Singapore Cancer Network (SCAN) Guidelines for Front

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421
SCAN Gynaecological Cancers Systemic Therapy Workgroup
Original Article
Singapore Cancer Network (SCAN) Guidelines for Front-Line Systemic Therapy of
Newly Diagnosed Advanced Epithelial Ovarian Cancer
The Singapore Cancer Network (SCAN) Gynaecological Cancers Systemic Therapy Workgroup
Abstract
Introduction: The SCAN gynaecological cancers systemic therapy workgroup aimed to
develop Singapore Cancer Network (SCAN) clinical practice guidelines for front-line systemic
therapy of advanced epithelial ovarian cancer. Materials and Methods: The workgroup
utilised a modified ADAPTE process to calibrate high quality international evidence-based
clinical practice guidelines to our local setting. Results: Five international guidelines were
evaluated—those developed by the National Comprehensive Cancer Network (2013), the
European Society of Medical Oncology (2013), the National Institute of Health and Clinical
Excellence (2011), the Scottish Intercollegiate Guidelines Network (2011) and the Greater
Metropolitan Clinical Taskforce (2009). Recommendations on the role of systemic therapy
with intravenous chemotherapy, intraperitoneal chemotherapy, anti-angiogenic agents
and neoadjuvant chemotherapy in newly diagnosed advanced epithelial ovarian cancer
were developed. Conclusion: These adapted guidelines form the SCAN Guidelines 2015
for front-line systemic therapy of advanced epithelial ovarian cancer.
Ann Acad Med Singapore 2015;44:421-33
Key words: Clinical practice guidelines, Chemotherapy, Anti-angiogenics
Introduction
Epithelial ovary cancer (EOC) is one of the most
challenging cancers to treat and remains the most lethal of
all gynaecological cancers worldwide.
Ovarian cancer is the fifth most common cancer and the
seventh most common cause of cancer mortality amongst
females in Singapore. Over the last 40 years, the incidence
of ovarian cancer has climbed continuously from 6.2 per
100,000 (1973 to 1977) to 12.4 per 100,000 (2008 to 2012).
A total of 1587 new cases of ovarian cancer were diagnosed
between 2008 and 2012. The majority of women (70%)
present with advanced disease (International Federation of
Gynecology and Obstetrics (FIGO) stage III or IV) due to
the lack of effective screening and “silent presentation”.
Prognosis for advanced stage disease is poor—the 5-year
age-standardised overall survival (OS) was 30.5% and 11.5%
for stage III and stage IV disease, respectively.1
Treatment of advanced EOC involves a 2-pronged
approach, with cytoreductive surgery and chemotherapy as
the mainstays of primary therapy.
Cytoreductive surgery aims to remove all macroscopic
disease as resection has consistently been shown by
retrospective studies to be associated with improved
progression-free survival (PFS) and OS.2,3 However,
prospective randomised studies are lacking and whether or
not diseases amendable to complete resection are biologically
different from those which cannot be completely resected
remains a controversial question.
For the last 15 years, the gold standard of care has been
to administer platinum-taxane chemotherapy intravenously
every 3 weeks postdebulking surgery. However, the optimal
method of administering platinum-taxane chemotherapy
remains to be determined. In recent years, variables such
as the scheduling (dose-dense vs 3-weekly), route of drug
administration (intraperitoneal (IP) vs intravenous (IV))
and the timing of chemotherapy (neoadjuvant vs frontline)
Address for Correspondence: Dr Lim Sheow Lei, Department of Gynaecological Oncology, KK Women’s and Children’s Hospital, 100 Bukit Timah Road,
Singapore 229899.
Email: [email protected]
Annals Academy of Medicine
SCAN Gynaecological Cancers Systemic Therapy Workgroup
have challenged the conventional platinum-taxane regimen.
Targeted therapy is also making inroads into the front-line
treatment of advanced EOC.
The SCAN Guidelines for Front-line Systemic Therapy
of Advanced EOC
The SCAN Guidelines are clinical practice guidelines
for the front-line systemic treatment of newly diagnosed
advanced EOC. It includes guidelines for the treatment of
FIGO stage II, III or IV EOC (based on the 1997 FIGO
staging for ovary cancer) but excludes carcinosarcoma and
non-epithelial cancer of the ovary.
These first edition guidelines are intended to serve as
treatment recommendations by members of this working
group reflecting their views on current existing international
guidelines for the management of advanced EOC. While it
hopes to harmonise the management of this disease, it is not
intended to serve as the standard of care or to replace good
clinical judgment and the individualisation of treatments.
Target Users of the Guidelines
The guidelines will be of interest to oncologists, oncology
nurse specialists, pharmacists, allied health workers and
general practitioners involved in the management of women
with ovarian cancer.
Guideline Recommendations/Development
The SCAN Gynaecological Cancers Workgroup comprises
a panel of 8 medical oncologists and 1 oncology pharmacist
from Singapore with special interests in the management of
gynaecological cancers. Membership of the workgroup was
by invitation. The workgroup elected its own chairperson and
decided on its own scope. Guideline selection was conducted
through workgroup consensus. Potential conflicts of interest
were declared by the International Committee of Medical
Journal Editors (ICMJE) guidelines. Secretarial support for
the overall guideline development effort was provided by
Annals, Academy of Medicine Singapore. No other financial
support was obtained. Guideline searching was conducted
by the section lead with input from the workgroup members.
The group met once in person, and completed guideline
development through email communication.
The ADAPTE framework4 was used as a pragmatic
structure and guidance for calibration of international high
quality guidelines to the Singapore context. The framework
involves 3 phases: set-up, adaptation and finalisation. During
the set-up phase, available resources were considered.
During the adaptation phase, high quality guidelines were
selected for evaluation and structured approaches developed
for guideline evaluation and selection. This involved the
October 2015, Vol. 44 No. 10
422
extraction of data on source guideline development, the
setting up of mechanisms for selecting recommendations and
also recognising possible dissent amongst panel members.
