMRT with prostatectomy,
data for patients with bone metastasis, data
comparing post-operative IMRT with postoperative 3DCRT, and overall survival (OS) data or
clinically measured disease-free survival data were
lacking. Only one abstract was identified on image
guided RT.110 Furthermore, available data were
not from RCTs and we do not know if there were
relevant trials that were not published in English;
however, methodology studies have indicated
56
that language restrictions do not often influence
the results of systematic reviews of conventional
medicines.133–135
The economic model developed is based on a
systematic review of the literature and is more
comprehensive in its scope than previous models.
The strength of the conclusions of the economic
analysis is, however, necessarily constrained by
the limitations of the clinical effectiveness data,
discussed above. As there was very limited data on
clinical outcomes, the model estimates progression
to clinical failure and PC death from the surrogate
outcome of PSA failure. The limitations of the
marker as a surrogate for long-term therapeutic
benefit have been discussed in the literature.136
Uncertainties
Radiotherapy treatment involves a series of
processes including planning, imaging, outlining,
as well as treatment itself. All of these may vary,
introducing heterogeneity to comparisons both
between and within some studies. There is a lack
of OS data, and although it is plausible that more
focused radiation at higher dose would increase
survival, this depends on the target being correctly
identified to include all cancer, and treatment
planned and delivered accordingly. This requires
highly trained and skilled staff. Given that
biochemical survival is not a perfect predictor of
OS, long-term OS data are needed to be sure that
IMRT is effective. Costs of IMRT and 3DCRT
were obtained only from a single institution,
which is at a relatively early stage of IMRT
implementation. The difference in treatment
time between IMRT and 3DCRT assumed is
consistent with that reported in the literature, but
the study does not report the experience of the
institution with IMRT.82 It is possible that the cost
differential between IMRT and 3DCRT will be less
at institutions with more experience of IMRT. The
utility values were taken from a study of Japanese
men, so their applicability to UK men is unknown.
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Chapter 7
Conclusions
Implications for service
provision
IMRT with 3DCRT. Studies are required both for
radiation to the prostate alone and WP radiation.
Clinical advice suggests that most RT centres
already possess the equipment required to deliver
IMRT, but that lack of available staff such as
medical physicists hinders implementation.76
3DCRT may be safely delivered at the currently
recommended total dose of 74 Gy,1 and there is no
evidence that PSA survival is improved by giving
IMRT at the same dose as 3DCRT. However,
there is evidence that IMRT reduces toxicity,
in particular late GI toxicity. The magnitude
of the difference is uncertain, which, together
with uncertainties in other variables such as the
difference in cost between IMRT and 3DCRT,
in turn makes the cost-effectiveness of IMRT in
comparison to 3DCRT uncertain. If a difference in
late GI toxicity of 15% is assumed the probability
of IMRT being more cost-effective than 3DCRT is
true for MAICERs of ≥ £25,000.
Dose escalation studies for 3DCRT have shown
how PSA survival and adverse effects vary with
dose, and similar studies are required for IMRT.
Stratification by risk group should be considered,
as those at highest risk of progression may benefit
differentially from those at low risk.
Suggested research
priorities
No RCTs comparing IMRT with 3DCRT were
identified. There is clearly a need for such studies
for the question of the clinical effectiveness
and cost-effectiveness of IMRT in comparison
to 3DCRT to be answered. However, given the
degree of adoption of IMRT into clinical practice,
it may be difficult to instigate RCTs comparing
Further evolution of RT technology has led
to IGRT. Randomised studies with IMRT and
3DCRT should be instigated before the technology
becomes widely adopted.
Fractionation regime was not considered within
this review, but there is ongoing uncertainty as to
the optimum. The CHHiP study is addressing this
issue in IMRT.137
Studies require adequate follow-up (at least 5 years)
to capture late AEs, and should include HRQoL,
ideally including the EQ-5D. Studies should report
the evolution of AEs with time. Ideally studies
would also report PC survival as PSA recurrence
is limited as a predictor of this, but these require
even longer follow-up. Long follow-up (at least
10 years) and large studies are likely to be
required to detect group differences in secondary
malignancies.64 Whether secondary malignancies
are an issue might be addressed through registry
studies.
57
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Acknowledgements
T
he authors wish to thank Professor David
Dearnaley, Professor of Uro-Oncology,
Institute of Cancer Research, Royal Marsden
Hospital, Surrey; Dr Colin Baker, Lecturer
in Radiotherapy Physics, School of Health
Sciences,University of Liverpool; Dr Philip
Mayles, Head of Physics, Clatterbridge Centre
for Oncology, Merseyside; Helen Mayles, Head
of Clinical Radiotherapy Physics, Clatterbridge
Centre for Oncology, Merseyside; Dr John
Staffurth, Clinical Senior Lecturer/Honorary
Consultant, Department of Clinical Oncology,
Velindre Hospital, Cardiff; and Jason Cashmore,
Consultant Physicist, Medical Physics, Queen
Elizabeth Hospital, Birmingham.
Ms Gill Rooney (the School of Health and Related
Research; ScHARR) organised the retrieval of
papers and helped in preparing and formatting
the report.
About ScHARR
The School of Health and Related Research is one
of the four Schools that comprise the Faculty of
Medicine at the University of Sheffield. ScHARR
brings together a wide range of medical- and
health-related disciplines including public health,
general practice, mental health, epidemiology,
health economics, management sciences, medical
statistics, operational research and information
science. It includes the Sheffield unit of the Trent
Institute for Health Services Research, which is
funded by NHS Research and Development to
facilitate high-quality health services research and
capacity development.
The ScHARR Technology Assessment Group
(ScHARR-TAG) synthesises research on the
effectiveness and cost-effectiveness of healthcare interventions for the NHS Research and
Development Health Technology Assessment
programme on behalf of a range of policy
makers, including NICE. ScHARR-TAG is part
of a wider collaboration of six units from other
regions. The other units are: Southampton
Health Technology Assessment Centre (SHTAC),
University of Southampton; Aberdeen Health
Technology Assessment Group (Aberdeen HTA
Group), University of Aberdeen; Liverpool Reviews
and Implementation Group (LRiG), University
of Liverpool; Peninsular Technology Assessment
Group (PenTAG), University of Exeter; NHS
Centre for Reviews and Dissemination, University
of York; and West Midlands Health Technology
Assessment Collaboration (WMHTAC), University
of Birmingham.
Contribution of authors
S Hummel led the project. S Hummel and
P Hemingway wrote the study protocol. S Hummel
and MD Stevenson were responsible for the
economic analysis, EL Simpson and P Hemingway
conducted the clinical review. A Rees carried out
the literature searches.
59
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Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
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© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Appendix 1
Literature search strategies
Search strategy for MEDLINE
1. Radiotherapy, Intensity-Modulated/
2. intensity modulated radiotherap*.tw.
3. intensity-modulated radiotherap*.tw.
4. intensity modulated radiation therap*.tw.
5. intensity-modulated radiation therap*.tw.
6. imrt.tw. (2343)
7. image guided radiotherap*.tw. (185)
8. igrt.tw.
9. dose compensation.tw.
10. electronic compensation.tw.
11. e compensation.tw.
12. forward planning.tw.
13. inverse planning.tw.
14. field in field.tw.
15. physical compensation.tw.
16. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10
or 11 or 12 or 13 or 14 or 15
17. Randomized controlled trials as Topic/
18. Randomized controlled trial/
19. Random allocation/
20. Double blind method/
21. Single blind method/
22. Clinical trial/
23. exp Clinical Trials as Topic/
24. 16 or 17 or 18 or 19 or 20 or 21 or 22
25. clinic$adj trial$1).tw.
26. ((singl$or doubl$or treb$or tripl$) adj
(blind$3 or mask$3)).tw.
27. Placebos/
28. Placebo$.tw.
29. Randomly allocated.tw.
30. (allocated adj2 random).tw.
31. 25 or 26 or 27 or 28 or 29 or 30
32. 24 or 31
33. prostatic neoplasms/
34. (prostat$adj5 (cancer$or carcin$or tumor$or
tumour$or neoplasm$)).tw.
35. ((carcinoma or neoplasia or neoplasm$or
adencarcinoma or cancer$or tumor$or
tumour$or malignan$) adj3 prostat$).tw.
36. 33 or 34 or 35
37. 16 and 32 and 36
73
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Appendix 2
Data abstraction tables
Study details
Sample size
Study
Total
Kupelian 84
282
Sanguineti 88
113
Shu29
Intervention
group
Control group
(IMRT)
(3DCRT)
Study design
Setting
116 (later report
of study 85 has
310 3DCRT,
compared
with 100 IMRT
patients)
Retrospective patient records study,
two contemporary case series IMRT
and 3DCRT, with post hoc QoL
questionnaire
Single centre USA
(Cleveland Clinic
Foundation, OH,
USA)
45
68
Retrospective patient records study,
comparison of IMRT with 3DCRT
historical controls from a different
hospital
Two centres, 1 IMRT
(University of Texas
Medical Branch, TX,
USA), 1 3DCRT
(National Institute
of Cancer Research,
Genoa, Italy)
44
18
26
Retrospective patient records study,
two contemporary case series, IMRT
and 3DCRT, data from departmental
charts or by direct patient interviews
Single centre USA
(University of
California, CA, USA)
Vora 89
416
145
271
Retrospective patient records study,
comparison of IMRT with 3DCRT
historical controls from same centre
Single centre USA
(Mayo Clinic,
Scottsdale, AZ,
USA)
Yoshimura41
144
60
84 (of which 46
dose 70.2 Gy; 38
dose 73.5 Gy)
Prospective comparison of case
series, IMRT with contemporary case
series of higher dose 3DCRT, and
historical case series of lower dose
3DCRT
Single centre Japan
(Kyoto University
Graduate School of
Medicine, Kyoto,
Japan)
Zelefsky 91
1571
741
830 (of which
472 at 75.6 Gy
dose;
358 at 66–
70.2 Gy dose)
Prospective96 case series, dose
escalation with successive case series
receiving higher doses
Single centre USA
(Memorial Sloan
Kettering Cancer
Center, New York,
NY, USA)
Ashman100
27
13
14
Subset of patients from Zelefsky et
al. study,91 retrospectively identified
patient records, comparison of IMRT
with 3DCRT historical controls from
same centre
Single centre USA
(Memorial Sloan
Kettering Cancer
Center, New York,
NY, USA)
170
92
78
Prospective comparison of case
series, comparison of IMRT with
3DCRT historical controls from same
centre
Single centre
The Netherlands
(University Medical
Center, Utrecht, the
Netherlands)
Lips43
166 (later
report of
study 86 has
770 IMRT
but no
comparator)
75
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Appendix 2
Study details
Study
Kupelian
76
Indication
Length of follow-up
Start date
Finish date
Localised PC Median follow-up for all cases was 25 months
IMRT October
(range 3–42). IMRT median follow-up 21 months 1998; 3DCRT
(range 3–31). 3DCRT 32 months (range 3–42)
January 1998
1999
Sanguineti 88
Localised PC Mean (SD) follow up IMRT 26.6 months(SD 7.9);
3DCRT 23.9 months (SD 8.9) (overall 25.9 SD
8.4 months)
IMRT 2002;
3DCRT 1995
IMRT 2004; 3DCRT
1999
Shu29
Localised PC Overall median 23.1 months (range 10.0 to
84.7). IMRT median follow-up 18.7 months.
3DCRT 30.1 months
1992
1998
Vora 89
Localised PC Overall median 5 years (range 3–10 years).
IMRT 48.1 months (range 36–68 months).
3DCRT 62.3 months (36–121 months)
IMRT 2000;
3DCRT 1993
IMRT 2005; 3DCRT
2000
Yoshimura41 Localised PC Data collected at 12 months follow-up for all
patients
IMRT or 3DCRT
73.5 Gy 2003;
3DCRT 70 Gy
2000
IMRT or 3DCRT
73.5 Gy 2004;
3DCRT 70 Gy 2003
Zelefsky 91
Localised PC Overall median 8 years (range 5–18). IMRT
median 6.5 years. 3DCRT median 10 years
IMRT 1995;97
3DCRT 70.2 Gy
1988; 75.6 Gy
1991; 81 Gy 199296
IMRT 2000; 3DCRT
70.2 Gy 1992;
75.6 Gy 2000; 81 Gy
200096
Ashman100
Locally
Overall median 30 months (range 3–87 months)
advanced PC
IMRT 2000;
3DCRT 1996
IMRT 2004; 3DCRT
1999
Lips43
Locally
Data collected at 6 months follow-up for all
advanced PC patients
IMRT 2003;
3DCRT 1997
IMRT 2004; 3DCRT
2001
84
Inclusion criteria
Inclusion: localised PC
Exclusion: neoadjuvant or adjuvant
androgen deprivation for a period of
more than 6 months or had no followup PSA levels available
Localised PC. IMRT 15% or more
risk of nodal involvement according
to Roach formula, exclude patients
whose PTV included reduced margins
around the prostate. 3DCRT exclude
if treated with 70 Gy and/or including
seminal vesicles
Clinically localised PC patients treated
with external beam RT for PC,
maximal dose (Dmax) of at least 82 Gy.
All pathology slides were reviewed at
UCSF for confirmation of diagnosis
Clinically localised PC
Clinically localised PC
Clinically localised stage T1–T3 PC
Study
Kupelian 84
Sanguineti 88
Shu29
Vora 89
Yoshimura41
Zelefsky 91
Population
Grade of cancer
(Gleason score)
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Gleason score ≤ 6 IMRT 17%,
3DCRT 29%; Gleason score
7 IMRT 52%, 3DCRT 33%;
Gleason score ≥ 8 IMRT 23%,
3DCRT 33%
Gleason score IMRT median 7
(range 2–9); 3DCRT median 6
(range 2–10)
Gleason score (pathology slides
were reviewed) ≤ 6 IMRT 22%,
3DCRT 65%; Gleason score
7 IMRT 44%, 3DCRT 23%;
Gleason score ≥ 8 IMRT 33%,
3DCRT 12%
Gleason Score 2–6 3DCRT
58.8% IMRT 6.7%; Gleason
Score 7 3DCRT 33.8% IMRT
44.4%; Gleason Score 8–10
3DCRT 5.9% IMRT 48.9%;
Gleason Score Unknown
3DCRT 1.5% IMRT 0.0%
significant difference between
groups < 0.01
NR (all T1–T3 as inclusion
NR
criterion) reports NCCN risk
group across both groups: low
risk 22%; intermediate 42%; high
36%
T-stage T1 IMRT 10%, 3DCRT
26%; T2 IMRT 15%, 3DCRT
31%; T3 IMRT 75%, 3DCRT 43%
T-stage T1 IMRT 36%, 3DCRT
16%; T2 IMRT 61%, 3DCRT
75%; T3 IMRT 2%, 3DCRT 10%
T-stage T1 IMRT 11%, 3DCRT
15%; T2 IMRT 56%, 3DCRT
65%; T3 IMRT 33%, 3DCRT
19%. AJCC stage II IMRT 67%,
3DCRT 81%; AJCC stage III
IMRT 33%, 3DCRT 19%
T-stage T1a–b 3DCRT 1.5%
IMRT 4.4%; T1c 3DCRT 14.7%
IMRT 46.7%; T2a–b 3DCRT
61.8% IMRT 22.2%; T3a–b
3DCRT 22.1% IMRT 22.2%;
T4 3DCRT 0.0% IMRT 4.4%
significant difference between
groups < 0.01
T1–T2a IMRT 87%, 3DCRT 67%; Biopsy Gleason score ≤ 6 IMRT
T2b–T2c IMRT 10%, 3DCRT
56%, 3DCRT 39%; Gleason
22%; T3 IMRT 4%, 3DCRT 11%
score ≥ 7 IMRT 44%, 3DCRT
61%
Stage of cancer
(% each group)
Baseline characteristics
NR
Mean PSA ng/ml IMRT 35.0 (SD
26.4); 3DCRT high dose 30.9
(SD 56.6); 3DCRT low dose
34.2 (SD 53.8)
PSA ng/ml IMRT median 6.8
(range 0.8 to 56.8); 3DCRT
median 8 (range 0.9 to 197.4)
Median (both
groups) 69
(range 46 to 86)
Mean IMRT
71.6 (SD 4.9)
3DCRT high
dose 72.6 (SD
7.2); 3DCRT low
dose 70.7 (SD
6.5)
NR
Median IMRT
70 (range 50 to
79); 3DCRT 69
(range 53 to 76)
3DCRT mean
70.7 (SD 5.8);
IMRT mean 66.9
(SD 7.9)
NR
Median (range) IMRT 12.0 (4.4
to 39.5), 3DCRT 9.8 (2.9 to
62.8)
Median (both
groups) 68
Age (years)
Pretreatment PSA ≤ 4 ng/ml
IMRT 4%, 3DRCT 3%; > 4 to
10 ng/ml IMRT 54%, 3DRCT
51%; > 10 to 20 ng/ml IMRT
26%, 3DRCT 28%; > 20 ng/ml
IMRT 17%, 3DRCT 18%
Initial PSA
DOI: 10.3310/hta14470
Health Technology Assessment 2010; Vol. 14: No. 47
77
78
100
Patients with locally advanced PC
Patients with PC treated with WPRT
using conformal techniques. All
patients had pelvic node involvement
as determined by imaging (n = 14) or
biopsy (n = 13)
Inclusion criteria
T-stage T1 IMRT 13%, 3DCRT
5.1%; T2 IMRT 5.4%, 3DCRT
16.7%; T3 IMRT 81.5%, 3DCRT
76.9%; T4 IMRT 0%, 3DCRT
1.3%
Across both groups
T1c 19%
T2 26%
T3 41%
T4 15%
Stage of cancer
(% each group)
Tumour grade G1 IMRT 12%,
3DCRT 12.8%; G2 IMRT 67.4%,
3DCRT 69.2%; G3 IMRT 20.7%,
3DCRT 17.9%
Across both groups
Gleason score 6 4%
score 7 37%
score 8 33%
score 9 26%
Grade of cancer
(Gleason score)
Across both
groups median
62 (range 42 to
80)
Across both groups
Median 26.0 ng/ml (range 4.5
to 207)
Mean PSA ng/ml IMRT 19 (range Mean (range)
2 to 90); 3DCRT 28 (range 0.2
IMRT 67 (49 to
to 400)
79); 3DCRT 67
(47 to 78)
Age (years)
Initial PSA
AJCC, American Joint Committee on Cancer; NR, not reported; UCSF, University of California, San Francisco; WPRT, whole pelvis radiotherapy.
Lips43
Ashman
Study
Baseline characteristics
Appendix 2
DOI: 10.3310/hta14470
Health Technology Assessment 2010; Vol. 14: No. 47
Treatment details IMRT
IMRT
Study
Treatment details
System
Kupelian 84
A nominal dose of 70 Gy delivered at 2.5 Gy/fraction in 28 fractions during 5.5 weeks.
The dose constraints used during inverse planning set the goal of the target volume at
70 Gy (range 65–78). The limits used for the bladder were up to 30% to receive more
than 55 Gy, with the maximal level at 74 Gy; and for the rectum, up to 30% to receive
more than 50 Gy, with the maximal level at 74 Gy. Radiation was delivered with 10 MV
photon beams using a dynamic multileaf collimator
Inverse planned. The field segments were created. The specific method of treatment
delivery was the sliding window or dynamic delivery of field segments. A five-field
beam arrangement was chosen: one anterior, two lateral, and two anterior oblique
beams. One of the lateral fields was occasionally annulled because of the presence
of a prosthetic hip. Patients were set up on the table with minimal immobilisation in
the supine position. Daily localisation for treatment was performed using the BAT
transabdominal ultrasound system
RT to prostate only for low-risk cases, prostate and SVs for high-risk cases
Planned
– Corvus
treatmentplanning
computer
BAT
transabdominal
ultrasound
system
Radiation
delivered by
Varian 2100-CD
Sanguineti 88
Immobilisation alpha cradle, planning CT 0.3/0.5 cm cuts, prostate apex uretrography
41 (91.1%), CT 0 (0.0%), MRI 4 (8.8%), margins for prostate PTV or PN/SV PTV (cm)
1.0 (all directions), mean (SD) prostate volume (cm3) 51.0 (17.4), mean (SD) prostate
PTV volume (cm3) 199.5 (45.6), mean (SD) rectal volume (cm3) 67.5 (21.9) 0.13, mean
(SD) dose to posterior rectum (Gy) 35.3 (8.6), mean (SD) dose to anterior rectum
(Gy) 74.8 (1.4). Planning process combined two phases, a boost to the prostate and a
pelvic treatment The initial boost delivers 16 Gy over eight fractions and it is followed
by a 6 MV X-ray eight-field coplanar inverse planning IMRT technique delivering an
additional 60 Gy over 30 fractions to the prostate (76 Gy total) and 54 Gy over 30
fractions to the SVs and PNs. The main reason to deliver the boost upfront is to allow
more time for QA of the IMRT plan
Inverse planned. Field sizes were determined by the inverse planning system, but were
initially set to allow exposure of the sum of all PTVs plus an additional margin of 1.5 cm
Pinnacle
(Philips Medical
Systems,
Madison,
WI, USA)
treatmentplanning system
Shu29
All patients received a maximal dose within the target volume (Dmax) of 82 Gy or
more. IMRT treatments were either forward planned, using um - plan with seven beam
positions and two to three segments per position, or inverse planned, using Corvus
(Nomos Corporation, Sewickley, PA, USA) with seven beam positions and multiple
segments per position. For the IMRT plans, two target volumes were used. One target
represented the entire prostate gland, and the other represented the DIL defined
by MRI/MRSI. The DIL was treated at a higher dose per fraction concurrently with
the entire prostate. Treatment duration (days) median 65 range 57–79, no. treatment
fractions median 41 range 40–45, Dmax (cGy) median 8530 range 8203–9672, minimal
prostate dose (cGy) median 7380 range 7200–7560, whole pelvis treated: yes 13 (72%)
no 5 (28%)
Inverse planned, with seven beam positions and multiple segments per position
Forward planned, using um - plan with seven beam positions and 2–3 segments per
position
Planned –
inverse planning
by Corvus
(Nomos
Corporation,
Sewickley, PA,
USA)
forward
planning
with um - plan
software
(University of
Michigan, Ann
Arbor, MI, USA)
Vora 89
Five-field IMRT with 10 MV photons, prostate and SVs in PTV with a 6–10 mm margin.
5040 cGy 0 SVs, median dose 7560 cGy to prostate (range 7020–7740 cGy). Daily
localisation for treatment was performed using transabdominal ultrasound. Dose–
volume restrictions were used in treatment planning: no more than 40% bladder and
rectal volume could receive more than 65 Gy; no more than 30% bladder and rectal
volume could receive more than 70 Gy; no more than 10% bladder and rectal volume
could receive more than 75 Gy; no more than 1.8 cm3 bladder and rectal volume could
receive 81 Gy; full thickness of femur should not receive >50 Gy
NR
Yoshimura41 IMRT 76.5 Gy dose, five-field dynamic MLC technique, target prostate or prostate and Planning Helios
SVs. Inverse treatment planning. Dose–volume constraints for PTV, rectal wall, bladder system (Varian
Medical System)
wall and bowels based on dose–volume histogram – no more than 1% rectal wall
volume more than prescription dose, no more than 25% rectal wall volume more than
70 Gy, no more than 35% rectal wall volume more than 60 Gy, no more than 60% rectal
wall volume more than 40 Gy; no more than 60% bladder wall volume more than 40 Gy,
no more than 35% bladder wall volume more than 70 Gy
79
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Appendix 2
IMRT
Treatment details
Study
Zelefsky
91
System
MSKCC planning
IMRT (81 Gy) with 15 MV X-rays in daily fractions of 1.8 Gy. Some patients received
system97
86.4 Gy 99
The PTV was derived from simulation CT scans and included the entire prostate and
SV plus a 10 mm safety margin, except at the prostate–rectum interface where a 6 mm
margin was used to decrease the risk of rectal toxicity. Treated in prone position
with thermoplastic body cast for immobilisation. The prescribed dose represented
the minimum dose to the PTV, but portions of the target volume received up to 7%
higher doses. Patients treated to 81 Gy received a separate multifield plan for the last
9 Gy which blocked the rectum in each field. Dose–volume histograms were used to
assure that no more than 30% of the rectal wall and/or 50% of bladder wall received a
maximum dose of 75.6 Gy. Beam intensity profiles were delivered by dynamic multi-leaf
collimation using the sliding window technique.95 QA before and during treatment by
the MSKCC record and verify computer
Ashman100
PTVs for prostate and bilateral pelvic lymph nodes were contoured separately. The
prostate PTV was derived from simulation CT scans and included the entire prostate
and SVs plus a 1 cm safety margin, except at the prostate–rectum interface where
a 6 mm margin was used to decrease the risk of rectal toxicity. Bilateral obturator,
internal iliac, and external iliac nodal regions contoured with approximately 1 cm
margin. Pelvic IMRT plans used five coplanar beam angles approx equally spaced
around the patient. Total dose typically 81 Gy (n = 12), for n = 1 75.6 Gy. 15 MV photons
with 1.8 daily fractions. Treated in prone position with thermoplastic body cast for
immobilisation. Dose–volume histograms were used to assure that no more than 30%
of the rectal wall and/or 50% of bladder wall received a maximum dose of 75.6 Gy
MSKCC planning
system
Lips43
Dose escalation to prostate, delineated on CT, 76 Gy in 35 fractions of 2.17 Gy with
MLC and 10 MV photons, transrectally implanted gold markers used for daily position
verification
NR
MLC, multi-leaf collimator; MSKCC, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; SVs, seminal
vesicles.
Treatment details 3DCRT
3DCRT
Study
Kupelian
84
Sanguineti 88
80
Treatment
System
A 10-field arrangement: the initial four fields delivering 42 Gy, followed by a six-field
boost delivering 36 Gy. The total dose was 78 Gy delivered at 2 Gy/fraction. The dose
was prescribed to an isodose line covering the prostate (mean isodose line 97%). The
margins were 1 cm posteriorly and 1.5 cm in all other dimensions from the edge of the
prostate or prostate/SV (gross target volume) to the edge of the block. The patients
were aligned to skin marks with lasers in a supine position with the feet taped (no
additional immobilisation devices). No daily localisation methods were performed for
the 3DCRT cases
RT to prostate only for low-risk cases, prostate and SVs for high-risk cases
NR
Patient position supine, immobilisation thermoplastic, rectum empty, bladder empty,
simulation to localise isocentre, planning CT 0.5/1 cm cuts, prostate apex uretrography
0 (0.0%), CT 58 (85.3%), MRI 10 (14.7%), margins for prostate PTV superior/inferior
(cm) 1.3, anterior/lateral (cm) 1.3, posterior (cm) 0.8, margins for PN/SV PTV (cm) NR,
mean (SD) prostate volume (cm3) 50.9 (17.0), mean (SD) prostate PTV volume (cm3)
191.7 (45.8), mean (SD) rectal volume (cm3) 59.9 (19.6), mean (SD) dose to posterior
rectum (Gy) 28.2 (10.0), mean (SD) dose to anterior rectum (Gy) 74.0 (1.6), 3DCRT
setup included three isocentric coplanar photon (15 MV) fields (0°, 110°, 250°; 3F-0°,
110°, 250°), with 76 Gy prescribed to the isocentre (ICRU point). A dose distribution at
central axis and at least at six to ten off-axis slices in order to optimise beam weights,
no wedges used
Dose
distribution
was obtained
with Plato
(Nucletron,
Veenendaal, the
Netherlands)
DOI: 10.3310/hta14470
Health Technology Assessment 2010; Vol. 14: No. 47
3DCRT
Study
Treatment
System
Shu
All patients received a maximal dose within the target volume (Dmax) of 82 Gy or more.
