First-line chemotherapy for women with
epithelial ovarian cancer
A systematic review
July 2013
First line chemotherapy for women with epithelial ovarian cancer: a systematic review was prepared and
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Cancer Australia
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© Cancer Australia (2013)
Online ISBN: 978-1-74127-186-7
Recommended citation
Cancer Australia. First line chemotherapy for women with epithelial ovarian cancer: a
systematic review. Cancer Australia, Surry Hills, NSW, 2013.
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First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
i
Contents
Acknowledgments ............................................................................................................................... iv
Executive summary ...............................................................................................................................v
1
2
3
Background ..............................................................................................................................1
1.1
Ovarian cancer in Australia .......................................................................................... 1
1.2
Use of chemotherapy for the treatment of ovarian cancer .................................. 1
1.3
Australian clinical practice guidelines ........................................................................ 1
Methods .....................................................................................................................................4
2.1
Inclusion criteria ............................................................................................................... 4
2.2
Literature search ............................................................................................................. 5
2.3
Data extraction ............................................................................................................... 7
2.4
Quality assessment.......................................................................................................... 7
Results ........................................................................................................................................9
3.1
International guidelines & recommendations ........................................................... 9
3.2
Research questions ......................................................................................................... 9
3.3
Other issues ..................................................................................................................... 46
3.4
Ongoing trials ................................................................................................................. 46
4
Discussion ................................................................................................................................47
5
Conclusion ..............................................................................................................................50
Appendix A Contributors...................................................................................................................51
Appendix B Literature databases searched ..................................................................................52
Appendix C Search strategy ............................................................................................................53
Appendix D Health technology assessment, guidelines and clinical trials websites
searched
54
Appendix E Flowchart-inclusion/exclusion of articles ..................................................................55
Appendix F International guidelines and recommendations .....................................................56
Appendix G Overall and progression free survival for studies investigating
different chemotherapy regimens ....................................................................................................60
Appendix H Overall and progression free survival for biological therapy studies ....................65
Appendix I Adverse events reported in trials investigating different
chemotherapy regimens (research question 1) .............................................................................66
Appendix J Adverse events reported in trials investigating biological therapies ....................70
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
ii
Appendix K ASCO clinical practice guideline recommendations for
chemotherapy dosing for obese adults with cancer76...................................................................71
Appendix L Ongoing trials ...............................................................................................................72
Abbreviations .......................................................................................................................................79
References ...........................................................................................................................................81
Tables
Table 1
Adjuvant chemotherapy following surgery compared with observation
following surgery for early stage ovarian cancer: overall survival ............................. 10
Table 2
Adjuvant chemotherapy following surgery compared with observation
following surgery for early stage ovarian cancer: progression free
survival .................................................................................................................................... 11
Table 3
Chemotherapy regimens investigated for first line adjuvant treatment
of ovarian cancer ................................................................................................................ 14
Table 4
Chemotherapy schedules investigated for first line adjuvant treatment
of ovarian cancer ................................................................................................................ 21
Table 5
Additional chemotherapy regimens and schedules investigated for first
line adjuvant treatment of ovarian cancer ................................................................... 24
Table 6
Study characteristics of studies reporting the outcomes of
chemotherapy in obese patients ..................................................................................... 39
Table 7
Study characteristics of studies reporting adverse event outcomes only ................ 40
Table 8
Chemotherapy characteristics of Suh 2011 ................................................................... 43
Table 9
Cumulative grade 3 and 4 toxicity based on BMI in Wright et al 2008 ..................... 44
Table 10
Treatment modifications based on BMI in Wright et al 2008 ....................................... 44
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
iii
Acknowledgments
Contributors
Cancer Australia gratefully acknowledges the support of the many individuals and
groups who contributed to the development of this review.