Calibration of guidelines to the local context based on
available Singapore data was encouraged. The finalisation
phase involved writing, external review, stakeholder
feedback, and the setting up of a mechanism for regular
updating. For each individual recommendation, agreement
was established by a simple majority for established
international recommendations and by a two-third majority
for independent local recommendations. Dissenting
workgroup members were invited to include comments
for each recommendation. International measures of costeffectiveness for each recommendation were obtained where
available but not used to inform the recommendations.
These guidelines set out to answer the following questions
pertaining to front-line systemic therapy for women with
newly diagnosed advanced EOC:
1. What is the optimal IV chemotherapy regimen for
advanced EOC following primary cytoreductive surgery?
2. What is the role of IP chemotherapy in women with
optimally debulked advanced EOC?
3. What is the role of front-line bevacizumab?
4. What is the role of neoadjuvant chemotherapy in
advanced EOC?
Five international guidelines were selected for review
(Supplementary Table 1):
•
“NCCN Guidelines for Ovarian Cancer Version
2.2013” by the National Cancer Comprehensive
Network (NCCN, USA)5
•
“Newly Diagnosed and Relapsed Epithelial Ovarian
Carcinoma: ESMO Clinical Practice Guidelines for
Diagnosis, Treatment and Follow-up” by the European
Society of Medical Oncology (ESMO), 20136
•
“SIGN 135. Management of Epithelial Ovarian
Cancer. A National Clinical Guideline” by the Scottish
Intercollegiate Guidelines Network (SIGN, UK),
November 20137
•
“Ovarian Cancer: the Recognition and Initial
Management of Ovarian Cancer (CG122)” by the
National Institute of Health and Clinical Excellence
(NICE, UK), 20118
•
“Best Clinical Practice. Gynaecological Cancer
Guidelines 2009” by the Greater Metropolitan Clinical
Taskforce (GMCT, Australasia)9
These guidelines will be reviewed or updated every 2
years. If there are significant new developments that impact
the management of advanced EOC, it will be reviewed
earlier.
423
SCAN Gynaecological Cancers Systemic Therapy Workgroup
1. What is the Optimal IV Chemotherapy Regimen for
Advanced EOC Following Primary Cytoreductive Surgery?
Platinum-taxane Chemotherapy
As advanced EOC has a high risk of recurrence when
treated with debulking surgery alone, chemotherapy
following surgery is recommended. Platinum-paclitaxel has
been the standard of care for the last 15 years, a consequence
of 2 high quality landmark phase III randomised controlled
trials (RCTs), the GOG 111 and EORTC-NCIC OV10. These
trials demonstrated that cisplatin-paclitaxel combinations
yield significant improvements in PFS and OS in women
with advanced EOC following primary cytoreductive
surgery as compared to cisplatin-cyclophosphamide
chemotherapy.10,11
Cisplatin versus Carboplatin
The combination carboplatin-paclitaxel has demonstrated
similar efficacy as cisplatin-paclitaxel but has advantages
such as a more favourable toxicity profile and added
convenience due to it being administered in an outpatient
setting. These advantages have been demonstrated in 2
non-inferiority phase III RCTs.12,13
Carboplatin-paclitaxel has since become the worldwide
standard of care in front-line treatment of EOC. The most
commonly used schedule is carboplatin (AUC 5-6) in
combination with paclitaxel (175 mg/m2), both administered
intravenously every 3 weeks. Typically, 6 cycles of
chemotherapy are given. There is no evidence to suggest
that improved outcomes will be obtained with more than
6 cycles of chemotherapy.
Paclitaxel Intolerance
For women who are allergic to or intolerant of paclitaxel,
carboplatin-pegylated liposomal doxorubicin (PLD) can be
considered as an alternative, based on a single phase III RCT,
the MITO-2 study.14 PLD (30 mg/m2) in combination with
carboplatin (AUC 5) given every 3 weeks yielded similar
PFS and OS as the paclitaxel (175 mg/m2) and carboplatin
(AUC 5) combination.
Patients Unfit for Combination Chemotherapy
Women who are unfit for combination chemotherapy
can be given single-agent carboplatin, as indicated by the
International Collaborative Ovarian Neoplasm (ICON) 3
findings.15
Adding in a Third Cytotoxic Drug
To date, there have been at least 5 good quality phase III
RCTs involving more than 6000 patients that investigate the
addition of a third cytotoxic drug to the standard platinum
and paclitaxel combination, either as triplet therapy16-19
or as sequential doublets.20 Not only did the addition of a
third drug not improve survival outcomes, it also enhanced
toxicities, in particular haematological toxicities.
Chemotherapy Scheduling: Dose-dense Chemotherapy
The rationale for dose-dense chemotherapy comes from
the Norton-Simon hypothesis, which states that increasing
the dose density of chemotherapy reduces the chance of
emergence of resistant clones and improves efficacy by
reducing the regrowth of tumour cells between treatment
cycles.21
This concept was tested in a single large phase III
RCT in Japan (NOVEL-JGOG 3062). In this trial, IV
paclitaxel (80 mg/m2) given weekly in combination with
IV carboplatin (AUC 6) given every 3 weeks resulted in
significant improvement in PFS and OS in women with
advanced EOC as compared to those of the standard IV
carboplatin and paclitaxel regimen.22 Long-term follow-up
results showed that at a median follow-up of 76.8 months,
the median PFS was 28.2 months in the dose-dense arm
(vs 17.5 months in the conventional group; HR = 0.76;
95% CI, 0.61 to 0.91; P = 0.0037) and the median OS was
100.5 months (vs 62.2 months in the conventional group;
HR = 0.79; 95% CI, 0.63 to 0.99; P = 0.039). However,
the dose-dense carboplatin-paclitaxel combination was
associated with greater haematological toxicities leading
to greater dose-delays and lower completion rates. Less
than half of the patients completed treatment according to
study protocol and 38% of patients stopped this regimen
prematurely (vs 21% in the conventional group). Incidence
of grade III or IV anaemia was significantly higher in the
dose-dense arm (69% vs 44%; P <0.001). Dose-dense
chemotherapy is also more inconvenient due to the weekly
treatment schedule. The overall quality of life (QoL) did
not differ significantly between the 2 treatment groups.23
However, according to the taxane subscale, QoL was
significantly lower in the dose-dense group, a consequence
of the increased neurotoxicity (P = 0.02).
