Follow-up of women with epithelial ovarian cancer

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Follow-up of women with
epithelial ovarian cancer:
a systematic review
July 2010
Funded by the Australian Government Department of Health and Ageing
Follow-up of women with epithelial ovarian cancer: a systematic review
was developed by:
National Breast and Ovarian Cancer Centre (NBOCC)
Level 1 Suite 103/355 Crown Street Surry Hills NSW 2010
Tel: 61 2 9357 9400 Fax: 61 2 9357 9477 Freecall: 1800 624 973
Website: www.nbocc.org.au
© National Breast and Ovarian Cancer Centre 2010
ISBN Online: 9781741271584
This work is copyright. Apart from any use as permitted under the Copyright Act 1968, no part
might be reproduced by any process without prior written permission from National Breast and
Ovarian Cancer Centre. Requests and enquiries concerning reproduction and rights should be
addressed to National Breast and Ovarian Cancer Centre.
Copies of this report can be downloaded from National Breast and Ovarian Cancer Centre’s
website: www.nbocc.org.au.
Recommended citation
National Breast and Ovarian Cancer Centre. Follow-up of women with epithelial ovarian cancer:
a systematic review. National Breast and Ovarian Cancer Centre, Surry Hills, NSW, 2010.
Disclaimer
National Breast and Ovarian Cancer Centre does not accept any liability for any injury, loss or
damage incurred by use of or reliance on the information. National Breast and Ovarian Cancer
Centre develops material based on the best available evidence, however it cannot guarantee
and assumes no legal liability or responsibility for the currency or completeness of the information.
National Breast and Ovarian Cancer Centre is funded by the Australian Government Department
of Health and Ageing.
Contents
Acknowledgments............................................................................................................................. v
Executive summary ........................................................................................................................... 1
1
2
3
Background ........................................................................................................................... 2
1.1
Ovarian cancer in Australia .........................................................................................2
1.2
Clinical practice guidelines .........................................................................................2
1.3
Follow-up of women with ovarian cancer ................................................................3
Methods ................................................................................................................................. 4
2.1
Inclusion criteria .............................................................................................................4
2.2
Literature search ............................................................................................................5
2.3
Data extraction..............................................................................................................7
Results..................................................................................................................................... 8
3.1
International guidelines ................................................................................................8
3.2
Systematic reviews ..................................................................................................... 10
3.3
Included studies .......................................................................................................... 10
3.4
Additional papers of interest .................................................................................... 30
3.5
Ongoing trials .............................................................................................................. 31
4
Discussion ............................................................................................................................ 32
5
Conclusions ......................................................................................................................... 34
Appendix A Contributors ................................................................................................................. 35
Appendix B Literature databases searched .................................................................................. 36
Appendix C Search strategy .......................................................................................................... 37
Appendix D Guideline and clinical trial sites searched ............................................................... 38
Appendix E Flowchart of inclusion/exclusion ............................................................................... 39
Abbreviations ................................................................................................................................... 40
References........................................................................................................................................ 41
Follow-up of women with epithelial ovarian cancer
Tables
Table 1. International guidelines for follow-up of invasive epithelial ovarian cancer .................. 8
Table 2. International guidelines for follow-up of borderline ovarian cancer..............................10
Table 3. Characteristics of included studies (full text papers) ........................................................12
Table 4. Diagnostic accuracy of PET to detect ovarian cancer recurrence...............................19
Table 5. Reported follow-up schedules ..............................................................................................22
Table 6. Follow-up schedule suggested by von Georgi 200424 ......................................................23
Table 7. Domains of information, advice and coping strategies for telephone followup14 .......................................................................................................................................28
Table 8. Follow-up schedule suggested by MacLaughlan 200931 for ovarian tumours of
low malignant potential ...................................................................................................29
iv
Follow-up of women with epithelial ovarian cancer
Acknowledgments
This report was developed by National Breast and Ovarian Cancer Centre (NBOCC).
Funding
Funding for the development of this report was provided by the Australian Government
Department of Health and Ageing.
Contributors
NBOCC gratefully acknowledges the support of the many individuals who contributed to the
development of this report.
See Appendix A for more information.
Follow-up of women with epithelial ovarian cancer
Executive summary
Follow-up has been defined as “a set of visits and examinations conducted in a systematic
manner in the perspective of a pre-defined program”.1 Previous clinical practice guidelines
from National Breast Cancer Centre (NBCC)* and Australian Cancer Network (ACN) on the
management of epithelial ovarian cancer, published in 2004, included information on followup care after treatment of ovarian cancer. National Breast and Ovarian Cancer Centre
(NBOCC) undertook a systematic review of literature published between January 2003 and
January 2010 to update this information.
There was limited high level evidence available, with only one randomised controlled trial
identified; the remaining studies were retrospective or observational. The systematic review
found that symptoms and measurement of CA125 levels were the most common method of
detection of recurrence, as part of follow-up. From the available evidence, it is unclear
whether the method of detection of recurrence impacts on overall survival. The randomised
controlled trial reported no differences in overall survival between early and delayed
treatment with chemotherapy based on rising CA125 levels alone. No studies were identified
which compared different follow-up intervals, sequence or duration. Common methods of
follow-up included history and physical examination, CA125 and ultrasound, while common
schedules included 3 monthly visits for years 1 and 2, 6 monthly visits for years 3 to 5, and
annually for years 6 to 10.
While there were similarities in preferences and perceptions of follow-up between patients
and health professionals in two studies identified, there were also some differences.
Monitoring of disease progression was perceived as important by both patients and health
professionals. Health professionals reported the most important part of the visit was the
consultation and another reason for follow-up was for women to talk about their concerns.
Patients and health professionals both acknowledged a potential role in follow-up for
general practitioners (GPs) and/or nurses, however the extent of this potential involvement
varied.
Ovarian cancer patients experience a range of psychological issues after treatment.
Improvements in psychological issues were reported after participation in pilot follow-up
studies.
While no trials comparing different models of follow-up care were identified, a pilot study of
nurse-led telephone follow-up was identified.
In February 2008 National Breast Cancer Centre incorporating the Ovarian Cancer Program (NBCC) changed its
name to National Breast and Ovarian Cancer Centre (NBOCC)
*
Follow-up of women with epithelial ovarian cancer
1
Background
1.1
Ovarian cancer in Australia
In 2006, ovarian cancer was the ninth most commonly diagnosed cancer among Australian
women (excluding non-reportable skin cancers) and the second most commonly diagnosed
gynaecological cancer, with a total of 1,226 ovarian cancer cases diagnosed.2 It is the sixth
most common cause of cancer-related death for Australian women, and the most common
cause of gynaecological cancer death, representing over half (55%) of such deaths.
Ovarian cancer is often diagnosed at an advanced stage, when treatment is less likely to be
effective. While most women respond to treatment initially, the cancer often recurs. There
has been some improvement in survival in the last twenty years, however the prognosis for
women with ovarian cancer is relatively poor, with only 40% of women likely to survive five
years post-diagnosis.2
1.2
Clinical practice guidelines
The need to review the evidence and revise existing information about follow-up for women
with epithelial ovarian cancer was identified following consultation with a range of
stakeholders and advisors.
National Breast Cancer Centre (NBCC) and Australian Cancer Network (ACN) released the
Clinical practice guidelines for the management of women with epithelial ovarian cancer in
2004,3 which included a chapter about follow-up.
There were no recommendations regarding follow-up. However, a common follow-up
program/schedule was included:

review every 23 months for 2 years then;

review every 4 months for the next 2 years then;

review 6 monthly for a year before moving to annual review.
The basic format for follow-up was stated as: an updated history, physical examination
including pelvic examination, and blood taken for CA125. Radiological imaging should not
be done routinely but should be performed if there is clinical or CA125 evidence of
recurrence.
2
Follow-up of women with epithelial ovarian cancer
1.3
Follow-up of women with ovarian cancer
Follow-up has been defined as “a set of visits and examinations conducted in a systematic
manner in the perspective of a pre-defined program”.1 While some common elements are
included in most follow-up regimens, they have usually been developed by consensus or to
reflect the approach of individual institutions, rather than on the basis of evidence.
While there is no evidence to show that follow-up of women with epithelial ovarian cancer
has any impact on survival outcomes, follow-up for women who have completed active
treatment, either first line or for subsequent recurrence, may be undertaken for a number of
reasons. These include appropriate medical review, detection of recurrence, treatment of
side effects and physical and emotional support for the woman.
A recent survey of Australian gynaecological oncologists investigated their current practice
for the follow-up of asymptomatic women following treatment for invasive ovarian cancer.
All respondents conducted a physical examination and most checked CA125 levels, but few
routinely used computed tomography (CT) scans. Most indicated that the woman’s
preference determined the format of the follow-up. When asked about their usual practice
for follow-up for an asymptomatic woman with a raised CA125 but negative clinical findings,
more variation in practice was evident in areas such as the use of serial CA125 and imaging
techniques (NBOCC/ASGO 2010, unpublished data).
Findings from a randomised controlled trial comparing early treatment of recurrence based
on elevated CA125 levels alone to delaying treatment until clinical indications were present4
has promoted discussion about follow-up practices amongst clinicians involved in the
management of women with ovarian cancer.
The purpose of this review was to identify evidence published from January 2003 to January
2010 about follow-up of women with epithelial ovarian cancer.
Follow-up of women with epithelial ovarian cancer
2
Methods
The objective of the review was to investigate follow-up procedures for women who have
completed active treatment for epithelial ovarian cancer.
Research questions addressed in this systematic review are:

Does the method of detection of a recurrence influence outcomes?