Working group members
The First line chemotherapy for the treatment of women with epithelial ovarian
cancer: a systematic review was developed with input from an expert
multidisciplinary Working Group with the following members:
Dr Christopher Steer (Chair)
Medical Oncologist
Mr Keith Cox OAM
Nurse Practitioner
Dr Jeffrey Goh
Medical Oncologist
Dr Susan Jordan
Epidemiologist
Ms Eugenia Koussidis
Consumer representative
Professor Yee Leung
Gynaecological Oncologist
A/Prof Penelope Webb
Epidemiologist
Ms Nicole Wilton
Consumer representative
See Appendix A for more information.
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
iv
Executive summary
In 2009, ovarian cancer was the second most commonly diagnosed gynaecological
cancer in Australia, with a total of 1,338 ovarian cancer cases diagnosed.1 It is the most
common cause of gynaecological cancer death, representing over half (56%) of such
deaths.1 The five year relative survival rate for Australian women with ovarian cancer has
increased significantly, from 32.4% in 1982-1987 to 43.3% in 2006-2010.2
Clinical practice guidelines for the management of women with epithelial ovarian
cancer were published by National Breast Cancer Centre (NBCC)* and the Australian
Cancer Network (ACN) in 2004.3 The recommendations for treatment with chemotherapy
include3:
Patients with stage IA or IB well or moderately differentiated tumours do not
require adjuvant chemotherapy because their risk of relapse is low, and the
toxicity not justified.
Neoadjuvant chemotherapy and interval cytoreduction may be considered if
optimal primary cytoreduction was not achieved.
The first line treatment of advanced ovarian cancer ideally should include a
platinum compound.
It is currently recommended that standard first line chemotherapy for advanced
ovarian cancer should be a combination of carboplatin (AUC x 6) and paclitaxel
(175 mg/m2) given every three weeks.
Although intraperitoneal chemotherapy is not recommended as standard
therapy its use may be considered on an individual patient basis at a designated
cancer centre.
In 2009−2011, National Breast and Ovarian Cancer Centre (NBOCC) † and the
Queensland Institute of Medical Research (QIMR) undertook a project to examine the
management pathways for women in Australia with ovarian cancer, using data for all
women diagnosed in 2005. These data indicate variations in chemotherapy treatment
compared to best practice, as recommended in the Guidelines.
This systematic review was undertaken by Cancer Australia in order to identify any
revisions required to recommendations for chemotherapy and ensure currency of the
2004 guidelines. Following consultation with a multidisciplinary working group, it was
agreed that the scope of the review would be limited to first line treatment of epithelial
ovarian cancer. A search of the literature published between January 2003 and March
2012 was undertaken using electronic databases. The primary search was limited to
randomised controlled trials conducted in humans published in the English language. A
*
In February 2008 National Breast Cancer Centre incorporating the Ovarian Cancer Program (NBCC) changed
its name to National Breast and Ovarian Cancer Centre (NBOCC)
† On 30 June 2011, National Breast and Ovarian Cancer Centre (NBOCC) amalgamated with Cancer Australia
to form a single national agency, Cancer Australia, to provide leadership in cancer control and improve
outcomes for Australians affected by cancer.
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
v
supplementary search was conducted to identify articles on subsets of the defined
population that have specific chemotherapy requirements; this search was not limited to
RCTs and included additional search terms related to the subpopulations. In October
2012 the multidisciplinary working group re-prioritised the other issue of obese patients to
be a research question. A systematic search was undertaken in November 2012 to
identify evidence for the new research question ‘What are the specific chemotherapy
requirements for women with epithelial ovarian cancer who are obese?’
Overall 75 articles and two conference abstracts were included in the systematic review.
Of the included citations, 35 were phase III randomised controlled trials (RCTs) addressing
the primary research questions, 10 were non-randomised controlled trials included in the
subgroup question and six were Cochrane reviews used as primary references.