For 3DCRT, the minimum prescription dose to the entire prostate was 72 to 79.2 Gy
with the prescription isodose ranging from 90% to 100%. This resulted in a region of
the target volume receiving at least 82 Gy. Treatment duration (days) median 63 range
57–77 no. treatment fractions median 44 range 37–44 Dmax (cGy) median 8448 range
8200–8732 minimal prostate dose (cGy) median 7920 range 7200–7920 whole pelvis
treated yes 1 (4%) no 25 (96%)
um - plan
software
(University of
Michigan, Ann
Arbor, MI,
USA)
3DCRT with a four-field box approach. prostate and SVs with 1–2cm margin from PTV
to block edge. photon of 10 MV, 180–200 cGy/dy. SVs approx 4500 cGy, prostate median
dose 6840 cGy (range 6600–7100 cGy)
NR
Yoshimura41 3DCRT old (years 2000–3) protocol: 70 Gy dose, delivered as 46 Gy in 23 fractions,
four-field box with MLC, followed by 24 Gy in 12 fractions, dynamic arc conformal
technique, target prostate or prostate and SVs, leaf margins 7 or 15 mm according to
local stage
3DCRT new protocol (years 2003–4): 73 Gy dose, target prostate or prostate and SVs,
two lateral dynamic arcs with 100 degree rotation, dynamic conformal fitting of MLCs
to PTV, 3 mm margins from edge of PTV to tips of MLCs. Dose volume constraints for
PTV, rectal wall, bladder wall and bowels based on dose-volume histogram – no more
than 1% rectal wall volume more than prescription dose, no more than 25% rectal wall
volume more than 70 Gy, no more than 35% rectal wall volume more than 60 Gy, no
more than 60% rectal wall volume more than 40 Gy; no more than 60% bladder wall
volume more than 40 Gy, no more than 35% bladder wall volume more than 70 Gy
NR
Zelefsky 91
The prostate PTV was derived from simulation CT scans and included the entire
prostate and SV plus a 1 cm safety margin, except at the prostate–rectum interface
where a 6 mm margin was used to decrease the risk of rectal toxicity. Treated in prone
position with thermoplastic body cast for immobilisation. Dose–volume histograms
were used to assure that no more than 30% of the rectal wall and/or 50% of bladder
wall received a maximum dose of 75.6 Gy 96
Memorial
Sloan-Kettering
Cancer Center
(New York,
NY, USA)
planning system
Ashman100
PTVs for prostate and bilateral pelvic lymph nodes were contoured separately. The
PTV was derived from simulation CT scans and included the entire prostate and SV plus
a 1 cm safety margin, except at the prostate–rectum interface where a 6 mm margin
was used to decrease the risk of rectal toxicity. Bilateral obturator, internal iliac, and
external iliac nodal regions contoured with approx 1 cm margin. Four-field box WP
plans were used. Total dose typically 75.6 Gy (n = 13), for n = 1 64.8 Gy. 15 MV photons
with 1.8 daily fractions. Treated in prone position with thermoplastic body cast for
immobilisation. Dose–volume histograms were used to assure that no more than 30%
of the rectal wall and/or 50% of bladder wall received a maximum dose of 75.6 Gy 96
Memorial
Sloan-Kettering
Cancer Center
(New York,
NY, USA)
planning system
Lips43
3DCRT external beam technique, dose of 70 Gy delivered at 2 Gy fractions, 5 fractions
per week. conformal three-field isocentric technique using 6 and 18 MV photons and
MLC, position verification by visualising bony anatomy using electronic portal imaging
devices (possible variation of position of prostate relative to bony anatomy)
NR
29
Vora 89
MLC, multi-leaf collimator; SV(s), seminal vesicle(s).
81
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Appendix 2
Other treatment
Study
Neoadjuvant/adjuvant hormonal therapy
Surgery
Chemotherapy/other
Adjuvant androgen deprivation IMRT 60%, 3DCRT
72% (hormonal therapy given to high risk patients)
Prior surgery (TURP)
IMRT 3%, 3DCRT 5%
NR
Sanguineti 88
Androgen deprivation none 3DCRT 32.4% IMRT
35.6%; neoadjuvant + concomitant 3DCRT 20.6%
IMRT 6.7%; neoadjuvant + concomitant + adjuvant
3DCRT 47.1% IMRT 57.8%
Prior surgery (TURP)
TURP No 3DCRT
89.7% IMRT 82.2%; Yes
3DCRT 10.3% IMRT
17.8%
NR
Shu29
Overall 35/44 patients had hormonal therapy
NR
NR
Vora 89
High-risk patients PSA > 20 ng/ml or Gleason score
8–10 received long course of androgen deprivation
therapy (2–3 years), IMRT 30.3%; 3DCRT 17.6%
NR
NR
Yoshimura41 All but two patients neoadjuvant hormonal therapy
Kupelian
84
NR
NR
Zelefsky 91
Androgen deprivation therapy overall yes 678 (43%),
no 893 (57%) neoadjuvant. No post radiation ADT
NR
None before PSA
relapse
Ashman100
All patients neoadjuvant and concurrent complete
androgen blockade
NR
30% (8/27) patients had
chemotherapy, seven in
the 3DCRT group, and
one IMRT
Lips43
Hormonal treatment IMRT 26%; 3DCRT 12%
NR
Hyperthermia
treatment IMRT 0%;
3DCRT 26%
ADT, androgen deprivation treatment; NR, not reported; TURP, transurethral resection of the prostate.
Additional study results reported
Study
Results
Kupelian 84 Kupelian 200585 considering each treatment group separately, multivariate analysis found no association
between hormonal therapy and biochemical relapse-free survival, but that pretreatment PSA and Gleason
score were significant predictors of biochemical relapse-free survival
A later report of this study 86 when the IMRT group had 770 patients with a median follow-up of 45 months,
reported less acute GI toxicity (p < 0.001) in patients treated at a later period as there had been a change in
treatment planning to reduce the volume of rectum receiving the prescription dose of 70 Gy. One patient
died but it was unclear if this was a treatment-related death due to late rectal toxicity or the patient’s
underlying medical condition 86
Vora 89
82
Vora ASTRO Phoenix definition, when investigating risk groups, 5-year survival for IMRT patients was
91.5% for low-risk patients, 79.0% for intermediate risk, and 90.6% for high-risk patients. For 3DCRT
the survival data by risk group were 89.3%, 68.0%, and 48.8% respectively. IMRT significantly improved
biochemical survival for intermediate (p = 0.0092) and high risk (p = 0.0078) patients, but for low-risk
patients there was no significant difference between treatment groups (p = 0.9166)
DOI: 10.3310/hta14470
Health Technology Assessment 2010; Vol. 14: No. 47
Study
Results
Zelefsky 91
Higher incidence of late GI toxicity in those patients who experienced acute GI toxicity (42%) than those
that didn’t (9%) (p < 0.0001). Median time to development of late GI grade 2 or higher toxicities 17 months
(range 4–102 months). Median time to development of late GU toxicity 30 months. GU toxicity took
longer to develop, but was of shorter duration than GI toxicity. Across both treatment groups, of patients
with late GI toxicity, 91% had resolution of symptoms, median time to resolution 26 months. Across both
treatment groups, of patients with late GU toxicity, 81% had resolution of symptoms, median time to
resolution 7 months. Higher incidence of late GU toxicity in those patients who experienced acute GU
toxicity (35%) than those that did not (12%) (p < 0.001). Within the 3DCRT group, dose difference in late
GI toxicity at 10 years, for dose 70.2 Gy 7% developed grade 2 or higher GI toxicity, for dose 75.6 Gy 18%.
IMRT at 81 Gy had 5% GI toxicity
Zelefsky 2003,94 740 patients, 96 of whom were 60 years or younger, 644 older than 60 years. Examined
effect of radiation dose on biochemical disease-free survival in patients aged 60 years or younger. For
younger patients given IMRT, 5-year PSA relapse-free survival rates were 96% for patients with favourable
prognosis, 87% for intermediate, and 50% for patients with unfavourable prognosis. A 5-year PSA relapsefree survival for dose < 66 Gy was 0% for dose 68.4–72 Gy was 47%, and for dose 75.6 Gy was 75%
(p < 0.001). Dose < 75.6 Gy was the most important predictor of biochemical relapse in younger patients.
Gleason score > 7 was also a predictor. Biochemical survival rates at 5 years 82% in younger men, 79% for
older men, at 7 years 79% and 78% respectively (p = 0.48). For intermediate or unfavourable risk patients
there was a significant benefit of dose ≥ 75.6 Gy (p = 0.003). Non-significant for favourable risk patients,
though lack of significance may be due to small number of patients
From a sample of 2047 patients with median follow-up 6.6 years,98 for low and intermediate-risk groups
IMRT dose levels of ≥ 81 Gy did not further improve biochemical outcomes compared with 3DCRT 75.6 Gy.
For high-risk patients 5-year PSA relapse-free survival outcomes for dose 86.4, 81, 75.6, and 70.2 Gy or
less were 71%, 66%, 61%, and 40%, respectively; dose was only significant by univariate analysis, with
multivariate analysis showing non-significant effect of dose, but significant neoadjuvant ADT (p = 001; HR,
0.623) – note that patients selected to receive neoadjuvant ADT were significantly more likely to receive
higher radiation doses (p < 0.0001).98 From a sample of 2047 patients with median follow-up 6.6 years from
the Zelefsky study,98 distant metastases-free survival was affected by dose in intermediate (p = 0.04) and
high risk (p = 0.01) patients, but not low-risk patients. Dose was not a significant predictor of cause-specific
mortality 98
Zelefsky 2002,92 no comparator data, IMRT data only, measure of sexual function, 52% of the 540 patients
who were potent before IMRT remained potent at 2 years follow-up
Data for IMRT 86.4 Gy,99 with no comparator data, high-dose IMRT in 478 patients, median follow-up 53
months, n = 37 (8%) acute grade 2 GI toxicity. n = 105 (22%) acute grade 2 GU toxicity, 3 (0.6%) grade 3
GU toxicity. n = 16 (3%) late grade 2 GI toxicity. n = 2 (<1%) late grade 3 GI toxicity. n = 60 (13%) late grade
2 GU toxicity. n = 12 (<3%) late grade 3 GU toxicity. A 5-year actuarial PSA relapse-free survival according
to the ASTRO Phoenix definition was 98%, 85% and 70% for the low, intermediate, and high-risk NCCN
prognostic groups99
Lips43
Toxicity (CTC measurement) – only one patient in the study (from the IMRT group) developed grade 3
acute toxicity – a urinary tract infection. None of the other patients developed acute toxicity above grade
2
Considering the time points baseline and 1 month post-RT, for six of the 29 items there was a significant
interaction between treatment group and time, with the 3DCRT group showing more deterioration than
the IMRT group. These items were RAND-36 social functioning (p = 0.006), pain (p = 0.01) and change in
health (p < 0.0001); EORTC QLQ-C30(+3) physical functioning (p = 0.006) and role functioning (p = 0.006);
EORTC QLQ-PR25 urinary symptoms/function (p < 0.0001). For baseline and 6 months post-RT, there
were no significant differences between groups on any of the items measured. For the other 23 items there
were no significant differences between groups and no significant interaction between treatment group and
time. These items were RAND-36 physical functioning, physical role restriction, emotional role restriction,
mental health, vitality, general health; EORTC QLQ-C30(+3) emotional functioning, cognitive functioning,
social functioning, global health/quality of life, fatigue, nausea and vomiting, pain, dyspnea, insomnia,
appetite loss, constipation, diarrhoea, financial difficulties; EORTC QLQ-PR25 bowel symptoms/function,
treatment-related symptoms, sexual functioning
Both groups showed clinically significant deterioration in RAND-36 physical role restriction at 1 month and
EORTC QLQ-PR25 sexual activity at 1 and 6 months post-RT, and a clinically significant improvement in
RAND-36 emotional role restriction at 6 months post-RT
Considering each treatment group separately, there were changes deemed clinically significant (change
in score of 10 or more points), for IMRT which had improvement in change in health at 1 month and 6
months, for 3DCRT there were deteriorations in pain, role functioning and urinary symptoms/function at 1
month post-RT, but not at 6 months post-RT
Comparing patients treated with hormonal therapy (n = 33) with without hormonal therapy (n = 137), the
only differences were that patients treated with hormonal therapy had more treatment-related symptoms
at 1 month, and better change in health at 6 months post-RT
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
83
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Appendix 3
Quality assessment of the eight studies fully
reported in peer-reviewed publications83
85
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
86
Yes
Yes
No
Yes
Yes
Partially
Partially
Yes
Yes
Yes
No
Yes
Main outcomes clearly described
Patient characteristics clearly
described
Study groups similar
Data collection methods similar
Interventions clearly described
Confounders clearly described
Similar treatment groups
Findings are clear
Estimates off random variability
AEs
Loss to follow up described
Actual probability values
Unable to
determine
Unable to
determine
Subjects who did participate are
representative
Location representative
No
No
Yes
Yes
Yes
Unable to
determine
Yes
Subjects blind
Assessors blind
Clarity re data dredging
Adjusted for follow-up lengths
Appropriate statistical tests
Reliable compliance
Outcomes measures valid/reliable
Internal validity-bias
Yes
Subjects asked to participate are
representative
External validity
Yes
Hypothesis clearly described
Reporting
Kupelian et
al. 84
Yes
Unable to
determine
Yes
Yes
Yes
No
Yes
Unable to
determine
Yes
Yes
Yes
No
No
Yes
Yes
No
Unable to
determine
Yes
Yes
No
Yes
No
Yes
No
No
Yes
Yes
No
Yes
Yes
Yes
Unable to
determine
Yes
Yes
No
No
Yes
Yes
No
Yes
Yes
No
No
Yes
Yes
Yes
Sanguineti et
al. 88
Shu et al. 29
Yes
Unable to
determine
Yes
No
Yes
No
No
Yes
Unable to
determine
Yes
Yes
No
Yes
Yes
Yes
No
No
Yes
Yes
No
Yes
Yes
Yes
Vora et al. 89
Yes
Unable to
determine
Yes
Unable to
determine
Yes
No
No
Yes
Unable to
determine
Yes
No
No
Yes
Yes
No
No
No
Yes
Yes
No
Yes
Yes
Yes
Yes
Unable to
determine
Yes
No
Yes
No
No
Yes
Unable to
determine
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
Yoshimura et Zelefsky et
al. 41
al.91
Yes
Unable to
determine
Yes
Yes
Yes
No
No
Yes
Unable to
determine
Yes
Yes
No
Yes
Yes
Yes
No
No
Yes
Yes
No
Yes
Yes
Yes
Ashman et
al.100
Yes
Unable to
determine
Yes
Yes
Yes
No
No
Yes
Unable to
determine
Yes
Yes
Unable to
determine
Yes
Yes
Yes
No
Partially
Yes
Yes
No
Yes
Yes
Yes
Lips et al. 43
Appendix 3
Yes
No
No
No
Yes
Unable to
determine
Same population in each group
Same time period
Randomised
Concealment
Confounding adjustment adequate
Losses of patients accounted for
Internal validity-confounding
Kupelian et
al. 84
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Unable to
determine
Yes
No
No
No
No
No
No
No
No
Yes
Yes
Sanguineti et
al. 88
Shu et al. 29
No
No
No
No
No
Yes
Vora et al. 89
Unable to
determine
No
No
No
No
Yes
Unable to
determine
Yes
No
No
No
Yes
Yoshimura et Zelefsky et
al. 41
al.91
No
No
No
No
No
Yes
Ashman et
al.100
Unable to
determine
No
No
No
No
Yes
Lips et al. 43
DOI: 10.3310/hta14470
Health Technology Assessment 2010; Vol. 14: No. 47
87
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Appendix 4
Quality assessment for the
five included abstracts83
Kirichenko
et al.105
Sharma et
al.106
Morgan et
al.107
Boehmer et
al.108
Martinez et
al.110
Hypothesis/aim clearly described
Yes
Yes
No
Yes
Yes
Main outcomes clearly described
Unable to
determine
Unable to
determine
Unable to
determine
Unable to
determine
Unable to
determine
Patient characteristics clearly
described
No
No
No
No
No
Study groups similar
Unable to
determine
Unable to
determine
Unable to
determine
No
No
Data collection methods similar
Unable to
determine
Unable to
determine
Unable to
determine
Unable to
determine
Unable to
determine
Interventions clearly described
Yes
Unable to
determine
Unable to
determine
Unable to
determine
Yes
Confounders clearly described
Yes
No
No
No
No
Similar treatment groups
Yes
Unable to
determine
Unable to
determine
Unable to
determine
Yes
Reporting
Findings are clear
Yes
Yes
Yes
Yes
Yes
Estimates of random variability
Unable to
determine
Unable to
determine
Unable to
determine
Unable to
determine
Unable to
determine
AEs
Yes
Yes
Yes
Yes
Yes
Loss to follow-up described
No
No
No
No
No
Actual probability values
Yes
Yes
Yes
Yes
Yes
Subjects asked to participate are
representative
Unable to
determine
Unable to
determine
Unable to
determine
Unable to
determine
Unable to
determine
Subjects who did participate are
representative
Unable to
determine
Unable to
determine
Unable to
determine
Unable to
determine
Unable to
determine
Location representative
Unable to
determine
Unable to
determine
Unable to
determine
Unable to
determine
Unable to
determine
No
No
No
No
No
External validity
Internal validity-bias
Subjects blind
Assessors blind
No
No
No
No
No
Clarity re data dredging
Unable to
determine
Unable to
determine
Unable to
determine
Unable to
determine
Unable to
determine
Adjusted for follow-up lengths
Unable to
determine
Yes
Yes
No
No
Appropriate statistical tests
Yes
Unable to
determine
Yes
Unable to
determine
Unable to
determine
Reliable compliance
Unable to
determine
Unable to
determine
Unable to
determine
Unable to
determine
Unable to
determine
Outcomes measures valid/reliable
Unable to
determine
Unable to
determine
Unable to
determine
Yes
Unable to
determine
89
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Appendix 4
Kirichenko
et al.105
Sharma et
al.106
Morgan et
al.107
Boehmer et
al.108
Martinez et
al.110
Same population in each group
Unable to
determine
Unable to
determine
Unable to
determine
Unable to
determine
Unable to
determine
Same time period
No
No
No
Yes
Unable to
determine
Randomised
No
No
No
No
No
Concealment
No
Internal validity-confounding
90
No
No
No
No
Confounding adjustment adequate Unable to
determine
Unable to
determine
Unable to
determine
Unable to
determine
Unable to
determine
Losses of patients accounted for
Unable to
determine
Unable to
determine
Unable to
determine
Unable to
determine
Unable to
determine
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Appendix 5
Table of key excluded studies with rationale
T
he name of the first author, year and reason for exclusion are reported below. The table includes
only studies that were examined at full-text sift and were potentially studies of interest, but were not
deemed relevant or valid on closer inspection.
First author (year)
Reasons for exclusion
Adkinson (2008)
No comparator group
Allison (2008)
No comparator group
138
139
Dosimetric study
Amer (2003)140
No comparator group
Bernard (2008)
141
Literature review
Bossi (2008)142
No comparator group
Bhatnagar (2006)
143
No comparator group
Bui (2006)68
Buyyounouski (2007)
No comparator group
Cahlon (2008)99
No comparator group
Catton (2002)
No comparator group
Chan (2004)
No comparator group
144
145
146
No comparator group
Chao (2004)147
Cheung (2008)
No comparator group
Cohen (2006)149
No comparator data
Daly (2009)
Protocol only
148
150
Dearnaley (1999)151
No IMRT group
Dearnaley (2007)
Dose escalation, not IMRT
62
De Meerleer (2007)108
No comparator group
De Meerleer (2008)
No comparator group
153
Djemil (2003)
No comparator group
Dogan (2006)154
No comparator group
Dogan (2006)
Planning study
Dong (2001)156
Planning study
Dubus (2002)
Literature review
152
155
157
Planning study
Engler (1997)158
Fonteyne (2006)
159
No comparator group
Guckenberger (2008)160
Not in English language
Guerrero (2004)
Literature review
Hsi (2007)
No comparator group
161
162
Not conformal RT
Jani (2007)94
Johnstone (2004)
No comparator data
Lane/NIHR (2009)164
Ongoing study, not re IMRT
Lee (2007)
Planning study
Liauw (2007)166
No separate data for 3DCRT
Livi (2006)
Planning study
Liu (2007)168
Dosimetric study
163
165
167
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
91
Appendix 5
First author (year)
Reasons for exclusion
Khoo (2008)169
Planning study
Kosakowski (2008)
Not in English language
Kry (2006)
Planning study
170
171
Kuczer (2008)172
Not in English language
Liauw (2007)
Not clear if 3DCRT
Lim (2008)173
No comparator group
Ma (2008)
No comparator group
166
174
Mahadevan (2006)175
No comparator group
Marchand (2008)
No comparator group
176
McCammon (2006)177
No comparator group
McCloskey (2005)
No meaningful comparative statistics
Melcon (2007)
Positioning study
Michalski (2006)180
Literature review
Molla (2007)
No comparator group
178
179
181
Namiki (2006)182
No separate comparator data
Perez (2000)
Not IMRT
183
Perez (2007)184
No comparator group
Pollack (2003)
Literature review re dose escalation
185
Pollack/NCI (2009)186
Ongoing study, no comparator data
Rembielek (2006)
No comparator group
Reuther (2006)
No comparator group
187
188
Dosimetric study
Ruben (2008)189
Sanders/MRC (2009)
Ongoing study, no 3DCRT data
Sanguineti (2003)191
No separate comparator data
Sanguineti (2004)
No separate comparator data
Scarbrough (2007)193
No comparator group
Singh (2007)
No comparator group
190
192
194
Shahar (2004)195
No comparator data
Soete (2008)
Not in English language
Su (2006)
Not conformal RT
196
197
Teh (2001)198
No comparator group
Teh (2003)
No comparator group
199
No comparator group
Teh (2007)200
Teslow (2001)
Planning study
201
Thakkar (2005)202
No comparator group
Yuen (2008)
Dosimetric study
203
Vaarkamp (2002)204
Letter only
Villa (2008)
No comparator group
205
Wahab (2005)
Dosimetric study
206
Dosimetric study
Wang (2004)207
Wang-Chesebro (2006)
Dosimetric study
Wong (2008)209
No comparator data
Wu (2002)
Planning study
210
Zelefsky (2002)211
92
208
Dosimetric review
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Appendix 6
Resource use and cost assumptions
for IMRT and 3DCRT
A
personal communication with Nuala Close (St Bartholomew’s Hospital, London, UK, 2009)
provided resource use and cost assumptions for IMRT and 3DCRT.
Resource
Time
(hours)
WTE
effort
Hourly
Time × WTE Band (average) rate (£)
Costs per
patient
3DCRT
Simulator
0.6
2
1.2
7
32.98
CT
0.6
Outlining
1
Plan
£39.58
2
1.2
7
32.98
£39.58
1
1
Consultant
75.26
£75.26
4
1
4
7
32.98
£131.92
Plan check
0.6
1
0.6
8a/b
37.75
£22.65
Simulator verification
0.6
2
1.2
7
32.98
£39.58
Image/plan approval (Dr)
0.3
1
0.3
Consultant
75.26
£22.58
Image referencing
0.3
1
0.3
7
32.98
£9.89
Pre-treatment data input and checks
Treat (37 fractures)
1.5
1
1.5
6.5
32.98
£49.47
11.1
3
33.3
6.5
32.98
£1098.23
Total WTE effort
44.6
£1528.73
IMRT
Simulator
0.6
2
1.2
7
32.98
£39.58
CT
0.6
2
1.2
7
32.98
£39.58
Outlining
1
1
1
Consultant
75.26
£75.26
Plan
8
1
8
8a
37.75
£301.97
QA
3
2
6
8a/b
37.75
£226.48
Plan check
2.5
1
2.5
8b
44.62
£111.55
Rad checks
2.75
1
2.75
7
32.98
£90.70
Simulator verification
0.6
2
1.2
7
32.98
£39.58
Image/plan approval (Dr)
1.33
1
1.33
Consultant
75.26
£100.09
Image referencing
0.3
1
0.3
7
32.98
£9.89
Pre-treatment data input and checks
1.5
1
1.5
6.5
32.98
£49.47
PI Review
Treat (37 fractures)
1.5
1
1.5
12.7
3
38.1
36.4 Total WTE
effort
7/8a
34.84
£52.25
6.5
32.98
£1255.12
66.5
£2391.51
Both
Nurse assessment
0.5
1
0.5
7
32.98
£16.49
Patient information review before
treatment
0.5
1
0.5
6
28.58
£14.29
Nurse on treatment review (weekly)
0.5
1
0.5
Band 7 (15
minutes per
consultation)
32.98
£16.49
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
93
Appendix 6
Resource
Time
(hours)
WTE
effort
Hourly
Time × WTE Band (average) rate (£)
Costs per
patient
Dr on treatment review (every
2 weeks)
0.75
1
0.75
Junior doctors
(15 minutes per
cons)
35.02
£26.27
Junior medical review (one visit)
0.5
1
0.5
30 minutes per
patient
35.02
£17.51
7
32.98
Secretarial
2
1
1
Dietic assessment and treatment
(one visit)
0.5
1
0.5
41.6
£207.03
£16.49
5.3
Sim/CT/planning
Per
course
2 per patient
£500.00
Physics commissioning, QA
Per
course
Plus capital costs linac/vision
Per
course
24,000 fractions
per annum
£452.64
Plus equipment maintenance costs
Per
course
Linacs/CT/
Software
£252.63
£320.00
Consumables (paper, toner, etc.)
Clerk: making up of folder,
organising appointments
£3.40
7.4
1
0.2
3
15.64
£115.75
Scheduling
1.5
1
1.5
8a
37.75
£56.62
In vivo dosimetry
0.5
1
0.5
6/7
29.32
£14.66
Non-chemo prescriptions
Pharmacy
Cost of information given to patient
Printing
Blood tests (FBC and LFT’s/U&Es)
1 of each test
once
£25.00
£2.50
£16.00
Other costs not covered above
Referral district nursing
Consumables
Gowns (five per patient)
£5.00
0.5
1
0.5
6
28.58
£14.29
£45.00
£25.00
£2163.04
FBC, full blood count; LFT, liver function test; PI, portal image; Rad, radiation; U&Es, urea and electrolytes; WTE,
whole time equivalent.
94
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Appendix 7
Critical appraisal checklist for the economic
evaluations using key components of
the British Medical Journal checklist for
economic evaluations together with the
Eddy checklist on mathematical models
employed in technology assessments
Authors
Konski et al.78
Year
2006
Modelling assessments should include:
Yes/No
1
A statement of the problem
Yes
2
A discussion of the need for modelling vs alternative methodologies
Yes
3
A description of the relevant factors and outcomes
Survival not clear
4
A description of the model including reasons for this type of model and a
specification of the scope including time frame, perspective, comparators and
setting
Timeframe unclear. Sensitivity
analysis on timeframe suggests
between 5 and 10 years.