What is the optimal interval, sequence and duration of follow-up care?

What are the patient’s preferences for follow-up care?

What are the health care providers’ preferences for follow-up care?

What evidence surrounds the role of follow-up care in psychosocial outcomes for
women?

Are there subsets of the defined population who have specific follow-up
requirements?

Do different models of conducting follow-up influence outcomes?
2.1
2.1.1
Inclusion criteria
Participants
Women who have completed active
radiotherapy) for epithelial ovarian cancer.
2.1.2
treatment
(surgery,
chemotherapy
and/or
Intervention
Routine follow-up care for the purpose of detecting recurrence and/or new primary cancer,
monitoring side effects of treatment and providing psychosocial care.
Standard follow-up procedures include medical history, physical examination including
pelvic examination and rectal examination, and CA125 blood test. Intensive follow-up
procedures include radiological imaging.
2.1.3
Comparison
Any comparisons of different types of follow-up care were recorded.
4
Follow-up of women with epithelial ovarian cancer
2.1.4
Outcome measures
Outcome measures of interest were:

overall survival (OS)

disease free survival (DFS)

detection of recurrence/new primary cancer

diagnostic accuracy

quality of life (QoL)

patient preferences

provider preferences

psychosocial outcomes

information needs

sexual health and sexuality

anxiety reduction.
2.1.5
Additional issues of interest
The following additional areas of interest were not specifically searched for, however any
information on these identified during the search was recorded:

are there differences in access to follow-up for women with epithelial ovarian cancer
in Australia?

follow-up for other cancers arising from treatment

high-risk mutation carriers

effects of treatment on long term survivors.
2.2
Literature search
A systematic literature search was conducted in January 2010 to identify relevant trials which
addressed the inclusion criteria. The search was conducted using several databases (see
Appendix B), including:

Medline (OVID)

Embase (OVID)
Follow-up of women with epithelial ovarian cancer

Pubmed

Cochrane library.
Additional papers identified from personal files and the reference lists of included papers
were also sourced.
The search strategy, developed with input from a multidisciplinary working group, used
combined key terms which described epithelial ovarian cancer and follow-up (see Appendix
C). The search was limited to trials conducted in humans which were published from January
2003 to January 2010 in the English language.
After the removal of duplicate citations and the addition of further citations sourced, a total
of 626 unique citations remained. The titles and abstracts of these citations were assessed by
two reviewers independently to determine eligibility for the current review based on the
criteria described above. Ineligible studies were classified using the exclusion criteria below.
For citations which provided insufficient information to assess eligibility, the full text was
retrieved for assessment, by the same two reviewers.
In addition to the above databases, guideline and clinical trial websites were searched for
relevant information. Specific international guideline organisations were searched as well as
the National Guidelines Clearinghouse and the Guidelines International Network (GIN)
guideline database. Further information on sites searched can be found in Appendix D.
The following conference websites were searched from January 2006 to March 2010 to
identify recently presented abstracts about follow-up for ovarian cancer:

American Society of Clinical Oncology (ASCO) annual meeting

International Gynecologic Cancer Society (IGCS) biennial meeting

Society of Gynecologic Oncologists (SGO) annual meeting.
2.2.1
Exclusion criteria
Papers were excluded if they met any of the following criteria:
6

not an original clinical study–publications not reporting the findings of original clinical
studies including non-systematic reviews, editorials, opinion pieces and letters

inappropriate population–studies conducted in a population other than patients
treated for epithelial ovarian cancer. Studies that were conducted in a general
cancer population were included only if data on ovarian cancer patients were
reported separately

inappropriate intervention–studies not investigating follow-up as defined in the
inclusion criteria. Studies investigating diagnostic follow-up procedures (after clinical
suspicion of recurrence) were not included

inappropriate outcomes–studies not reporting on the effect of follow-up
Follow-up of women with epithelial ovarian cancer

not published in the English language

published prior to 2003.
Based on these criteria, 560 articles were excluded. The full texts of the remaining 66 citations
were retrieved and assessed to identify which met the inclusion criteria for the review. After
full text assessment, 14 citations were identified as eligible for the current review (see
Appendix E). An additional paper reporting full results of a randomised controlled trial in one
of the included abstracts was published after the search was completed. This has been
incorporated into the relevant sections, bringing the number of citations included in the
review to 15.
Full text citations for the review included:

one guideline recommendation

two systematic reviews – both on diagnostic accuracy for detection of recurrence

one randomised controlled trial on early vs. delayed chemotherapy for recurrence

five retrospective cohort studies on method of detection

two pilot studies

four qualitative/observational papers – one on patterns of care, three on patient
preferences/satisfaction.
In addition to the peer-reviewed publications, two national guidelines were identified, along
with two guidelines for individual Canadian provinces. The conference search identified
eight abstracts of interest including one for the randomised controlled trial now published
and included in this systematic review.
2.3
Data extraction
Data extraction was performed by one reviewer and verified by a second reviewer to ensure
accuracy. Descriptive data extracted from the studies included characteristics such as
population, interventions and primary outcomes. Schedules and procedures of follow-up
care performed were also recorded.
Outcome data extracted from the studies included OS, DFS, QoL and detection of
recurrence.
Qualitative data was also extracted on patient and/or health professional views of follow-up,
with key themes and findings reported rather than specific outcome data.
Follow-up of women with epithelial ovarian cancer
3
Results
3.1
International guidelines
A limited number of international guidelines were identified regarding follow-up of ovarian
cancer. National Comprehensive Cancer Network (NCCN) and European Society of Medical
Oncology (ESMO) provide guidance for follow-up of ovarian cancer. However many of the
statements made are based on consensus. Individual Canadian provinces have developed
their own guidelines for follow-up. The main recommendations of the guidelines are
summarised in Table 1 below. The recommendations relate to clinical visits and use of CA125,
blood tests, computed tomography (CT), magnetic resonance imaging (MRI), positron
emission tomography (PET) and chest X-rays.
Table 1. International guidelines for follow-up of invasive epithelial ovarian cancer
Guideline
Clinical visit
(history & physical
examination)
CA125
ACN/NBCC
2004†3
Every 2-3 months
for 2 years; then
every 4 months for
2 years; then 6
monthly for year 5
and annually
thereafter
May be done
each visit if
initially
elevated
Blood tests
Imaging
studies (CT,
MRI, PET)
Chest Xray
Only if
clinically
indicated
Including pelvic
examination
NCCN 20095
2-4 months for 2
years; then 3-6
months for 3
years; then
annually after 5
years
CA125 or other
tumour
markers every
visit if initially
elevated
Complete
blood
count and
chemistry
profile
as
indicated
As clinically
indicated
Physical
examination
including pelvic
examination
ESMO 20096
†
8
History, physical
examination
including pelvic
May
be
performed
This is noted as a common program not a recommended program
Follow-up of women with epithelial ovarian cancer
CT scans
should be
performed if
As
clinically
indicate
d
Guideline
Clinical visit
(history & physical
examination)
CA125
Blood tests
examination
every 3 months for
2 years, every 4
months during the
third year and
every 6 months
during years 4
and 5 or until
progression is
documented
Saskatchewan
Cancer
Agency 20097
Patients to be
followed by a
gynaecologic
oncologist every
3-4 months for two
years, then every
six months for a
total of five years
Follow-up
examination
includes physical
examination, Pap
smear and pelvic
examination
BC Cancer
Agency 20078
Every 3 months for
year 1; every 4
months year 2-3;
every 6 months
year 4-5; annually
after 5 years
General
examination,
pelvic
examination and
pelvic-rectal
examination
National
Academy of
Clinical
Biochemistry
20089
Imaging
studies (CT,
MRI, PET)
Chest Xray
there is
clinical or
CA125
evidence of
progressive
disease.
FDG-PET-CT
scans may
be superior
to CT scans
in detecting
small volume
operable
relapses
A decision as
to whether to
routinely
determine
CA125 with
each return
visit should be
individualised
following a
realistic
discussion of
the pros and
cons of such
monitoring
between the
patient and
physician
Routine
complete
blood
count
or
liver
function
tests
are
not
recommen
ded unless
clinically
indicated
Not required
other than for
the satisfaction
of research
protocol and
for specific
indications
when they
arise
Every 2
to 4 months for
2 years and
then less
frequently
Follow-up of women with epithelial ovarian cancer
Only if
clinically
indicated
Not required
other than
for the
satisfaction
of research
protocol
and for
specific
indications
when they
arise
Only if
clinically
indicate
d
ACN=Australian Cancer Network; BC=British Columbia; CT=computed tomography;
ESMO=European Society for Medical Oncology; FDG=fluorodeoxyglucose; MRI=magnetic
resonance imaging; NBCC=National Breast Cancer Centre; NCCN=National Comprehensive
Cancer Network; PET=positron emission tomography
In addition, NCCN provides guidance for follow-up of borderline epithelial ovarian cancer
(low malignant potential), as in Table 2.
Table 2. International guidelines for follow-up of borderline ovarian cancer
Guideline
NCCN
20095
Clinical visit
(history &
physical
examination)
3-6 months for
5 years; then
annually after
5 years
CA125
Blood tests
Imaging
studies (CT,
MRI, PET)
Other
CA125 or
other
tumour
markers
every visit if
initially
elevated
Complete
blood
count and
chemistry
profile
as
indicated
Ultrasound
as indicated
for patients
with fertilitysparing
surgery
After completion of
childbearing in
patients who
underwent
unilateral salpingooophorectomy,
consider
completion surgery
Physical
examination
including
pelvic
examination
CT=computed tomography; MRI=magnetic resonance imaging;
Comprehensive Cancer Network; PET=positron emission tomography
3.2
NCCN=National
Systematic reviews
A Cochrane protocol was identified on ‘Evaluation of follow-up strategies for patients with
epithelial ovarian cancer following completion of treatment’.10 The protocol was registered in
2006 but was unpublished at the time of the systematic review.
Two systematic reviews were identified focusing on diagnostic accuracy of various methods
used to detect ovarian cancer recurrence. Results are reported in the section about
Outcomes of method of detection.
3.3
Included studies
Full text papers
Only one randomised controlled trial on follow-up for ovarian cancer was identified in the
published literature. The remaining studies were retrospective or observational. However
some subgroup analyses provided survival comparisons. Some studies were identified on
diagnostic accuracy of methods of detection of recurrence. Qualitative studies reported on
patient and/or health professional views of follow-up care.
10
Follow-up of women with epithelial ovarian cancer
Abstracts
Eight abstracts were identified, including one randomised controlled trial investigating early
compared to delayed chemotherapy based on CA125 findings which has been superseded
by the full text publication.4,11 Four abstracts reported on various methods of detection, one
reported on patterns of care, one reported on patient views of follow-up and one suggested
follow-up guidelines for borderline tumours.
Follow-up of women with epithelial ovarian cancer
Table 3. Characteristics of included studies (full text papers)
Study
Design
Amsterdam
200612
Retrospective
review/cohort
Chan 200813
Retrospective
study
N=80 with ovarian cancer recurrence
Cox 200814
Retrospective
study, before &
after study
N=56
Mean 62 yrs (SD 10.89) . 49% had stage I/II and
51% had stage III/IV
Fehm 200515
Retrospective
study
N=58
Median age was 58yrs (range 25-85 years).
Majority of patients were stage III (56.9%)
Gadducci
200916
Retrospective
review of
medical records
GarciaVelloso
200717
Gu 200918
Retrospective
study
N=412 patients with recurrent ovarian cancer.
6.8% stage I, 6.6% stage II, 73% stage III (64.3%
stage IIIC), 11.4% stage IV, 2.2% unknown.
Median age at diagnosis 58 years (range 25-86
years)
N=86 (31 sub-group clinically disease free) 80%
stage III/IV
Median age 57 years (range 49-63 years)
34 studies
Havrilesky
200519
12
Systematic
review and
meta-analysis
Systematic
review
Population and ovarian cancer stage (where
available)
N=26 (27%) ovarian cancer patients
Median age: 51yrs (range 25-76 years)
92% postmenopausal
10 ovarian cancer papers; 5 of which
addressed use of surveillance PET in the
Follow-up of women with epithelial ovarian cancer
Question addressed
Outcomes
Role of follow-up in
psychosocial outcomes
Sexual symptomatology
Method of detection:
CA125, symptoms and
physical findings
Role of follow-up in
psychosocial outcomes
and other models of
follow-up
First method of detection,
survival
Method of detection:
symptoms, X-ray
diagnostics, tumour
markers (CA125),
gynaecological
examination and US
Method of detection:
clinical examination, CT
scan, US, CA125
Method of detection: PET,
CA125, conventional
radiological imaging
Method of detection:
CA125, PET alone, PET–CT,
CT and MRI
Method of detection: PET,
conventional imaging,
Detection of recurrent disease
and the identification and
management of physical and
psychological morbidity,
quality of life
Diagnostic accuracy
Overall survival, survival from
recurrence, method of
detection of recurrence
Diagnostic accuracy
Diagnostic accuracy
Diagnostic accuracy
Study
Design
Kew 200620
Observational
survey
Kew 200721
Observational
survey
Lydon
200922
Observational
focus groups
Palmer
200623
Observational
survey
Rustin 20104
Randomised
controlled trial
Population and ovarian cancer stage (where
available)
absence of clinical suspicion of which 3 were
used to calculated pooled diagnostic accuracy
24 responses. 23 out of 24 responses were from
cancer centres. 75% networks had written
guidelines
96 patients (92% response rate), 32 health
professionals (58% response rate) patients with
gynaecological malignancy: 32% ovarian, 14%
corpus, 24% cervix, 9% vulva, 1% vagina, 19%
unknown
Median age 58 years (29-88 years)
Patient focus group (n=6); health professionals
focus group (n=7)
Patients who had completed treatment for
ovarian cancer: mean 64yrs, time since
completion of first-line chemotherapy treatment
mean 5yrs and 3mths. Health professionals
responsible for follow-up care of ovarian cancer
patients: a nurse clinician, two research
registrars, two senior registrars, one junior
registrar and a consultant oncologist
Patients on follow-up for epithelial ovarian
cancer
First survey n=90 (90% response rate), second
survey n=26 out of 30 surviving patients (87%
response rate)
N=529 patients in remission after first-line
treatment for epithelial ovarian, fallopian tube,
or serous primary peritoneal cancer, in whom
CA125 concentration increased to twice the
upper limit of normal during follow-up. ~8%
stage I, 11% stage II, 68% stage III, 12% stage IV
Follow-up of women with epithelial ovarian cancer
Question addressed
Outcomes
CA125
Optimal interval,
sequence and duration
of follow-up care
Patterns of follow-up care provider of follow-up care,
frequency & duration
Patients’ & health care
provider’s preferences
and perceptions for
follow-up care
Views on follow-up
Patients’ & health care
provider’s preferences
and perceptions for
follow-up care
Views on routine follow-up
after treatment for ovarian
cancer
Patient’s & health
provider preferences and
perceptions for follow-up
care
Questionnaire 1: assess
patients in the follow-up clinic
with their current CA125 result
Questionnaire 2: assessment of
change in practice & patient
satisfaction
Overall survival, time to
second-line chemotherapy,
time to third-line treatment or
death, quality of life
Method of detection:
CA125, symptoms
Study
Population and ovarian cancer stage (where
available)
Median age 60-61 years (53-68 years)
Retrospective
von Georgi
N=704 with ovarian cancer:42.5% stage I,
review of
200424
23.7% stage II, 29.3% stage III, 4.5% stage IV;
medical records Mean age at time of diagnosis 56.9yrs
N=186 cases with documented primary
recurrence
CT=computed
tomography;
MRI=magnetic
resonance
imaging;
14
Design
Follow-up of women with epithelial ovarian cancer
Question addressed
Outcomes
Method of detection:
CA125, symptoms, X-ray
and physical findings
Efficiency of follow-up
measures
PET=positron
emission
tomography;
US=ultrasound
3.3.1
Impact of method of detection on patient outcomes
Five full text papers and two abstracts reported on the method by which ovarian cancer
recurrence was first detected. Three full text papers and one abstract reported on overall
survival based on method of detection of recurrence and two full text papers and one
abstract provided survival information by time to treatment of recurrence. Four papers
reported the diagnostic accuracy of methods to detect ovarian cancer recurrence,
including two systematic reviews.
Method of detection of recurrences
Full text papers
Five full text papers reported on the method by which ovarian cancer recurrence was first
detected.
Chan et al (2008) retrospectively reviewed records from 80 women with ovarian cancer
recurrences to determine how the recurrences were first detected (method of detection).13
At each follow-up visit, a history of any symptoms was obtained and a physical examination
performed. Physical examination included routine palpation for enlarged lymph nodes and
abdominal or pelvic masses and a pelvic examination including a speculum examination
and a vaginal and recto-vaginal bimanual examination, as well as any symptom-directed
examination. CA125 was checked at each visit. If recurrence was suspected, further
investigations such as CT or PET scans or biopsy of the suspected recurrence were arranged.
Forty-nine patients first presented with a raised CA125 level. Twenty-eight patients first
presented with symptoms and only three first presented with physical findings. Overall, 91%
had raised CA125, 55% had symptoms and 52.5% had positive physical findings. Of the 9%
without a raised CA125, all had symptoms with (6.3%) or without (2.5%) physical findings. No
patient presented with physical findings alone.13
The distribution of patients with elevated CA125, symptoms and physical findings at tumour
recurrence was as follows:13