Summary of results
Chemotherapy regimens for first line adjuvant treatment of epithelial ovarian cancer
Five systematic reviews were identified which investigated various chemotherapy
regimens for epithelial ovarian cancer. One of these reviews included only patients with
early stage ovarian cancer (stage I-IIa). Some sub-group analyses were performed for
surgical staging and histological subtype. This Cochrane review found that overall and
progression-free survival was improved in early stage ovarian cancer patients who had
chemotherapy compared with those on observation. Subgroup analysis suggested that
women who had optimal surgical staging of their disease were unlikely to benefit from
adjuvant chemotherapy, whereas those who had sub-optimal staging did. The remaining
reviews included ovarian cancer patients of all stages, however provided little to no
information on chemotherapy in the first line setting.
Eighteen phase III and seven phase II randomised controlled trials were identified which
investigated different chemotherapy regimens in populations with a majority of
advanced stage ovarian cancer patients. While a range of regimens have been
investigated, including addition of chemotherapy agents to standard regimens or
substitution of different agents, almost all failed to demonstrate an overall or progressionfree survival benefit compared with standard chemotherapy (most often
platinum/taxane combination). Trials which did show survival differences were either in
specific patient populations or compared older chemotherapy regimens no longer
considered standard.
Biological therapies for first line adjuvant treatment of epithelial ovarian cancer
Two randomised controlled trials have shown improved progression-free survival for the
biological therapy bevacizumab used in addition to carboplatin and paclitaxel. One of
these studies also indicated for patients at high risk of progression, overall survival benefit
with bevacizumab, and greater benefit in progression free survival than for patients at
lower risk.
Adverse effect profiles reflected the various agents used however, mostly there were few
differences in toxicities experienced between treatment arms. Similarly, most trials
reported no significant differences in quality of life between treatment arms investigated.
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
vi
Schedules for chemotherapy regimens for first line adjuvant treatment of epithelial
ovarian cancer
Six phase III and one phase II trials were identified which investigated different schedules
for chemotherapy regimens for first line adjuvant treatment of epithelial ovarian cancer.
No systematic reviews in this topic were identified. A range of schedules were
investigated including dose-dense chemotherapy, different doses of the same agent or
different timing/cycles of the same regimen. Only one trial, JGOG 3016, showed survival
benefits between treatment arms. This study investigated dose-dense paclitaxel
compared with standard paclitaxel and reported improved overall survival and
progression-free survival in the dose-dense paclitaxel group compared to the
conventional group, at short-term follow-up (up to 3 years) and at long-term follow-up
(median 6.4 years). While adverse events were often similar between treatment arms,
some increased toxicity was observed in the higher dose, more intensive chemotherapy
intervention arms compared with standard arms. Quality of life was not assessed in any of
the trials.
Two trials were identified which investigated complex chemotherapy regimens including
peripheral blood stem cell support. Neither of these trials reported any survival differences
between intervention and standard treatment arms. Only one trial provided detailed
data on adverse events, with higher toxicity experienced in the complex high-dose
chemotherapy arm. Quality of life was not assessed in either trial.
Mode of administration for chemotherapy regimens for first line adjuvant treatment of
epithelial ovarian cancer
One recent high quality Cochrane systematic review was identified which reported on
the effectiveness of intraperitoneal (IP) chemotherapy in treating ovarian cancer. The
review found that the inclusion of an IP component of chemotherapy improved overall
and progression-free survival. However, women receiving IP chemotherapy reported
more adverse events than those on standard chemotherapy. Limited data on quality of
life have been reported.
Time of administration of chemotherapy regimens for first line adjuvant treatment of
epithelial ovarian cancer
One randomised controlled trial has been published comparing neoadjuvant
chemotherapy with primary surgery. No survival differences between treatment arms
were observed. More adverse events were observed in the primary surgery group than
the neoadjuvant group, however whether this was statistically significant was not
reported. There were no differences in quality of life between treatment arms.
A small phase II trial reported no differences in outcomes between patients who had 3
cycles versus 2 cycles of neoadjuvant chemotherapy.