Perspective: Medicare
5
A description of data sources (including subjective estimates), with a
description of the strengths and weaknesses of each source, with reference
to a specific classification or hierarchy of evidence
Mostly. Source of utilities for
some states not stated. Lack
of comparative trial clinical
data not discussed
6
A list of assumptions pertaining to: the structure of the model (e.g. factors
included, relationships and distributions) and the data
Yes
7
A list of parameter values that will be used for a base-case analysis, and a list
of the ranges in those values that represent appropriate confidence limits and
that will be used in a sensitivity analysis
Yes
8
The results derived from applying the model for the base case
Yes
9
The results of the sensitivity analyses; unidimensional; best/worst case;
multidimensional (Monte Carlo/parametric); threshold
Yes
10
A discussion of how the modelling assumptions might affect the results,
indicating both the direction of the bias and the approximate magnitude of
the effect
Fairly well covered with
sensitivity analysis
11
A description of the validation undertaken including; concurrence of experts;
internal consistency; external consistency; predictive validity
No
12
A description of the settings to which the results of the analysis can be
applied and a list of factors that could limit the applicability of the results
No
13
A description of research in progress that could yield new data that could
alter the results of the analysis
No
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
95
Appendix 7
96
Authors
Pearson et al. 64
Year
2007
Modelling assessments should include:
Yes/No
1
A statement of the problem
Yes
2
A discussion of the need for modelling vs alternative methodologies
No
Yes
3
A description of the relevant factors and outcomes
4
A description of the model including reasons for this type of model and a
Yes
specification of the scope including; time frame, perspective, comparators and
setting
5
A description of data sources (including subjective estimates), with a
description of the strengths and weaknesses of each source, with reference
to a specific classification or hierarchy of evidence
Yes
6
A list of assumptions pertaining to: the structure of the model (e.g. factors
included, relationships and distributions) and the data
Yes
7
A list of parameter values that will be used for a base-case analysis, and a list
of the ranges in those values that represent appropriate confidence limits and
that will be used in a sensitivity analysis
Base case values. No
distributions – limited
sensitivity analysis
8
The results derived from applying the model for the base case
Yes
9
The results of the sensitivity analyses; unidimensional; best/worst case;
multidimensional (Monte Carlo/parametric); threshold
Limited sensitivity analysis
(univariate and threshold)
10
A discussion of how the modelling assumptions might affect the results,
indicating both the direction of the bias and the approximate magnitude of
the effect
Limited
11
A description of the validation undertaken including; concurrence of experts;
internal consistency; external consistency; predictive validity
No
12
A description of the settings to which the results of the analysis can be
applied and a list of factors that could limit the applicability of the results
No
13
A description of research in progress that could yield new data that could
alter the results of the analysis
Yes
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Appendix 8
Example search for cost and costeffectiveness evidence (MEDLINE)
38. Economics/ (25834)
39. “costs and cost analysis”/ (37460)
40. Cost allocation/ (1864)
41. Cost-benefit analysis/ (44373)
42. Cost control/ (18019)
43. Cost savings/ (6144)
44. Cost of illness/ (10938)
45. Cost sharing/ (1430)
46. “deductibles and coinsurance”/ (1204)
47. Medical savings accounts/ (396)
48. Health care costs/ (17205)
49. Direct service costs/ (860)
50. Drug costs/ (8865)
51. Employer health costs/ (995)
52. Hospital costs/ (5709)
53. Health expenditures/ (10360)
54. Capital expenditures/ (1839)
55. Value of life/ (5057)
56. exp economics, hospital/ (15764)
57. exp economics, medical/ (12120)
58. Economics, nursing/ (3849)
59. Economics, pharmaceutical/ (1958)
60. exp “fees and charges”/ (24129)
61. exp budgets/ (9937)
62. (low adj cost).mp. (12442)
63. (high adj cost).mp. (5477)
64. (health?care adj cost$).mp. (2047)
65. (fiscal or funding or financial or finance$).tw.
(51383)
66. (cost adj estimate$).mp. (955)
67. (cost adj variable).mp. (25)
68. (unit adj cost$).mp. (976)
69. (economic$ or pharmacoeconomic$ or price$
or pricing).tw. (108532)
70. budget$.tw. (12665)
71. (cost$ adj2 (effective$ or utilit$ or benefit$ or
minimi$)).tw. (59198)
72. (fee or fees).tw. (9053)
73. (value adj2 (money or monetary)).tw. (787)
74. or/1-36 (371937)
75. Radiotherapy, Intensity-Modulated/ (896)
76. intensity modulated radiotherap*.tw. (1254)
77. intensity-modulated radiotherap*.tw. (1254)
78. intensity modulated radiation therap*.tw.
(1364)
79. intensity-modulated radiation therap*.tw.
(1364)
80. imrt.tw. (2402)
81. image guided radiotherap*.tw. (193)
82. igrt.tw. (123)
83. dose compensation.tw. (30)
84. electronic compensation.tw. (28)
85. e compensation.tw. (0)
86. forward planning.tw. (100)
87. inverse planning.tw. (334)
88. field in field.tw. (18)
89. physical compensation.tw. (4)
90. 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or
46 or 47 or 48 or 49 or 50 or 51 or 52 (3718)
91. prostatic neoplasms/ (63810)
92. (prostat$ adj5 (cancer$ or carcin$ or tumor$ or
tumour$ or neoplasm$)).tw. (63945)
93. ((carcinoma or neoplasia or neoplasm$ or
adencarcinoma or cancer$ or tumor$ or
tumour$ or malignan$) adj3 prostat$).tw.
(61853)
94. 54 or 55 or 56 (78190)
95. 53 and 57 and 37 (19)
96. from 58 keep 1-19 (19)
97
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Appendix 9
Summary study survival and
toxicity data by dose
99
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
81
78
76
70 a
76
Sharma106
68
72
80
75.6
76
81
145
96
472
123
100
188
172
271
91
358
170
310
188
556
3DCRT
5
Not actuarial
mean 1.6 years
10
5
5
4
5
74
85
Phoenix
–
Consensus
–
–
88
Phoenix
–
85
82
–
Consensus
Phoenix
–
74
60
–
–
–
78
81
–
RTOG (not
actuarial
– median
4/5 years
IMRT/3D)
NCI-CTC
(not actuarial
– mean 1.6
years)
NCI-CTC
NS
RTOG
NCI-CTC
24
10
5
9
4
5
IMRT
16
11
18
22
9
18
3DCRT
Toxicity
measure
IMRT
Time in years
(actuarial)
Measure
Late GI toxicity (grades 2 and 3) (%)
PSA survival
NS, not specified.
a 70 Gy given in 2.5 Gy fractions biologically equivalent dose to 78 Gy in 2 Gy fractions.
Vora 89
108
Boehmer
Zelefsky 91
Higher dose IMRT
107
Morgan
80
80
80
Kupelian
200585
Martinez110
3DCRT
IMRT
IMRT
3DCRT
Number in cohort
IMRT/3DCRT same dose
100
Dose
Appendix 9
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Appendix 10
Biological equivalent radiotherapy doses
I
f N is the total number of fractions of RT given
in a treatment course, and d is the dose per
fraction, the biological equivalent dose (BED) is
calculated as:
BED = N × d × [1+d/(α/ß)]
The α/ß ratio is a measure of the effect of radiation
on different tissues. Kupelian et al. assumed an
(α/ß) ratio of 3.85
For the 3DCRT group given a total dose of 78 Gy
by 39 fractions of 2 Gy each the BED is:
The IMRT group was given a hypofractionated
regime of 28 fractions of 2.5 Gy each to give a total
dose of 70 Gy.
BED (IMRT) = 28 × 2.5 × [1+2/3] = 128
Thus Kupelian assumed that although the IMRT
group received a total dose of 70 Gy compared
to a dose of 78 Gy for the 3DCRT group, the
hypofractionated regime of the IMRT group
meant that the BED doses of the two regimes were
comparable.58
BED (3DCRT) = 39 × 2 × [1+2/3] = 130
101
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Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Appendix 11
Example search for utility values in
prostate cancer (MEDLINE)
1. prostatic neplasms/
2. (prostat* adj5 (cancer* or carcinoma* or
tumor* or tumour* or neoplasm*)).tw.
3. ((carcinoma* or neoplasia or neoplasm* or
adenocarcinoma* or cancer* or tumor* or
tumour* or malignan*) adj3 prostat*).tw.
4. 1 or 2 or 3
5. (utillity or utilities or eq5d or eq-5d or europol
or qwb or hui2 or hui3 or 15d or sf-6d or sf6d
or aqol).mp. [mp=title, original title, abstract,
name of substance word, subject heading word]
6. 4 and 5
103
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Appendix 12
Unit cost
Item
Year
Source
£6
1995–6
Chamberlain 1997
GP attendance
£36
2007–8
Curtis 2008
£36.97
Oncology outpatient
£86
2007–8
National reference costs 200951
£88.33
Nurse (GP practice)
£10
2007–8
Curtis 2008127
CT scan (one area)
£110
2007–8
National reference costs 200951
£112.98
Bone scan
£164
2007–8
National reference costs 200951
£168.44
Dexa scan
£71
PSA test
Cost
Cost 2008–9
£10.19
17
127
£10.27
51
£72.92
2007–8
National reference costs 2009
Goserelin (Zoladex LA) 10.8 mg syringe
£267
2009
British National Formulary March
2009128
£267.48
Flexible sigmoidoscopy ± colonoscopy,
biopsy
£484
2007–8
National reference costs 200951
£496.63
Laser therapy
£1170
2007–8
National reference costs 200951
£1201.31
£26
2007–8
Curtis 2008
Enemas (community nurse)
127
£26.70
105
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Appendix 13
Prostate-specific antigen variable
distribution parameters
Variable
Distribution
Mean
Source
Utility values
Utility decrement late bowel
toxicity
Beta (56.6, 75.0) scaled
between 0 and 0.2
0.086
Mean Shimizu,116 Ara126 (see Utility values),
uncertainty in mean ± 20%, author assumption
Utility multiplier hormone
treatment
Beta (37.8, 4.1)
0.903
Mean Shimizu,116 Ara126 (see Utility values),
uncertainty in mean ± 20%, author assumption
Difference between HT utility
multiplier and hormonerefractory multiplier
Beta (61.6,100.5) scaled
between 0 and 0.3
0.114
Mean Shimizu,116 Ara126 (see Utility values),
uncertainty in mean ± 20%, author assumption
Costs
Cost of post-RT patient
monitoring
Normal (mean 47.2,
se 4.81)
47.2
Mean – see Chapter 4, Resource use/costs,
uncertainty in mean ± 20%, author estimate
Cost of post-PSA fail patient
monitoring
Normal (mean 670.7,
se 68.4)
671
Mean – see Chapter 4, Resource use/costs,
uncertainty in mean ± 20%, author estimate
Cost on HT
Normal (mean 1324,
se 135.1)
1324
Mean – see Chapter 4, Resource use/costs,
uncertainty in mean ± 20%, author estimate
Cost hormone refractory
Normal (mean 7385,
se 753.6)
7385
Mean – see Chapter 4, Resource use/costs,
uncertainty in mean ± 20%, author estimate
Cost terminal care
Normal (mean 4007,
se 408.9)
4007
Mean – see Chapter 4, Resource use/costs,
uncertainty in mean ± 20%, author estimate
Cost treating late GI toxicity – Normal (mean 335,
annual
se 34.2)
335
Mean – see Chapter 4, Resource use/costs,
uncertainty in mean ± 20%, author estimate
Cost treating late GI toxicity – Normal (mean 2139
per patient
se 218.3)
2139
Mean – see Chapter 4, Resource use/costs,
uncertainty in mean ± 20%, author estimate
Incidence late GI toxicity
Vora IMRT
Beta (35, 110)
0.24
Vora 89
Vora 3DCRT
Beta (43,228)
0.16
Vora 89
Kupelian IMRT
Beta (11,89)
0.11
Kupelian 200585
Kupelian 3DCRT
Beta (14,102) scaled by
0.12/0.05
0.12
Kupelian 2002, 84 scale also Kupelian 200585
Morgan IMRT
Beta (8,180)
0.04
Morgan107
Morgan 3DCRT
Beta (17,171)
0.09
Morgan107
Time start to finish GI incident Normal (mean 4.5,
tox (years) Vora
se 0.46)
4.5
Mean Vora, 89 uncertainty in mean ± 20%,
author estimate
Time start to finish GI incident Normal (mean 4.5,
tox (years) Kupelian
se 0.46)
4.5
Mean Kupelian 2005, 85 uncertainty in
mean ± 20%, author estimate
Time start to finish GI incident Normal (mean 3.5,
tox (years) Morgan
se 0.36)
3.5
Mean Morgan,107 uncertainty in mean ± 20%,
author estimate
Duration of late GI toxicity
3
Mean derived from Zelefsky 91 (see Chapter
4, Other clinical parameters), uncertainty in
mean ± 20%, author estimate
Timing/duration
Normal (mean 3.0,
se 0.31)
107
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Appendix 13
Variable
Distribution
Duration hormone-refractory
disease
Normal (mean 1.87,
se 0.19)
Mean
1.87
Source
Mean Collins, uncertainty in mean ± 20%,
author estimate
For all distributions, unless otherwise specified, it was assumed the uncertainty in the mean was ± 20%, i.e. one SE
is approximately 10% of the mean value. For the incidence of late GI toxicity the alpha and beta parameters of the
beta distribution were calculated directly from the number of patients affected (or the actuarial %) and the total
number of patients. Note the Kupelian 3DCRT distribution is scaled by the incidence ratio of the incidence for
(IMRT at 5 years)/(IMRT at 2.5 years) as the incidence of late GI toxicity for 3DCRT was only available at 2.5 years.
For the Weibull parameters for each of the survival curves (from PSA failure, clinical failure and PC death) Cholesky
decomposition was used to provide correlated samples of the two Weibull parameters from a bivariate normal
distribution.
HT, hormone therapy; se, standard error.
108
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DOI: 10.3310/hta14470
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published to date
Volume 1, 1997
No. 1
Home parenteral nutrition: a systematic
review.
By Richards DM, Deeks JJ, Sheldon
TA, Shaffer JL.
No. 2
Diagnosis, management and screening
of early localised prostate cancer.
A review by Selley S, Donovan J,
Faulkner A, Coast J, Gillatt D.
No. 3
The diagnosis, management, treatment
and costs of prostate cancer in England
and Wales.
A review by Chamberlain J, Melia J,
Moss S, Brown J.
No. 4
Screening for fragile X syndrome.
A review by Murray J, Cuckle H,
Taylor G, Hewison J.
No. 5
A review of near patient testing in
primary care.
By Hobbs FDR, Delaney BC,
Fitzmaurice DA, Wilson S, Hyde CJ,
Thorpe GH, et al.
No. 6
Systematic review of outpatient services
for chronic pain control.
By McQuay HJ, Moore RA, Eccleston
C, Morley S, de C Williams AC.
No. 7
Neonatal screening for inborn errors of
metabolism: cost, yield and outcome.
A review by Pollitt RJ, Green A,
McCabe CJ, Booth A, Cooper NJ,
Leonard JV, et al.
No. 11
Newborn screening for inborn errors of
metabolism: a systematic review.
By Seymour CA, Thomason MJ,
Chalmers RA, Addison GM, Bain MD,
Cockburn F, et al.
No. 12
Routine preoperative testing: a
systematic review of the evidence.
By Munro J, Booth A, Nicholl J.
No. 13
Systematic review of the effectiveness of
laxatives in the elderly.
By Petticrew M, Watt I, Sheldon T.
No. 14
When and how to assess fast-changing
technologies: a comparative study of
medical applications of four generic
technologies.
A review by Mowatt G, Bower DJ,
Brebner JA, Cairns JA, Grant AM, McKee
L.
Volume 2, 1998
No. 1
Antenatal screening for Down’s
syndrome.
A review by Wald NJ, Kennard A,
Hackshaw A, McGuire A.
No. 2
Screening for ovarian cancer: a
systematic review.
By Bell R, Petticrew M, Luengo S,
Sheldon TA.
No. 8
Preschool vision screening.
A review by Snowdon SK,
Stewart-Brown SL.
No. 3
Consensus development methods,
and their use in clinical guideline
development.
A review by Murphy MK, Black NA,
Lamping DL, McKee CM, Sanderson
CFB, Askham J, et al.
No. 9
Implications of socio-cultural contexts
for the ethics of clinical trials.
A review by Ashcroft RE, Chadwick
DW, Clark SRL, Edwards RHT, Frith L,
Hutton JL.
No. 4
A cost–utility analysis of interferon beta
for multiple sclerosis.
By Parkin D, McNamee P, Jacoby A,
Miller P, Thomas S, Bates D.
No. 10
A critical review of the role of neonatal
hearing screening in the detection of
congenital hearing impairment.
By Davis A, Bamford J, Wilson I,
Ramkalawan T, Forshaw M, Wright S.
No. 5
Effectiveness and efficiency of methods
of dialysis therapy for end-stage renal
disease: systematic reviews.
By MacLeod A, Grant A, Donaldson
C, Khan I, Campbell M, Daly C, et al.
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Effectiveness of hip prostheses in
primary total hip replacement: a critical
review of evidence and an economic
model.
By Faulkner A, Kennedy LG, Baxter
K, Donovan J, Wilkinson M, Bevan G.
No. 7
Antimicrobial prophylaxis in colorectal
surgery: a systematic review of
randomised controlled trials.
By Song F, Glenny AM.
No. 8
Bone marrow and peripheral
blood stem cell transplantation for
malignancy.
A review by Johnson PWM,
Simnett SJ, Sweetenham JW, Morgan GJ,
Stewart LA.
No. 9
Screening for speech and language
delay: a systematic review of the
literature.
By Law J, Boyle J, Harris F,
Harkness A, Nye C.
No. 10
Resource allocation for chronic
stable angina: a systematic review of
effectiveness, costs and cost-effectiveness
of alternative interventions.
By Sculpher MJ, Petticrew M,
Kelland JL, Elliott RA, Holdright DR,
Buxton MJ.
No. 11
Detection, adherence and control of
hypertension for the prevention of
stroke: a systematic review.
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Postoperative analgesia and vomiting,
with special reference to day-case
surgery: a systematic review.
By McQuay HJ, Moore RA.
No. 13
Choosing between randomised and
nonrandomised studies: a systematic
review.
By Britton A, McKee M, Black N,
McPherson K, Sanderson C, Bain C.
No. 14
Evaluating patient-based outcome
measures for use in clinical trials.
A review by Fitzpatrick R, Davey C,
Buxton MJ, Jones DR.
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Ethical issues in the design and conduct
of randomised controlled trials.
A review by Edwards SJL, Lilford RJ,
Braunholtz DA, Jackson JC, Hewison J,
Thornton J.
No. 16
Qualitative research methods in health
technology assessment: a review of the
literature.
By Murphy E, Dingwall R,
Greatbatch D, Parker S, Watson P.
No. 17
The costs and benefits of paramedic
skills in pre-hospital trauma care.
By Nicholl J, Hughes S, Dixon S,
Turner J, Yates D.
No. 18
Systematic review of endoscopic
ultrasound in gastro-oesophageal
cancer.
By Harris KM, Kelly S, Berry E,
Hutton J, Roderick P, Cullingworth J,
et al.
No. 19
Systematic reviews of trials and other
studies.
By Sutton AJ, Abrams KR, Jones DR,
Sheldon TA, Song F.
No. 20
Primary total hip replacement surgery:
a systematic review of outcomes
and modelling of cost-effectiveness
associated with different prostheses.
A review by Fitzpatrick R, Shortall
E, Sculpher M, Murray D, Morris R,
Lodge M, et al.
Volume 3, 1999
No. 1
Informed decision making: an
annotated bibliography and systematic
review.
By Bekker H, Thornton JG,
Airey CM, Connelly JB, Hewison J,
Robinson MB, et al.
No. 2
Handling uncertainty when performing
economic evaluation of healthcare
interventions.
A review by Briggs AH, Gray AM.
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The role of expectancies in the placebo
effect and their use in the delivery of
health care: a systematic review.
By Crow R, Gage H, Hampson S,
Hart J, Kimber A, Thomas H.
No. 4
A randomised controlled trial of
different approaches to universal
antenatal HIV testing: uptake and
acceptability. Annex: Antenatal HIV
testing – assessment of a routine
voluntary approach.
By Simpson WM, Johnstone FD,
Boyd FM, Goldberg DJ, Hart GJ,
Gormley SM, et al.
No. 5
Methods for evaluating area-wide and
organisation-based interventions in
health and health care: a systematic
review.
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Chinn S, Sterne JAC, Burney PGJ.
No. 6
Assessing the costs of healthcare
technologies in clinical trials.
A review by Johnston K, Buxton MJ,
Jones DR, Fitzpatrick R.
No. 7
Cooperatives and their primary care
emergency centres: organisation and
impact.
By Hallam L, Henthorne K.
No. 8
Screening for cystic fibrosis.
A review by Murray J, Cuckle H,
Taylor G, Littlewood J, Hewison J.
No. 9
A review of the use of health status
measures in economic evaluation.
By Brazier J, Deverill M, Green C,
Harper R, Booth A.
No. 10
Methods for the analysis of qualityof-life and survival data in health
technology assessment.
A review by Billingham LJ,
Abrams KR, Jones DR.
No. 11
Antenatal and neonatal
haemoglobinopathy screening in the
UK: review and economic analysis.
By Zeuner D, Ades AE, Karnon J,
Brown J, Dezateux C, Anionwu EN.
No. 12
Assessing the quality of reports of
randomised trials: implications for the
conduct of meta-analyses.
A review by Moher D, Cook DJ,
Jadad AR, Tugwell P, Moher M,
Jones A, et al.
No. 13
‘Early warning systems’ for identifying
new healthcare technologies.
By Robert G, Stevens A, Gabbay J.
No. 14
A systematic review of the role of
human papillomavirus testing within a
cervical screening programme.
By Cuzick J, Sasieni P, Davies P,
Adams J, Normand C, Frater A, et al.
No. 15
Near patient testing in diabetes clinics:
appraising the costs and outcomes.
By Grieve R, Beech R, Vincent J,
Mazurkiewicz J.
No. 16
Positron emission tomography:
establishing priorities for health
technology assessment.
A review by Robert G, Milne R.
No. 17 (Pt 1)
The debridement of chronic wounds: a
systematic review.
By Bradley M, Cullum N, Sheldon T.
No. 17 (Pt 2)
Systematic reviews of wound care
management: (2) Dressings and topical
agents used in the healing of chronic
wounds.
By Bradley M, Cullum N, Nelson EA,
Petticrew M, Sheldon T, Torgerson D.
No. 18
A systematic literature review of
spiral and electron beam computed
tomography: with particular reference
to clinical applications in hepatic
lesions, pulmonary embolus and
coronary artery disease.
By Berry E, Kelly S, Hutton J,
Harris KM, Roderick P, Boyce JC, et al.
No. 19
What role for statins? A review and
economic model.
By Ebrahim S, Davey Smith
G, McCabe C, Payne N, Pickin M,
Sheldon TA, et al.
No. 20
Factors that limit the quality, number
and progress of randomised controlled
trials.
A review by Prescott RJ, Counsell CE,
Gillespie WJ, Grant AM, Russell IT,
Kiauka S, et al.
No. 21
Antimicrobial prophylaxis in total hip
replacement: a systematic review.
By Glenny AM, Song F.
No. 22
Health promoting schools and health
promotion in schools: two systematic
reviews.
By Lister-Sharp D, Chapman S,
Stewart-Brown S, Sowden A.
No. 23
Economic evaluation of a primary
care-based education programme for
patients with osteoarthritis of the knee.
A review by Lord J, Victor C,
Littlejohns P, Ross FM, Axford JS.
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No. 1
The estimation of marginal time
preference in a UK-wide sample
(TEMPUS) project.
A review by Cairns JA,
van der Pol MM.
No. 2
Geriatric rehabilitation following
fractures in older people: a systematic
review.
By Cameron I, Crotty M, Currie C,
Finnegan T, Gillespie L, Gillespie W,
et al.
No. 3
Screening for sickle cell disease and
thalassaemia: a systematic review with
supplementary research.
By Davies SC, Cronin E, Gill M,
Greengross P, Hickman M, Normand C.
No. 4
Community provision of hearing aids
and related audiology services.
A review by Reeves DJ, Alborz A,
Hickson FS, Bamford JM.
No. 5
False-negative results in screening
programmes: systematic review of
impact and implications.
By Petticrew MP, Sowden AJ,
Lister-Sharp D, Wright K.
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Costs and benefits of community
postnatal support workers: a
randomised controlled trial.
By Morrell CJ, Spiby H, Stewart P,
Walters S, Morgan A.
No. 7
Implantable contraceptives (subdermal
implants and hormonally impregnated
intrauterine systems) versus other
forms of reversible contraceptives: two
systematic reviews to assess relative
effectiveness, acceptability, tolerability
and cost-effectiveness.
By French RS, Cowan FM,
Mansour DJA, Morris S, Procter T,
Hughes D, et al.
No. 8
An introduction to statistical methods
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A review by White SJ, Ashby D,
Brown PJ.
No. 9
Disease-modifying drugs for multiple
sclerosis: a rapid and systematic review.
By Clegg A, Bryant J, Milne R.
No. 10
Publication and related biases.
A review by Song F, Eastwood AJ,
Gilbody S, Duley L, Sutton AJ.
No. 11
Cost and outcome implications of the
organisation of vascular services.
By Michaels J, Brazier J,
Palfreyman S, Shackley P, Slack R.
No. 12
Monitoring blood glucose control in
diabetes mellitus: a systematic review.
By Coster S, Gulliford MC, Seed PT,
Powrie JK, Swaminathan R.
No. 13
The effectiveness of domiciliary
health visiting: a systematic review of
international studies and a selective
review of the British literature.
By Elkan R, Kendrick D, Hewitt M,
Robinson JJA, Tolley K, Blair M, et al.
No. 14
The determinants of screening uptake
and interventions for increasing
uptake: a systematic review.
By Jepson R, Clegg A, Forbes C,
Lewis R, Sowden A, Kleijnen J.
No. 15
The effectiveness and cost-effectiveness
of prophylactic removal of wisdom
teeth.
A rapid review by Song F, O’Meara S,
Wilson P, Golder S, Kleijnen J.
No. 16
Ultrasound screening in pregnancy:
a systematic review of the clinical
effectiveness, cost-effectiveness and
women’s views.
By Bricker L, Garcia J, Henderson J,
Mugford M, Neilson J, Roberts T, et al.
No. 17
A rapid and systematic review of the
effectiveness and cost-effectiveness of
the taxanes used in the treatment of
advanced breast and ovarian cancer.
By Lister-Sharp D, McDonagh MS,
Khan KS, Kleijnen J.
No. 18
Liquid-based cytology in cervical
screening: a rapid and systematic
review.
By Payne N, Chilcott J, McGoogan E.
No. 19
Randomised controlled trial of nondirective counselling, cognitive–
behaviour therapy and usual general
practitioner care in the management of
depression as well as mixed anxiety and
depression in primary care.
By King M, Sibbald B, Ward E,
Bower P, Lloyd M, Gabbay M, et al.
No. 20
Routine referral for radiography of
patients presenting with low back pain:
is patients’ outcome influenced by GPs’
referral for plain radiography?
By Kerry S, Hilton S, Patel S,
Dundas D, Rink E, Lord J.
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No. 21
Systematic reviews of wound care
management: (3) antimicrobial agents
for chronic wounds; (4) diabetic foot
ulceration.
By O’Meara S, Cullum N, Majid M,
Sheldon T.
No. 22
Using routine data to complement
and enhance the results of randomised
controlled trials.
By Lewsey JD, Leyland AH, Murray
GD, Boddy FA.
No. 23
Coronary artery stents in the treatment
of ischaemic heart disease: a rapid and
systematic review.
By Meads C, Cummins C, Jolly K,
Stevens A, Burls A, Hyde C.
No. 24
Outcome measures for adult critical
care: a systematic review.
By Hayes JA, Black NA, Jenkinson C,
Young JD, Rowan KM, Daly K, et al.
No. 25
A systematic review to evaluate the
effectiveness of interventions to
promote the initiation of breastfeeding.
By Fairbank L, O’Meara S,
Renfrew MJ, Woolridge M, Sowden AJ,
Lister-Sharp D.
No. 26
Implantable cardioverter defibrillators:
arrhythmias. A rapid and systematic
review.
By Parkes J, Bryant J, Milne R.
No. 27
Treatments for fatigue in multiple
sclerosis: a rapid and systematic review.
By Brañas P, Jordan R, Fry-Smith A,
Burls A, Hyde C.
No. 28
Early asthma prophylaxis, natural
history, skeletal development and
economy (EASE): a pilot randomised
controlled trial.
By Baxter-Jones ADG, Helms PJ,
Russell G, Grant A, Ross S, Cairns JA,
et al.
No. 29
Screening for hypercholesterolaemia
versus case finding for familial
hypercholesterolaemia: a systematic
review and cost-effectiveness analysis.
By Marks D, Wonderling
D, Thorogood M, Lambert H,
Humphries SE, Neil HAW.
No. 30
A rapid and systematic review of
the clinical effectiveness and costeffectiveness of glycoprotein IIb/
IIIa antagonists in the medical
management of unstable angina.