A second dose-dense study, the MITO-7, was a recently
published24 phase III RCT that used a different chemotherapy
schedule from the JGOG 3062. It administered IV
carboplatin (AUC 2) in combination with paclitaxel (80
mg/m2) weekly in the treatment of EOC following primary
debulking surgery. Although the weekly regimen has a more
favourable toxicity profile compared with the conventional
3-weekly chemotherapy, contrary to the JGOG 3062, there
was no difference in PFS between the 2 treatment arms. The
OS data was immature. The findings of 2 other dose-dense
studies, the GOG 262 (NCT 00951496) and the ICON 8
(NCT 01654146), are yet to be published.25,26
Annals Academy of Medicine
SCAN Gynaecological Cancers Systemic Therapy Workgroup
Cost-effectiveness Analyses for Dose-dense Chemotherapy
An actual cost data collection was not performed by the
JGOG 3062. However, a cost-effectiveness analysis using
the Markov economic decision model found that dose-dense
paclitaxel administered weekly is a cost-effective treatment
option for advanced ovarian cancer.27 The incremental
cost-effectiveness ratio was USD $4859 per progressionfree life-year saved for the dose-dense weekly regimen as
compared to the conventional 3-weekly regimen.
424
Recommendations for Front-line IV Chemotherapy
Following Primary Cytoreductive Surgery
The SCAN workgroup has voted 6 to 2 in favour of
the adoption of the SIGN guidelines7 for front-line IV
chemotherapy following cytoreductive surgery (Table 1 and
Supplementary Table 1) due to its comprehensive nature.
The workgroup also recommends the discussion of dosedense chemotherapy as a treatment option with patients.
There is unanimous agreement amongst the working
Table 1. Singapore Cancer Network (SCAN) Guidelines for Front-line Systemic Treatment for Advanced Epithelial Ovary Cancer
Guideline Recommendations
SIGN Guidelines: Carboplatin is the platinum drug of choice in both single and combination therapy (A).
Paclitaxel is recommended in combination therapy with platinum in the first-line postsurgery treatment of EOC where
the potential benefits justify the toxicity of the therapy.
What is the Optimal IV
Chemotherapy Postprimary
Cytoreductive Surgery?
In those unable to tolerate paclitaxel, pegylated liposomal doxorubicin or gemcitabine in combination with
carboplatin can be used as an alternative (A).
Patients who are unfit for combination therapy should be offered single-agent carboplatin (A).
A third cytotoxic agent should not be added to carboplatin and paclitaxel (A).
Dose-dense chemotherapy: Carboplatin AUC 6 (day 1 q21) and paclitaxel 80 mg/m2 (days 1, 8, 15 q21) may be
considered for the treatment of first-line ovarian cancer. The increased toxicity and frequency of visits need to be
discussed with the patient (B).
ESMO Guidelines: IP treatment has not been adopted as standard of care in view of its greater toxicity and difficulty
delivering all the planned treatment.
What is the Role of IP
Chemotherapy in Optimally
Debulked Advanced EOC?
Lack of current standard intravenous chemotherapy in the standard arms of the IP trials has made the interpretation of
the results difficult.
Recommends IP chemotherapy in the context of clinical trial.
What is the Role of Upfront
Bevacizumab in Advanced EOC?
ESMO Guidelines: Bevacizumab is recommended for patients with poor prognostic features (as defined in ICON7
Trial):
•
stage IV
•
suboptimal debulking (I,B)
Bevacizumab should be given with paclitaxel and carboplatin with a treatment duration of 1 year.
Bevacizumab has been licensed by the EMA at 15 mg/kg for use with carboplatin and paclitaxel for ≤15 months or
until progression.
What is the Role of Neoadjuvant
Chemotherapy in Advanced
EOC?
NCCN Guidelines: Consider neoadjuvant chemotherapy/primary interval cytoreduction (diagnosis by fine needle
aspiration, biopsy or paracentesis) for patients with bulky stage III/IV who are poor surgical candidates due to highrisk comorbidity conditions or disease factors (Category I).
Published data demonstrates that primary assessments and debulking by a gynaecologic oncologist results in a
survival advantage. Patients being evaluated for neoadjuvant chemotherapy should be seen by a fellowship-trained
gynaecologic oncologist prior to being considered a poor surgical candidate.
EMA: European Medicines Agency; EOC: Epithelial ovary cancer; ESMO: European Society for Medical Oncology; IP: Intraperitoneal; IV: Intravenous;
NCCN: National Comprehensive Cancer Network; SIGN: Scottish Intercollegiate Guidelines Network
October 2015, Vol. 44 No. 10
425
SCAN Gynaecological Cancers Systemic Therapy Workgroup
group members that platinum-taxane is the standard of care
for front-line chemotherapy and that the SIGN guidelines
are the most comprehensive of all guidelines reviewed as
it recommends:
•
Single-agent carboplatin in patients who are unable
to tolerate combination chemotherapy.
•
Carboplatin-pegylated liposomal doxorubicin in cases
of taxane-intolerance.
•
Against the addition of a third cytotoxic agent to
platinum-taxane.
The role of dose-dense chemotherapy was more
contentious. Two working group members felt that based on
the JGOG 3062 data,22 there is sufficient evidence to support
the use of dose-dense chemotherapy as a standard treatment.
They therefore voted for the NCCN guidelines5 (Table 1)
which endorses this mode of treatment as a Category 1
treatment. Six working group members felt that although the
JGOG 3062 is a potentially practice-changing study, there
exists a possibility that the results may be a chance finding
or could be due to pharmacogenomics differences between
the Japanese and Caucasian populations. In the absence of
confirmatory trial data and in view of the increased toxicities
and increased hospital visits associated with dose-dense
treatment, they opined that pending the results of other
dose-dense studies, dose-dense chemotherapy can only
be considered an option and not a standard of care. Hence,
they endorsed the SIGN guidelines which recommend dosedense chemotherapy as a treatment option to be discussed
with patients.