Subsets of the defined population for first line adjuvant treatment of epithelial ovarian
cancer with specific chemotherapy requirements
Limited information was identified to suggest that there are specific chemotherapy
requirements for particular subgroups such as BRCA mutation carriers, elderly patients or
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
vii
different histological subgroups. Trials were not designed to investigate the effectiveness
of different chemotherapy regimens across different subgroups.
Specific chemotherapy requirements for women with epithelial ovarian cancer who are
obese
No studies were identified which specifically compared different doses of chemotherapy
among obese patients for survival outcomes. In most of the studies, chemotherapy
dosing was based on actual body weight, whereas in some studies the formula used did
not include body weight or body surface area (BSA). No significant differences in overall,
progression-free or disease-free survival were reported between obese and non-obese
patients in most of the studies. One study (Hanna et al 2013) determined BSA greater
than 2m2 and BMI >30kg/m2 to be predictors of reduced planned relative dose intensity
(RDI) <85% and reduced delivered RDI <85%. In both univariate analysis and multivariate
analysis, delivered RDI <85% was negatively associated with overall survival. Adverse
events reported and any differences between BMI groups varied between studies.
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
viii
1
Background
1.1
Ovarian cancer in Australia
In 2009, ovarian cancer was the second most commonly diagnosed gynaecological cancer
in Australia, with a total of 1,338 ovarian cancer cases diagnosed.1 It is the most common
cause of gynaecological cancer death, representing over half (56%) of such deaths.1 The
five year relative survival rate for Australian women with ovarian cancer has increased
significantly, from 32.4% in 1982-1987 to 43.3% in 2006-2010.2 At the end of 2007, it was
estimated that there were 8,564 women alive who had been diagnosed with ovarian cancer
in the previous 26 years.2
1.2
Use of chemotherapy for the treatment of ovarian cancer
Most women diagnosed with epithelial ovarian cancer are treated with surgery, and
chemotherapy with the aim of reducing detectable disease to zero. Primary cytoreduction
aims to remove as much of the tumour as possible, to allow adjuvant treatment to be more
effective. The Gynecologic Oncology Group (GOG) defines optimal cytoreduction as
having residual tumour nodules each measuring 1 cm or less in in maximal diameter, with
complete cytoreduction (microscopic disease) being the ideal surgical outcome.4 Ovarian
cancer is surgically staged, based on the extent of the disease, using the guidelines
established by FIGO (International Federation of Gynecology and Obstetrics).5 Epithelial
ovarian cancer (EOC) is a highly chemosensitive tumour, but most women with advanced
EOC initially responding to first-line chemotherapy will eventually relapse.6
1.3
Australian clinical practice guidelines
The chemotherapy chapter in the ACN and NBCC Clinical practice guidelines for the
management of women with epithelial ovarian cancer (2004)3 covers the following areas:
Which patients with early ovarian cancer should receive chemotherapy?
Adjuvant treatment of early ovarian cancer
First line treatment of advanced disease
Information on particular drugs/combinations – including cisplatin, carboplatin,
paclitaxel
Newer agents and current research
Special chemotherapy strategies –
intense/dose dense, stem cell support
Monitoring and duration
Maintenance chemotherapy
including
intraperitoneal
therapy,
dose
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
1
Relapsed disease
In regards to chemotherapy treatment, the ACN and NBCC Clinical practice guidelines for
the management of women with epithelial ovarian cancer (2004) recommend:
Early stage
Adjuvant chemotherapy with a platinum agent is recommended for patients with
high grade or clear cell histology because they are known to have a higher relapse
rate.
Patients with stage IA or IB well or moderately differentiated tumours do not require
adjuvant chemotherapy because their risk of relapse is low, and the toxicity not
justified.
Adjuvant chemotherapy is not indicated in patients with borderline tumours (unless
invasive implants are confirmed histologically).
Platinum-based adjuvant chemotherapy improves recurrence-free and overall
survival in women with surgically resected early ovarian cancer, who are at high risk
of relapse.