By McDonagh MS, Bachmann LM,
Golder S, Kleijnen J, ter Riet G.
111
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No. 31
A randomised controlled trial
of prehospital intravenous fluid
replacement therapy in serious trauma.
By Turner J, Nicholl J, Webber L,
Cox H, Dixon S, Yates D.
No. 32
Intrathecal pumps for giving opioids in
chronic pain: a systematic review.
By Williams JE, Louw G,
Towlerton G.
No. 33
Combination therapy (interferon
alfa and ribavirin) in the treatment
of chronic hepatitis C: a rapid and
systematic review.
By Shepherd J, Waugh N,
Hewitson P.
No. 34
A systematic review of comparisons of
effect sizes derived from randomised
and non-randomised studies.
By MacLehose RR, Reeves BC,
Harvey IM, Sheldon TA, Russell IT,
Black AMS.
No. 35
Intravascular ultrasound-guided
interventions in coronary artery
disease: a systematic literature review,
with decision-analytic modelling, of
outcomes and cost-effectiveness.
By Berry E, Kelly S, Hutton J,
Lindsay HSJ, Blaxill JM, Evans JA, et al.
No. 36
A randomised controlled trial to
evaluate the effectiveness and costeffectiveness of counselling patients
with chronic depression.
By Simpson S, Corney R,
Fitzgerald P, Beecham J.
No. 37
Systematic review of treatments for
atopic eczema.
By Hoare C, Li Wan Po A,
Williams H.
No. 38
Bayesian methods in health technology
assessment: a review.
By Spiegelhalter DJ, Myles JP,
Jones DR, Abrams KR.
112
Volume 5, 2001
No. 1
Clinical and cost-effectiveness
of donepezil, rivastigmine and
galantamine for Alzheimer’s disease: a
rapid and systematic review.
By Clegg A, Bryant J, Nicholson T,
McIntyre L, De Broe S, Gerard K, et al.
No. 2
The clinical effectiveness and costeffectiveness of riluzole for motor
neurone disease: a rapid and systematic
review.
By Stewart A, Sandercock J, Bryan S,
Hyde C, Barton PM, Fry-Smith A, et al.
No. 3
Equity and the economic evaluation of
healthcare.
By Sassi F, Archard L, Le Grand J.
No. 4
Quality-of-life measures in chronic
diseases of childhood.
By Eiser C, Morse R.
No. 5
Eliciting public preferences for
healthcare: a systematic review of
techniques.
By Ryan M, Scott DA, Reeves C, Bate
A, van Teijlingen ER, Russell EM, et al.
No. 6
General health status measures for
people with cognitive impairment:
learning disability and acquired brain
injury.
By Riemsma RP, Forbes CA,
Glanville JM, Eastwood AJ, Kleijnen J.
No. 7
An assessment of screening strategies
for fragile X syndrome in the UK.
By Pembrey ME, Barnicoat AJ,
Carmichael B, Bobrow M, Turner G.
No. 8
Issues in methodological research:
perspectives from researchers and
commissioners.
By Lilford RJ, Richardson A, Stevens
A, Fitzpatrick R, Edwards S, Rock F, et al.
No. 39
The management of dyspepsia: a
systematic review.
By Delaney B, Moayyedi P, Deeks J,
Innes M, Soo S, Barton P, et al.
No. 9
Systematic reviews of wound
care management: (5) beds;
(6) compression; (7) laser therapy,
therapeutic ultrasound, electrotherapy
and electromagnetic therapy.
By Cullum N, Nelson EA,
Flemming K, Sheldon T.
No. 40
A systematic review of treatments for
severe psoriasis.
By Griffiths CEM, Clark CM,
Chalmers RJG, Li Wan Po A,
Williams HC.
No. 10
Effects of educational and psychosocial
interventions for adolescents with
diabetes mellitus: a systematic review.
By Hampson SE, Skinner TC, Hart J,
Storey L, Gage H, Foxcroft D, et al.
No. 11
Effectiveness of autologous chondrocyte
transplantation for hyaline cartilage
defects in knees: a rapid and systematic
review.
By Jobanputra P, Parry D, Fry-Smith
A, Burls A.
No. 12
Statistical assessment of the learning
curves of health technologies.
By Ramsay CR, Grant AM, Wallace
SA, Garthwaite PH, Monk AF, Russell IT.
No. 13
The effectiveness and cost-effectiveness
of temozolomide for the treatment of
recurrent malignant glioma: a rapid
and systematic review.
By Dinnes J, Cave C, Huang S,
Major K, Milne R.
No. 14
A rapid and systematic review of
the clinical effectiveness and costeffectiveness of debriding agents in
treating surgical wounds healing by
secondary intention.
By Lewis R, Whiting P, ter Riet G,
O’Meara S, Glanville J.
No. 15
Home treatment for mental health
problems: a systematic review.
By Burns T, Knapp M, Catty J,
Healey A, Henderson J, Watt H, et al.
No. 16
How to develop cost-conscious
guidelines.
By Eccles M, Mason J.
No. 17
The role of specialist nurses in multiple
sclerosis: a rapid and systematic review.
By De Broe S, Christopher F,
Waugh N.
No. 18
A rapid and systematic review
of the clinical effectiveness and
cost-effectiveness of orlistat in the
management of obesity.
By O’Meara S, Riemsma R,
Shirran L, Mather L, ter Riet G.
No. 19
The clinical effectiveness and costeffectiveness of pioglitazone for
type 2 diabetes mellitus: a rapid and
systematic review.
By Chilcott J, Wight J, Lloyd Jones
M, Tappenden P.
No. 20
Extended scope of nursing practice:
a multicentre randomised controlled
trial of appropriately trained nurses
and preregistration house officers in
preoperative assessment in elective
general surgery.
By Kinley H, Czoski-Murray C,
George S, McCabe C, Primrose J,
Reilly C, et al.
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
No. 21
Systematic reviews of the effectiveness
of day care for people with severe
mental disorders: (1) Acute day hospital
versus admission; (2) Vocational
rehabilitation; (3) Day hospital versus
outpatient care.
By Marshall M, Crowther R,
Almaraz-Serrano A, Creed F, Sledge W,
Kluiter H, et al.
No. 22
The measurement and monitoring of
surgical adverse events.
By Bruce J, Russell EM, Mollison J,
Krukowski ZH.
No. 23
Action research: a systematic review and
guidance for assessment.
By Waterman H, Tillen D, Dickson R,
de Koning K.
No. 24
A rapid and systematic review of
the clinical effectiveness and costeffectiveness of gemcitabine for the
treatment of pancreatic cancer.
By Ward S, Morris E, Bansback N,
Calvert N, Crellin A, Forman D, et al.
No. 25
A rapid and systematic review of the
evidence for the clinical effectiveness
and cost-effectiveness of irinotecan,
oxaliplatin and raltitrexed for the
treatment of advanced colorectal
cancer.
By Lloyd Jones M, Hummel S,
Bansback N, Orr B, Seymour M.
No. 31
Design and use of questionnaires: a
review of best practice applicable to
surveys of health service staff and
patients.
By McColl E, Jacoby A, Thomas L,
Soutter J, Bamford C, Steen N, et al.
No. 32
A rapid and systematic review of
the clinical effectiveness and costeffectiveness of paclitaxel, docetaxel,
gemcitabine and vinorelbine in nonsmall-cell lung cancer.
By Clegg A, Scott DA, Sidhu M,
Hewitson P, Waugh N.
No. 33
Subgroup analyses in randomised
controlled trials: quantifying the risks
of false-positives and false-negatives.
By Brookes ST, Whitley E, Peters TJ,
Mulheran PA, Egger M, Davey Smith G.
No. 34
Depot antipsychotic medication
in the treatment of patients with
schizophrenia: (1) Meta-review; (2)
Patient and nurse attitudes.
By David AS, Adams C.
No. 35
A systematic review of controlled
trials of the effectiveness and costeffectiveness of brief psychological
treatments for depression.
By Churchill R, Hunot V, Corney R,
Knapp M, McGuire H, Tylee A, et al.
No. 26
Comparison of the effectiveness of
inhaler devices in asthma and chronic
obstructive airways disease: a systematic
review of the literature.
By Brocklebank D, Ram F, Wright J,
Barry P, Cates C, Davies L, et al.
No. 36
Cost analysis of child health
surveillance.
By Sanderson D, Wright D, Acton C,
Duree D.
No. 27
The cost-effectiveness of magnetic
resonance imaging for investigation of
the knee joint.
By Bryan S, Weatherburn G, Bungay
H, Hatrick C, Salas C, Parry D, et al.
Volume 6, 2002
No. 28
A rapid and systematic review of
the clinical effectiveness and costeffectiveness of topotecan for ovarian
cancer.
By Forbes C, Shirran L, Bagnall A-M,
Duffy S, ter Riet G.
No. 29
Superseded by a report published in a
later volume.
No. 30
The role of radiography in primary
care patients with low back pain of at
least 6 weeks duration: a randomised
(unblinded) controlled trial.
By Kendrick D, Fielding K, Bentley
E, Miller P, Kerslake R, Pringle M.
No. 1
A study of the methods used to select
review criteria for clinical audit.
By Hearnshaw H, Harker R,
Cheater F, Baker R, Grimshaw G.
No. 2
Fludarabine as second-line therapy for
B cell chronic lymphocytic leukaemia: a
technology assessment.
By Hyde C, Wake B, Bryan S, Barton
P, Fry-Smith A, Davenport C, et al.
No. 3
Rituximab as third-line treatment for
refractory or recurrent Stage III or IV
follicular non-Hodgkin’s lymphoma:
a systematic review and economic
evaluation.
By Wake B, Hyde C, Bryan S, Barton
P, Song F, Fry-Smith A, et al.
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
No. 4
A systematic review of discharge
arrangements for older people.
By Parker SG, Peet SM, McPherson
A, Cannaby AM, Baker R, Wilson A, et al.
No. 5
The clinical effectiveness and costeffectiveness of inhaler devices used
in the routine management of chronic
asthma in older children: a systematic
review and economic evaluation.
By Peters J, Stevenson M, Beverley C,
Lim J, Smith S.
No. 6
The clinical effectiveness and costeffectiveness of sibutramine in the
management of obesity: a technology
assessment.
By O’Meara S, Riemsma R, Shirran
L, Mather L, ter Riet G.
No. 7
The cost-effectiveness of magnetic
resonance angiography for carotid
artery stenosis and peripheral vascular
disease: a systematic review.
By Berry E, Kelly S, Westwood ME,
Davies LM, Gough MJ, Bamford JM,
et al.
No. 8
Promoting physical activity in South
Asian Muslim women through ‘exercise
on prescription’.
By Carroll B, Ali N, Azam N.
No. 9
Zanamivir for the treatment of
influenza in adults: a systematic review
and economic evaluation.
By Burls A, Clark W, Stewart T,
Preston C, Bryan S, Jefferson T, et al.
No. 10
A review of the natural history and
epidemiology of multiple sclerosis:
implications for resource allocation and
health economic models.
By Richards RG, Sampson FC,
Beard SM, Tappenden P.
No. 11
Screening for gestational diabetes:
a systematic review and economic
evaluation.
By Scott DA, Loveman E, McIntyre
L, Waugh N.
No. 12
The clinical effectiveness and costeffectiveness of surgery for people with
morbid obesity: a systematic review and
economic evaluation.
By Clegg AJ, Colquitt J, Sidhu MK,
Royle P, Loveman E, Walker A.
No. 13
The clinical effectiveness of
trastuzumab for breast cancer: a
systematic review.
By Lewis R, Bagnall A-M, Forbes C,
Shirran E, Duffy S, Kleijnen J, et al.
113
Health Technology Assessment reports published to date
No. 14
The clinical effectiveness and costeffectiveness of vinorelbine for breast
cancer: a systematic review and
economic evaluation.
By Lewis R, Bagnall A-M, King S,
Woolacott N, Forbes C, Shirran L, et al.
No. 23
A systematic review and economic
evaluation of pegylated liposomal
doxorubicin hydrochloride for ovarian
cancer.
By Forbes C, Wilby J, Richardson G,
Sculpher M, Mather L, Riemsma R.
No. 32
The measurement of satisfaction with
healthcare: implications for practice
from a systematic review of the
literature.
By Crow R, Gage H, Hampson S,
Hart J, Kimber A, Storey L, et al.
No. 15
A systematic review of the effectiveness
and cost-effectiveness of metal-onmetal hip resurfacing arthroplasty for
treatment of hip disease.
By Vale L, Wyness L, McCormack K,
McKenzie L, Brazzelli M, Stearns SC.
No. 24
A systematic review of the effectiveness
of interventions based on a stages-ofchange approach to promote individual
behaviour change.
By Riemsma RP, Pattenden J, Bridle
C, Sowden AJ, Mather L, Watt IS, et al.
No. 33
The effectiveness and cost-effectiveness
of imatinib in chronic myeloid
leukaemia: a systematic review.
By Garside R, Round A, Dalziel K,
Stein K, Royle R.
No. 16
The clinical effectiveness and costeffectiveness of bupropion and nicotine
replacement therapy for smoking
cessation: a systematic review and
economic evaluation.
By Woolacott NF, Jones L, Forbes CA,
Mather LC, Sowden AJ, Song FJ, et al.
No. 25
A systematic review update of the
clinical effectiveness and costeffectiveness of glycoprotein IIb/IIIa
antagonists.
By Robinson M, Ginnelly L, Sculpher
M, Jones L, Riemsma R, Palmer S, et al.
No. 35
A systematic review of the costs and
effectiveness of different models of
paediatric home care.
By Parker G, Bhakta P, Lovett CA,
Paisley S, Olsen R, Turner D, et al.
No. 26
A systematic review of the effectiveness,
cost-effectiveness and barriers to
implementation of thrombolytic and
neuroprotective therapy for acute
ischaemic stroke in the NHS.
By Sandercock P, Berge E, Dennis M,
Forbes J, Hand P, Kwan J, et al.
Volume 7, 2003
No. 18
Clinical effectiveness and costeffectiveness of growth hormone in
children: a systematic review and
economic evaluation.
By Bryant J, Cave C, Mihaylova B,
Chase D, McIntyre L, Gerard K, et al.
No. 27
A randomised controlled crossover trial
of nurse practitioner versus doctorled outpatient care in a bronchiectasis
clinic.
By Caine N, Sharples LD,
Hollingworth W, French J, Keogan M,
Exley A, et al.
No. 1
How important are comprehensive
literature searches and the assessment
of trial quality in systematic reviews?
Empirical study.
By Egger M, Jüni P, Bartlett C,
Holenstein F, Sterne J.
No. 19
Clinical effectiveness and costeffectiveness of growth hormone
in adults in relation to impact on
quality of life: a systematic review and
economic evaluation.
By Bryant J, Loveman E, Chase D,
Mihaylova B, Cave C, Gerard K, et al.
No. 28
Clinical effectiveness and cost –
consequences of selective serotonin
reuptake inhibitors in the treatment of
sex offenders.
By Adi Y, Ashcroft D, Browne K,
Beech A, Fry-Smith A, Hyde C.
No. 17
A systematic review of effectiveness
and economic evaluation of new drug
treatments for juvenile idiopathic
arthritis: etanercept.
By Cummins C, Connock M,
Fry-Smith A, Burls A.
No. 20
Clinical medication review by a
pharmacist of patients on repeat
prescriptions in general practice: a
randomised controlled trial.
By Zermansky AG, Petty DR, Raynor
DK, Lowe CJ, Freementle N, Vail A.
No. 21
The effectiveness of infliximab and
etanercept for the treatment of
rheumatoid arthritis: a systematic
review and economic evaluation.
By Jobanputra P, Barton P, Bryan S,
Burls A.
114
No. 34
A comparative study of hypertonic
saline, daily and alternate-day rhDNase
in children with cystic fibrosis.
By Suri R, Wallis C, Bush A,
Thompson S, Normand C, Flather M,
et al.
No. 22
A systematic review and economic
evaluation of computerised cognitive
behaviour therapy for depression and
anxiety.
By Kaltenthaler E, Shackley P,
Stevens K, Beverley C, Parry G,
Chilcott J.
No. 29
Treatment of established osteoporosis:
a systematic review and cost–utility
analysis.
By Kanis JA, Brazier JE, Stevenson
M, Calvert NW, Lloyd Jones M.
No. 30
Which anaesthetic agents are costeffective in day surgery? Literature
review, national survey of practice and
randomised controlled trial.
By Elliott RA, Payne K, Moore JK,
Davies LM, Harper NJN, St Leger AS,
et al.
No. 31
Screening for hepatitis C among
injecting drug users and in
genitourinary medicine clinics:
systematic reviews of effectiveness,
modelling study and national survey of
current practice.
By Stein K, Dalziel K, Walker A,
McIntyre L, Jenkins B, Horne J, et al.
No. 2
Systematic review of the effectiveness
and cost-effectiveness, and economic
evaluation, of home versus hospital or
satellite unit haemodialysis for people
with end-stage renal failure.
By Mowatt G, Vale L, Perez J, Wyness
L, Fraser C, MacLeod A, et al.
No. 3
Systematic review and economic
evaluation of the effectiveness of
infliximab for the treatment of Crohn’s
disease.
By Clark W, Raftery J, Barton P,
Song F, Fry-Smith A, Burls A.
No. 4
A review of the clinical effectiveness
and cost-effectiveness of routine anti-D
prophylaxis for pregnant women who
are rhesus negative.
By Chilcott J, Lloyd Jones M, Wight
J, Forman K, Wray J, Beverley C, et al.
No. 5
Systematic review and evaluation of the
use of tumour markers in paediatric
oncology: Ewing’s sarcoma and
neuroblastoma.
By Riley RD, Burchill SA,
Abrams KR, Heney D, Lambert PC,
Jones DR, et al.
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
No. 6
The cost-effectiveness of screening for
Helicobacter pylori to reduce mortality
and morbidity from gastric cancer and
peptic ulcer disease: a discrete-event
simulation model.
By Roderick P, Davies R, Raftery J,
Crabbe D, Pearce R, Bhandari P, et al.
No. 15
Early thrombolysis for the treatment
of acute myocardial infarction: a
systematic review and economic
evaluation.
By Boland A, Dundar Y, Bagust A,
Haycox A, Hill R, Mujica Mota R, et al.
No. 7
The clinical effectiveness and costeffectiveness of routine dental checks:
a systematic review and economic
evaluation.
By Davenport C, Elley K, Salas
C, Taylor-Weetman CL, Fry-Smith A,
Bryan S, et al.
No. 16
Screening for fragile X syndrome: a
literature review and modelling.
By Song FJ, Barton P, Sleightholme
V, Yao GL, Fry-Smith A.
No. 8
A multicentre randomised controlled
trial assessing the costs and benefits
of using structured information and
analysis of women’s preferences in the
management of menorrhagia.
By Kennedy ADM, Sculpher MJ,
Coulter A, Dwyer N, Rees M, Horsley S,
et al.
No. 9
Clinical effectiveness and cost–utility
of photodynamic therapy for wet
age-related macular degeneration:
a systematic review and economic
evaluation.
By Meads C, Salas C, Roberts T,
Moore D, Fry-Smith A, Hyde C.
No. 10
Evaluation of molecular tests for
prenatal diagnosis of chromosome
abnormalities.
By Grimshaw GM, Szczepura A,
Hultén M, MacDonald F, Nevin NC,
Sutton F, et al.
No. 11
First and second trimester antenatal
screening for Down’s syndrome:
the results of the Serum, Urine and
Ultrasound Screening Study (SURUSS).
By Wald NJ, Rodeck C, Hackshaw
AK, Walters J, Chitty L, Mackinson AM.
No. 12
The effectiveness and cost-effectiveness
of ultrasound locating devices for
central venous access: a systematic
review and economic evaluation.
By Calvert N, Hind D, McWilliams
RG, Thomas SM, Beverley C,
Davidson A.
No. 13
A systematic review of atypical
antipsychotics in schizophrenia.
By Bagnall A-M, Jones L, Lewis R,
Ginnelly L, Glanville J, Torgerson D,
et al.
No. 14
Prostate Testing for Cancer and
Treatment (ProtecT) feasibility study.
By Donovan J, Hamdy F, Neal D,
Peters T, Oliver S, Brindle L, et al.
No. 17
Systematic review of endoscopic sinus
surgery for nasal polyps.
By Dalziel K, Stein K, Round A,
Garside R, Royle P.
No. 18
Towards efficient guidelines: how to
monitor guideline use in primary care.
By Hutchinson A, McIntosh A,
Cox S, Gilbert C.
No. 19
Effectiveness and cost-effectiveness
of acute hospital-based spinal cord
injuries services: systematic review.
By Bagnall A-M, Jones L, Richardson
G, Duffy S, Riemsma R.
No. 20
Prioritisation of health technology
assessment. The PATHS model:
methods and case studies.
By Townsend J, Buxton M,
Harper G.
No. 21
Systematic review of the clinical
effectiveness and cost-effectiveness of
tension-free vaginal tape for treatment
of urinary stress incontinence.
By Cody J, Wyness L, Wallace S,
Glazener C, Kilonzo M, Stearns S, et al.
No. 22
The clinical and cost-effectiveness of
patient education models for diabetes:
a systematic review and economic
evaluation.
By Loveman E, Cave C, Green C,
Royle P, Dunn N, Waugh N.
No. 23
The role of modelling in prioritising
and planning clinical trials.
By Chilcott J, Brennan A, Booth A,
Karnon J, Tappenden P.
No. 24
Cost–benefit evaluation of routine
influenza immunisation in people
65–74 years of age.
By Allsup S, Gosney M, Haycox A,
Regan M.
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
No. 25
The clinical and cost-effectiveness of
pulsatile machine perfusion versus cold
storage of kidneys for transplantation
retrieved from heart-beating and nonheart-beating donors.
By Wight J, Chilcott J, Holmes M,
Brewer N.
No. 26
Can randomised trials rely on existing
electronic data? A feasibility study to
explore the value of routine data in
health technology assessment.
By Williams JG, Cheung WY,
Cohen DR, Hutchings HA, Longo MF,
Russell IT.
No. 27
Evaluating non-randomised
intervention studies.
By Deeks JJ, Dinnes J, D’Amico R,
Sowden AJ, Sakarovitch C, Song F, et al.
No. 28
A randomised controlled trial to assess
the impact of a package comprising a
patient-orientated, evidence-based selfhelp guidebook and patient-centred
consultations on disease management
and satisfaction in inflammatory bowel
disease.
By Kennedy A, Nelson E, Reeves D,
Richardson G, Roberts C, Robinson A,
et al.
No. 29
The effectiveness of diagnostic tests for
the assessment of shoulder pain due
to soft tissue disorders: a systematic
review.
By Dinnes J, Loveman E, McIntyre L,
Waugh N.
No. 30
The value of digital imaging in diabetic
retinopathy.
By Sharp PF, Olson J, Strachan F,
Hipwell J, Ludbrook A, O’Donnell M,
et al.
No. 31
Lowering blood pressure to prevent
myocardial infarction and stroke: a new
preventive strategy.
By Law M, Wald N, Morris J.
No. 32
Clinical and cost-effectiveness of
capecitabine and tegafur with uracil for
the treatment of metastatic colorectal
cancer: systematic review and economic
evaluation.
By Ward S, Kaltenthaler E, Cowan J,
Brewer N.
No. 33
Clinical and cost-effectiveness of new
and emerging technologies for early
localised prostate cancer: a systematic
review.
By Hummel S, Paisley S, Morgan A,
Currie E, Brewer N.
115
Health Technology Assessment reports published to date
No. 34
Literature searching for clinical and
cost-effectiveness studies used in health
technology assessment reports carried
out for the National Institute for
Clinical Excellence appraisal system.
By Royle P, Waugh N.
No. 35
Systematic review and economic
decision modelling for the prevention
and treatment of influenza A and B.
By Turner D, Wailoo A, Nicholson K,
Cooper N, Sutton A, Abrams K.
No. 36
A randomised controlled trial
to evaluate the clinical and costeffectiveness of Hickman line insertions
in adult cancer patients by nurses.
By Boland A, Haycox A, Bagust A,
Fitzsimmons L.
No. 37
Redesigning postnatal care: a
randomised controlled trial of protocolbased midwifery-led care focused
on individual women’s physical and
psychological health needs.
By MacArthur C, Winter HR,
Bick DE, Lilford RJ, Lancashire RJ,
Knowles H, et al.
No. 38
Estimating implied rates of discount in
healthcare decision-making.
By West RR, McNabb R, Thompson
AGH, Sheldon TA, Grimley Evans J.
No. 39
Systematic review of isolation policies
in the hospital management of
methicillin-resistant Staphylococcus
aureus: a review of the literature
with epidemiological and economic
modelling.
By Cooper BS, Stone SP, Kibbler CC,
Cookson BD, Roberts JA, Medley GF,
et al.
116
Volume 8, 2004
No. 1
What is the best imaging strategy for
acute stroke?
By Wardlaw JM, Keir SL, Seymour J,
Lewis S, Sandercock PAG, Dennis MS,
et al.
No. 10
A systematic review and economic
evaluation of magnetic resonance
cholangiopancreatography compared
with diagnostic endoscopic retrograde
cholangiopancreatography.
By Kaltenthaler E, Bravo Vergel Y,
Chilcott J, Thomas S, Blakeborough T,
Walters SJ, et al.
No. 2
Systematic review and modelling of the
investigation of acute and chronic chest
pain presenting in primary care.
By Mant J, McManus RJ, Oakes RAL,
Delaney BC, Barton PM, Deeks JJ, et al.
No. 11
The use of modelling to evaluate
new drugs for patients with a chronic
condition: the case of antibodies
against tumour necrosis factor in
rheumatoid arthritis.
By Barton P, Jobanputra P, Wilson J,
Bryan S, Burls A.
No. 3
The effectiveness and cost-effectiveness
of microwave and thermal balloon
endometrial ablation for heavy
menstrual bleeding: a systematic review
and economic modelling.
By Garside R, Stein K, Wyatt K,
Round A, Price A.
No. 12
Clinical effectiveness and costeffectiveness of neonatal screening
for inborn errors of metabolism using
tandem mass spectrometry: a systematic
review.
By Pandor A, Eastham J, Beverley C,
Chilcott J, Paisley S.
No. 4
A systematic review of the role of
bisphosphonates in metastatic disease.
By Ross JR, Saunders Y,
Edmonds PM, Patel S, Wonderling D,
Normand C, et al.
No. 5
Systematic review of the clinical
effectiveness and cost-effectiveness
of capecitabine (Xeloda®) for locally
advanced and/or metastatic breast
cancer.
By Jones L, Hawkins N, Westwood M,
Wright K, Richardson G, Riemsma R.
No. 6
Effectiveness and efficiency of guideline
dissemination and implementation
strategies.
By Grimshaw JM, Thomas RE,
MacLennan G, Fraser C, Ramsay CR,
Vale L, et al.
No. 40
Treatments for spasticity and pain in
multiple sclerosis: a systematic review.
By Beard S, Hunn A, Wight J.
No. 7
Clinical effectiveness and costs of the
Sugarbaker procedure for the treatment
of pseudomyxoma peritonei.
By Bryant J, Clegg AJ, Sidhu MK,
Brodin H, Royle P, Davidson P.
No. 41
The inclusion of reports of randomised
trials published in languages other than
English in systematic reviews.
By Moher D, Pham B, Lawson ML,
Klassen TP.
No. 8
Psychological treatment for insomnia
in the regulation of long-term hypnotic
drug use.
By Morgan K, Dixon S, Mathers N,
Thompson J, Tomeny M.
No. 42
The impact of screening on future
health-promoting behaviours and
health beliefs: a systematic review.
By Bankhead CR, Brett J, Bukach C,
Webster P, Stewart-Brown S, Munafo M,
et al.
No. 9
Improving the evaluation of
therapeutic interventions in multiple
sclerosis: development of a patientbased measure of outcome.
By Hobart JC, Riazi A, Lamping DL,
Fitzpatrick R, Thompson AJ.