The workgroup acknowledges that there is no local data
regarding front-line IV chemotherapy for advanced EOC.
2. What is the Role of IP Chemotherapy in Optimally
Debulked Advanced EOC?
The natural history of ovarian cancer is transcoelomic
spread and the disease is frequently confined to the peritoneal
compartment at diagnosis and relapse. The benefit of
administering chemotherapy directly into the peritoneal
compartment is supported by pharmacokinetic data showing
a multifold higher concentration of drug in the abdominal
cavity. In 2006, the National Cancer Institute (NCI) published
a meta-analysis of 8 randomised studies evaluating the
benefit of IP chemotherapy. In the combined analysis of 6 of
the 8 randomised studies, the hazard ratio (HR) for OS for
IP versus IV therapy was 0.79 (95% CI, 0.70 to 0.89). The
latest study by Armstrong et al comparing IP cisplatin and
IP paclitaxel with the standard IV cisplatin and IV paclitaxel
(GOG 172) was included. Although only 42% of patients on
the IP chemotherapy arm completed all 6 cycles of therapy,
on an intention-to-treat analysis, IP chemotherapy extended
median OS by 16 months (66 months vs 50 months) in a
comparison with standard IV paclitaxel and IV cisplatin.28
The most common toxicities were related to port catheter
complications, increased nausea, vomiting and abdominal
pain, and higher haematologic, metabolic and neurotoxicity.
Consequently, the NCI issued a clinical announcement
in January 2006 regarding their position on the preferred
treatment for optimally debulked stage III ovarian cancer.29
This stated that, “Based on the results of 8 phase III clinical
trials, the NCI is encouraging doctors to follow surgery
with a combination of 2-drug delivery methods: IV and IP.
The combined approach, though more toxic, extends OS
for women with advanced ovarian cancer by about a year
compared to IV drip alone.”
The NCCN guideline,5 in line with NCI, has recommended
that stage II and III optimally debulked (<1 cm) patients
with ovarian cancer who are eligible for chemotherapy
should be informed of the option of IP chemotherapy versus
IV chemotherapy (or be considered for participation in a
clinical trial). The guideline recommends for all women to
be counselled about the benefit of IP chemotherapy prior
to surgery.
In contrast, the 2011 NICE guidelines8 were explicit in their
recommendation against the use of IP chemotherapy except
in the context of a clinical trial. While the NICE guideline
development group placed importance on the improvements
in disease-free survival (DFS) and OS associated with IP
chemotherapy, they also recognised that IP chemotherapy
was more toxic, complex to administer and expensive.
The ESMO 2013 guidelines has also highlighted that IP
chemotherapy has not been adopted as a standard of care in
the majority of institutions and countries due to its greater
toxicity and the difficulty in delivering the entirety of the
planned treatment.6 The guidelines further recognise that
much of the IV chemotherapy used in the control arms of
reported IP chemotherapy trials are no longer considered
current IV treatment standards.
In 2013, SIGN emphasised that IP chemotherapy may be
considered as a first-line therapy for eligible women with
advanced ovarian cancer, provided that it is delivered in
a centre with appropriate expertise and that the potential
for toxicities is fully explained.7 In contrast, the Australian
2009 GMCT guidelines indicate that IP chemotherapy is
not recommended for patients who have significant intraabdominal adhesions at the conclusion of their surgery as
these adhesions may limit the distribution of the chemotherapy
drug within the abdomen.9
Ongoing trials such as PETROC/OV21 (NCT00993655),30
JGOG 3109 (NCT01506856) 31 and GOG 252
(NCT00951496)32 are seeking to evaluate the benefit of IP
chemotherapy against standard arms that incorporate weekly
IV paclitaxel, bevacizumab and the use of IP carboplatin
vis-à-vis cisplatin for the reduction of toxicity.
Annals Academy of Medicine
SCAN Gynaecological Cancers Systemic Therapy Workgroup
Cost-effectiveness Analyses
No cost-effectiveness analyses using local cost data and
societal norms in Singapore have been performed. An
analysis performed by the GOG based on an American
perspective showed that compared to the IV paclitaxel
and carboplatin regimen, the IP paclitaxel and cisplatin
combination has an incremental cost-effectiveness ratio
of USD $180,022 per quality-adjusted life year (QALY)
saved (using a 7-year time horizon).33
Recommendations for IP Chemotherapy in Optimally
Debulked Advanced EOC
The SCAN workgroup has voted 5 to 3 in favour of the
adoption of the 2013 ESMO guidelines.6 The workgroup
recognises that there exists no local efficacy and toxicity
data on IP chemotherapy. The workgroup agreed that the
current evidence-based schedule for IP chemotherapy as
described in GOG 172 is associated with excess toxicity,
more complex to administer and also that there is a lack
of experience and familiarity with the procedure locally.
In Singapore, the most commonly used regimen is the
JGOG dose-dense chemotherapy which has been shown
to be superior to the standard 3-weekly IV paclitaxel and
carboplatin regimen.22 As such, the SCAN workgroup
has voted in support of the adoption of the 2013 ESMO
guidelines6 for local patients (Supplementary Table 1).
3. What is the Role of Front-line Bevacizumab in
Advanced EOC?
Bevacizumab is a humanised monoclonal antibody
that binds vascular endothelial growth factor (VEGF)
and prevents it from binding to its receptor. This blocks
the growth and maintenance of tumour-associated blood
vessels. In women with newly diagnosed EOC, postsurgical
chemotherapy is given with a curative intent. Unfortunately,
the vast majority of women still relapse. The incorporation
of bevacizumab as part of the upfront treatment programme
was evaluated in 2 randomised studies.