CA125 alone 26.3%

symptoms alone 2.5%

physical findings alone 0%

CA125 + symptoms 20%

CA125 + physical findings 18.8%

symptoms + physical findings 6.3%

CA125 + symptoms + physical findings 26.3%.
Follow-up of women with epithelial ovarian cancer
The most commonly reported symptoms were abdominal pain, abdominal
discomfort/distension, nausea/vomiting and shortness of breath. Physical findings reported
included a mass, ascites, enlarged lymph node and pleural effusion.13
A retrospective review conducted by von Georgi and colleagues (2004)24 of 704 ovarian
cancer patients with no evidence of disease post primary therapy and reported on the
effect of follow-up, including method and time of detection on patients’ overall survival. The
study recorded if and where follow-up was provided, and what method led to the diagnosis
of recurrence.24 Of those attending follow-up (n=610): 47.2% attended follow-up visits at the
university clinic, 7.5% at other clinics, 9.5% at gynaecologists, or a combination 35.7%. Ninetyfour patients (13.4%) did not attend any follow-up. There were 186 cases with documented
primary recurrence. The methods which led to the diagnosis of cancer recurrence were
reported as follows: 28% by patients' complaints, 29% by X-ray diagnostic, 19.4% tumour
marker serum levels, 15.1% gynaecological examination, 8.6% by ultrasound.24
A retrospective study by Fehm et al (2005) of 58 patients with recurrent ovarian cancer
compared the sensitivity of tumour marker measurement and physical findings with
radiological findings in detecting recurrence.15 At the time of diagnosis of the recurrence,
60% of patients complained about symptoms which were mainly abdominal pain and
constipation, 40% were symptom-free and reported well-being. The physical examination
resulted in pathological findings in 78% of patients. Physical findings reported included pelvic
tumour masses, ascites, enlarged lymph node and tumour infiltration of the rectum. CA125
serum levels were available from 54 of the 58 patients when recurrent disease was
diagnosed. In 83% of patients, CA125 serum levels were elevated.15 In 47 out of 54 patients,
vaginal and abdominal ultrasound were performed when recurrent disease was diagnosed.
Thirty-three of the 47 patients had pathological findings. Forty-two patients received CT scans
of the pelvis and abdomen. Tumour recurrence was detected in 33 of these patients (80%).
Combination of physical examination, gynaecological examination and CA125
determination was able to identify 98% of patients with ovarian cancer recurrence without
any imaging techniques. CA125 had the highest sensitivity followed by CT scan and physical
examination.15 For patients with a pelvic recurrence, vaginal examination had the highest
sensitivity, followed by vaginal ultrasound and CT scan. Note that none of these procedures
provided false-positive results.15
Gadducci et al (2009) conducted a retrospective review of 412 patients with recurrent
ovarian cancer.16 Among the 331 asymptomatic ovarian cancer patients, the surveillance
procedures which raised suspicion of recurrent disease were:
16

clinical examination 14.8%

CT scan 26.6%

ultrasound 0.6%

CA125 23.3%

CA125 and imaging technique 34.7%.
Follow-up of women with epithelial ovarian cancer
In a retrospective study on the use of PET to detect recurrence reported by Garcia-Velloso et
al17 (2007), the findings on PET changed management in 11 (out of 31) patients considered
clinically disease-free, with positive findings altering the plan from follow-up to treatment. In
55 patients with suspected recurrence, PET changed management in 27 patients: four were
changed from surgery to follow-up, 23 were changed from follow-up to treatment.17
Abstracts
Results on detection of recurrence from a retrospective study of 79 stage IIIC or IV epithelial
ovarian cancer patients who developed recurrence were presented at the SGO 2009
meeting.25 The first evidence of recurrence was CA125 elevation (78.5%), positive clinical
findings on physical examination (11.4%) and positive CT scan (8.9%). In addition, one patient
was incidentally found to have recurrent cancer during hernia repair. The majority of patients
with recurrence detected by physical examination presented with symptoms (7 out of 9,
77.7%). For those with asymptomatic recurrence, one had an elevated CA125 and the other
had an abnormal CT scan.25
Taylor et al (2006) reported a prospective comparison of methods of surveillance at the SGO
2006 meeting.26 One-hundred and forty-five patients were enrolled in a randomised
controlled trial comparing consolidation treatment with placebo. The follow-up procedures
used were intensive and included interval history, physical examination, and imaging (CT of
abdomen and pelvic, chest X-ray and/or ultrasound). Imaging occurred every 3 months in
the first year and every 6 months thereafter until relapse. CA125 levels were blinded and not
used to determine relapse.26 The median time to relapse from randomisation was 33 weeks.
At relapse, of the 91 patients who relapsed:

72.5% had abnormal radiologic findings without clinical findings

23.1% had abnormal clinical findings

4.4% were diagnosed surgically

33% had normal CA125 (<35).
Outcomes by method of detection
Overall survival
Three full text papers and one abstract reported overall survival based on method of
detection of recurrence. In all studies, CA125 was routinely measured, please refer to Table 3.
Chan et al (2008) reported the median survival from the time of recurrence for those who first
presented with CA125, symptoms and physical findings were 25 months, 17 months and 11
months respectively.13 There were no significant differences in survival between those who
first presented with raised CA125 and those with symptoms. Patients who first presented with
abnormal physical findings had significantly worse survival however the number in the group
was too small to draw firm survival conclusions.13 Those who had raised CA125 had
significantly worse survival than those in whom CA125 remained normal (p=0.011). The
median time to recurrence from completion of primary treatment was 12 months (range 2 –
62 months).13
Follow-up of women with epithelial ovarian cancer
von Georgi et al (2004) reported that 86.6% of patients attended follow-up, while 13.4% did
not attend any follow-up visits. Patients who attended follow-up visits had an improved
chance of survival compared to those who did not attend (p=0.004).24 There was no
difference in survival between those examined in the investigators’ university clinic
compared to those examined by generalist gynaecologists in their practices. The study found
no significant difference in prognosis between patients whose recurrences were diagnosed
by a general gynaecological examination and those by X-ray or CA125 determination. Also
there was no significant difference for time between diagnosis and death by the way
recurrence was diagnosed.24 Neither early nor delayed therapy had a statistically significant
influence on survival.
A retrospective review by Gadducci et al (2009) reported overall survival was equivalent for
patients with or without symptoms at recurrence (no vs. yes, odds ratio: 0.90, 95% CI: 0.64 to
1.27, p=0.90).16 Variables predictive of overall survival included stage of disease, residual
disease after initial surgery >1cm, time to recurrence, site of recurrence and treatment at
recurrence. Variables predictive of survival from recurrence included stage of disease,
residual disease >1cm, time to recurrence and treatment at recurrence.16
The abstract presented by Taylor et al (2009) reported that overall survival and post-relapse
survival were similar in patients diagnosed clinically or radiographically despite statistically
significantly higher CA125 levels at time of relapse (p=0.0182) in those diagnosed clinically.26
There were no differences in survival between those with normal vs. elevated CA125.26
A randomised controlled trial compared early chemotherapy for recurrence based on
elevated CA125 levels alone (n=264) to delaying treatment until clinically indicated (n=263).4
Second line chemotherapy started 4.8 months (95% CI: 3.6 to 5.3) earlier in the early
treatment arm and 64% of women in this group received six or more cycles of chemotherapy
compared to 51% in the delayed treatment group. After a median follow-up of 57 months
from randomisation, the authors reported no difference in overall survival between the early
(median survival 25.7 months) and delayed arms (median survival 27.1 months) (HR: 0.98, 95%
CI: 0.80 to 1.20, p=0.85).4 Seventy per cent of patients in both groups had died, of which
approximately 96% were disease related. Two-year survival was 53.7% in the early treatment
group and 54.7% in the delayed treatment group.4
von Georgi et al (2004) reported no difference in survival between patients who
commenced therapy for cancer recurrence 0 – 10 days, 11 – 30 days, or more than 31 days
after diagnosis of recurrence.24
A smaller US study was reported by Fleming et al as an abstract at SGO 2010 on a
retrospective review of patients with recurrent epithelial ovarian cancer (n=74) who
underwent secondary cytoreductive surgery.27 In this selected group of patients, the authors
report a correlation between a shorter length of time between ‘study interval’ (time between
CA125 elevation and date of secondary surgery) and increased incidence of optimal
cytoreduction (HR: 1.22, 95% CI: 1.00 to 1.49, p=0.05). Patients with optimal cytoreduction
were reported to have significantly longer survival than those with suboptimal cytoreduction
(47 vs. 23 months respectively, p<0.0001).27
18
Follow-up of women with epithelial ovarian cancer
Diagnostic accuracy
Studies were included if they investigated follow-up as defined in the inclusion criteria. Studies
specifically investigating diagnostic follow-up procedures (after clinical suspicion of
recurrence) were not included. Two systematic reviews were included, one separated results
between patients undergoing PET after clinical suspicion and those undergoing PET without
clinical suspicion.19 The other review18 investigated CA125, PET, CT and MRI but did not report
separate results on whether tests were performed with or without clinical suspicion. In
addition, one original study retrospectively evaluated the diagnostic yield of
fluorodeoxyglucose-positron emission tomography (FDG-PET) for the diagnosis of recurrent
ovarian cancer.17 The study included a subgroup of 31 clinically disease-free patients who
had 45 FDG-PET scans performed.
Diagnostic accuracy results from the two reviews (pooled results reported) and the
retrospective study are provided in Table 4.
Table 4. Diagnostic accuracy of PET to detect ovarian cancer recurrence
Study
Test
Sensitivity
(%)
Specificity
(%)
NPV
(%)
PPV
(%)
Accuracy
(%)
FN
FP
GarciaVelloso
200717
CIM*
53
82
39
89
61
43/125
6/125
CA125*
58
94
44
96
67
39/125
2/125
PET*
87
79
68
92
85
12/125
7/125
PET
in
clinically
disease-free
patients only
55
88
71
78
73%
9/45
3/45
PET
in
clinically
disease-free
patients
54
73
PET with rising
CA125 and
negative or
equivocal
CIM
96
80
CA125*
69
93
PET*
88
89
Havrilesky
2005^19
Gu
2009^18
Follow-up of women with epithelial ovarian cancer
PET-CT*
91
88
CT*
79
84
MRI*
75
78
CIM=conventional imaging modalities (CT scans/MRI); FN=false negative; FP=false positive;
NPV=negative predictive value; PPV=positive predictive value
*Results for whole patient cohort which included patients both with and without clinical
suspicion of recurrence; ^meta-analysis; pooled results
In a retrospective study by Garcia-Velloso et al (2007), recurrence was correctly identified in
patients clinically considered disease-free by FDG-PET studies in 11 cases (24%), with a mean
standardised uptake value (SUV) of 4.2±1.9 (median 4, range 0.8-6.5).17 This study reported
that the median relapse-free interval after a negative PET scan was 18 months compared
with 2 months if the PET scan was positive.17
One systematic review assessed the diagnostic performance of FDG-PET in comparison to
conventional imaging modalities in the assessment of patients with ovarian and cervical
cancer, and results for each cancer were reported separately19. For the review, ten papers
met the inclusion criteria for ovarian cancer. Five studies addressed use of surveillance PET to
detect recurrent or persistent ovarian cancer in the absence of clinical suspicion. Three of
these studies included at least 12 patients and required both negative CA125 and
conventional imaging studies for classification as “no clinical suspicion” prior to PET imaging.19
The pooled sensitivity and specificity of PET in these three studies was 0.54 and 0.73
respectively. Three studies addressed use of PET to detect recurrent ovarian cancer in the
setting of rising CA125 and negative or equivocal conventional imaging studies. The pooled
sensitivity and specificity were 0.96 and 0.80 respectively. Six studies addressed use of PET to
detect recurrent ovarian cancer when clinical suspicion exists. Pooled sensitivity and
specificity was 0.90 and 0.86 respectively.19
A systematic review and meta-analysis was published in 2009 evaluating the accuracy of
CA125, PET alone, PET-CT, CT and MRI in diagnosing recurrent ovarian cancer.18 Use in
clinically disease-free patients and use in those in which recurrence was suspected was not
distinguished in the review.18 From the 34 included studies, CA125 had the highest pooled
specificity (0.93) and PET-CT had the highest pooled sensitivity (0.91). PET, whether interpreted
with or without the use of CT, had higher area under a curve (AUC) than that of CT or MR
(p<0.05). No statistically significant difference was shown between PET alone and PET-CT.18
When comparing different methods of detection, specificity was highest for CA12517-18 and
sensitivity was highest for PET/PET-CT.17-18 It should be noted that these comparisons used
groups that include both clinically disease-free and those with suspicion of relapse. PET has
lower sensitivity when performed in a clinically disease-free setting compared to under
suspicion of recurrence.17,19
Taskiran et al presented an abstract at IGCS 2006 on the value of PET-CT in follow-up of
ovarian cancer patients.28 Nineteen patients were included in the analysis, four underwent
PET-CT before second look laparotomy, and 15 were examined in the follow-up period to
detect recurrence. In the follow-up group, PET-CT detected true recurrence in eight patients,
20
Follow-up of women with epithelial ovarian cancer
one patient had recurrence which was not detected by PET, the remaining six patients with
negative PET findings had no recurrence in the follow-up period (mean 21 months).28
3.3.2
Optimal interval, sequence and duration of follow-up care
No trials were identified which compared different intervals, sequence or duration of followup care for ovarian cancer patients.
Most trials reported the follow-up schedule utilised in their individual setting and details on the
different schedules reported in individual trials are provided in Table 5.
Follow-up of women with epithelial ovarian cancer
Table 5. Reported follow-up schedules
Study
Follow-up methods
Chan
200813
History and physical examination,
CA125. If recurrences suspected
further investigations such as CT or
PET scans or biopsy of the suspected
recurrence would be arranged
Physical and gynaecological vaginal
examination, CA125 and vaginal
ultrasound examination. Abdominal
ultrasound and CT scans were
performed in patients considered to
have a recurrence. Imaging
techniques were also performed at
regular intervals in patients who were
enrolled in various clinical trials
6 centres with different surveillance
protocols. CA125 regularly performed
each visit; ultrasound, CT and/or
chest X-ray were used at fixed times
by some centres and only in the
presence of suspicious symptoms or
signs as well as rising CA125 levels by
other centres
Pelvic examination and routine
CA125 measurement mirrored followup visits, while diagnostic imaging
was not a routine follow-up modality
CA125 was routinely tested by 67% of
cancer networks surveyed
Not reported
Fehm
200515
Gadducci
200916
Gibb
2006^29
Kew
2006^20
Lydon
200922
Palmer
200623
CA125
Rustin
20104
Physical and gynaecological
examinations, ultrasound and
22
Follow-up of women with epithelial ovarian cancer
Years after primary treatment
1st & 2nd
3rd to 5th
6th to 10th year
year
year
3
6
Annually≠
monthly
monthly
3
monthly
6
monthly*
6 monthly≠ *
34
monthly
46
monthly
Annually
3
monthly
6 monthly
Annually
3
monthly
3
monthly
6 monthly
2
monthly
for first
year,
3
monthly
for the
second
year
3
monthly
4 monthly
for third
year,
6 monthly
for further
2 years
6 monthly
6 monthly. At
10 years,
patients were
discharged
back to their
GP
Discharged or
reviewed
annually
according to
their wishes
radiological examinations according
to local practice, quality of life
assessment, CA125 blood test
≠follow-up continues beyond 10 years; *seen at outpatient department; ^most commonly
reported schedule/suggested schedule
von Georgi et al (2004) have suggested the following treatment schedule (Table 6):24
Table 6. Follow-up schedule suggested by von Georgi 200424
Method
Years after primary treatment
1st & 2nd year
3rd to 5th year
6th to 10th year
Every 3 months
Every 6 months
Every 12 months
Gynaecologic
examination
including
transvaginal
ultrasound
Every 3 months
Every 6 months
Every 12 months
Tumour
markers
CA125, CA72-4
Suspected
only
Every 6 months
Every 12 months
MRI, CT scans, X-ray
diagnostic,
ultrasound
In cases of suspected relapse only, especially for the development of
treatment plans
Mammography
Every 12 months
Medical
consultation
history
relapse
CT=computed tomography; MRI=magnetic resonance imaging
Kew et al (2006) report on a survey of practice of 24 cancer networks in UK providing routine
follow-up after treatment for a gynaecological cancer.20 Seventy-five per cent of the
networks had written guidelines on frequency and timing of follow-up for gynaecological
cancer. Very few routine investigations were undertaken to detect recurrence. The