No. 13
Clinical effectiveness and costeffectiveness of pioglitazone and
rosiglitazone in the treatment of type
2 diabetes: a systematic review and
economic evaluation.
By Czoski-Murray C, Warren E,
Chilcott J, Beverley C, Psyllaki MA,
Cowan J.
No. 14
Routine examination of the newborn:
the EMREN study. Evaluation of an
extension of the midwife role including
a randomised controlled trial of
appropriately trained midwives and
paediatric senior house officers.
By Townsend J, Wolke D, Hayes J,
Davé S, Rogers C, Bloomfield L, et al.
No. 15
Involving consumers in research and
development agenda setting for the
NHS: developing an evidence-based
approach.
By Oliver S, Clarke-Jones L, Rees R,
Milne R, Buchanan P, Gabbay J, et al.
No. 16
A multi-centre randomised controlled
trial of minimally invasive direct
coronary bypass grafting versus
percutaneous transluminal coronary
angioplasty with stenting for proximal
stenosis of the left anterior descending
coronary artery.
By Reeves BC, Angelini GD, Bryan
AJ, Taylor FC, Cripps T, Spyt TJ, et al.
No. 17
Does early magnetic resonance imaging
influence management or improve
outcome in patients referred to
secondary care with low back pain? A
pragmatic randomised controlled trial.
By Gilbert FJ, Grant AM, Gillan
MGC, Vale L, Scott NW, Campbell MK,
et al.
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
No. 18
The clinical and cost-effectiveness
of anakinra for the treatment of
rheumatoid arthritis in adults: a
systematic review and economic
analysis.
By Clark W, Jobanputra P, Barton P,
Burls A.
No. 27
Methods for expected value of
information analysis in complex health
economic models: developments on
the health economics of interferon-β
and glatiramer acetate for multiple
sclerosis.
By Tappenden P, Chilcott JB,
Eggington S, Oakley J, McCabe C.
No. 19
A rapid and systematic review and
economic evaluation of the clinical
and cost-effectiveness of newer drugs
for treatment of mania associated with
bipolar affective disorder.
By Bridle C, Palmer S, Bagnall A-M,
Darba J, Duffy S, Sculpher M, et al.
No. 28
Effectiveness and cost-effectiveness
of imatinib for first-line treatment
of chronic myeloid leukaemia in
chronic phase: a systematic review and
economic analysis.
By Dalziel K, Round A, Stein K,
Garside R, Price A.
No. 20
Liquid-based cytology in cervical
screening: an updated rapid and
systematic review and economic
analysis.
By Karnon J, Peters J, Platt J,
Chilcott J, McGoogan E, Brewer N.
No. 29
VenUS I: a randomised controlled trial
of two types of bandage for treating
venous leg ulcers.
By Iglesias C, Nelson EA, Cullum
NA, Torgerson DJ, on behalf of the
VenUS Team.
No. 21
Systematic review of the long-term
effects and economic consequences of
treatments for obesity and implications
for health improvement.
By Avenell A, Broom J, Brown TJ,
Poobalan A, Aucott L, Stearns SC, et al.
No. 30
Systematic review of the effectiveness
and cost-effectiveness, and economic
evaluation, of myocardial perfusion
scintigraphy for the diagnosis and
management of angina and myocardial
infarction.
By Mowatt G, Vale L, Brazzelli M,
Hernandez R, Murray A, Scott N, et al.
No. 22
Autoantibody testing in children
with newly diagnosed type 1 diabetes
mellitus.
By Dretzke J, Cummins C,
Sandercock J, Fry-Smith A, Barrett T,
Burls A.
No. 23
Clinical effectiveness and costeffectiveness of prehospital intravenous
fluids in trauma patients.
By Dretzke J, Sandercock J, Bayliss
S, Burls A.
No. 24
Newer hypnotic drugs for the shortterm management of insomnia: a
systematic review and economic
evaluation.
By Dündar Y, Boland A, Strobl J,
Dodd S, Haycox A, Bagust A, et al.
No. 25
Development and validation of
methods for assessing the quality of
diagnostic accuracy studies.
By Whiting P, Rutjes AWS, Dinnes J,
Reitsma JB, Bossuyt PMM, Kleijnen J.
No. 26
EVALUATE hysterectomy trial:
a multicentre randomised trial
comparing abdominal, vaginal and
laparoscopic methods of hysterectomy.
By Garry R, Fountain J, Brown J,
Manca A, Mason S, Sculpher M, et al.
No. 31
A pilot study on the use of decision
theory and value of information
analysis as part of the NHS Health
Technology Assessment programme.
By Claxton K, Ginnelly L, Sculpher
M, Philips Z, Palmer S.
No. 32
The Social Support and Family Health
Study: a randomised controlled trial
and economic evaluation of two
alternative forms of postnatal support
for mothers living in disadvantaged
inner-city areas.
By Wiggins M, Oakley A, Roberts I,
Turner H, Rajan L, Austerberry H, et al.
No. 33
Psychosocial aspects of genetic
screening of pregnant women and
newborns: a systematic review.
By Green JM, Hewison J, Bekker HL,
Bryant LD, Cuckle HS.
No. 34
Evaluation of abnormal uterine
bleeding: comparison of three
outpatient procedures within cohorts
defined by age and menopausal status.
By Critchley HOD, Warner P, Lee AJ,
Brechin S, Guise J, Graham B.
No. 35
Coronary artery stents: a rapid
systematic review and economic
evaluation.
By Hill R, Bagust A, Bakhai A,
Dickson R, Dündar Y, Haycox A, et al.
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
No. 36
Review of guidelines for good practice
in decision-analytic modelling in health
technology assessment.
By Philips Z, Ginnelly L, Sculpher M,
Claxton K, Golder S, Riemsma R, et al.
No. 37
Rituximab (MabThera®) for aggressive
non-Hodgkin’s lymphoma: systematic
review and economic evaluation.
By Knight C, Hind D, Brewer N,
Abbott V.
No. 38
Clinical effectiveness and costeffectiveness of clopidogrel and
modified-release dipyridamole in the
secondary prevention of occlusive
vascular events: a systematic review and
economic evaluation.
By Jones L, Griffin S, Palmer S, Main
C, Orton V, Sculpher M, et al.
No. 39
Pegylated interferon α-2a and -2b
in combination with ribavirin in the
treatment of chronic hepatitis C:
a systematic review and economic
evaluation.
By Shepherd J, Brodin H, Cave C,
Waugh N, Price A, Gabbay J.
No. 40
Clopidogrel used in combination with
aspirin compared with aspirin alone
in the treatment of non-ST-segmentelevation acute coronary syndromes:
a systematic review and economic
evaluation.
By Main C, Palmer S, Griffin S, Jones
L, Orton V, Sculpher M, et al.
No. 41
Provision, uptake and cost of cardiac
rehabilitation programmes: improving
services to under-represented groups.
By Beswick AD, Rees K, Griebsch I,
Taylor FC, Burke M, West RR, et al.
No. 42
Involving South Asian patients in
clinical trials.
By Hussain-Gambles M, Leese B,
Atkin K, Brown J, Mason S, Tovey P.
No. 43
Clinical and cost-effectiveness of
continuous subcutaneous insulin
infusion for diabetes.
By Colquitt JL, Green C, Sidhu MK,
Hartwell D, Waugh N.
No. 44
Identification and assessment of
ongoing trials in health technology
assessment reviews.
By Song FJ, Fry-Smith A, Davenport
C, Bayliss S, Adi Y, Wilson JS, et al.
No. 45
Systematic review and economic
evaluation of a long-acting insulin
analogue, insulin glargine
By Warren E, Weatherley-Jones E,
Chilcott J, Beverley C.
117
Health Technology Assessment reports published to date
No. 46
Supplementation of a home-based
exercise programme with a classbased programme for people
with osteoarthritis of the knees: a
randomised controlled trial and health
economic analysis.
By McCarthy CJ, Mills PM, Pullen R,
Richardson G, Hawkins N, Roberts CR,
et al.
No. 47
Clinical and cost-effectiveness of oncedaily versus more frequent use of same
potency topical corticosteroids for
atopic eczema: a systematic review and
economic evaluation.
By Green C, Colquitt JL, Kirby J,
Davidson P, Payne E.
No. 48
Acupuncture of chronic headache
disorders in primary care: randomised
controlled trial and economic analysis.
By Vickers AJ, Rees RW, Zollman CE,
McCarney R, Smith CM, Ellis N, et al.
No. 49
Generalisability in economic evaluation
studies in healthcare: a review and case
studies.
By Sculpher MJ, Pang FS, Manca A,
Drummond MF, Golder S, Urdahl H,
et al.
No. 50
Virtual outreach: a randomised
controlled trial and economic
evaluation of joint teleconferenced
medical consultations.
By Wallace P, Barber J, Clayton W,
Currell R, Fleming K, Garner P, et al.
Volume 9, 2005
118
No. 4
Randomised evaluation of alternative
electrosurgical modalities to treat
bladder outflow obstruction in men
with benign prostatic hyperplasia.
By Fowler C, McAllister W, Plail R,
Karim O, Yang Q.
No. 13
Cervical screening programmes: can
automation help? Evidence from
systematic reviews, an economic
analysis and a simulation modelling
exercise applied to the UK.
By Willis BH, Barton P, Pearmain P,
Bryan S, Hyde C.
No. 5
A pragmatic randomised controlled
trial of the cost-effectiveness of
palliative therapies for patients with
inoperable oesophageal cancer.
By Shenfine J, McNamee P, Steen N,
Bond J, Griffin SM.
No. 14
Laparoscopic surgery for inguinal
hernia repair: systematic review of
effectiveness and economic evaluation.
By McCormack K, Wake B, Perez J,
Fraser C, Cook J, McIntosh E, et al.
No. 6
Impact of computer-aided detection
prompts on the sensitivity and
specificity of screening mammography.
By Taylor P, Champness J, GivenWilson R, Johnston K, Potts H.
No. 7
Issues in data monitoring and interim
analysis of trials.
By Grant AM, Altman DG, Babiker
AB, Campbell MK, Clemens FJ,
Darbyshire JH, et al.
No. 8
Lay public’s understanding of equipoise
and randomisation in randomised
controlled trials.
By Robinson EJ, Kerr CEP,
Stevens AJ, Lilford RJ, Braunholtz DA,
Edwards SJ, et al.
No. 9
Clinical and cost-effectiveness of
electroconvulsive therapy for depressive
illness, schizophrenia, catatonia
and mania: systematic reviews and
economic modelling studies.
By Greenhalgh J, Knight C, Hind D,
Beverley C, Walters S.
No. 15
Clinical effectiveness, tolerability and
cost-effectiveness of newer drugs for
epilepsy in adults: a systematic review
and economic evaluation.
By Wilby J, Kainth A, Hawkins N,
Epstein D, McIntosh H, McDaid C, et al.
No. 16
A randomised controlled trial to
compare the cost-effectiveness of
tricyclic antidepressants, selective
serotonin reuptake inhibitors and
lofepramine.
By Peveler R, Kendrick T, Buxton M,
Longworth L, Baldwin D, Moore M, et al.
No. 17
Clinical effectiveness and costeffectiveness of immediate angioplasty
for acute myocardial infarction:
systematic review and economic
evaluation.
By Hartwell D, Colquitt J, Loveman
E, Clegg AJ, Brodin H, Waugh N, et al.
No. 18
A randomised controlled comparison of
alternative strategies in stroke care.
By Kalra L, Evans A, Perez I,
Knapp M, Swift C, Donaldson N.
No. 19
The investigation and analysis of
critical incidents and adverse events in
healthcare.
By Woloshynowych M, Rogers S,
Taylor-Adams S, Vincent C.
No. 1
Randomised controlled multiple
treatment comparison to provide a costeffectiveness rationale for the selection
of antimicrobial therapy in acne.
By Ozolins M, Eady EA, Avery A,
Cunliffe WJ, O’Neill C, Simpson NB,
et al.
No. 10
Measurement of health-related quality
of life for people with dementia:
development of a new instrument
(DEMQOL) and an evaluation of
current methodology.
By Smith SC, Lamping DL, Banerjee
S, Harwood R, Foley B, Smith P, et al.
No. 2
Do the findings of case series studies
vary significantly according to
methodological characteristics?
By Dalziel K, Round A, Stein K,
Garside R, Castelnuovo E, Payne L.
No. 11
Clinical effectiveness and costeffectiveness of drotrecogin alfa
(activated) (Xigris®) for the treatment
of severe sepsis in adults: a systematic
review and economic evaluation.
By Green C, Dinnes J, Takeda A,
Shepherd J, Hartwell D, Cave C, et al.
No. 21
Clinical and cost-effectiveness of newer
immunosuppressive regimens in renal
transplantation: a systematic review and
modelling study.
By Woodroffe R, Yao GL, Meads C,
Bayliss S, Ready A, Raftery J, et al.
No. 12
A methodological review of how
heterogeneity has been examined in
systematic reviews of diagnostic test
accuracy.
By Dinnes J, Deeks J, Kirby J,
Roderick P.
No. 22
A systematic review and economic
evaluation of alendronate, etidronate,
risedronate, raloxifene and teriparatide
for the prevention and treatment of
postmenopausal osteoporosis.
By Stevenson M, Lloyd Jones M, De
Nigris E, Brewer N, Davis S, Oakley J.
No. 3
Improving the referral process
for familial breast cancer genetic
counselling: findings of three
randomised controlled trials of two
interventions.
By Wilson BJ, Torrance N,
Mollison J, Wordsworth S, Gray JR,
Haites NE, et al.
No. 20
Potential use of routine databases in
health technology assessment.
By Raftery J, Roderick P, Stevens A.
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
No. 23
A systematic review to examine
the impact of psycho-educational
interventions on health outcomes
and costs in adults and children with
difficult asthma.
By Smith JR, Mugford M, Holland
R, Candy B, Noble MJ, Harrison BDW,
et al.
No. 32
No. 24
An evaluation of the costs, effectiveness
and quality of renal replacement
therapy provision in renal satellite units
in England and Wales.
By Roderick P, Nicholson T, Armitage
A, Mehta R, Mullee M, Gerard K, et al.
Cost-effectiveness and safety of
epidural steroids in the management
of sciatica.
No. 25
Imatinib for the treatment of patients
with unresectable and/or metastatic
gastrointestinal stromal tumours:
systematic review and economic
evaluation.
By Wilson J, Connock M, Song F,
Yao G, Fry-Smith A, Raftery J, et al.
No. 26
Indirect comparisons of competing
interventions.
By Glenny AM, Altman DG, Song F,
Sakarovitch C, Deeks JJ, D’Amico R,
et al.
No. 27
Cost-effectiveness of alternative
strategies for the initial medical
management of non-ST elevation acute
coronary syndrome: systematic review
and decision-analytical modelling.
By Robinson M, Palmer S, Sculpher
M, Philips Z, Ginnelly L, Bowens A, et al.
No. 28
Outcomes of electrically stimulated
gracilis neosphincter surgery.
By Tillin T, Chambers M, Feldman R.
No. 29
The effectiveness and cost-effectiveness
of pimecrolimus and tacrolimus for
atopic eczema: a systematic review and
economic evaluation.
By Garside R, Stein K, Castelnuovo
E, Pitt M, Ashcroft D, Dimmock P, et al.
No. 30
Systematic review on urine albumin
testing for early detection of diabetic
complications.
By Newman DJ, Mattock MB,
Dawnay ABS, Kerry S, McGuire A,
Yaqoob M, et al.
No. 31
Randomised controlled trial of the costeffectiveness of water-based therapy for
lower limb osteoarthritis.
By Cochrane T, Davey RC,
Matthes Edwards SM.
Longer term clinical and economic
benefits of offering acupuncture care to
patients with chronic low back pain.
By Thomas KJ, MacPherson
H, Ratcliffe J, Thorpe L, Brazier J,
Campbell M, et al.
No. 33
By Price C, Arden N, Coglan L,
Rogers P.
No. 34
The British Rheumatoid Outcome
Study Group (BROSG) randomised
controlled trial to compare the
effectiveness and cost-effectiveness of
aggressive versus symptomatic therapy
in established rheumatoid arthritis.
By Symmons D, Tricker K, Roberts C,
Davies L, Dawes P, Scott DL.
No. 35
Conceptual framework and systematic
review of the effects of participants’
and professionals’ preferences in
randomised controlled trials.
By King M, Nazareth I, Lampe F,
Bower P, Chandler M, Morou M, et al.
No. 36
The clinical and cost-effectiveness of
implantable cardioverter defibrillators:
a systematic review.
By Bryant J, Brodin H, Loveman E,
Payne E, Clegg A.
No. 37
A trial of problem-solving by
community mental health nurses for
anxiety, depression and life difficulties
among general practice patients. The
CPN-GP study.
By Kendrick T, Simons L,
Mynors-Wallis L, Gray A, Lathlean J,
Pickering R, et al.
No. 38
The causes and effects of sociodemographic exclusions from clinical
trials.
By Bartlett C, Doyal L, Ebrahim S,
Davey P, Bachmann M, Egger M, et al.
No. 39
Is hydrotherapy cost-effective?
A randomised controlled trial of
combined hydrotherapy programmes
compared with physiotherapy land
techniques in children with juvenile
idiopathic arthritis.
By Epps H, Ginnelly L, Utley M,
Southwood T, Gallivan S, Sculpher M,
et al.
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
No. 40
A randomised controlled trial and
cost-effectiveness study of systematic
screening (targeted and total
population screening) versus routine
practice for the detection of atrial
fibrillation in people aged 65 and over.
The SAFE study.
By Hobbs FDR, Fitzmaurice DA,
Mant J, Murray E, Jowett S, Bryan S,
et al.
No. 41
Displaced intracapsular hip fractures
in fit, older people: a randomised
comparison of reduction and fixation,
bipolar hemiarthroplasty and total hip
arthroplasty.
By Keating JF, Grant A, Masson M,
Scott NW, Forbes JF.
No. 42
Long-term outcome of cognitive
behaviour therapy clinical trials in
central Scotland.
By Durham RC, Chambers JA,
Power KG, Sharp DM, Macdonald RR,
Major KA, et al.
No. 43
The effectiveness and cost-effectiveness
of dual-chamber pacemakers compared
with single-chamber pacemakers for
bradycardia due to atrioventricular
block or sick sinus syndrome: systematic
review and economic evaluation.
By Castelnuovo E, Stein K, Pitt M,
Garside R, Payne E.
No. 44
Newborn screening for congenital heart
defects: a systematic review and costeffectiveness analysis.
By Knowles R, Griebsch I,
Dezateux C, Brown J, Bull C, Wren C.
No. 45
The clinical and cost-effectiveness of
left ventricular assist devices for endstage heart failure: a systematic review
and economic evaluation.
By Clegg AJ, Scott DA, Loveman E,
Colquitt J, Hutchinson J, Royle P, et al.
No. 46
The effectiveness of the Heidelberg
Retina Tomograph and laser diagnostic
glaucoma scanning system (GDx) in
detecting and monitoring glaucoma.
By Kwartz AJ, Henson DB, Harper
RA, Spencer AF, McLeod D.
No. 47
Clinical and cost-effectiveness of
autologous chondrocyte implantation
for cartilage defects in knee joints:
systematic review and economic
evaluation.
By Clar C, Cummins E, McIntyre L,
Thomas S, Lamb J, Bain L, et al.
119
Health Technology Assessment reports published to date
No. 48
Systematic review of effectiveness of
different treatments for childhood
retinoblastoma.
By McDaid C, Hartley S, Bagnall
A-M, Ritchie G, Light K, Riemsma R.
No. 49
Towards evidence-based guidelines
for the prevention of venous
thromboembolism: systematic
reviews of mechanical methods, oral
anticoagulation, dextran and regional
anaesthesia as thromboprophylaxis.
By Roderick P, Ferris G, Wilson K,
Halls H, Jackson D, Collins R, et al.
No. 50
The effectiveness and cost-effectiveness
of parent training/education
programmes for the treatment
of conduct disorder, including
oppositional defiant disorder, in
children.
By Dretzke J, Frew E, Davenport C,
Barlow J, Stewart-Brown S, Sandercock J,
et al.
Volume 10, 2006
No. 1
The clinical and cost-effectiveness of
donepezil, rivastigmine, galantamine
and memantine for Alzheimer’s
disease.
By Loveman E, Green C, Kirby J,
Takeda A, Picot J, Payne E, et al.
No. 2
FOOD: a multicentre randomised trial
evaluating feeding policies in patients
admitted to hospital with a recent
stroke.
By Dennis M, Lewis S, Cranswick G,
Forbes J.
No. 3
The clinical effectiveness and costeffectiveness of computed tomography
screening for lung cancer: systematic
reviews.
By Black C, Bagust A, Boland A,
Walker S, McLeod C, De Verteuil R, et al.
No. 4
A systematic review of the effectiveness
and cost-effectiveness of neuroimaging
assessments used to visualise the seizure
focus in people with refractory epilepsy
being considered for surgery.
By Whiting P, Gupta R, Burch J,
Mujica Mota RE, Wright K, Marson A,
et al.
120
No. 5
Comparison of conference abstracts
and presentations with full-text articles
in the health technology assessments of
rapidly evolving technologies.
By Dundar Y, Dodd S, Dickson R,
Walley T, Haycox A, Williamson PR.
No. 6
Systematic review and evaluation
of methods of assessing urinary
incontinence.
By Martin JL, Williams KS, Abrams
KR, Turner DA, Sutton AJ, Chapple C,
et al.
No. 7
The clinical effectiveness and costeffectiveness of newer drugs for
children with epilepsy. A systematic
review.
By Connock M, Frew E, Evans B-W,
Bryan S, Cummins C, Fry-Smith A, et al.
No. 8
Surveillance of Barrett’s oesophagus:
exploring the uncertainty through
systematic review, expert workshop and
economic modelling.
By Garside R, Pitt M, Somerville M,
Stein K, Price A, Gilbert N.
No. 9
Topotecan, pegylated liposomal
doxorubicin hydrochloride and
paclitaxel for second-line or subsequent
treatment of advanced ovarian cancer:
a systematic review and economic
evaluation.
By Main C, Bojke L, Griffin S,
Norman G, Barbieri M, Mather L, et al.
No. 10
Evaluation of molecular techniques
in prediction and diagnosis
of cytomegalovirus disease in
immunocompromised patients.
By Szczepura A, Westmoreland D,
Vinogradova Y, Fox J, Clark M.
No. 11
Screening for thrombophilia in highrisk situations: systematic review
and cost-effectiveness analysis. The
Thrombosis: Risk and Economic
Assessment of Thrombophilia
Screening (TREATS) study.
By Wu O, Robertson L, Twaddle S,
Lowe GDO, Clark P, Greaves M, et al.
No. 15
Measurement of the clinical and costeffectiveness of non-invasive diagnostic
testing strategies for deep vein
thrombosis.
By Goodacre S, Sampson F,
Stevenson M, Wailoo A, Sutton A,
Thomas S, et al.
No. 16
Systematic review of the effectiveness
and cost-effectiveness of HealOzone®
for the treatment of occlusal pit/fissure
caries and root caries.
By Brazzelli M, McKenzie L, Fielding
S, Fraser C, Clarkson J, Kilonzo M, et al.
No. 17
Randomised controlled trials of
conventional antipsychotic versus
new atypical drugs, and new atypical
drugs versus clozapine, in people with
schizophrenia responding poorly to, or
intolerant of, current drug treatment.
By Lewis SW, Davies L, Jones PB,
Barnes TRE, Murray RM, Kerwin R,
et al.
No. 18
Diagnostic tests and algorithms used
in the investigation of haematuria:
systematic reviews and economic
evaluation.
By Rodgers M, Nixon J, Hempel S,
Aho T, Kelly J, Neal D, et al.
No. 19
Cognitive behavioural therapy in
addition to antispasmodic therapy for
irritable bowel syndrome in primary
care: randomised controlled trial.
By Kennedy TM, Chalder T,
McCrone P, Darnley S, Knapp M,
Jones RH, et al.
No. 12
A series of systematic reviews to inform
a decision analysis for sampling and
treating infected diabetic foot ulcers.
By Nelson EA, O’Meara S, Craig D,
Iglesias C, Golder S, Dalton J, et al.
No. 20
A systematic review of the
clinical effectiveness and costeffectiveness of enzyme replacement
therapies for Fabry’s disease and
mucopolysaccharidosis type 1.
By Connock M, Juarez-Garcia A,
Frew E, Mans A, Dretzke J, Fry-Smith A,
et al.
No. 13
Randomised clinical trial, observational
study and assessment of costeffectiveness of the treatment of
varicose veins (REACTIV trial).
By Michaels JA, Campbell WB,
Brazier JE, MacIntyre JB, Palfreyman SJ,
Ratcliffe J, et al.
No. 21
Health benefits of antiviral therapy for
mild chronic hepatitis C: randomised
controlled trial and economic
evaluation.
By Wright M, Grieve R, Roberts J,
Main J, Thomas HC, on behalf of the
UK Mild Hepatitis C Trial Investigators.
No. 14
The cost-effectiveness of screening for
oral cancer in primary care.
By Speight PM, Palmer S, Moles DR,
Downer MC, Smith DH, Henriksson M,
et al.
No. 22
Pressure relieving support surfaces: a
randomised evaluation.
By Nixon J, Nelson EA, Cranny G,
Iglesias CP, Hawkins K, Cullum NA, et al.
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
No. 23
A systematic review and economic
model of the effectiveness and costeffectiveness of methylphenidate,
dexamfetamine and atomoxetine
for the treatment of attention deficit
hyperactivity disorder in children and
adolescents.
By King S, Griffin S, Hodges Z,
Weatherly H, Asseburg C, Richardson G,
et al.
No. 24
The clinical effectiveness and costeffectiveness of enzyme replacement
therapy for Gaucher’s disease: a
systematic review.
By Connock M, Burls A, Frew E,
Fry-Smith A, Juarez-Garcia A, McCabe C,
et al.
No. 25
Effectiveness and cost-effectiveness
of salicylic acid and cryotherapy for
cutaneous warts. An economic decision
model.
By Thomas KS, Keogh-Brown MR,
Chalmers JR, Fordham RJ, Holland RC,
Armstrong SJ, et al.
No. 26
A systematic literature review of the
effectiveness of non-pharmacological
interventions to prevent wandering in
dementia and evaluation of the ethical
implications and acceptability of their
use.
By Robinson L, Hutchings D, Corner
L, Beyer F, Dickinson H, Vanoli A, et al.
No. 27
A review of the evidence on the effects
and costs of implantable cardioverter
defibrillator therapy in different
patient groups, and modelling of costeffectiveness and cost–utility for these
groups in a UK context.
By Buxton M, Caine N, Chase D,
Connelly D, Grace A, Jackson C, et al.
No. 31
Etanercept and infliximab for the
treatment of psoriatic arthritis: a
systematic review and economic
evaluation.
By Woolacott N, Bravo Vergel Y,
Hawkins N, Kainth A, Khadjesari Z,
Misso K, et al.
No. 32
The cost-effectiveness of testing for
hepatitis C in former injecting drug
users.
By Castelnuovo E, Thompson-Coon
J, Pitt M, Cramp M, Siebert U, Price A,
et al.
No. 33
Computerised cognitive behaviour
therapy for depression and anxiety
update: a systematic review and
economic evaluation.
By Kaltenthaler E, Brazier J,
De Nigris E, Tumur I, Ferriter M,
Beverley C, et al.
No. 34
Cost-effectiveness of using prognostic
information to select women with breast
cancer for adjuvant systemic therapy.
By Williams C, Brunskill S, Altman D,
Briggs A, Campbell H, Clarke M, et al.
No. 35
Psychological therapies including
dialectical behaviour therapy for
borderline personality disorder: a
systematic review and preliminary
economic evaluation.
By Brazier J, Tumur I, Holmes M,
Ferriter M, Parry G, Dent-Brown K, et al.
No. 36
Clinical effectiveness and costeffectiveness of tests for the diagnosis
and investigation of urinary tract
infection in children: a systematic
review and economic model.