The first study conducted by GOG 0218 was a phase
III randomised placebo-controlled study involving 1873
women with stage III or IV EOC who had undergone
surgical cytoreduction.34 At a median follow-up of 17
months, there was a significant increase in the median
PFS in patients receiving upfront followed by maintenance
bevacizumab as compared to when chemotherapy-alone
is administered (14.1 vs 10.3 months, P <0.001). This
translates into a significant reduction in the risk of disease
progression or death (HR = 0.72, 95% CI, 0.63 to 0.82).
There was no improvement in OS (39.7 vs 39.3 months
for the maintenance bevacizumab and chemotherapy-alone
group respectively). PFS was not significantly increased
October 2015, Vol. 44 No. 10
426
in patients who did not receive maintenance bevacizumab
(they received upfront with placebo maintenance) when
compared with the chemotherapy-alone group.
The second study by the ICON7 randomly assigned 1528
previously untreated women with high-risk early stage (I or
IIA, clear cell or grade III) or advanced EOC to standard
chemotherapy for 6 cycles with or without bevacizumab
during chemotherapy, followed by maintenance treatment
for 12 additional cycles. 35 Compared to standard
chemotherapy, the incorporation of bevacizumab resulted
in a significant improvement of the median PFS by 1.7
months at a follow-up of 42 months. For women with a
high risk of progression (stage III with >1.0 cm residual
disease at the end of surgery or stage IV), bevacizumab
was associated with significant improvement in PFS (18.1
vs 14.5 months) and OS (36.6 vs 28.8 months). However,
this analysis was a posthoc subgroup analysis. In the final
survival analysis at a median follow-up of 49 months, there
was no difference in median OS (58 months for both arms
using restricted means analysis). Women with high risk of
progression experienced a lengthening of survival by 4.8
months from 34.5 months to 39.3 months.
In both studies, bevacizumab-containing treatments
were associated with greater toxicities. There were higher
incidences of grade III and IV adverse events (66% vs 56%
in control group),35 hypertension and gastrointestinal-wall
disruption.34-35 Global QoL was not improved by the addition
of bevacizumab.34-37
Cost-effectiveness Analyses
Actual cost data was not collected in GOG 0218 or ICON
7. However, independent modelled cost-effectiveness
analyses using available data on PFS and OS report that
without improvement in OS, the use of bevacizumab as
part of the front-line therapy for ovarian cancer is not cost
effective.8,38-41 These analyses include an analysis by the
UK NICE appraisal committee which reported a range
of incremental cost-effectiveness ratios from £128,000
to £161,000 per QALY for the use of bevacizumab at its
licensed dose of 15 mg/kg body weight with a treatment
duration of 15 months or time horizon of 25 years or both.8
Treatment with maintenance bevacizumab leads to improved
PFS but is associated with both direct and indirect costs.
Recommendations for Front-line Bevacizumab
The SCAN workgroup has voted in favour of the adoption
of the ESMO guidelines. ESMO guidelines recommend the
use of upfront bevacizumab with chemotherapy followed by
maintenance bevacizumab for patients with poor prognostic
features as defined in the ICON 7 trial.6 Bevacizumab is
currently licensed by the European Medicines Agency
427
SCAN Gynaecological Cancers Systemic Therapy Workgroup
(EMA) at a dosage of 15 mg/kg for use with carboplatin
and paclitaxel for less than 15 months or until progression.
The NCCN guidelines listed upfront bevacizumab
with chemotherapy followed by maintenance therapy
as a Category III recommendation as there were major
disagreements within the NCCN Panel. Less than 50% of
panel members agreed with the recommendation. It was
felt that data from GOG 0218 and ICON 7 had not shown a
statistically significant increase in OS and/or improved QoL.
Four out of 8 SCAN workgroup members concurred with
the ESMO guidelines as it defined the role of bevacizumab
comprehensively. However, while bevacizumab is licensed
at a dose of 15 mg/kg in the European Union, SCAN
workgroup members unanimously agreed that a dose of
7.5 mg/kg based on the ICON7 regimen is preferable due
to the lower toxicities and cost involved. Three members
expressed disagreement with regard to the NCCN guidelines,
endorsing the widely differing opinions regarding the use of
bevacizumab. One member agreed with the recommendation
by the SIGN guidelines against upfront bevacizumab as
cost-effectiveness analyses have shown that the treatment’s
cost does not justify its health benefits.
The workgroup acknowledges that there is currently no
local data on upfront bevacizumab. The diverse views of
the SCAN workgroup are reflected in the NCCN guidelines.
The workgroup has voted in favour of the ESMO guidelines
(Supplementary Table 1) but recommends the careful
selection of patients when considering the use of upfront
bevacizumab. Only patients with poor prognostic features
as defined in ICON7 should be considered for upfront
bevacizumab. The preferred dose of bevacizumab is 7.5
mg/kg as defined by the ICON7 regimen.
4. What is the Role of Neoadjuvant Chemotherapy in
Advanced EOC?
There are 2 phase III trials on neoadjuvant chemotherapy
in advanced EOC. The EORTC 5597142 randomised 718
women with stage III or IV ovarian cancer to neoadjuvant
chemotherapy followed by interval debulking surgery
or primary debulking surgery. There were no significant
differences between the study groups with regards to OS
(HR = 0.98; 95% CI, 0.82 to 1.18) or PFS (HR = 1.01; 95%
CI, 0.86 to 1.17). In the EORTC 55971 study, there was
increased debulking rate and reduced surgical complications
in the neoadjuvant chemotherapy group. In the CHORUS
study, a phase III randomised trial to investigate the timing of
initial surgery in ovarian cancer,43 patients with clinical stage
III or IV ovarian cancer were randomised to primary surgery
followed by 6 cycles of platinum-based chemotherapy or 3
cycles of neoadjuvant chemotherapy followed by surgery
before another 3 cycles of platinum-based chemotherapy.
CHORUS was designed to demonstrate non-inferiority
of neoadjuvant chemotherapy based on a 3-year survival
of 50% with primary debulking surgery. A total of 550
women were randomised. Median tumour size was 8 cm,
25% FIGO IV and 19% World Health Organization (WHO)
performance status 2. At a median follow-up of 3 years, the
OS is superior for the neoadjuvant chemotherapy group (24.5
months vs 22.8 months; HR = 0.87; 80% CI, 0.76 to 0.98).