exception was CA125 levels following treatment for ovarian cancer with 16 out of 24
networks (67%) routinely performed this test at each follow-up review.20 The most common
schedule for ovarian cancer follow-up was Year 1: 3 monthly (88%); Year 2: 3 monthly (46%);
Year 3: 6 monthly (42%); Year 4: 6 monthly (50%); Year 5: 6 monthly (42%). The most commonly
reported duration of follow-up was for 5 years (62.5%) followed by 10 years (29.2%), and
lifelong (4.2%); data were missing for one network (4.2%). Twenty-five per cent of the
networks reported using ‘open access’ as part of their follow-up service.20
Gibb et al (2006) reported an abstract on patterns of follow-up care for ovarian cancer
patients at SGO 2006.29 A questionnaire was completed by 323 SGO members (of 943
members, response rate 34%) to assess current follow-up care practice for stage I, II and III,
optimally and suboptimally debulked patients who had not yet recurred.29 After exclusion
Follow-up of women with epithelial ovarian cancer
due to incomplete responses or lack of long-term follow-up, responses from 283 members
were used for analysis. Patients were seen, on average, every 3 months for years 1 and 2,
every 6 months in years 3 to 5 and annually at year 10. Pelvic exams and CA125
measurement were routinely used, however diagnostic imaging was not.29
3.3.3
Patients’ & health care provider’s preferences and perceptions of
follow-up care
Four full text papers and two abstracts provided information on patients’ and/or health
professionals’ views on follow-up. In a small study from the UK, Lydon et al22 (2009) reported
views of follow-up care from two focus groups in the UK: an ovarian cancer patient focus
group (6 participants); and a health professional’s focus group (7 participants). Kew et al21
(2007) report results from a survey of 96 gynaecological cancer patients and 34 health
professionals in the UK. Cox et al14 (2008) reported on women’s experience after participating
in nurse-led telephone follow-up and Palmer et al23 (2006) assessed patients’ satisfaction with
follow-up, particularly with regards to CA125. The abstracts reported on a survey of health
professionals29 or of patients.30
Detection of disease
Patient perceptions
Lydon et al (2009) reported that patients viewed follow-up visits as 'reassuring' and saw the
main purpose of their visits as being for medical staff to monitor their disease status and
check for signs of further problems.22 Patients accepted discomfort associated with internal
examinations undertaken as part of routine care, with the perception of these examinations
as necessary for the detection of progression. The discomfort experienced was outweighed
by the reassurance of negative findings from clinical examinations. Opinions were divided on
the necessity of physically attending clinics, one patient was 10 years from diagnosis and felt
confident in her own ability to monitor for potential signs of progression, however those not as
far from diagnosis were not as confident.22
Similarly, Kew et al (2007) reported that patients thought the most important part of the visit
was the examination (70 out of 96, 73%), and the most important reason for follow-up was “to
detect recurrence”.21 This finding was supported by the results of a large survey conducted in
Germany of over 1000 patients with ovarian cancer presented at ASCO 2009 which found
that patients thought the main objective for the follow-up is the early detection of relapse
and a prolongation of overall survival (95.8%).30
Health professional perceptions
Kew et al (2007) reported that professionals thought the most important part of the visit was
the consultation (27 out of 34, 79%), compared with 43% of patients (p<0.001), and the most
important reason for follow-up was “to talk about concerns” with relation to their disease and
treatment.21
The study by Lydon et al (2009) found that health professionals reported the primary reason
for follow-up was related to the monitoring of symptoms of relapse following treatment.22 It
was also appreciated by the health professionals that it was uncommon to find evidence of
relapse at consultations, based on physical examination alone.22 Comments were also made
24
Follow-up of women with epithelial ovarian cancer
regarding usefulness of CA125 in confirming disease progression. It was reported the
presence of symptoms, raised CA125 count, usually results in further investigations to confirm
disease progression.
In an abstract at SGO 2006, Gibb et al (2006) reported on patterns of follow-up care for
ovarian cancer patients.29 Questionnaire responses from 283 SGO members found that most
(66%) felt routine follow-up was unlikely to result in a recurrent cancer diagnosis that was
potentially curative. However, 80% felt long-term follow-up resulted in a moderate to great
impact on survival.29
Information and support needs
Patient preferences
Lydon et al (2009) reported patient views about the need for specialist information and
support from health professionals.22 Immediate access to information and support was
considered essential. In the study, participants could telephone the oncology service for
information if needed. Patients reported that the structure of appointments could inhibit
reporting any concerns or seeking information as they didn’t want to bother busy doctors
and nurses when they had an upcoming appointment.
Patient participants reported feeling most 'vulnerable' in the time between the end of
treatment and the first follow-up visit (usually 3 months) and reported they would like to have
more contact with the hospital at the time but considered it inappropriate to contact the
hospital with their concerns.22 Patients discussed the need for support from health
professionals, such as a telephone call between the end of treatment and first follow-up
appointment from a nurse asking how they were, would have been appreciated.
Participants commented on the relationship they had established with specialist oncology
nurses.22 Waiting times for appointments were often long (1-2 hours), although patients spoke
about the informal contact with other patients whilst waiting for their appointment.22
In a questionnaire of 90 patients in the UK evaluating the use of CA125 in follow-up, an
improvement in patient education and basic understanding was seen following the
implementation of a fact sheet on CA125 monitoring.23
Health professionals preferences
The health professionals reported that patients in the follow-up stage of their disease
trajectory, could self-manage their own care needs if given sufficient support and
guidance.22 Health professionals agreed they should be more proactive in helping patients
to identify signs of progression and/or late onset side effects and that patients should be
given guidelines and 'what to do' should they have concerns or problems. This information
should be given towards the end of treatment, verbally and in writing.22 Self-management
and less frequent visits to hospital clinics were seen as having a positive impact on patient
well being.
Follow-up of women with epithelial ovarian cancer
Provision of care
Patient preferences
Patients in a UK focus group did not consider that general practitioners (GPs) could take the
place of the oncology team in managing their follow-up care.22 GPs were perceived as
having less time available to discuss concerns, lacking specialist knowledge, and therefore,
the ability to effectively monitor post-treatment progress. Telephone follow-up was
considered appropriate for some people, but some concerns were raised. Patients did not
question the need for physical examinations, and were concerned how examinations would
be organised if followed up by telephone.22 Practical advantages to telephone follow-up
were also reported, and including the need to rely less on family/friends to provide transport
to hospital clinics, and the possible benefit of individually negotiated appointments.22
In a questionnaire of 96 gynaecological cancer patients in the UK by Kew et al (2007), most
patients thought they should see a hospital doctor for follow-up (82 out of 96, 85%).21 Patients
were less likely to think that specialist nurses (22 out of 92, 24%) and/or GPs (6 out of 92, 6%)
should be involved in providing follow-up care.21
Cox et al (2008) conducted a pilot study of nurse-led telephone follow-up for 52 women
following treatment for ovarian cancer.14 Follow-up consisted of a telephone call every 3
months over a 10 month period. The follow-up telephone call initially focused on the
detection of recurrent disease. The nurse gave the patient their recent blood test results and
discussed any implications of this result.14 A discussion/assessment of current symptoms
followed, protocols for care algorithms were consulted for any reported symptoms with an
immediate referral back into medical care if necessary. The intervention then focussed on
providing tailored information, practical advice and coping strategies in physical,
psychological and social domains. Patients were asked to rate the support they had
received during telephone follow-up. On a scale from 1 'dreadful' to 10 'excellent' the mean
rating score was 8.24. Of the 44 women who answered the question on preference for
method of follow-up, 73% preferred telephone appointments.14 Advantages of telephone
follow-up cited were: the relationship and discussions between the patient and the nurse,
and the convenience of having follow-up appointments over the phone instead of having to
attend clinic.14 Palmer et al (2006)23 conducted a questionnaire of 90 patients in the UK to
evaluate the use of CA125 in follow-up. Only 50% of patients were satisfied with the original
service, with 81% wanting their current CA125 result available in clinic. Eighty-two per cent
were willing to attend their GP surgery in advance of their follow-up appointment to have
the relevant blood sample taken. Following a change in CA125 follow-up procedure a
second survey was conducted. From the second survey 92.3% of the 26 patients evaluated
felt that the quality of their follow-up had been enhanced as a result of the change in
practice and having their CA125 results available in the clinic.23
Results of the survey presented by Oskay-Oezcelik et al (2009) of ovarian cancer patients
found that routine follow-up visits were mostly performed by gynaecologists in a
gynaecological practice (56.9%) and in hospitals (49.5%).30 Most patients (89%) were satisfied
with their management of cancer care.30
Health professional preferences
Lydon et al (2009) found a consensus from their health professionals focus group on the need
to modernise the current system and reduce frequency of clinic visits for asymptomatic
26
Follow-up of women with epithelial ovarian cancer
patients (given lack of evidence to support approach or of a survival benefit with early
treatment).22 Health professionals acknowledged the importance of follow-up in patients
who were at risk of disease progression, but questioned the effectiveness of current follow-up
procedures for asymptomatic patients. Local follow-up policy was perceived as excessive,
generating unnecessary workload. The health professionals were in agreement that there
should be a change in current follow-up procedures and were aware that there was little
evidence for the current follow-up system. The benefits of nurse-led and telephone follow-up
were discussed, especially for patients who were at low risk of relapse. Health professionals
noted that telephone follow-up could be acceptable if CA125 tests were conducted at a
local hospital or GP practice with a copy of results sent to hospital consultants. Shared care
with GPs was seen to be a positive means of improving follow-up care. Improvements in
service and more time for patients who needed to be seen would result from a reduced
number of patients physically attending clinics, however this was tempered with an
appreciation that patients may hold a different view. Health professionals thought nurses
should play a pivotal role in follow-up.22
In a questionnaire of 34 healthcare professionals by Kew et al (2007), most professionals
thought that the woman should see a hospital doctor (25 out of 34, 73%).21 Professionals were
more likely than patients to think that specialist nurses (19 out of 34, 56%) and/or GPs (8 out of
34, 24%) should be involved in providing follow-up care.21
Kew et al (2007)21 found that both patients and professionals agreed that the specialist nurse
had a potential role in follow-up by listening to concerns and answering questions. However
both groups were uncertain about whether or not it was within the nurse's role to detect
recurrence. Patients agreed that the nurse could take blood but professionals disagreed.21
Kew et al (2006) report on a survey of practice of 24 cancer networks in UK providing routine
follow-up after treatment for a gynaecological cancer.20 All routine follow-up reported took
place in secondary care and was consultant based:

30% consultant only

62% consultant and specialist registrar

8% consultant and staff grade doctor

0% GP

4% senior house officer (present in addition to senior medical staff)

21% clinical nurse specialist (present in addition to senior medical staff).
Anxiety
In the questionnaire conducted by Kew et al (2007) of 89 women who responded to a
question on how they feel before and after attending follow-up, 54% reported feeling more
anxious before the visit (44% reported feeling the same as usual, 2% reported feeling less
anxious) and 38% reported feeling less anxious after the visit (52% reported feeling the same
as usual, 10% reported feeling more anxious).21 Professionals put more emphasis on the
anxiety that women suffered and relief obtained from follow-up visits than women.21
Follow-up of women with epithelial ovarian cancer
Results of the survey presented by Oskay-Oezcelik et al (2009) found more than 90% of the
patients had CA125 measurements which was the procedure with the highest anxiety but
was also regarded as the most important procedure for the patient.30
3.3.4
Role of follow-up care in psychosocial outcomes for women
Two papers were identified which included information on follow-up care and psychosocial
outcomes.
A pilot study was conducted of nurse-led telephone follow-up in ovarian cancer from a
psychosocial perspective.14 Patients received a follow-up telephone call from a specialist
nurse every 3 months over a 10-month period. The initial focus of the call was on detection of
recurrent disease with the nurse providing recent blood test results and then the nurse
discussed implications of this result, current symptoms and referred the patient back to
medical care immediately if necessary. The second focus of the call was to provide tailored
information, practical advice and coping strategies in physical, psychological and social
domains. Aspects discussed in these domains are presented in Table 7 below.14 Fifty-two
women received telephone follow-up, of which 46 completed pre- and post-data
collection.14
Table 7. Domains of information, advice and coping strategies for telephone follow-up14
Domain
Discussion points
Physical
Menopausal symptoms; altered body image; hair loss/growth; weight
loss/gain; nutrition & fatigue
Psychological
Anxiety/depression; fear of recurrence; familial risk
Social
Sexual intimacy issues; family; work & finances; spirituality
Pre-intervention data showed that women had good QoL.14 Scores between pre- and postmeasures were relatively stable with few changes in physical wellbeing, social/family
wellbeing and functional wellbeing.14 Women reported significant improvement in emotional
wellbeing (p=0.016). Thirty-three women were recorded as having discussed issues in the
psychological domain, of which 10 (30%) were referred on for counselling. Thirty-nine women
were recorded as having discussed issues in the social domain which led to 9 referrals (23%)
for support to social services.14
Amsterdam and Krychman12 reviewed 259 sequential charts of patients who attended the
Sexual Health Program at Memorial Sloan Kettering Cancer Center from March 1 2003 to
December 31 2004 and identified 96 patients with a history of gynaecologic neoplasm (27%
ovarian). All patients were evaluated by a gynaecologist specialising in sexual medicine as
part of routine, well-woman care.12 The most frequent presenting sexual complaint
encountered was dyspareunia (72%), followed by atrophic vaginitis (65%), hypoactive desire
(43%), and orgasmic dysfunction (17%). Treatment recommendations included hormone
therapy alternatives (89%), psychosexual counselling (46%), minimally absorbed vaginal
28
Follow-up of women with epithelial ovarian cancer
estrogens (34%) and vaginal dilations (25%). At a median of 6 months, 60 patients (63%) had
received follow-up, and of them 42 (70%) self-reported improvement in their symptoms.12
3.3.5
Quality of life following initiation of treatment for recurrence
The RCT by Rustin et al4 assessed quality of life measures such as duration of good quality of
life in the global health score and time of first global health-related deterioration. Quality of
life was assessed before each chemotherapy cycle until the end of third-line treatment with
the EORTC QLQ-C30 questionnaire. The median time spent with good global health score
was 7.2 months for women assigned to early treatment (based on elevated CA125 levels
alone) and 9.2 months for those assigned to delayed treatment (when clinical symptoms
were evident) (statistical significance was not reported). Time from randomisation to first
deterioration in global health score or death was shorter (median 3.2 months) in the early
group compared with delayed (median 5.8 months; HR: 0.71, 95% CI: 0.58 to 0.88, p=0.002).
Subgroup analyses of individual components of the QLQ-C30 subscales showed evidence of
significant disadvantages for role, emotional, social and fatigue subscales with early
treatment.4
3.3.6
Subsets of the defined population with specific follow-up
requirements
No particular subsets of the women with ovarian cancer with specific follow-up requirements
were identified in full text papers.
A group from the US suggested follow-up guidelines for women with ovarian tumours of low
malignant potential in an abstract at the SGO meeting in 2009.31 The results of their literature
review found that the reported mean times to first recurrence were from 22 to 90 months. The
authors proposed the following follow-up strategy for low-malignant-potential tumours (Table
8):
Table 8. Follow-up schedule suggested by MacLaughlan 200931 for ovarian tumours of low
malignant potential
Study
MacLaughlan
200931
Methods
Serum CA125 assessment; pelvic
ultrasound for patients with intact
adnexae; CT as indicated for
symptoms
CT=computed tomography
Years after primary treatment
1st & 2nd
3rd to 10th After 10
year
year
years
Annually
6
Annually
monthly
Follow-up of women with epithelial ovarian cancer
3.3.7
Different models of conducting follow-up
No studies were identified which compared different models of conducting follow-up for
ovarian cancer.
The previously described pilot study of nurse-led telephone follow-up suggested that this
model offered an acceptable opportunity for psychosocial support for women with ovarian
cancer.14 Of 44 women who answered a question on preference of method, the majority of
women (73%) expressed a preference for nurse-led telephone follow-up, 18% preferred
doctor/consultant appointments and 9% were unsure. The main advantages of nurse-led
telephone follow-up were reported as the relationship and discussions between the patient
and the nurse, and the convenience of having follow-up appointments over the phone
instead of attending clinic.14 However, 21 women (30% of those approached) were unable
to or refused to participate in this pilot study.14
Patient and health professional preferences reported in the literature for the conduct of
follow-up differ; see section 3.3.3 under provision of care. Patients were unsure if GPs and/or
nurses could manage their follow-up care.21-22 However a potential role in follow-up for GPs
and/or nurses was acknowledged by both patients and health care professionals.21-22
3.4
Additional papers of interest
The following retrospective case-control study which was published after the literature search
was completed, was considered of interest.
Tanner et al (2010) reported results of a retrospective study of 121 patients with recurrent
ovarian cancer which compared the survival impact of diagnosing recurrent disease by
routine surveillance testing versus clinical symptomatology.32
Surveillance included physical examinations and serum CA125 levels at every visit and CT
scans of the abdomen and pelvis at the physician’s discretion.32 Follow-up visits were 3
monthly for the first two to three years, and 6 monthly for an additional two to three years.
The prevailing practice for performing CT scans was 6 monthly for first two years, then
annually for an additional three years.32
Asymptomatic recurrences (82% of patients) were defined as those diagnosed with the use
of a regularly scheduled physical examination, CA125 levels and/or radiographic study.
Additionally, asymptomatic patients did not present with symptoms consistent with
recurrence at the time of diagnosing the recurrence. Symptomatic patients were defined as
those in which recurrent disease was diagnosed based on clinical symptomatology at an
unscheduled office visit or hospitalisation. Asymptomatic recurrence had a median primary
progression-free survival of 24.8 months compared with 22.6 months for symptomatic
recurrences (p=0.36). Post-recurrence survival for asymptomatic and symptomatic
recurrences was 45 months and 29.4 months respectively (p=0.006).32 Patients with
asymptomatic recurrence had a median overall survival of 71.9 months compared with 50.7
months for symptomatic recurrence (p=0.004).32 A greater proportion of symptomatic
patients presented with evidence of recurrent disease outside of the abdomen or pelvis (41%
vs. 15% for asymptomatic patients).32
30
Follow-up of women with epithelial ovarian cancer
3.5
Ongoing trials
Two clinical trials registries (Clinical trials.gov: www.clinicaltrials.gov and Current Controlled
Trials: www.controlled-trials.com) were searched to identify any additional follow-up studies
which have not yet reported.
One ongoing trial was identified. This randomised study compares satisfaction with follow-up
led by a trained cancer nurse compared to conventional medical follow-up after primary
treatment for ovarian cancer (ISRCTN5914955133). The trial aimed to recruit 100 patients from
the UK. Primary outcome measures of the study included patient satisfaction and QoL. The
study has now been completed and published results are awaited.
Follow-up of women with epithelial ovarian cancer
4
Discussion
Limited international and national guidelines on follow-up after ovarian cancer were
identified, with the majority based on consensus. Common elements include
recommendations around clinical visits, CA125 and imaging.
Two systematic reviews were identified in the review, both of these focused on the diagnostic
accuracy of different methods of follow-up in detecting ovarian cancer recurrence. A
Cochrane protocol,10 published in 2006, was also identified and publication of this Cochrane
review is awaited with interest.
Limited high level evidence was available; only one randomised controlled trial on follow-up
for ovarian cancer was identified. In addition, five cohort studies, two pilot studies and four
qualitative/observational studies were identified. Another limitation of the evidence was that
many studies had small patient numbers.
Does the method of detection of a recurrence influence outcomes?
Most ovarian cancer patients present with symptoms or raised CA125. The most common
symptom reported is abdominal pain. It is unclear whether the method of detection of
recurrence impacts on overall survival. Findings by Rustin et al4 from a randomised controlled
trial comparing early chemotherapy for recurrence based on elevated CA125 levels alone
to delaying treatment until clinical indications were present, found there was no difference in
overall survival between the early and delayed treatment arms. In assessing quality of life,
the study by Rustin et al4 found that women in the delayed treatment arm reported good
global health scores for longer than those in the early treatment arm (for 9.2 months
compared to 7.2 months). The findings of this study may be limited as the extent of initial
surgery was not recorded and not used as a stratification factor,4 contemporary therapies
were not available to most trial participants34 and patients had relatively short platinum-free
intervals.34 In addition, the Rustin trial investigated only early initiation of chemotherapy for
recurrence, not surgical intervention.4,34 Only 7% of the randomised patients received surgical
intervention.4,34
Some papers reported on the diagnostic accuracy of different methods. PET appears to
have high specificity and positive predictive value. Sensitivity is highest in patients with a
clinical suspicion of recurrence prior to PET, such as elevated CA125. Specificity was highest
for CA125. Results of the diagnostic accuracy study by Garcia-Velloso et al (2007)17 are
limited as verification of diagnosis was obtained by means of histology or cytology (gold
standard) in only 54 cases, and based on clinical follow-up in the majority (71 cases).
Fehm et al (2005)15 recommends that imaging procedures should not be included into
standard follow-up examinations and be limited to patients in which a tumour recurrence is
already suspected. The combination of physical and gynaecological examination in
combination with serial CA125 analysis offers sufficient sensitivity to detect recurrence and
should therefore be regarded as the standard procedure for follow-up.
Gu et al (2009)18 concluded that PET-CT might be a useful supplement to current surveillance
techniques, particularly for those patients with an increasing CA125 level and negative CT or
32
Follow-up of women with epithelial ovarian cancer
MR imaging. However, regarding diagnostic accuracy, interpreted CT images may have
limited additional value to PET in detecting recurrent ovarian cancer. Similarly, the review by
Havrilesky et al (2005)19 also noted that while PET is less useful for detecting microscopic
residual ovarian cancer, it does have fair sensitivity to detect recurrence in the setting of a
rising CA125 and negative conventional imaging studies.
What is the optimal interval, sequence and duration of follow-up care?
No studies were identified which compared different intervals, sequences or durations of
follow-up care for ovarian cancer patients, therefore an optimal regimen cannot be
determined. Studies report either institutional programs or common regimens followed.
Methods of follow-up commonly reported included history and physical examination, CA125
and ultrasound. Commonly reported follow-up schedule included 3 monthly visits for year 1
and 2, 6 monthly visits for year 3 to 5 and the annually for year 6 to 10.
What are the patient’s/health care provider’s preferences for follow-up care?
Data on preferences vary in the literature. Patients were unsure if GPs and/or nurses could
manage their follow-up care,21-22 however a potential role in follow-up for GPs and/or nurses
was acknowledged by both patients and health professionals.21-22 Kew et al (2007)21
postulate that a reason why the majority of women want to see a hospital doctor is because
they see the main reason to attend follow-up is to detect recurrence whereas health
professionals see the main reason to attend is to discuss concerns, therefore specialist nurses
and/or GPs may be appropriate.21
What evidence surrounds the role of follow-up care in psychosocial outcomes for women?
Ovarian cancer patients experience a range of psychosocial issues following treatment.
Women reported significant improvement in emotional wellbeing after participating in nurseled telephone follow-up which provided psychosocial support.14 In another pilot study, a
majority of gynaecologic cancer patients attending a sexual health clinic reported
improvements in symptoms.12
Are there subsets of the defined population who have specific follow-up requirements?
No trials were identified which addressed specific subsets of patients requiring specific followup care requirements. One abstract suggested a follow-up program for ovarian tumours of
low malignant potential.31
Do different models of conducting follow-up influence outcomes?
No trials were identified which compare different models of conducting follow-up care for
ovarian cancer patients. A pilot study of nurse-led telephone intervention suggests this may
be an appropriate model for some patients.14 Note 30% of those invited to participate were
unable to or refused to be part of the study.
The use of alternate models of follow-up care for women with ovarian cancer, such as GP or
nurse-led follow-up, telephone follow-up and patient initiated care is an area for future
research.
Follow-up of women with epithelial ovarian cancer
5
Conclusions
This NBOCC review on follow-up for women with epithelial ovarian cancer included
evidence published between January 2003 and January 2010, however there was limited
high level evidence available.
One aim of follow-up is to detect recurrences. History and physical examination, CA125,
ultrasound, and PET are methods used for the detection of recurrence. The most common
methods of detection of recurrence were symptoms and raised CA125. There is some
evidence that there are no differences in survival between patients in whom recurrence was
detected by different methods. The results of the Rustin randomised controlled trial,4 that
there is no difference in overall survival between early and delayed chemotherapy
treatment based on CA125 levels, have raised discussion about the utility of CA125 in followup.
No studies were identified that compared different follow-up intervals, sequence and
duration, therefore no optimal regimen for follow-up was identified. However, studies
reported institutional programs or commonly followed regimens.
While there were similarities in preferences and perceptions of follow-up between patients
and health professionals in two studies identified, there were also some differences.
Monitoring of disease progression was perceived as important by both patients and health
professionals. Health professionals reported the most important part of the visit was the
consultation and another reason for follow-up was to talk about concerns. Patients and
health professionals both acknowledged a potential role in follow-up for GPs and/or nurses,
however the extent of this potential involvement varied.
Ovarian cancer patients experience a range of psychological issues after treatment. The
reported studies found improvements in psychological issues after participation in pilot followup studies.
While no trials comparing different models of follow-up care were identified, a pilot study of
nurse-led telephone follow-up was identified14 and this is also being investigated in an
ongoing trial.33
Overall, due to a lack of high-quality evidence, it is unclear which method of detection of
recurrence is most effective and what the optimal interval sequence and duration of followup may be. New models of follow-up care have been proposed, such as nurse-led
telephone follow-up, however these have not been compared to other follow-up models.
34
Follow-up of women with epithelial ovarian cancer
Appendix A
Contributors
Working group members
The follow-up of women with epithelial ovarian cancer systematic review was developed
with input from an expert multidisciplinary Working Group with the following members:

A/Prof Penny Blomfield (Chair)
Gynaecological oncologist

Dr Lynne Brothers Radiologist

Ms Cecily Dollman Social Worker

Prof Michael Friedlander Medical oncologist

Ms Tish Lancaster Clinical nurse consultant – Gynaecological oncology

Ms Wanda Lawson
Consumer representative

A/Prof Danielle Mazza
General Practitioner

Ms Susanne Melia Consumer representative

A/Prof Anthony Proietto
Gynaecological oncologist
National Breast and Ovarian Cancer Centre staff
The following NBOCC staff were involved in the development of the systematic review

Ms Katrina Anderson
Project Officer – Research

Ms Jane Francis
Program Manager – Ovarian Cancer

Ms Phillipa Hastings
Project Officer

Dr Karen Luxford
General Manager

Dr Anne Nelson
Evidence Review & Research Leader

Ms Rosemary Wade
Senior Project Officer – Research
Follow-up of women with epithelial ovarian cancer
Appendix B
Literature databases searched
Database
Results/Retrievals
Pubmed
213
Medline and Embase (Ovid)
516
Cochrane Library
1
36
Follow-up of women with epithelial ovarian cancer
Appendix C
Ovarian cancer
Search strategy
Ovarian Neoplasms/
Ovarian and (cancer or carcinoma or
tumour)
Follow-up
“follow up care” or “follow up plan” or
“follow up visit” or “follow up examination”
or “clinical follow up” or “routine follow up”
or “follow up model” or “follow up
strategies” or “follow up methods” or
“follow up program” or “routine test” or
“postoperative surveillance” or “ovarian
cancer surveillance” or (surveillance and
survivors)
aftercare/
postoperative care/
Follow-up of women with epithelial ovarian cancer
Appendix D
Guideline and clinical trial sites searched
Acronym
Organisation
Website
CCO
Cancer Care Ontario (Canada)
http://www.cancercare.on.ca/
ESMO
European Society of Medical Oncology
http://www.esmo.org/
GIN
Guidelines International Network
http://www.g-i-n.net/
NCCN
National Comprehensive Cancer Network
(US)
http://www.nccn.org/index.asp
NGC
National Guideline Clearinghouse (US)
http://www.guideline.gov/
NICE
National Institute for Health and Clinical
Excellence (UK)
http://www.nice.org.uk/
SIGN
Scottish Intercollegiate Guidelines Network
http://www.sign.ac.uk/
ClinicalTrials.gov
http://www.clinicaltrials.gov/
Current Controlled Trials
http://
trials.com/
38
Follow-up of women with epithelial ovarian cancer
www.controlled-
Appendix E
Flowchart of inclusion/exclusion
Follow-up of women with epithelial ovarian cancer
Abbreviations
ACN
Australian Cancer Network
ASCO
American Society Of Clinical Oncology
ASGO
Australian Society Of Gynaecologic Oncologists
AUC
area under curve
CI
confidence interval
CT
computed tomography
DFS
disease free survival
FDG
fluorodeoxyglucose
GIN
Guidelines International Network
GP
general practitioner
IGCS
International Gynecologic Cancer Society
MRI
magnetic resonance imaging
NBOCC
National Breast And Ovarian Cancer Centre
NCCN
National Comprehensive Cancer Network
OC
ovarian cancer
OS
overall survival
PET
positron emission tomography
QoL
quality of life
RCT
randomised controlled trial
SGO
Society Of Gynecologic Oncologists
SUV
standardised uptake value
US
ultrasound
40
Follow-up of women with epithelial ovarian cancer
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Follow-up of women with epithelial ovarian cancer

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