By Whiting P, Westwood M, Bojke L,
Palmer S, Richardson G, Cooper J, et al.
No. 28
Adefovir dipivoxil and pegylated
interferon alfa-2a for the treatment of
chronic hepatitis B: a systematic review
and economic evaluation.
By Shepherd J, Jones J, Takeda A,
Davidson P, Price A.
No. 37
Cognitive behavioural therapy
in chronic fatigue syndrome: a
randomised controlled trial of an
outpatient group programme.
By O’Dowd H, Gladwell P, Rogers
CA, Hollinghurst S, Gregory A.
No. 29
An evaluation of the clinical and costeffectiveness of pulmonary artery
catheters in patient management in
intensive care: a systematic review and a
randomised controlled trial.
By Harvey S, Stevens K, Harrison D,
Young D, Brampton W, McCabe C, et al.
No. 38
A comparison of the cost-effectiveness
of five strategies for the prevention
of nonsteroidal anti-inflammatory
drug-induced gastrointestinal toxicity:
a systematic review with economic
modelling.
By Brown TJ, Hooper L, Elliott RA,
Payne K, Webb R, Roberts C, et al.
No. 30
Accurate, practical and cost-effective
assessment of carotid stenosis in the
UK.
By Wardlaw JM, Chappell FM,
Stevenson M, De Nigris E, Thomas S,
Gillard J, et al.
No. 39
The effectiveness and cost-effectiveness
of computed tomography screening
for coronary artery disease: systematic
review.
By Waugh N, Black C, Walker S,
McIntyre L, Cummins E, Hillis G.
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
No. 40
What are the clinical outcome and costeffectiveness of endoscopy undertaken
by nurses when compared with doctors?
A Multi-Institution Nurse Endoscopy
Trial (MINuET).
By Williams J, Russell I, Durai D,
Cheung W-Y, Farrin A, Bloor K, et al.
No. 41
The clinical and cost-effectiveness of
oxaliplatin and capecitabine for the
adjuvant treatment of colon cancer:
systematic review and economic
evaluation.
By Pandor A, Eggington S, Paisley S,
Tappenden P, Sutcliffe P.
No. 42
A systematic review of the effectiveness
of adalimumab, etanercept and
infliximab for the treatment of
rheumatoid arthritis in adults and
an economic evaluation of their costeffectiveness.
By Chen Y-F, Jobanputra P, Barton P,
Jowett S, Bryan S, Clark W, et al.
No. 43
Telemedicine in dermatology: a
randomised controlled trial.
By Bowns IR, Collins K, Walters SJ,
McDonagh AJG.
No. 44
Cost-effectiveness of cell salvage and
alternative methods of minimising
perioperative allogeneic blood
transfusion: a systematic review and
economic model.
By Davies L, Brown TJ, Haynes S,
Payne K, Elliott RA, McCollum C.
No. 45
Clinical effectiveness and costeffectiveness of laparoscopic surgery
for colorectal cancer: systematic reviews
and economic evaluation.
By Murray A, Lourenco T, de Verteuil
R, Hernandez R, Fraser C, McKinley A,
et al.
No. 46
Etanercept and efalizumab for the
treatment of psoriasis: a systematic
review.
By Woolacott N, Hawkins N,
Mason A, Kainth A, Khadjesari Z, Bravo
Vergel Y, et al.
No. 47
Systematic reviews of clinical decision
tools for acute abdominal pain.
By Liu JLY, Wyatt JC, Deeks JJ,
Clamp S, Keen J, Verde P, et al.
No. 48
Evaluation of the ventricular assist
device programme in the UK.
By Sharples L, Buxton M, Caine N,
Cafferty F, Demiris N, Dyer M, et al.
121
Health Technology Assessment reports published to date
No. 49
A systematic review and economic
model of the clinical and costeffectiveness of immunosuppressive
therapy for renal transplantation in
children.
By Yao G, Albon E, Adi Y, Milford D,
Bayliss S, Ready A, et al.
No. 50
Amniocentesis results: investigation of
anxiety. The ARIA trial.
By Hewison J, Nixon J, Fountain J,
Cocks K, Jones C, Mason G, et al.
Volume 11, 2007
No. 1
Pemetrexed disodium for the treatment
of malignant pleural mesothelioma:
a systematic review and economic
evaluation.
By Dundar Y, Bagust A, Dickson R,
Dodd S, Green J, Haycox A, et al.
No. 2
A systematic review and economic
model of the clinical effectiveness
and cost-effectiveness of docetaxel
in combination with prednisone or
prednisolone for the treatment of
hormone-refractory metastatic prostate
cancer.
By Collins R, Fenwick E, Trowman R,
Perard R, Norman G, Light K, et al.
No. 3
A systematic review of rapid diagnostic
tests for the detection of tuberculosis
infection.
By Dinnes J, Deeks J, Kunst H,
Gibson A, Cummins E, Waugh N, et al.
No. 4
The clinical effectiveness and costeffectiveness of strontium ranelate for
the prevention of osteoporotic fragility
fractures in postmenopausal women.
By Stevenson M, Davis S, Lloyd-Jones
M, Beverley C.
No. 5
A systematic review of quantitative and
qualitative research on the role and
effectiveness of written information
available to patients about individual
medicines.
By Raynor DK, Blenkinsopp
A, Knapp P, Grime J, Nicolson DJ,
Pollock K, et al.
122
No. 6
Oral naltrexone as a treatment for
relapse prevention in formerly opioiddependent drug users: a systematic
review and economic evaluation.
By Adi Y, Juarez-Garcia A, Wang D,
Jowett S, Frew E, Day E, et al.
No. 7
Glucocorticoid-induced osteoporosis:
a systematic review and cost–utility
analysis.
By Kanis JA, Stevenson M,
McCloskey EV, Davis S, Lloyd-Jones M.
No. 8
Epidemiological, social, diagnostic and
economic evaluation of population
screening for genital chlamydial
infection.
By Low N, McCarthy A, Macleod J,
Salisbury C, Campbell R, Roberts TE,
et al.
No. 9
Methadone and buprenorphine for the
management of opioid dependence:
a systematic review and economic
evaluation.
By Connock M, Juarez-Garcia A,
Jowett S, Frew E, Liu Z, Taylor RJ, et al.
No. 10
Exercise Evaluation Randomised
Trial (EXERT): a randomised trial
comparing GP referral for leisure
centre-based exercise, community-based
walking and advice only.
By Isaacs AJ, Critchley JA, See Tai
S, Buckingham K, Westley D, Harridge
SDR, et al.
No. 11
Interferon alfa (pegylated and nonpegylated) and ribavirin for the
treatment of mild chronic hepatitis
C: a systematic review and economic
evaluation.
By Shepherd J, Jones J, Hartwell D,
Davidson P, Price A, Waugh N.
No. 12
Systematic review and economic
evaluation of bevacizumab and
cetuximab for the treatment of
metastatic colorectal cancer.
By Tappenden P, Jones R, Paisley S,
Carroll C.
No. 13
A systematic review and economic
evaluation of epoetin alfa, epoetin
beta and darbepoetin alfa in anaemia
associated with cancer, especially that
attributable to cancer treatment.
By Wilson J, Yao GL, Raftery J,
Bohlius J, Brunskill S, Sandercock J,
et al.
No. 14
A systematic review and economic
evaluation of statins for the prevention
of coronary events.
By Ward S, Lloyd Jones M, Pandor A,
Holmes M, Ara R, Ryan A, et al.
No. 15
A systematic review of the effectiveness
and cost-effectiveness of different
models of community-based respite
care for frail older people and their
carers.
By Mason A, Weatherly H, Spilsbury
K, Arksey H, Golder S, Adamson J, et al.
No. 16
Additional therapy for young
children with spastic cerebral palsy: a
randomised controlled trial.
By Weindling AM, Cunningham CC,
Glenn SM, Edwards RT, Reeves DJ.
No. 17
Screening for type 2 diabetes: literature
review and economic modelling.
By Waugh N, Scotland G, McNamee
P, Gillett M, Brennan A, Goyder E, et al.
No. 18
The effectiveness and cost-effectiveness
of cinacalcet for secondary
hyperparathyroidism in end-stage renal
disease patients on dialysis: a systematic
review and economic evaluation.
By Garside R, Pitt M, Anderson R,
Mealing S, Roome C, Snaith A, et al.
No. 19
The clinical effectiveness and costeffectiveness of gemcitabine for
metastatic breast cancer: a systematic
review and economic evaluation.
By Takeda AL, Jones J, Loveman E,
Tan SC, Clegg AJ.
No. 20
A systematic review of duplex
ultrasound, magnetic resonance
angiography and computed
tomography angiography for
the diagnosis and assessment of
symptomatic, lower limb peripheral
arterial disease.
By Collins R, Cranny G, Burch J,
Aguiar-Ibáñez R, Craig D, Wright K,
et al.
No. 21
The clinical effectiveness and costeffectiveness of treatments for children
with idiopathic steroid-resistant
nephrotic syndrome: a systematic
review.
By Colquitt JL, Kirby J, Green C,
Cooper K, Trompeter RS.
No. 22
A systematic review of the routine
monitoring of growth in children of
primary school age to identify growthrelated conditions.
By Fayter D, Nixon J, Hartley S,
Rithalia A, Butler G, Rudolf M, et al.
No. 23
Systematic review of the effectiveness of
preventing and treating Staphylococcus
aureus carriage in reducing peritoneal
catheter-related infections.
By McCormack K, Rabindranath K,
Kilonzo M, Vale L, Fraser C, McIntyre L,
et al.
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
No. 24
The clinical effectiveness and cost
of repetitive transcranial magnetic
stimulation versus electroconvulsive
therapy in severe depression: a
multicentre pragmatic randomised
controlled trial and economic analysis.
By McLoughlin DM, Mogg A, Eranti
S, Pluck G, Purvis R, Edwards D, et al.
No. 25
A randomised controlled trial and
economic evaluation of direct versus
indirect and individual versus group
modes of speech and language therapy
for children with primary language
impairment.
By Boyle J, McCartney E, Forbes J,
O’Hare A.
No. 26
Hormonal therapies for early breast
cancer: systematic review and economic
evaluation.
By Hind D, Ward S, De Nigris E,
Simpson E, Carroll C, Wyld L.
No. 27
Cardioprotection against the toxic
effects of anthracyclines given to
children with cancer: a systematic
review.
By Bryant J, Picot J, Levitt G,
Sullivan I, Baxter L, Clegg A.
No. 28
Adalimumab, etanercept and infliximab
for the treatment of ankylosing
spondylitis: a systematic review and
economic evaluation.
By McLeod C, Bagust A, Boland A,
Dagenais P, Dickson R, Dundar Y, et al.
No. 29
Prenatal screening and treatment
strategies to prevent group B
streptococcal and other bacterial
infections in early infancy: costeffectiveness and expected value of
information analyses.
By Colbourn T, Asseburg C, Bojke L,
Philips Z, Claxton K, Ades AE, et al.
No. 30
Clinical effectiveness and costeffectiveness of bone morphogenetic
proteins in the non-healing of fractures
and spinal fusion: a systematic review.
By Garrison KR, Donell S, Ryder J,
Shemilt I, Mugford M, Harvey I, et al.
No. 31
A randomised controlled trial of
postoperative radiotherapy following
breast-conserving surgery in a
minimum-risk older population. The
PRIME trial.
By Prescott RJ, Kunkler IH, Williams
LJ, King CC, Jack W, van der Pol M, et al.
No. 32
Current practice, accuracy, effectiveness
and cost-effectiveness of the school
entry hearing screen.
By Bamford J, Fortnum H, Bristow K,
Smith J, Vamvakas G, Davies L, et al.
No. 33
The clinical effectiveness and costeffectiveness of inhaled insulin in
diabetes mellitus: a systematic review
and economic evaluation.
By Black C, Cummins E, Royle P,
Philip S, Waugh N.
No. 41
The clinical effectiveness and costeffectiveness of screening for open
angle glaucoma: a systematic review
and economic evaluation.
By Burr JM, Mowatt G, Hernández
R, Siddiqui MAR, Cook J, Lourenco T,
et al.
No. 34
Surveillance of cirrhosis for
hepatocellular carcinoma: systematic
review and economic analysis.
By Thompson Coon J, Rogers G,
Hewson P, Wright D, Anderson R,
Cramp M, et al.
No. 42
Acceptability, benefit and costs of early
screening for hearing disability: a study
of potential screening tests and models.
By Davis A, Smith P, Ferguson M,
Stephens D, Gianopoulos I.
No. 35
The Birmingham Rehabilitation
Uptake Maximisation Study (BRUM).
Homebased compared with hospitalbased cardiac rehabilitation in a multiethnic population: cost-effectiveness
and patient adherence.
By Jolly K, Taylor R, Lip GYH,
Greenfield S, Raftery J, Mant J, et al.
No. 36
A systematic review of the clinical,
public health and cost-effectiveness of
rapid diagnostic tests for the detection
and identification of bacterial intestinal
pathogens in faeces and food.
By Abubakar I, Irvine L, Aldus CF,
Wyatt GM, Fordham R, Schelenz S, et al.
No. 37
A randomised controlled trial
examining the longer-term outcomes
of standard versus new antiepileptic
drugs. The SANAD trial.
By Marson AG, Appleton R, Baker
GA, Chadwick DW, Doughty J, Eaton B,
et al.
No. 38
Clinical effectiveness and costeffectiveness of different models
of managing long-term oral anticoagulation therapy: a systematic
review and economic modelling.
By Connock M, Stevens C, Fry-Smith
A, Jowett S, Fitzmaurice D, Moore D,
et al.
No. 39
A systematic review and economic
model of the clinical effectiveness
and cost-effectiveness of interventions
for preventing relapse in people with
bipolar disorder.
By Soares-Weiser K, Bravo Vergel Y,
Beynon S, Dunn G, Barbieri M, Duffy S,
et al.
No. 40
Taxanes for the adjuvant treatment of
early breast cancer: systematic review
and economic evaluation.
By Ward S, Simpson E, Davis S, Hind
D, Rees A, Wilkinson A.
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
No. 43
Contamination in trials of educational
interventions.
By Keogh-Brown MR, Bachmann
MO, Shepstone L, Hewitt C, Howe A,
Ramsay CR, et al.
No. 44
Overview of the clinical effectiveness of
positron emission tomography imaging
in selected cancers.
By Facey K, Bradbury I, Laking G,
Payne E.
No. 45
The effectiveness and cost-effectiveness
of carmustine implants and
temozolomide for the treatment of
newly diagnosed high-grade glioma:
a systematic review and economic
evaluation.
By Garside R, Pitt M, Anderson R,
Rogers G, Dyer M, Mealing S, et al.
No. 46
Drug-eluting stents: a systematic review
and economic evaluation.
By Hill RA, Boland A, Dickson R,
Dündar Y, Haycox A, McLeod C, et al.
No. 47
The clinical effectiveness and
cost-effectiveness of cardiac
resynchronisation (biventricular pacing)
for heart failure: systematic review and
economic model.
By Fox M, Mealing S, Anderson R,
Dean J, Stein K, Price A, et al.
No. 48
Recruitment to randomised trials:
strategies for trial enrolment and
participation study. The STEPS study.
By Campbell MK, Snowdon C,
Francis D, Elbourne D, McDonald AM,
Knight R, et al.
No. 49
Cost-effectiveness of functional
cardiac testing in the diagnosis and
management of coronary artery
disease: a randomised controlled trial.
The CECaT trial.
By Sharples L, Hughes V, Crean A,
Dyer M, Buxton M, Goldsmith K, et al.
123
Health Technology Assessment reports published to date
No. 50
Evaluation of diagnostic tests when
there is no gold standard. A review of
methods.
By Rutjes AWS, Reitsma
JB, Coomarasamy A, Khan KS,
Bossuyt PMM.
No. 51
Systematic reviews of the clinical
effectiveness and cost-effectiveness of
proton pump inhibitors in acute upper
gastrointestinal bleeding.
By Leontiadis GI, Sreedharan A,
Dorward S, Barton P, Delaney B, Howden
CW, et al.
No. 6
Methods of prediction and prevention
of pre-eclampsia: systematic reviews of
accuracy and effectiveness literature
with economic modelling.
By Meads CA, Cnossen JS, Meher S,
Juarez-Garcia A, ter Riet G, Duley L, et al.
No. 52
A review and critique of modelling in
prioritising and designing screening
programmes.
By Karnon J, Goyder E, Tappenden P,
McPhie S, Towers I, Brazier J, et al.
No. 7
The use of economic evaluations in
NHS decision-making: a review and
empirical investigation.
By Williams I, McIver S, Moore D,
Bryan S.
No. 53
An assessment of the impact of the
NHS Health Technology Assessment
Programme.
By Hanney S, Buxton M, Green C,
Coulson D, Raftery J.
No. 8
Stapled haemorrhoidectomy
(haemorrhoidopexy) for the treatment
of haemorrhoids: a systematic review
and economic evaluation.
By Burch J, Epstein D, Baba-Akbari
A, Weatherly H, Fox D, Golder S, et al.
Volume 12, 2008
No. 1
A systematic review and economic
model of switching from
nonglycopeptide to glycopeptide
antibiotic prophylaxis for surgery.
By Cranny G, Elliott R, Weatherly H,
Chambers D, Hawkins N, Myers L, et al.
No. 2
‘Cut down to quit’ with nicotine
replacement therapies in smoking
cessation: a systematic review of
effectiveness and economic analysis.
By Wang D, Connock M, Barton P,
Fry-Smith A, Aveyard P, Moore D.
No. 3
A systematic review of the effectiveness
of strategies for reducing fracture risk
in children with juvenile idiopathic
arthritis with additional data on longterm risk of fracture and cost of disease
management.
By Thornton J, Ashcroft D, O’Neill T,
Elliott R, Adams J, Roberts C, et al.
124
No. 5
A multi-centre retrospective cohort
study comparing the efficacy, safety
and cost-effectiveness of hysterectomy
and uterine artery embolisation for
the treatment of symptomatic uterine
fibroids. The HOPEFUL study.
By Hirst A, Dutton S, Wu O, Briggs A,
Edwards C, Waldenmaier L, et al.
No. 4
Does befriending by trained lay workers
improve psychological well-being and
quality of life for carers of people
with dementia, and at what cost? A
randomised controlled trial.
By Charlesworth G, Shepstone L,
Wilson E, Thalanany M, Mugford M,
Poland F.
No. 9
The clinical effectiveness of diabetes
education models for Type 2 diabetes: a
systematic review.
By Loveman E, Frampton GK,
Clegg AJ.
No. 10
Payment to healthcare professionals for
patient recruitment to trials: systematic
review and qualitative study.
By Raftery J, Bryant J, Powell J,
Kerr C, Hawker S.
No. 11
Cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs
(etodolac, meloxicam, celecoxib,
rofecoxib, etoricoxib, valdecoxib and
lumiracoxib) for osteoarthritis and
rheumatoid arthritis: a systematic review
and economic evaluation.
By Chen Y-F, Jobanputra P, Barton P,
Bryan S, Fry-Smith A, Harris G, et al.
No. 12
The clinical effectiveness and costeffectiveness of central venous catheters
treated with anti-infective agents in
preventing bloodstream infections:
a systematic review and economic
evaluation.
By Hockenhull JC, Dwan K, Boland
A, Smith G, Bagust A, Dundar Y, et al.
No. 13
Stepped treatment of older adults on
laxatives. The STOOL trial.
By Mihaylov S, Stark C, McColl E,
Steen N, Vanoli A, Rubin G, et al.
No. 14
A randomised controlled trial of
cognitive behaviour therapy in
adolescents with major depression
treated by selective serotonin reuptake
inhibitors. The ADAPT trial.
By Goodyer IM, Dubicka B, Wilkinson
P, Kelvin R, Roberts C, Byford S, et al.
No. 15
The use of irinotecan, oxaliplatin
and raltitrexed for the treatment of
advanced colorectal cancer: systematic
review and economic evaluation.
By Hind D, Tappenden P, Tumur I,
Eggington E, Sutcliffe P, Ryan A.
No. 16
Ranibizumab and pegaptanib for
the treatment of age-related macular
degeneration: a systematic review and
economic evaluation.
By Colquitt JL, Jones J, Tan SC,
Takeda A, Clegg AJ, Price A.
No. 17
Systematic review of the clinical
effectiveness and cost-effectiveness
of 64-slice or higher computed
tomography angiography as an
alternative to invasive coronary
angiography in the investigation of
coronary artery disease.
By Mowatt G, Cummins E, Waugh N,
Walker S, Cook J, Jia X, et al.
No. 18
Structural neuroimaging in psychosis:
a systematic review and economic
evaluation.
By Albon E, Tsourapas A, Frew E,
Davenport C, Oyebode F, Bayliss S, et al.
No. 19
Systematic review and economic analysis
of the comparative effectiveness of
different inhaled corticosteroids and
their usage with long-acting beta2
agonists for the treatment of chronic
asthma in adults and children aged
12 years and over.
By Shepherd J, Rogers G, Anderson
R, Main C, Thompson-Coon J,
Hartwell D, et al.
No. 20
Systematic review and economic analysis
of the comparative effectiveness of
different inhaled corticosteroids and
their usage with long-acting beta2
agonists for the treatment of chronic
asthma in children under the age of
12 years.
By Main C, Shepherd J, Anderson R,
Rogers G, Thompson-Coon J, Liu Z, et al.
No. 21
Ezetimibe for the treatment of
hypercholesterolaemia: a systematic
review and economic evaluation.
By Ara R, Tumur I, Pandor A, Duenas
A, Williams R, Wilkinson A, et al.
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
No. 22
Topical or oral ibuprofen for chronic
knee pain in older people. The TOIB
study.
By Underwood M, Ashby D, Carnes
D, Castelnuovo E, Cross P, Harding G,
et al.
No. 23
A prospective randomised comparison
of minor surgery in primary and
secondary care. The MiSTIC trial.
By George S, Pockney P, Primrose J,
Smith H, Little P, Kinley H, et al.
No. 24
A review and critical appraisal
of measures of therapist–patient
interactions in mental health settings.
By Cahill J, Barkham M, Hardy G,
Gilbody S, Richards D, Bower P, et al.
No. 25
The clinical effectiveness and costeffectiveness of screening programmes
for amblyopia and strabismus in
children up to the age of 4–5 years:
a systematic review and economic
evaluation.
By Carlton J, Karnon J, CzoskiMurray C, Smith KJ, Marr J.
No. 26
A systematic review of the clinical
effectiveness and cost-effectiveness and
economic modelling of minimal incision
total hip replacement approaches in
the management of arthritic disease of
the hip.
By de Verteuil R, Imamura M, Zhu S,
Glazener C, Fraser C, Munro N, et al.
No. 27
A preliminary model-based assessment
of the cost–utility of a screening
programme for early age-related
macular degeneration.
By Karnon J, Czoski-Murray C, Smith
K, Brand C, Chakravarthy U, Davis S,
et al.
No. 28
Intravenous magnesium sulphate
and sotalol for prevention of atrial
fibrillation after coronary artery
bypass surgery: a systematic review and
economic evaluation.
By Shepherd J, Jones J, Frampton
GK, Tanajewski L, Turner D, Price A.
No. 29
Absorbent products for urinary/faecal
incontinence: a comparative evaluation
of key product categories.
By Fader M, Cottenden A, Getliffe K,
Gage H, Clarke-O’Neill S, Jamieson K,
et al.
No. 30
A systematic review of repetitive
functional task practice with modelling
of resource use, costs and effectiveness.
By French B, Leathley M, Sutton C,
McAdam J, Thomas L, Forster A, et al.
No. 31
The effectiveness and cost-effectivness
of minimal access surgery amongst
people with gastro-oesophageal reflux
disease – a UK collaborative study. The
reflux trial.
By Grant A, Wileman S, Ramsay C,
Bojke L, Epstein D, Sculpher M, et al.
No. 3
Surgical procedures and non-surgical
devices for the management of nonapnoeic snoring: a systematic review of
clinical effects and associated treatment
costs.
By Main C, Liu Z, Welch K, Weiner G,
Quentin Jones S, Stein K.
No. 32
Time to full publication of studies of
anti-cancer medicines for breast cancer
and the potential for publication bias: a
short systematic review.
By Takeda A, Loveman E, Harris P,
Hartwell D, Welch K.
No. 4
Continuous positive airway pressure
devices for the treatment of obstructive
sleep apnoea–hypopnoea syndrome: a
systematic review and economic analysis.
By McDaid C, Griffin S, Weatherly H,
Durée K, van der Burgt M, van Hout S,
Akers J, et al.
No. 33
Performance of screening tests for
child physical abuse in accident and
emergency departments.
By Woodman J, Pitt M, Wentz R,
Taylor B, Hodes D, Gilbert RE.
No. 5
Use of classical and novel biomarkers
as prognostic risk factors for localised
prostate cancer: a systematic review.
By Sutcliffe P, Hummel S, Simpson E,
Young T, Rees A, Wilkinson A, et al.
No. 34
Curative catheter ablation in atrial
fibrillation and typical atrial flutter:
systematic review and economic
evaluation.
By Rodgers M, McKenna C, Palmer S,
Chambers D, Van Hout S, Golder S, et al.
No. 6
The harmful health effects of recreational
ecstasy: a systematic review of
observational evidence.
By Rogers G, Elston J, Garside R,
Roome C, Taylor R, Younger P, et al.
No. 35
Systematic review and economic
modelling of effectiveness and cost
utility of surgical treatments for men
with benign prostatic enlargement.
By Lourenco T, Armstrong N, N’Dow
J, Nabi G, Deverill M, Pickard R, et al.
No. 36
Immunoprophylaxis against respiratory
syncytial virus (RSV) with palivizumab
in children: a systematic review and
economic evaluation.
By Wang D, Cummins C, Bayliss S,
Sandercock J, Burls A.
Volume 13, 2009
No. 1
Deferasirox for the treatment of iron
overload associated with regular
blood transfusions (transfusional
haemosiderosis) in patients suffering
with chronic anaemia: a systematic
review and economic evaluation.
By McLeod C, Fleeman N, Kirkham
J, Bagust A, Boland A, Chu P, et al.
No. 2
Thrombophilia testing in people with
venous thromboembolism: systematic
review and cost-effectiveness analysis.
By Simpson EL, Stevenson MD,
Rawdin A, Papaioannou D.
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
No. 7
Systematic review of the clinical
effectiveness and cost-effectiveness
of oesophageal Doppler monitoring
in critically ill and high-risk surgical
patients.
By Mowatt G, Houston G, Hernández
R, de Verteuil R, Fraser C, Cuthbertson
B, et al.
No. 8
The use of surrogate outcomes in modelbased cost-effectiveness analyses: a survey
of UK Health Technology Assessment
reports.
By Taylor RS, Elston J.
No. 9
Controlling Hypertension and
Hypotension Immediately Post Stroke
(CHHIPS) – a randomised controlled
trial.
By Potter J, Mistri A, Brodie F,
Chernova J, Wilson E, Jagger C, et al.
No. 10
Routine antenatal anti-D prophylaxis
for RhD-negative women: a systematic
review and economic evaluation.
By Pilgrim H, Lloyd-Jones M, Rees A.
No. 11
Amantadine, oseltamivir and zanamivir
for the prophylaxis of influenza
(including a review of existing guidance
no. 67): a systematic review and
economic evaluation.
By Tappenden P, Jackson R, Cooper
K, Rees A, Simpson E, Read R, et al.
125
Health Technology Assessment reports published to date
No. 12
Improving the evaluation of therapeutic
interventions in multiple sclerosis: the
role of new psychometric methods.
By Hobart J, Cano S.
No. 13
Treatment of severe ankle sprain: a
pragmatic randomised controlled trial
comparing the clinical effectiveness
and cost-effectiveness of three types of
mechanical ankle support with tubular
bandage. The CAST trial.
By Cooke MW, Marsh JL, Clark M,
Nakash R, Jarvis RM, Hutton JL, et al.,
on behalf of the CAST trial group.