No cost-effectiveness analysis was done.
With regard to the EORTC trial, we are mindful of the
fact that the accrued patients have very extensive and
bulky disease as 73% had tumours of >5 cm and 47% had
tumours of >10 cm at randomisation. Similarly, the median
size of tumour in the CHORUS trial was 8 cm. Hence, the
results of the trials on the role of neoadjuvant chemotherapy
cannot be extrapolated to patients with less bulky disease.
Furthermore, in a posthoc analysis in the EORTC trial,
amongst patients with metastatic disease <5 cm in diameter
at randomisation, the OS was slightly longer in the primary
surgery group than in the neoadjuvant chemotherapy group
(HR = 0.64; 95% CI, 0.45 to 0.93). Hence, rather than
recommending neoadjuvant chemotherapy as an alternative
for ovarian cancer patients with any stage or disease bulk,
it is preferable to reserve neoadjuvant chemotherapy for
selected patients with bulky stage III or IV disease, at the
same time taking into account the resectability, age, stage,
histology and performance status.44
SCAN Workgroup Recommendations for Neoadjuvant
Chemotherapy in Advanced EOC
All members of the workgroup unanimously voted for
the NCCN guidelines as it endorses the use of neoadjuvant
chemotherapy in patients who are poor surgical candidates
due to comorbidities and disease factors. The NCCN
recommends the involvement of gynaecologic oncologists in
deciding if neoadjuvant chemotherapy should be given. As
it does not specify the neoadjuvant chemotherapy regimen,
it accommodates for the treating oncologist to make the
judgement that best suits the patient’s interests as some
patients may not be able to tolerate standard combination
chemotherapy.
Conflicts of Interest
Dr Chia reports receiving advisory board fees from GSK, Astra Zeneca
and Bayer; Dr Lim, receiving travel support from Roche; Dr See, receiving
accommodation and travel grants from GSK, conference support from GSK
and Sirtex and advisory fees from Roche; Ms Foo, Dr Lim, Dr Lim, Dr Ngo,
Dr Soh and Dr Tan have nothing to disclose.
Annals Academy of Medicine
SCAN Gynaecological Cancers Systemic Therapy Workgroup
Workgroup Members
The Members of the SCAN Gynaecological Cancers Systemic Therapy
Workgroup are Section Lead and Workgroup Chairperson: Sheow Lei Lim,
MBBS (Hons, Aust), MRCP (UK), MD (UK), Department of Gynaecological
Oncology, KK Women’s and Children’s Hospital, Singapore; Workgroup
Members (Voting): John WK Chia, MBBS, MRCP (UK), FAM (S’pore),
Department of Medical Oncology, National Cancer Centre Singapore,
Singapore; Siew Eng Lim, MBBCh, Medl Onco (ABIM), Med Onco (FAMS),
Department of Haematology-Oncology, National University Cancer
Institute, Singapore; Yi Wan Lim, MBBChir, MRCP (UK), Department of
Haematology-Oncology, National University Cancer Institute, Singapore;
Lynette Ngo, MBBS (S’pore), MMed (Int Med), MRCP (UK), Department of
Medical Oncology, Raffles Cancer Centre, Singapore; Hui Ti See, MB ChB
(Leicester), MRCP, FAMS (Med Oncology), Department of Medical Oncology,
Parkway Cancer Centre, Singapore; Lay Tin Soh, MBBS (S’pore), FRCP
(UK), FAMS, Department of Medical Oncology, National Cancer Centre
Singapore, Singapore; David SP Tan, MRCP (UK) (Medical Oncology), PhD,
Department of Haematology-Oncology, National University Cancer Institute,
Singapore; Non-Voting Member: Koon Mian Foo, BSc (Pharmacy), BCOP,
Department of Pharmacy, KK Women’s and Children’s Hospital, Singapore.
Reviewers
Invited reviewers were Peter Ang, MBBS (S’pore), MRCP (UK), M Med
(Int Med), OncoCare Cancer Centre, Singapore; Xiaohua Wu, MD, PhD,
Department of Gynecologic Oncology, Fudan University Shanghai Cancer
Center, People’s Republic of China. An additional invited reviewer chose
to be anonymous.
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36. Stark D, Nankivell M, Pujade-Lauraine E, Kristensen G, Elit L, Stockler
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Annals Academy of Medicine
October 2015, Vol. 44 No. 10
Statement of evidence and
consensus of the authors
regarding their views of currently
accepted approaches to treatment.
Validation method not specified.
Advanced epithelial ovarian
cancer.
Guideline Developer
Description of
Method of Guideline
Validation
Target Population
Dose-dense Chemotherapy:
Carboplatin AUC 6 (Day 1)/
paclitaxel 80 mg/m2 (Days 1, 8,
15); q3wk 6 cycles (Category I)
Carboplatin (AUC 5 – 6)/
docetaxel 60 – 75 mg/m2 q3wk 6
cycles (Category I)
Patients who develop an allergy
to or do not tolerate paclitaxel –
alternative regimen:
•
Carboplatin/docetaxel or
•
Carboplatin/pegylated
lipopsomal doxorubicin
(II,A)
Standard Chemotherapy:
Paclitaxel 175 mg/m2 and
carboplatin AUC 5 – 6,
administered intravenously
q3wks (I,A)
Advanced epithelial ovarian
cancer.
Guidelines are endorsed by the
JSMO.
Group decision-making that seeks
the consensus of experts and the
fulfillment of objectives.
In those unable to tolerate
paclitaxel, pegylated liposomal
doxorubicin or gemcitabine in
combination with carboplatin can
be used as an alternative (A).
Paclitaxel is recommended
in combination therapy with
platinum in the first line
postsurgery treatment of
epithelial ovarian cancer where
the potential benefits justify the
toxicity of the therapy.
Carboplatin is the platinum drug
of choice in both single and
combination therapy (A).