No. 14
Non-occupational postexposure
prophylaxis for HIV: a systematic review.
By Bryant J, Baxter L, Hird S.
No. 22
Randomised controlled trial to
determine the clinical effectiveness
and cost-effectiveness of selective
serotonin reuptake inhibitors plus
supportive care, versus supportive care
alone, for mild to moderate depression
with somatic symptoms in primary
care: the THREAD (THREshold for
AntiDepressant response) study.
By Kendrick T, Chatwin J, Dowrick C,
Tylee A, Morriss R, Peveler R, et al.
No. 15
Blood glucose self-monitoring in type 2
diabetes: a randomised controlled trial.
By Farmer AJ, Wade AN, French DP,
Simon J, Yudkin P, Gray A, et al.
No. 23
Diagnostic strategies using DNA testing
for hereditary haemochromatosis in
at-risk populations: a systematic review
and economic evaluation.
By Bryant J, Cooper K, Picot J, Clegg
A, Roderick P, Rosenberg W, et al.
No. 16
How far does screening women for
domestic (partner) violence in different
health-care settings meet criteria for
a screening programme? Systematic
reviews of nine UK National Screening
Committee criteria.
By Feder G, Ramsay J, Dunne D, Rose
M, Arsene C, Norman R, et al.
No. 24
Enhanced external counterpulsation
for the treatment of stable angina and
heart failure: a systematic review and
economic analysis.
By McKenna C, McDaid C, Suekarran
S, Hawkins N, Claxton K, Light K, et al.
No. 17
Spinal cord stimulation for chronic
pain of neuropathic or ischaemic
origin: systematic review and economic
evaluation.
By Simpson EL, Duenas A, Holmes
MW, Papaioannou D, Chilcott J.
No. 18
The role of magnetic resonance imaging
in the identification of suspected
acoustic neuroma: a systematic review
of clinical and cost-effectiveness and
natural history.
By Fortnum H, O’Neill C, Taylor R,
Lenthall R, Nikolopoulos T, Lightfoot
G, et al.
No. 19
Dipsticks and diagnostic algorithms in
urinary tract infection: development
and validation, randomised trial,
economic analysis, observational cohort
and qualitative study.
By Little P, Turner S, Rumsby K,
Warner G, Moore M, Lowes JA, et al.
126
No. 21
Neuroleptics in the treatment of
aggressive challenging behaviour for
people with intellectual disabilities:
a randomised controlled trial
(NACHBID).
By Tyrer P, Oliver-Africano P, Romeo
R, Knapp M, Dickens S, Bouras N, et al.
No. 20
Systematic review of respite care in the
frail elderly.
By Shaw C, McNamara R, Abrams K,
Cannings-John R, Hood K, Longo M,
et al.
No. 25
Development of a decision support
tool for primary care management of
patients with abnormal liver function
tests without clinically apparent liver
disease: a record-linkage population
cohort study and decision analysis
(ALFIE).
By Donnan PT, McLernon D, Dillon
JF, Ryder S, Roderick P, Sullivan F, et al.
No. 26
A systematic review of presumed
consent systems for deceased organ
donation.
By Rithalia A, McDaid C, Suekarran
S, Norman G, Myers L, Sowden A.
No. 27
Paracetamol and ibuprofen for the
treatment of fever in children: the
PITCH randomised controlled trial.
By Hay AD, Redmond NM, Costelloe
C, Montgomery AA, Fletcher M,
Hollinghurst S, et al.
No. 28
A randomised controlled trial to
compare minimally invasive glucose
monitoring devices with conventional
monitoring in the management of
insulin-treated diabetes mellitus
(MITRE).
By Newman SP, Cooke D, Casbard A,
Walker S, Meredith S, Nunn A, et al.
No. 29
Sensitivity analysis in economic
evaluation: an audit of NICE current
practice and a review of its use and
value in decision-making.
By Andronis L, Barton P, Bryan S.
Suppl. 1
Trastuzumab for the treatment of
primary breast cancer in HER2-positive
women: a single technology appraisal.
By Ward S, Pilgrim H, Hind D.
Docetaxel for the adjuvant treatment
of early node-positive breast cancer: a
single technology appraisal.
By Chilcott J, Lloyd Jones M,
Wilkinson A.
The use of paclitaxel in the
management of early stage breast
cancer.
By Griffin S, Dunn G, Palmer S,
Macfarlane K, Brent S, Dyker A, et al.
Rituximab for the first-line treatment
of stage III/IV follicular non-Hodgkin’s
lymphoma.
By Dundar Y, Bagust A, Hounsome J,
McLeod C, Boland A, Davis H, et al.
Bortezomib for the treatment of
multiple myeloma patients.
By Green C, Bryant J, Takeda A,
Cooper K, Clegg A, Smith A, et al.
Fludarabine phosphate for the firstline treatment of chronic lymphocytic
leukaemia.
By Walker S, Palmer S, Erhorn S,
Brent S, Dyker A, Ferrie L, et al.
Erlotinib for the treatment of relapsed
non-small cell lung cancer.
By McLeod C, Bagust A, Boland A,
Hockenhull J, Dundar Y, Proudlove C,
et al.
Cetuximab plus radiotherapy for the
treatment of locally advanced squamous
cell carcinoma of the head and neck.
By Griffin S, Walker S, Sculpher M,
White S, Erhorn S, Brent S, et al.
Infliximab for the treatment of adults
with psoriasis.
By Loveman E, Turner D, Hartwell D,
Cooper K, Clegg A.
No. 30
Psychological interventions for postnatal
depression: cluster randomised trial
and economic evaluation. The PoNDER
trial.
By Morrell CJ, Warner R, Slade P,
Dixon S, Walters S, Paley G, et al.
No. 31
The effect of different treatment
durations of clopidogrel in patients
with non-ST-segment elevation acute
coronary syndromes: a systematic review
and value of information analysis.
By Rogowski R, Burch J, Palmer S,
Craigs C, Golder S, Woolacott N.
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
No. 32
Systematic review and individual patient
data meta-analysis of diagnosis of heart
failure, with modelling of implications
of different diagnostic strategies in
primary care.
By Mant J, Doust J, Roalfe A, Barton
P, Cowie MR, Glasziou P, et al.
No. 33
A multicentre randomised controlled
trial of the use of continuous positive
airway pressure and non-invasive
positive pressure ventilation in the early
treatment of patients presenting to the
emergency department with severe
acute cardiogenic pulmonary oedema:
the 3CPO trial.
By Gray AJ, Goodacre S, Newby
DE, Masson MA, Sampson F, Dixon
S, et al., on behalf of the 3CPO study
investigators.
No. 34
Early high-dose lipid-lowering therapy
to avoid cardiac events: a systematic
review and economic evaluation.
By Ara R, Pandor A, Stevens J, Rees
A, Rafia R.
No. 35
Adefovir dipivoxil and pegylated
interferon alpha for the treatment
of chronic hepatitis B: an updated
systematic review and economic
evaluation.
By Jones J, Shepherd J, Baxter L,
Gospodarevskaya E, Hartwell D, Harris
P, et al.
No. 36
Methods to identify postnatal
depression in primary care: an
integrated evidence synthesis and value
of information analysis.
By Hewitt CE, Gilbody SM, Brealey S,
Paulden M, Palmer S, Mann R, et al.
No. 37
A double-blind randomised placebocontrolled trial of topical intranasal
corticosteroids in 4- to 11-year-old
children with persistent bilateral otitis
media with effusion in primary care.
By Williamson I, Benge S, Barton S,
Petrou S, Letley L, Fasey N, et al.
No. 38
The effectiveness and cost-effectiveness
of methods of storing donated kidneys
from deceased donors: a systematic
review and economic model.
By Bond M, Pitt M, Akoh J, Moxham
T, Hoyle M, Anderson R.
No. 39
Rehabilitation of older patients: day
hospital compared with rehabilitation at
home. A randomised controlled trial.
By Parker SG, Oliver P, Pennington
M, Bond J, Jagger C, Enderby PM, et al.
No. 40
Breastfeeding promotion for infants in
neonatal units: a systematic review and
economic analysis.
By Renfrew MJ, Craig D, Dyson L,
McCormick F, Rice S, King SE, et al.
No. 41
The clinical effectiveness and costeffectiveness of bariatric (weight loss)
surgery for obesity: a systematic review and
economic evaluation.
By Picot J, Jones J, Colquitt JL,
Gospodarevskaya E, Loveman E, Baxter
L, et al.
No. 42
Rapid testing for group B streptococcus
during labour: a test accuracy study with
evaluation of acceptability and costeffectiveness.
By Daniels J, Gray J, Pattison H,
Roberts T, Edwards E, Milner P, et al.
No. 43
Screening to prevent spontaneous
preterm birth: systematic reviews of
accuracy and effectiveness literature
with economic modelling.
By Honest H, Forbes CA, Durée KH,
Norman G, Duffy SB, Tsourapas A, et al.
No. 44
The effectiveness and cost-effectiveness
of cochlear implants for severe to
profound deafness in children and
adults: a systematic review and
economic model.
By Bond M, Mealing S, Anderson R,
Elston J, Weiner G, Taylor RS, et al.
Suppl. 2
Gemcitabine for the treatment of
metastatic breast cancer.
By Jones J, Takeda A, Tan SC, Cooper
K, Loveman E, Clegg A.
Varenicline in the management of
smoking cessation: a single technology
appraisal.
By Hind D, Tappenden P, Peters J,
Kenjegalieva K.
Alteplase for the treatment of acute
ischaemic stroke: a single technology
appraisal.
By Lloyd Jones M, Holmes M.
Rituximab for the treatment of
rheumatoid arthritis.
By Bagust A, Boland A, Hockenhull
J, Fleeman N, Greenhalgh J, Dundar Y,
et al.
Omalizumab for the treatment of severe
persistent allergic asthma.
By Jones J, Shepherd J, Hartwell D,
Harris P, Cooper K, Takeda A, et al.
Rituximab for the treatment of relapsed
or refractory stage III or IV follicular
non-Hodgkin’s lymphoma.
By Boland A, Bagust A, Hockenhull J,
Davis H, Chu P, Dickson R.
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Adalimumab for the treatment of
psoriasis.
By Turner D, Picot J, Cooper K,
Loveman E.
Dabigatran etexilate for the prevention
of venous thromboembolism in patients
undergoing elective hip and knee
surgery: a single technology appraisal.
By Holmes M, Carroll C,
Papaioannou D.
Romiplostim for the treatment
of chronic immune or idiopathic
thrombocytopenic purpura: a single
technology appraisal.
By Mowatt G, Boachie C, Crowther
M, Fraser C, Hernández R, Jia X, et al.
Sunitinib for the treatment of
gastrointestinal stromal tumours: a
critique of the submission from Pfizer.
By Bond M, Hoyle M, Moxham T,
Napier M, Anderson R.
No. 45
Vitamin K to prevent fractures in older
women: systematic review and economic
evaluation.
By Stevenson M, Lloyd-Jones M,
Papaioannou D.
No. 46
The effects of biofeedback for the
treatment of essential hypertension: a
systematic review.
By Greenhalgh J, Dickson R,
Dundar Y.
No. 47
A randomised controlled trial of the
use of aciclovir and/or prednisolone for
the early treatment of Bell’s palsy: the
BELLS study.
By Sullivan FM, Swan IRC, Donnan
PT, Morrison JM, Smith BH, McKinstry
B, et al.
Suppl. 3
Lapatinib for the treatment of HER2overexpressing breast cancer.
By Jones J, Takeda A, Picot J, von
Keyserlingk C, Clegg A.
Infliximab for the treatment of
ulcerative colitis.
By Hyde C, Bryan S, Juarez-Garcia A,
Andronis L, Fry-Smith A.
Rimonabant for the treatment of
overweight and obese people.
By Burch J, McKenna C, Palmer S,
Norman G, Glanville J, Sculpher M, et al.
Telbivudine for the treatment of chronic
hepatitis B infection.
By Hartwell D, Jones J, Harris P,
Cooper K.
Entecavir for the treatment of chronic
hepatitis B infection.
By Shepherd J, Gospodarevskaya E,
Frampton G, Cooper K.
Febuxostat for the treatment of
hyperuricaemia in people with gout: a
single technology appraisal.
By Stevenson M, Pandor A.
127
Health Technology Assessment reports published to date
Rivaroxaban for the prevention of
venous thromboembolism: a single
technology appraisal.
By Stevenson M, Scope A, Holmes M,
Rees A, Kaltenthaler E.
Cetuximab for the treatment of
recurrent and/or metastatic squamous
cell carcinoma of the head and neck.
By Greenhalgh J, Bagust A, Boland A,
Fleeman N, McLeod C, Dundar Y, et al.
Mifamurtide for the treatment of
osteosarcoma: a single technology
appraisal.
By Pandor A, Fitzgerald P, Stevenson
M, Papaioannou D.
Ustekinumab for the treatment of
moderate to severe psoriasis.
By Gospodarevskaya E, Picot J,
Cooper K, Loveman E, Takeda A.
No. 48
Endovascular stents for abdominal
aortic aneurysms: a systematic review
and economic model.
By Chambers D, Epstein D, Walker S,
Fayter D, Paton F, Wright K, et al.
No. 49
Clinical and cost-effectiveness of
epoprostenol, iloprost, bosentan,
sitaxentan and sildenafil for pulmonary
arterial hypertension within their
licensed indications: a systematic review
and economic evaluation.
By Chen Y-F, Jowett S, Barton P,
Malottki K, Hyde C, Gibbs JSR, et al.
No. 50
Cessation of attention deficit
hyperactivity disorder drugs
in the young (CADDY) – a
pharmacoepidemiological and
qualitative study.
By Wong ICK, Asherson P, Bilbow A,
Clifford S, Coghill D, DeSoysa R, et al.
No. 51
ARTISTIC: a randomised trial of
human papillomavirus (HPV) testing in
primary cervical screening.
By Kitchener HC, Almonte M,
Gilham C, Dowie R, Stoykova B, Sargent
A, et al.
No. 52
The clinical effectiveness of glucosamine
and chondroitin supplements in slowing
or arresting progression of osteoarthritis
of the knee: a systematic review and
economic evaluation.
By Black C, Clar C, Henderson R,
MacEachern C, McNamee P, Quayyum
Z, et al.
128
No. 53
Randomised preference trial of medical
versus surgical termination of pregnancy
less than 14 weeks’ gestation (TOPS).
By Robson SC, Kelly T, Howel D,
Deverill M, Hewison J, Lie MLS, et al.
No. 54
Randomised controlled trial of the use
of three dressing preparations in the
management of chronic ulceration of
the foot in diabetes.
By Jeffcoate WJ, Price PE, Phillips CJ,
Game FL, Mudge E, Davies S, et al.
No. 55
VenUS II: a randomised controlled trial
of larval therapy in the management of
leg ulcers.
By Dumville JC, Worthy G, Soares
MO, Bland JM, Cullum N, Dowson C,
et al.
No. 56
A prospective randomised controlled
trial and economic modelling of
antimicrobial silver dressings versus
non-adherent control dressings for
venous leg ulcers: the VULCAN trial.
By Michaels JA, Campbell WB,
King BM, MacIntyre J, Palfreyman SJ,
Shackley P, et al.
No. 57
Communication of carrier status
information following universal
newborn screening for sickle cell
disorders and cystic fibrosis: qualitative
study of experience and practice.
By Kai J, Ulph F, Cullinan T,
Qureshi N.
No. 58
Antiviral drugs for the treatment of
influenza: a systematic review and
economic evaluation.
By Burch J, Paulden M, Conti S, Stock
C, Corbett M, Welton NJ, et al.
No. 59
Development of a toolkit and glossary
to aid in the adaptation of health
technology assessment (HTA) reports
for use in different contexts.
By Chase D, Rosten C, Turner S,
Hicks N, Milne R.
No. 60
Colour vision testing for diabetic
retinopathy: a systematic review of
diagnostic accuracy and economic
evaluation.
By Rodgers M, Hodges R, Hawkins
J, Hollingworth W, Duffy S, McKibbin
M, et al.
No. 61
Systematic review of the effectiveness
and cost-effectiveness of weight
management schemes for the under
fives: a short report.
By Bond M, Wyatt K, Lloyd J, Welch
K, Taylor R.
No. 62
Are adverse effects incorporated in
economic models? An initial review of
current practice.
By Craig D, McDaid C, Fonseca T,
Stock C, Duffy S, Woolacott N.
Volume 14, 2010
No. 1
Multicentre randomised controlled
trial examining the cost-effectiveness of
contrast-enhanced high field magnetic
resonance imaging in women with
primary breast cancer scheduled for
wide local excision (COMICE).
By Turnbull LW, Brown SR, Olivier C,
Harvey I, Brown J, Drew P, et al.
No. 2
Bevacizumab, sorafenib tosylate,
sunitinib and temsirolimus for renal
cell carcinoma: a systematic review and
economic evaluation.
By Thompson Coon J, Hoyle M,
Green C, Liu Z, Welch K, Moxham T,
et al.
No. 3
The clinical effectiveness and costeffectiveness of testing for cytochrome
P450 polymorphisms in patients
with schizophrenia treated with
antipsychotics: a systematic review and
economic evaluation.
By Fleeman N, McLeod C, Bagust A,
Beale S, Boland A, Dundar Y, et al.
No. 4
Systematic review of the clinical
effectiveness and cost-effectiveness of
photodynamic diagnosis and urine
biomarkers (FISH, ImmunoCyt,
NMP22) and cytology for the detection
and follow-up of bladder cancer.
By Mowatt G, Zhu S, Kilonzo M,
Boachie C, Fraser C, Griffiths TRL, et al.
No. 5
Effectiveness and cost-effectiveness of
arthroscopic lavage in the treatment
of osteoarthritis of the knee: a mixed
methods study of the feasibility of
conducting a surgical placebo-controlled
trial (the KORAL study).
By Campbell MK, Skea ZC,
Sutherland AG, Cuthbertson BH,
Entwistle VA, McDonald AM, et al.
No. 6
A randomised 2 × 2 trial of community
versus hospital pulmonary rehabilitation
for chronic obstructive pulmonary
disease followed by telephone or
conventional follow-up.
By Waterhouse JC, Walters SJ,
Oluboyede Y, Lawson RA.
No. 7
The effectiveness and cost-effectiveness
of behavioural interventions for the
prevention of sexually transmitted
infections in young people aged 13–19:
a systematic review and economic
evaluation.
By Shepherd J, Kavanagh J, Picot J,
Cooper K, Harden A, Barnett-Page E,
et al.
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
No. 8
Dissemination and publication of
research findings: an updated review of
related biases.
By Song F, Parekh S, Hooper L, Loke
YK, Ryder J, Sutton AJ, et al.
No. 16
Randomised controlled trials for policy
interventions: a review of reviews and
meta-regression.
By Oliver S, Bagnall AM, Thomas J,
Shepherd J, Sowden A, White I, et al.
No. 9
The effectiveness and cost-effectiveness
of biomarkers for the prioritisation
of patients awaiting coronary
revascularisation: a systematic review
and decision model.
By Hemingway H, Henriksson
M, Chen R, Damant J, Fitzpatrick N,
Abrams K, et al.
No. 17
Paracetamol and selective and
non-selective non-steroidal antiinflammatory drugs (NSAIDs) for the
reduction of morphine-related side
effects after major surgery: a systematic
review.
By McDaid C, Maund E, Rice S,
Wright K, Jenkins B, Woolacott N.
No. 10
Comparison of case note review
methods for evaluating quality and
safety in health care.
By Hutchinson A, Coster JE, Cooper
KL, McIntosh A, Walters SJ, Bath PA,
et al.
No. 11
Clinical effectiveness and costeffectiveness of continuous
subcutaneous insulin infusion for
diabetes: systematic review and
economic evaluation.
By Cummins E, Royle P, Snaith A,
Greene A, Robertson L, McIntyre L, et al.
No. 18
A systematic review of outcome
measures used in forensic mental health
research with consensus panel opinion.
By Fitzpatrick R, Chambers J, Burns
T, Doll H, Fazel S, Jenkinson C, et al.
No. 19
The clinical effectiveness and costeffectiveness of topotecan for small cell
lung cancer: a systematic review and
economic evaluation.
By Loveman E, Jones J, Hartwell D,
Bird A, Harris P, Welch K, et al.
No. 12
Self-monitoring of blood glucose in type
2 diabetes: systematic review.
By Clar C, Barnard K, Cummins E,
Royle P, Waugh N.
No. 20
Antenatal screening for
haemoglobinopathies in primary care:
a cohort study and cluster randomised
trial to inform a simulation model. The
Screening for Haemoglobinopathies in
First Trimester (SHIFT) trial.
By Dormandy E, Bryan S, Gulliford
MC, Roberts T, Ades T, Calnan M, et al.
No. 13
North of England and Scotland Study of
Tonsillectomy and Adeno-tonsillectomy
in Children (NESSTAC): a pragmatic
randomised controlled trial with a
parallel non-randomised preference
study.
By Lock C, Wilson J, Steen N, Eccles
M, Mason H, Carrie S, et al.
No. 21
Early referral strategies for
management of people with markers of
renal disease: a systematic review of the
evidence of clinical effectiveness, costeffectiveness and economic analysis.
By Black C, Sharma P, Scotland G,
McCullough K, McGurn D, Robertson
L, et al.
No. 14
Multicentre randomised controlled trial
of the clinical and cost-effectiveness of
a bypass-surgery-first versus a balloonangioplasty-first revascularisation
strategy for severe limb ischaemia due
to infrainguinal disease. The Bypass
versus Angioplasty in Severe Ischaemia
of the Leg (BASIL) trial.
By Bradbury AW, Adam DJ, Bell J,
Forbes JF, Fowkes FGR, Gillespie I, et al.
No. 22
A randomised controlled trial of
cognitive behaviour therapy and
motivational interviewing for people
with Type 1 diabetes mellitus with
persistent sub-optimal glycaemic
control: A Diabetes and Psychological
Therapies (ADaPT) study.
By Ismail K, Maissi E, Thomas S,
Chalder T, Schmidt U, Bartlett J, et al.
No. 15
A randomised controlled multicentre
trial of treatments for adolescent
anorexia nervosa including assessment
of cost-effectiveness and patient
acceptability – the TOuCAN trial.
By Gowers SG, Clark AF, Roberts C,
Byford S, Barrett B, Griffiths A, et al.
No. 23
A randomised controlled equivalence
trial to determine the effectiveness
and cost–utility of manual chest
physiotherapy techniques in the
management of exacerbations of
chronic obstructive pulmonary disease
(MATREX).
By Cross J, Elender F, Barton G,
Clark A, Shepstone L, Blyth A, et al.
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
No. 24
A systematic review and economic
evaluation of the clinical effectiveness
and cost-effectiveness of aldosterone
antagonists for postmyocardial
infarction heart failure.
By McKenna C, Burch J, Suekarran S,
Walker S, Bakhai A, Witte K, et al.
No. 25
Avoiding and identifying errors in
health technology assessment models:
qualitative study and methodological
review.
By Chilcott JB, Tappenden P, Rawdin
A, Johnson M, Kaltenthaler E, Paisley S,
et al.
No. 26
BoTULS: a multicentre randomised
controlled trial to evaluate the clinical
effectiveness and cost-effectiveness of
treating upper limb spasticity due to
stroke with botulinum toxin type A.
By Shaw L, Rodgers H, Price C, van
Wijck F, Shackley P, Steen N, et al., on
behalf of the BoTULS investigators.
No. 27
Weighting and valuing quality-adjusted
life-years using stated preference
methods: preliminary results from the
Social Value of a QALY Project.
By Baker R, Bateman I, Donaldson C,
Jones-Lee M, Lancsar E, Loomes G, et al.
Suppl. 1
Cetuximab for the first-line treatment of
metastatic colorectal cancer.
By Meads C, Round J, Tubeuf S,
Moore D, Pennant M, Bayliss S.
Infliximab for the treatment of acute
exacerbations of ulcerative colitis.
By Bryan S, Andronis L, Hyde C,
Connock M, Fry-Smith A, Wang D.
Sorafenib for the treatment of advanced
hepatocellular carcinoma.
By Connock M, Round J, Bayliss S,
Tubeuf S, Greenheld W, Moore D.
Tenofovir disoproxil fumarate for
the treatment of chronic hepatitis B
infection.
By Jones J, Colquitt J, Shepherd J,
Harris P, Cooper K.
Prasugrel for the treatment of acute
coronary artery syndromes with
percutaneous coronary intervention.
By Greenhalgh J, Bagust A, Boland
A, Saborido CM, Fleeman N, McLeod
C, et al.
Alitretinoin for the treatment of severe
chronic hand eczema.
By Paulden M, Rodgers M, Griffin S,
Slack R, Duffy S, Ingram JR, et al.
Pemetrexed for the first-line treatment
of locally advanced or metastatic nonsmall cell lung cancer.
By Fleeman N, Bagust A, McLeod C,
Greenhalgh J, Boland A, Dundar Y, et al.
129
Health Technology Assessment reports published to date
Topotecan for the treatment of
recurrent and stage IVB carcinoma of
the cervix.
By Paton F, Paulden M, Saramago P,
Manca A, Misso K, Palmer S, et al.
Trabectedin for the treatment of
advanced metastatic soft tissue sarcoma.
By Simpson EL, Rafia R, Stevenson
MD, Papaioannou D.
Azacitidine for the treatment of
myelodysplastic syndrome, chronic
myelomonocytic leukaemia and acute
myeloid leukaemia.
By Edlin R, Connock M, Tubeuf S,
Round J, Fry-Smith A, Hyde C, et al.
No. 28
The safety and effectiveness of
different methods of earwax removal:
a systematic review and economic
evaluation.
By Clegg AJ, Loveman E,
Gospodarevskaya E, Harris P, Bird A,
Bryant J, et al.
No. 29
Systematic review of the clinical
effectiveness and cost-effectiveness
of rapid point-of-care tests for the
detection of genital chlamydia infection
in women and men.
By Hislop J, Quayyum Z, Flett G,
Boachie C, Fraser C, Mowatt G.
No. 30
School-linked sexual health services for
young people (SSHYP): a survey and
systematic review concerning current
models, effectiveness, cost-effectiveness
and research opportunities.
By Owen J, Carroll C, Cooke J,
Formby E, Hayter M, Hirst J, et al.
130
No. 34
Exploring the needs, concerns and
behaviours of people with existing
respiratory conditions in relation to the
H1N1 ‘swine influenza’ pandemic: a
multicentre survey and qualitative study.
By Caress A-L, Duxbury P, Woodcock
A, Luker KA, Ward D, Campbell M, et al.
No. 38
Towards single embryo transfer?
Modelling clinical outcomes of potential
treatment choices using multiple data
sources: predictive models and patient
perspectives.
By Roberts SA, McGowan L, Hirst
WM, Brison DR, Vail A, Lieberman BA.
Influenza A/H1N1v in pregnancy: an
investigation of the characteristics and
management of affected women and the
relationship to pregnancy outcomes for
mother and infant.
By Yates L, Pierce M, Stephens S, Mill
AC, Spark P, Kurinczuk JJ, et al.
No. 39
Sugammadex for the reversal of muscle
relaxation in general anaesthesia:
a systematic review and economic
assessment.
By Chambers D, Paulden M, Paton F,
Heirs M, Duffy S, Craig D, et al.
The impact of communications about
swine flu (influenza A H1N1v) on public
responses to the outbreak: results from
36 national telephone surveys in the
UK.
By Rubin GJ, Potts HWW, Michie S.
The impact of illness and the impact
of school closure on social contact
patterns.
By Eames KTD, Tilston NL, White PJ,
Adams E, Edmunds WJ.
Vaccine effectiveness in pandemic
influenza – primary care reporting
(VIPER): an observational study to
assess the effectiveness of the pandemic
influenza A (H1N1)v vaccine.
By Simpson CR, Ritchie LD,
Robertson C, Sheikh A, McMenamin J.
Physical interventions to interrupt or
reduce the spread of respiratory viruses:
a Cochrane review.