Paclitaxel in combination with a
platinum-based therapy (cisplatin
or carboplatin) should be the
standard chemotherapy:
•
Paclitaxel 175 mg/m2 in a
3-hour intravenous infusion,
followed by a platinum
every 3 weeks
Current recommendation is
carboplatin/paclitaxel q3wks for
6 cycles.
Advanced epithelial ovarian
cancer.
Guideline development
group made up of health
professionals, representatives
of patient and carer groups and
technical experts assesses the
available evidence and makes
recommendations. After the
guideline development group
finalises the recommendations,
the collaborating centre produces
the final guideline. NICE
formally approves the final
guideline and issues its guidance
to the NHS.
SIGN is a collaborative network
of clinicians, healthcare
professionals and patient
organisations that develops
guidelines using a standard
methodology based on a
systematic review of the evidence
for the NHS in Scotland.
Recommendations are explicitly
linked to the supporting evidence.
NHS evidence has accredited the
process used by SIGN to develop
guidelines.
Advanced epithelial ovarian
cancer.
Guidelines development
working group that consists of
gynaecological oncologists,
radiation oncologists, medical
oncologists, gynaecologcial
pathologists, palliative medicine
consultants, nurse oncologists
from Australia’s New South
Wales, Queensland, Tasmania and
New Zealand. The workgroup
was tasked by the GMCT to
review the Gynaecological
Oncology Clinical Practice
Guidelines that were originally
published in 2004, using updated
references and are intended to
be evidence-based wherever
possible.
Advanced epithelial ovarian
cancer.
Greater Metropolitan Clinical
Taskforce (GMCT)
National Institute of Health and
Clinical Excellence (NICE),
United Kingdom
Scottish Intercollegiate
Guidelines Network (SIGN),
United Kingdom
2009
Best Clinical Practice
Gynaecological Cancer
Guidelines 2009, GMCT
May 2013
Ovarian Cancer: The
Recognition and Initial
Management of Ovarian
Cancer (CG122)
November 2013
SIGN - Management of
Epithelial Ovarian Cancer. A
National Clinical Guideline.
SIGN Publication No. 135
EMA: European Medicines Agency; IP: Intraperitoneal; JSMO: Japanese Society of Medical Oncology; NHS: National Health Service; QOL: Quality of life; RCT: Randomised controlled trial
Front-line
Postoperative
Chemotherapy
National Cancer Comprehensive
Network (NCCN), United States
Date Released
Carboplatin (AUC 5 – 7.5)/
paclitaxel 175 mg/m2 q3wk 6
cycles (Category I)
European Society for Medical
Oncology (ESMO)
13 June 2013
Guidelines Title
Recommendations developed
from discussion at consensus
conferences.
July 2013
NCCN Clinical Practice
Guidelines in Ovarian Cancer
Including Fallopian Tube
Cancer and Primary Peritoneal
Cancer Version 2.2013
Newly Diagnosed and
Relapsed Epithelial Ovarian
Carcinomas: ESMO Clinical
Practice Guidelines for
Diagnosis, Treatment and
Follow-up
Supplementary Table 1. International Guidelines for the Systemic Treatment of Advanced Epithelial Ovarian Cancer
SCAN Gynaecological Cancers Systemic Therapy Workgroup
430
Option to use bevacizumabcontaining regimens per ICON-7
and GOG-218:
Carboplatin AUC 6 /paclitaxel
175 mg/m2 /bevacizumab 7.5
mg/kg q3wk x 5 – 6 cycles →
continue bevacizumab for up to 12
additional cycles (Category III).
NCCN Clinical Practice
Guidelines in Ovarian Cancer
Including Fallopian Tube Cancer
and Primary Peritoneal Cancer
Version 2.2013
Bevacizumab should be given with
paclitaxel and carboplatin with a
treatment duration of 1 year.
poor prognostic features:
•
stage IV,
•
suboptimal debulking
(as defined in ICON7 trial)
(I,B).
Recommended for patients with
Dose-dense chemotherapy:
In the absence of confirmatory
data, dose-dense administration
of paclitaxel currently can only be
considered an option, and not as a
standard of care (I,B).
Newly Diagnosed and Relapsed
Epithelial Ovarian Carcinomas:
ESMO Clinical Practice
Guidelines for Diagnosis,
Treatment and Follow-up
Not recommended – costeffectiveness analysis has shown
that the treatment’s cost in
relation to its health benefits is not
sufficient.
6 of 8 votes
Dose-dense chemotherapy:
Carboplatin AUC 6 (day 1) and
paclitaxel 80 mg/m2 (days 1, 8,
15) q3wk may be considered for
the treatment of first-line ovarian
cancer. The increased toxicity
and frequency of visits need to be
discussed with the patient (B).
Recommendation: Where possible,
patients should be enrolled in
ongoing clinical trials in order
to establish if this regime should
become the standard of care. There
are several ongoing studies that
assess the efficacy of dose-dense
paclitaxel (ICON8, GOG262,
MITO7) and results are awaited.
A third cytotoxic agent should
not be added to carboplatin and
paclitaxel (A).
Patients who are unfit for
combination therapy should be
offered single-agent carboplatin
(A).
SIGN - Management of
Epithelial Ovarian Cancer. A
National Clinical Guideline.
SIGN Publication No. 135
Not recommended – bevacizumab
does not provide benefit to justify
its high cost.
Ovarian Cancer: The
Recognition and Initial
Management of Ovarian Cancer
(CG122)
Nil
Best Clinical Practice
Gynaecological Cancer
Guidelines 2009, GMCT
EMA: European Medicines Agency; IP: Intraperitoneal; JSMO: Japanese Society of Medical Oncology; NHS: National Health Service; QOL: Quality of life; RCT: Randomised controlled trial
Front-line
Bevacizumab –
Chemotherapy
Member Votes
Guidelines
Title
Supplementary Table 1. International Guidelines for the Systemic Treatment of Advanced Epithelial Ovarian Cancer (Con't)
431
SCAN Gynaecological Cancers Systemic Therapy Workgroup
Annals Academy of Medicine
October 2015, Vol. 44 No. 10
Stage II and III optimally debulked
to <1 cm:
•
All women should be
counselled regardinig benefit
of IP chemotherapy prior to
surgery.