By Jefferson T, Del Mar C, Dooley L,
Ferroni E, Al-Ansary LA, Bawazeer GA,
et al.
No. 31
Systematic review and cost-effectiveness
evaluation of ‘pill-in-the-pocket’ strategy
for paroxysmal atrial fibrillation
compared to episodic in-hospital
treatment or continuous antiarrhythmic
drug therapy.
By Martin Saborido C, Hockenhull J,
Bagust A, Boland A, Dickson R, Todd D.
No. 35
Randomised controlled trial and
parallel economic evaluation of
conventional ventilatory support versus
extracorporeal membrane oxygenation
for severe adult respiratory failure
(CESAR).
By Peek GJ, Elbourne D, Mugford M,
Tiruvoipati R, Wilson A, Allen E, et al.
No. 32
Chemoprevention of colorectal cancer:
systematic review and economic
evaluation.
By Cooper K, Squires H, Carroll C,
Papaioannou D, Booth A, Logan RF, et al.
No. 36
Newer agents for blood glucose control
in type 2 diabetes: systematic review and
economic evaluation.
By Waugh N, Cummins E, Royle P,
Clar C, Marien M, Richter B, et al.
No. 33
Cross-trimester repeated measures
testing for Down’s syndrome screening:
an assessment.
By Wright D, Bradbury I, Malone F,
D’Alton M, Summers A, Huang T, et al.
No. 37
Barrett’s oesophagus and cancers of the
biliary tract, brain, head and neck, lung,
oesophagus and skin.
By Fayter D, Corbett M, Heirs M, Fox
D, Eastwood A.
No. 40
Systematic review and economic
modelling of the effectiveness and costeffectiveness of non-surgical treatments
for women with stress urinary
incontinence.
By Imamura M, Abrams P, Bain C,
Buckley B, Cardozo L, Cody J, et al.
No. 41
A multicentred randomised controlled
trial of a primary care-based cognitive
behavioural programme for low back
pain. The Back Skills Training (BeST)
trial.
By Lamb SE, Lall R, Hansen Z,
Castelnuovo E, Withers EJ, Nichols V,
et al.
No. 42
Recombinant human growth hormone
for the treatment of growth disorders
in children: a systematic review and
economic evaluation.
By Takeda A, Cooper K,
Bird A, Baxter L, Frampton GK,
Gospodarevskaya E, et al.
No. 43
A pragmatic randomised controlled
trial to compare antidepressants with
a community-based psychosocial
intervention for the treatment of
women with postnatal depression: the
RESPOND trial.
By Sharp DJ, Chew-Graham C, Tylee
A, Lewis G, Howard L, Anderson I, et al.
No. 44
Group cognitive behavioural therapy
for postnatal depression: a systematic
review of clinical effectiveness, costeffectiveness and value of information
analyses.
By Stevenson MD, Scope A, Sutcliffe
PA, Booth A, Slade P, Parry G, et al.
No. 45
Screening for hyperglycaemia in
pregnancy: a rapid update for the
National Screening Committee.
By Waugh N, Royle P, Clar C,
Henderson R, Cummins E, Hadden D,
et al.
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
No. 46
Open-label, randomised, parallelgroup, multicentre study to evaluate the
safety, tolerability and immunogenicity
of an AS03B/oil-in-water emulsionadjuvanted (AS03B) split-virion versus
non-adjuvanted wholevirion H1N1
influenza vaccine in UK children
6 months to 12 years of age.
By Waddington CS, Andrews N,
Hoschler K, Walker WT, Oeser C, Reiner
A, et al.
Evaluation of droplet dispersion during
non-invasive ventilation, oxygen
therapy, nebuliser treatment and chest
physiotherapy in clinical practice:
implications for management of
pandemic influenza and other airborne
infections.
By Simonds AK, Hanak A, Chatwin
M, Morrell MJ, Hall A, Parker KH, et al.
Evaluation of triage methods used to
select patients with suspected pandemic
influenza for hospital admission: cohort
study.
By Goodacre S, Challen, K, Wilson R,
Campbell M.
Virus shedding and environmental
deposition of novel A (H1N1) pandemic
influenza virus: interim findings.
By Killingley B, Greatorex J,
Cauchemez S, Enstone JE, Curran M,
Read R, et al.
Neuraminidase inhibitors for
preventing and treating influenza in
healthy adults: a Cochrane review.
By Jefferson T, Jones M, Doshi P, Del
Mar C, Dooley L, Foxlee R.
131
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Health Technology Assessment
programme
Director,
Professor Tom Walley,
Director, NIHR HTA
programme, Professor of
Clinical Pharmacology,
University of Liverpool
Deputy Director,
Professor Jon Nicholl,
Director, Medical Care Research
Unit, University of Sheffield
Prioritisation Strategy Group
Members
Chair,
Professor Tom Walley,
Director, NIHR HTA
programme, Professor of
Clinical Pharmacology,
University of Liverpool
Deputy Chair,
Professor Jon Nicholl,
Director, Medical Care Research
Unit, University of Sheffield
Dr Bob Coates,
Consultant Advisor, NETSCC,
HTA
Dr Andrew Cook,
Consultant Advisor, NETSCC,
HTA
Professor Paul Glasziou,
Professor of Evidence-Based
Medicine, University of Oxford
Ms Lynn Kerridge,
Chief Executive Officer,
NETSCC and NETSCC, HTA
Dr Peter Davidson,
Director of NETSCC, Health
Technology Assessment
Dr Nick Hicks,
Consultant Adviser, NETSCC,
HTA
Professor Ruairidh Milne,
Director of NETSCC External
Relations
Professor Robin E Ferner,
Consultant Physician and
Director, West Midlands Centre
for Adverse Drug Reactions,
City Hospital NHS Trust,
Birmingham
Dr Edmund Jessop,
Medical Adviser, National
Specialist, National
Commissioning Group (NCG),
Department of Health, London
Ms Kay Pattison,
Senior NIHR Programme
Manager, Department of
Health
Ms Pamela Young,
Specialist Programme Manager,
NETSCC, HTA
HTA Commissioning Board
Members
Programme Director,
Professor Tom Walley,
Director, NIHR HTA
programme, Professor of
Clinical Pharmacology,
University of Liverpool
Chairs,
Professor Sallie Lamb,
Director, Warwick Clinical Trials
Unit
Professor Hywel Williams,
Director, Nottingham Clinical
Trials Unit
Deputy Chair,
Dr Andrew Farmer,
Senior Lecturer in General
Practice, Department of
Primary Health Care,
University of Oxford
Professor Ann Ashburn,
Professor of Rehabilitation
and Head of Research,
Southampton General Hospital
Professor Deborah Ashby,
Professor of Medical Statistics,
Queen Mary, University of
London
Professor John Cairns,
Professor of Health Economics,
London School of Hygiene and
Tropical Medicine
Professor Peter Croft,
Director of Primary Care
Sciences Research Centre, Keele
University
Professor Nicky Cullum,
Director of Centre for EvidenceBased Nursing, University of
York
Professor Jenny Donovan,
Professor of Social Medicine,
University of Bristol
Professor Steve Halligan,
Professor of Gastrointestinal
Radiology, University College
Hospital, London
Professor Freddie Hamdy,
Professor of Urology,
University of Sheffield
Professor Allan House,
Professor of Liaison Psychiatry,
University of Leeds
Dr Martin J Landray,
Reader in Epidemiology,
Honorary Consultant Physician,
Clinical Trial Service Unit,
University of Oxford
Professor Stuart Logan,
Director of Health & Social
Care Research, The Peninsula
Medical School, Universities of
Exeter and Plymouth
Dr Rafael Perera,
Lecturer in Medical Statisitics,
Department of Primary Health
Care, University of Oxford
Professor Ian Roberts,
Professor of Epidemiology &
Public Health, London School
of Hygiene and Tropical
Medicine
Professor Mark Sculpher,
Professor of Health Economics,
University of York
Professor Helen Smith,
Professor of Primary Care,
University of Brighton
Professor Kate Thomas,
Professor of Complementary &
Alternative Medicine Research,
University of Leeds
Professor David John
Torgerson,
Director of York Trials Unit,
University of York
Observers
Ms Kay Pattison,
Section Head, NHS R&D
Programme, Department of
Health
Dr Morven Roberts,
Clinical Trials Manager,
Medical Research Council
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
133
Health Technology Assessment programme
Diagnostic Technologies and Screening Panel
Members
Chair,
Professor Paul Glasziou,
Professor of Evidence-Based
Medicine, University of Oxford
Deputy Chair,
Dr David Elliman,
Consultant Paediatrician and
Honorary Senior Lecturer,
Great Ormond Street Hospital,
London
Professor Judith E Adams,
Consultant Radiologist,
Manchester Royal Infirmary,
Central Manchester &
Manchester Children’s
University Hospitals NHS
Trust, and Professor of
Diagnostic Radiology, Imaging
Science and Biomedical
Engineering, Cancer &
Imaging Sciences, University of
Manchester
Mr A S Arunkalaivanan,
Honorary Senior Lecturer,
University of Birmingham and
Consultant Urogynaecologist
and Obstetrician, City Hospital
Dr Dianne Baralle,
Consultant & Senior Lecturer
in Clinical Genetics, Human
Genetics Division & Wessex
Clinical Genetics Service,
Southampton, University of
Southampton
Dr Stephanie Dancer,
Consultant Microbiologist,
Hairmyres Hospital, East
Kilbride
Dr Ron Gray,
Consultant, National Perinatal
Epidemiology Unit, Institute of
Health Sciences, University of
Oxford
Professor Paul D Griffiths,
Professor of Radiology,
Academic Unit of Radiology,
University of Sheffield
Professor Anthony Robert
Kendrick,
Professor of Primary
Medical Care, University of
Southampton
Dr Susanne M Ludgate,
Director, Medical Devices
Agency, London
Dr Anne Mackie,
Director of Programmes, UK
National Screening Committee
Dr David Mathew
Service User Representative
Dr Michael Millar, Lead
Consultant in Microbiology,
Department of Pathology &
Microbiology, Barts and The
London NHS Trust, Royal
London Hospital
Mr Martin Hooper,
Service User Representative
Mr Stephen Pilling,
Director, Centre for Outcomes,
Research & Effectiveness,
University College London
Dr Catherine Moody,
Programme Manager,
Neuroscience and Mental
Health Board
Dr Ursula Wells,
Principal Research Officer,
Department of Health
Mrs Una Rennard,
Service User Representative
Ms Jane Smith,
Consultant Ultrasound
Practitioner, Ultrasound
Department, Leeds Teaching
Hospital NHS Trust, Leeds
Dr W Stuart A Smellie,
Consultant, Bishop Auckland
General Hospital
Professor Lindsay Wilson
Turnbull,
Scientific Director of the
Centre for Magnetic Resonance
Investigations and YCR
Professor of Radiology, Hull
Royal Infirmary
Dr Alan J Williams,
Consultant in General
Medicine, Department of
Thoracic Medicine, The Royal
Bournemouth Hospital
Observers
Dr Tim Elliott,
Team Leader, Cancer
Screening, Department of
Health
Disease Prevention Panel
Members
Chair,
Dr Edmund Jessop,
Medical Adviser, National
Specialist Commissioning
Advisory Group (NSCAG),
Department of Health
Deputy Chair,
Professor Margaret
Thorogood,
Professor of Epidemiology,
University of Warwick Medical
School, Coventry
Dr Robert Cook
Clinical Programmes Director,
Bazian Ltd, London
Dr Elizabeth Fellow-Smith,
Medical Director, West London
Mental Health Trust, Middlesex
Dr Colin Greaves
Senior Research Fellow,
Peninsular Medical School
(Primary Care)
Dr John Jackson,
General Practitioner, Parkway
Medical Centre, Newcastle
upon Tyne
Dr Russell Jago,
Senior Lecturer in Exercise,
Nutrition and Health, Centre
for Sport, Exercise and Health,
University of Bristol
Dr Chris McCall,
General Practitioner, The
Hadleigh Practice, Corfe
Mullen, Dorset
Professor Ian Roberts,
Professor of Epidemiology and
Public Health, London School
of Hygiene & Tropical Medicine
Miss Nicky Mullany,
Service User Representative
Professor Carol Tannahill,
Glasgow Centre for Population
Health
Dr Julie Mytton,
Locum Consultant in Public
Health Medicine, Bristol
Primary Care Trust
Professor Irwin Nazareth,
Professor of Primary Care
and Director, Department of
Primary Care and Population
Sciences, University College
London
Mrs Jean Thurston,
Service User Representative
Professor David Weller,
Head, School of Clinical
Science and Community
Health, University of
Edinburgh
Observers
Ms Christine McGuire,
Research & Development,
Department of Health
Ms Kay Pattison
Senior NIHR Programme
Manager, Department of
Health
Dr Caroline Stone,
Programme Manager, Medical
Research Council
134
Current and past membership details of all HTA programme ‘committees’ are available from the HTA website (www.hta.ac.uk)
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
External Devices and Physical Therapies Panel
Members
Chair,
Dr John Pounsford,
Consultant Physician North
Bristol NHS Trust, Bristol
Deputy Chair,
Professor E Andrea Nelson,
Reader in Wound Healing and
Director of Research, University
of Leeds, Leeds
Professor Bipin Bhakta
Charterhouse Professor in
Rehabilitation Medicine,
University of Leeds, Leeds
Mrs Penny Calder
Service User Representative
Professor Paul Carding,
Professor of Voice Pathology,
Newcastle Hospital NHS Trust,
Newcastle
Dr Dawn Carnes,
Senior Research Fellow, Barts
and the London School of
Medicine and Dentistry,
London
Dr Emma Clark,
Clinician Scientist Fellow
& Cons. Rheumatologist,
University of Bristol, Bristol
Mrs Anthea De Barton-Watson,
Service User Representative
Professor Christopher Griffiths,
Professor of Primary Care,
Barts and the London School
of Medicine and Dentistry,
London
Dr Shaheen Hamdy,
Clinical Senior Lecturer
and Consultant Physician,
University of Manchester,
Manchester
Dr Peter Martin,
Consultant Neurologist,
Addenbrooke’s Hospital,
Cambridge
Dr Lorraine Pinnigton,
Associate Professor in
Rehabilitation, University of
Nottingham, Nottingham
Dr Kate Radford,
Division of Rehabilitation and
Ageing, School of Community
Health Sciences. University of
Nottingham, Nottingham
Dr Pippa Tyrrell,
Stroke Medicine, Senior
Lecturer/Consultant Stroke
Physician, Salford Royal
Foundation Hospitals’ Trust,
Salford
Dr Sarah Tyson,
Senior Research Fellow &
Associate Head of School,
University of Salford, Salford
Dr Nefyn Williams,
Clinical Senior Lecturer, Cardiff
University, Cardiff
Mr Jim Reece,
Service User Representative
Professor Maria Stokes,
Professor of
Neuromusculoskeletal
Rehabilitation, University of
Southampton, Southampton
Observers
Dr Phillip Leech,
Principal Medical Officer for
Primary Care, Department of
Health , London
Ms Kay Pattison
Senior NIHR Programme
Manager, Department of
Health
Dr Morven Roberts,
Clinical Trials Manager, MRC,
London
Dr Ursula Wells
PRP, DH, London
Interventional Procedures Panel
Members
Chair,
Professor Jonathan Michaels,
Consultant Surgeon &
Honorary Clinical Lecturer,
University of Sheffield
Mr David P Britt,
Service User Representative,
Cheshire
Mr Sankaran
ChandraSekharan,
Consultant Surgeon, Colchester
Hospital University NHS
Foundation Trust
Professor Nicholas Clarke,
Consultant Orthopaedic
Surgeon, Southampton
University Hospitals NHS Trust
Mr Seamus Eckford,
Consultant in Obstetrics &
Gynaecology, North Devon
District Hospital
Dr Nadim Malik,
Consultant Cardiologist/
Honorary Lecturer, University
of Manchester
Professor David Taggart,
Consultant Cardiothoracic
Surgeon, John Radcliffe
Hospital
Mr Hisham Mehanna,
Consultant & Honorary
Associate Professor, University
Hospitals Coventry &
Warwickshire NHS Trust
Dr Matthew Hatton,
Consultant in Clinical
Oncology, Sheffield Teaching
Hospital Foundation Trust
Dr John Holden,
General Practitioner, Garswood
Surgery, Wigan
Dr Jane Montgomery,
Consultant in Anaesthetics and
Critical Care, South Devon
Healthcare NHS Foundation
Trust
Dr Simon Padley,
Consultant Radiologist, Chelsea
& Westminster Hospital
Dr Ashish Paul,
Medical Director, Bedfordshire
PCT
Dr Sarah Purdy,
Consultant Senior Lecturer,
University of Bristol
Mr Michael Thomas,
Consultant Colorectal Surgeon,
Bristol Royal Infirmary
Professor Yit Chiun Yang,
Consultant Ophthalmologist,
Royal Wolverhampton Hospitals
NHS Trust
Mrs Isabel Boyer,
Service User Representative,
London
135
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
Health Technology Assessment programme
Pharmaceuticals Panel
Members
Chair,
Professor Imti Choonara,
Professor in Child Health,
University of Nottingham
Deputy Chair,
Dr Lesley Wise,
Unit Manager,
Pharmacoepidemiology
Research Unit, VRMM,
Medicines & Healthcare
Products Regulatory Agency
Mrs Nicola Carey,
Senior Research Fellow,
School of Health and Social
Care, The University of
Reading
Mr John Chapman,
Service User Representative
Dr Peter Elton,
Director of Public Health,
Bury Primary Care Trust
Professor Robin Ferner,
Consultant Physician and
Director, West Midlands Centre
for Adverse Drug Reactions,
City Hospital NHS Trust,
Birmingham
Dr Ben Goldacre,
Research Fellow, Division of
Psychological Medicine and
Psychiatry, King’s College
London
Dr Dyfrig Hughes,
Reader in Pharmacoeconomics
and Deputy Director, Centre
for Economics and Policy in
Health, IMSCaR, Bangor
University
Dr Yoon K Loke,
Senior Lecturer in Clinical
Pharmacology, University of
East Anglia
Professor Femi Oyebode,
Consultant Psychiatrist
and Head of Department,
University of Birmingham
Dr Bill Gutteridge,
Medical Adviser, London
Strategic Health Authority
Dr Andrew Prentice,
Senior Lecturer and Consultant
Obstetrician and Gynaecologist,
The Rosie Hospital, University
of Cambridge
Mr Simon Reeve,
Head of Clinical and CostEffectiveness, Medicines,
Pharmacy and Industry Group,
Department of Health
Dr Heike Weber,
Programme Manager,
Medical Research Council
Dr Martin Shelly,
General Practitioner, Leeds,
and Associate Director, NHS
Clinical Governance Support
Team, Leicester
Dr Gillian Shepherd,
Director, Health and Clinical
Excellence, Merck Serono Ltd
Mrs Katrina Simister,
Assistant Director New
Medicines, National Prescribing
Centre, Liverpool
Mr David Symes,
Service User Representative
Observers
Ms Kay Pattison
Senior NIHR Programme
Manager, Department of
Health
Dr Ursula Wells,
Principal Research Officer,
Department of Health
Psychological and Community Therapies Panel
Members
Chair,
Professor Scott Weich,
Professor of Psychiatry,
University of Warwick
Dr Steve Cunningham,
Consultant Respiratory
Paediatrician, Lothian Health
Board
Professor Jane Barlow,
Professor of Public Health in
the Early Years, Health Sciences
Research Institute, Warwick
Medical School
Dr Anne Hesketh,
Senior Clinical Lecturer in
Speech and Language Therapy,
University of Manchester
Dr Sabyasachi Bhaumik,
Consultant Psychiatrist,
Leicestershire Partnership NHS
Trust
Mrs Val Carlill,
Service User Representative,
Gloucestershire
Ms Mary Nettle,
Mental Health User Consultant,
Gloucestershire
Professor John Potter,
Professor of Ageing and Stroke
Medicine, University of East
Anglia
Dr Howard Ring,
Consultant & University
Lecturer in Psychiatry,
University of Cambridge
Dr Karen Roberts,
Nurse/Consultant, Dunston Hill
Hospital, Tyne and Wear
Dr Yann Lefeuvre,
GP Partner, Burrage Road
Surgery, London
Dr Greta Rait,
Senior Clinical Lecturer and
General Practitioner, University
College London
Dr Karim Saad,
Consultant in Old Age
Psychiatry, Coventry &
Warwickshire Partnership Trust
Dr Jeremy J Murphy,
Consultant Physician &
Cardiologist, County Durham &
Darlington Foundation Trust
Dr Paul Ramchandani,
Senior Research Fellow/Cons.
Child Psychiatrist, University of
Oxford
Dr Alastair Sutcliffe,
Senior Lecturer, University
College London
Professor Tom Walley,
HTA Programme Director,
Liverpool
Dr Ursula Wells,
Policy Research Programme,
DH, London
Mr John Needham,
Service User, Buckingmashire
Dr Simon Wright,
GP Partner, Walkden Medical
Centre, Manchester
Observers
Ms Kay Pattison
Senior NIHR Programme
Manager, Department of
Health
Dr Morven Roberts,
Clinical Trials Manager, MRC,
London
136
Current and past membership details of all HTA programme ‘committees’ are available from the HTA website (www.hta.ac.uk)
Health Technology Assessment 2010; Vol. 14: No. 47
DOI: 10.3310/hta14470
Expert Advisory Network
Members
Professor Douglas Altman,
Professor of Statistics in
Medicine, Centre for Statistics
in Medicine, University of
Oxford
Professor John Bond,
Professor of Social Gerontology
& Health Services Research,
University of Newcastle upon
Tyne
Professor Andrew Bradbury,
Professor of Vascular Surgery,
Solihull Hospital, Birmingham
Mr Shaun Brogan,
Chief Executive, Ridgeway
Primary Care Group, Aylesbury
Mrs Stella Burnside OBE,
Chief Executive, Regulation
and Improvement Authority,
Belfast
Ms Tracy Bury,
Project Manager, World
Confederation for Physical
Therapy, London
Professor Iain T Cameron,
Professor of Obstetrics and
Gynaecology and Head of the
School of Medicine, University
of Southampton
Dr Christine Clark,
Medical Writer and Consultant
Pharmacist, Rossendale
Professor Collette Clifford,
Professor of Nursing and
Head of Research, The
Medical School, University of
Birmingham
Mr Jonothan Earnshaw,
Consultant Vascular Surgeon,
Gloucestershire Royal Hospital,
Gloucester
Professor Allen Hutchinson,
Director of Public Health and
Deputy Dean of ScHARR,
University of Sheffield
Professor Miranda Mugford,
Professor of Health Economics
and Group Co-ordinator,
University of East Anglia
Professor Martin Eccles,
Professor of Clinical
Effectiveness, Centre for Health
Services Research, University of
Newcastle upon Tyne
Professor Peter Jones,
Professor of Psychiatry,
University of Cambridge,
Cambridge
Professor Jim Neilson,
Head of School of Reproductive
& Developmental Medicine
and Professor of Obstetrics
and Gynaecology, University of
Liverpool
Professor Pam Enderby,
Dean of Faculty of Medicine,
Institute of General Practice
and Primary Care, University of
Sheffield
Professor Gene Feder,
Professor of Primary Care
Research & Development,
Centre for Health Sciences,
Barts and The London School
of Medicine and Dentistry
Mr Leonard R Fenwick,
Chief Executive, Freeman
Hospital, Newcastle upon Tyne
Mrs Gillian Fletcher,
Antenatal Teacher and Tutor
and President, National
Childbirth Trust, Henfield
Professor Jayne Franklyn,
Professor of Medicine,
University of Birmingham
Mr Tam Fry,
Honorary Chairman, Child
Growth Foundation, London
Professor Fiona Gilbert,
Consultant Radiologist and
NCRN Member, University of
Aberdeen
Professor Barry Cookson,
Director, Laboratory of Hospital
Infection, Public Health
Laboratory Service, London
Professor Paul Gregg,
Professor of Orthopaedic
Surgical Science, South Tees
Hospital NHS Trust
Dr Carl Counsell,
Clinical Senior Lecturer in
Neurology, University of
Aberdeen
Bec Hanley,
Co-director, TwoCan Associates,
West Sussex
Professor Howard Cuckle,
Professor of Reproductive
Epidemiology, Department
of Paediatrics, Obstetrics &
Gynaecology, University of
Leeds
Dr Katherine Darton,
Information Unit, MIND – The
Mental Health Charity, London
Professor Carol Dezateux,
Professor of Paediatric
Epidemiology, Institute of Child
Health, London
Mr John Dunning,
Consultant Cardiothoracic
Surgeon, Papworth Hospital
NHS Trust, Cambridge
Dr Maryann L Hardy,
Senior Lecturer, University of
Bradford
Mrs Sharon Hart,
Healthcare Management
Consultant, Reading
Professor Robert E Hawkins,
CRC Professor and Director
of Medical Oncology, Christie
CRC Research Centre,
Christie Hospital NHS Trust,
Manchester
Professor Richard Hobbs,
Head of Department of Primary
Care & General Practice,
University of Birmingham
Professor Alan Horwich,
Dean and Section Chairman,
The Institute of Cancer
Research, London
Professor Stan Kaye,
Cancer Research UK Professor
of Medical Oncology, Royal
Marsden Hospital and Institute
of Cancer Research, Surrey
Dr Duncan Keeley,
General Practitioner (Dr Burch
& Ptnrs), The Health Centre,
Thame
Dr Donna Lamping,
Research Degrees Programme
Director and Reader in
Psychology, Health Services
Research Unit, London School
of Hygiene and Tropical
Medicine, London
Mr George Levvy,
Chief Executive, Motor
Neurone Disease Association,
Northampton
Mrs Julietta Patnick,
National Co-ordinator, NHS
Cancer Screening Programmes,
Sheffield
Professor Robert Peveler,
Professor of Liaison Psychiatry,
Royal South Hants Hospital,
Southampton
Professor Chris Price,
Director of Clinical Research,
Bayer Diagnostics Europe,
Stoke Poges
Professor William Rosenberg,
Professor of Hepatology
and Consultant Physician,
University of Southampton
Professor James Lindesay,
Professor of Psychiatry for the
Elderly, University of Leicester
Professor Peter Sandercock,
Professor of Medical Neurology,
Department of Clinical
Neurosciences, University of
Edinburgh
Professor Julian Little,
Professor of Human Genome
Epidemiology, University of
Ottawa
Dr Susan Schonfield,
Consultant in Public Health,
Hillingdon Primary Care Trust,
Middlesex
Professor Alistaire McGuire,
Professor of Health Economics,
London School of Economics
Dr Eamonn Sheridan,
Consultant in Clinical Genetics,
St James’s University Hospital,
Leeds
Professor Rajan Madhok,
Medical Director and Director
of Public Health, Directorate
of Clinical Strategy & Public
Health, North & East Yorkshire
& Northern Lincolnshire
Health Authority, York
Professor Alexander Markham,
Director, Molecular Medicine
Unit, St James’s University
Hospital, Leeds
Dr Peter Moore,
Freelance Science Writer,
Ashtead
Dr Andrew Mortimore,
Public Health Director,
Southampton City Primary
Care Trust
Dr Sue Moss,
Associate Director, Cancer
Screening Evaluation Unit,
Institute of Cancer Research,
Sutton
Dr Margaret Somerville,
Director of Public Health
Learning, Peninsula Medical
School, University of Plymouth
Professor Sarah Stewart-Brown,
Professor of Public Health,
Division of Health in the
Community, University of
Warwick, Coventry
Professor Ala Szczepura,
Professor of Health Service
Research, Centre for Health
Services Studies, University of
Warwick, Coventry
Mrs Joan Webster,
Consumer Member, Southern
Derbyshire Community Health
Council
Professor Martin Whittle,
Clinical Co-director, National
Co-ordinating Centre for
Women’s and Children’s
Health, Lymington
137
© 2010 Queen’s Printer and Controller of HMSO. All rights reserved.
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your views about this report.
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your comments. If you prefer, you can send your comments
to the address below, telling us whether you would like
us to transfer them to the website.
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