•
Day 1: IV paclitaxel 135 mg/
m2 over 3 or 24 hours; Day 2:
IP cisplatin 75 – 100 mg/m2
Day 8: IP paclitaxel 60 mg/
m2; q3wk 6 cycles.
(Category I for stage III)
Encourage participation in ongoing
clinical trials involving antiangiogenesis agents.
Major disagreements among panel
members, therefore Category 3.
Recommendation:
(data from the 2 phase III RCTs
have not shown a statistically
significant increase in overall
survival and/or improved QOL)
Carboplatin AUC 6/paclitaxel
175 mg/m2/bevacizumab 15 mg/
kg q3wk x 6 cycles. Bevacizumab
started on Day 1 of cycle 2 q3wk
for up to 22 cycles (Category III).
NCCN Clinical Practice
Guidelines in Ovarian Cancer
Including Fallopian Tube Cancer
and Primary Peritoneal Cancer
Version 2.2013
5 of 8 votes
IP treatment has not been adopted
as standard of care in view of
its greater toxicity and difficulty
delivering all the planned
treatment. Lack of current standard
intravenous chemotherapy in the
standard arrms of the IP trials has
made the interpretation of the
results difficult. Recommends IP
chemotherapy in the context of
clinical trial.
4 of 8 votes (majority)
Bevacizumab has been licensed by
the EMA at 15 mg/kg for use with
carboplatin and paclitaxel for ≤15
months or until progression.
Newly Diagnosed and Relapsed
Epithelial Ovarian Carcinomas:
ESMO Clinical Practice
Guidelines for Diagnosis,
Treatment and Follow-up
Where possible, women receiving
IP chemotherapy should be
enrolled into ongoing clinical
trials.
Chemotherapy which includes
an IP element can be considered
for women with a new diagnosis
of epithelial ovarian cancer
and residual disease ≤1 cm
after primary surgery provided
a regimen of proven benefit
in a clinical trial compared to
intravenous therapy is used,
it is delivered in a centre with
appropriate expertise and the
potential toxicities are fully
explained (B).
SIGN – Management of
Epithelial Ovarian Cancer. A
National Clinical Guideline.
SIGN Publication No. 135
Do not offer IP chemotherapy
except in clinical trial.
Toxicity +++, complex and
expensive.
Ovarian Cancer: The
Recognition and Initial
Management of Ovarian Cancer
(CG122)
IP chemotherapy is not
recommended for patients who
have significant intra-abdominal
adhesions at the conclusion of their
surgery as the adhesions may limit
the distribution of chemotherapy
within the abdomen.
IP chemotherapy is an option
supported by Phase III trials
for patients with low volume
residual disease following surgery.
However the reported benefits
need to be balanced against
the drawbacks of catheterrelated morbidity, infection,
and discomfort associated with
treatment.
Best Clinical Practice
Gynaecological Cancer
Guidelines 2009, GMCT
EMA: European Medicines Agency; IP: Intraperitoneal; JSMO: Japanese Society of Medical Oncology; NHS: National Health Service; QOL: Quality of life; RCT: Randomised controlled trial
Member Votes
Front-line IP
Chemotherapy
Member Votes
Guidelines
Title
Supplementary Table 1. International Guidelines for the Systemic Treatment of Advanced Epithelial Ovarian Cancer (Con't)
SCAN Gynaecological Cancers Systemic Therapy Workgroup
432
8 of 8 votes
Published data demonstrate that
primary assessment and debulking
by a gynaecologic oncologist
results in a survival advantage.
Patients being evaluated for
neoadjuvant chemotherapy should
be seen by a fellowship-trained
gynaecologic oncologist prior to
being considered a poor surgical
candidate.
Consider neoadjuvant
chemotherapy/primary interval
cytoreduction (diagnosis by
fine needle aspiration, biopsy or
paracentesis) for patients with
bulky stage III/IV who are poor
surgical candidates due to highrisk comorbidity conditions or
disease factors (Category I).
NCCN Clinical Practice
Guidelines in Ovarian Cancer
Including Fallopian Tube Cancer
and Primary Peritoneal Cancer
Version 2.2013
Validation of this approach may
come from further trials that are
ongoing.
The use of chemotherapy with
interval surgery is becoming more
widely accepted and is offered to
patients with poor performance
status, low albumin levels and in
those with very extensive tumour
dissemination.
Newly Diagnosed and Relapsed
Epithelial Ovarian Carcinomas:
ESMO Clinical Practice
Guidelines for Diagnosis,
Treatment and Follow-up
Good practice points: With regard
to selecting who will benefit
from neoadjuvant chemotherapy,
treatment should be individualised
to the patient taking into account
resectability, age, histology,
performance status and after ruling
out the possibility of other primary
tumours and full discussion at
multidisciplinary meetings.
The use of neoadjuvant
chemotherapy in women
with stage IIIC or IV ovarian
cancer may be considered as an
alternative to primary debulking
surgery (A).
SIGN – Management of
Epithelial Ovarian Cancer. A
National Clinical Guideline.
SIGN Publication No. 135
If performing surgery for women
with ovarian cancer, whether
before chemotherapy or after
neoadjuvant chemotherapy, the
objective should be complete
resection of all macroscopic
disease.
Ovarian Cancer: The
Recognition and Initial
Management of Ovarian Cancer
(CG122)
NIL
Best Clinical Practice
Gynaecological Cancer
Guidelines 2009, GMCT
EMA: European Medicines Agency; IP: Intraperitoneal; JSMO: Japanese Society of Medical Oncology; NHS: National Health Service; QOL: Quality of life; RCT: Randomised controlled trial
Member Votes
Front-line
Neoadjuvant
Chemotherapy
Guidelines
Title
Supplementary Table 1. International Guidelines for the Systemic Treatment of Advanced Epithelial Ovarian Cancer (Con't)
433
SCAN Gynaecological Cancers Systemic Therapy Workgroup
Annals Academy of Medicine
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