Advanced
The first line treatment of advanced ovarian cancer ideally should include a platinum
compound.
It is currently recommended that standard first line chemotherapy should be a
combination of carboplatin (AUC 6) and paclitaxel (175 mg/m 2) given every three
weeks.
In patients unsuitable for combination therapy (on the basis of either concurrent
medical conditions, performance status or by patient preference) single agent
carboplatin is an effective and acceptable treatment for advanced ovarian cancer.
Intraperitoneal chemotherapy
Although intraperitoneal chemotherapy is not recommended as standard therapy its
use may be considered on an individual patient basis at a designated cancer centre.
High-dose chemotherapy with stem cell support
The use of chemotherapy protocols utilising high dose therapy should only be offered
as part of an appropriately designed clinical trial.
In 2009−2011, National Breast and Ovarian Cancer Centre (NBOCC) and the Queensland
Institute of Medical Research (QIMR) undertook a project to examine the management
pathways for women in Australia with ovarian cancer, using data for all women diagnosed in
2005. These data indicate variations in chemotherapy treatment compared to best practice,
as recommended in the Guidelines.
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
2
Based on the data from the NBOCC/QIMR study, while almost 90% of women for whom it is
recommended were given chemotherapy treatment, with almost all of these treated with a
platinum-based drug and 70% treated with the recommended combination of carboplatinpaclitaxel:
2% of women with borderline tumours and 33% of those with low-grade stage IA/IB
cancers were treated with chemotherapy despite this not being recommended in
the guidelines. The reasons for this were unknown.
74% of women with IA/IB cancers of high-grade or clear cell histology for whom
chemotherapy is recommended were treated with chemotherapy and 97% of these
were treated with a platinum compound.
70% of women for whom chemotherapy is recommended were initially treated with
the standard carboplatin-paclitaxel combination, however only 78% of women who
started this treatment (55% of all those treated with chemotherapy) completed the
standard six cycles and, of these, 41% of these required a dose reduction and/or one
or more cycles was delayed, usually because of toxicity.
Women over the age of 70 were significantly less likely to start standard treatment
than younger women (30% vs. 85%), however, completion rates did not differ
appreciably by age (79% vs. 70%).
A review of the literature was necessary to ensure currency of the 2004 guidelines and to
identify any revisions required, in order to maximise outcomes for women in Australia with
ovarian cancer. Following consultation with a multidisciplinary working group, it was agreed
that the scope of the review would be limited to first line treatment of epithelial ovarian
cancer.
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
3
2
Methods
This systematic review addresses six research questions which were developed with input
from a multidisciplinary working group. The questions addressed were:
1) What is the most effective chemotherapy regimen for first line adjuvant treatment of
epithelial ovarian cancer?
2) What is the most effective schedule (duration/dose/frequency) for chemotherapy
regimens for first line adjuvant treatment of epithelial ovarian cancer?
3) What is the most effective mode of administration for chemotherapy regimens for first
line adjuvant treatment of epithelial ovarian cancer?
4) When is the most effective time to administer chemotherapy for first line treatment of
epithelial ovarian cancer?
5) Are there subsets of the defined population for first line adjuvant treatment of
epithelial ovarian cancer that have specific chemotherapy requirements?
6) What are the specific chemotherapy requirements for women with epithelial ovarian
cancer who are obese?
2.1
2.1.1
Inclusion criteria
Participants
For questions 1) to 4): women with newly diagnosed invasive epithelial ovarian cancer (stage
I-IV) with no previous chemotherapy treatment.
For question 5): subsets of women with epithelial ovarian cancer (BRCA mutation carriers,
younger/older women, histological subtypes).
For question 6): obese women with newly diagnosed invasive epithelial ovarian cancer
(stage I-IV) with no previous chemotherapy treatment.
2.1.2
Intervention/Comparison
For question 1): various chemotherapy regimens (including platinum agents, taxanes, antiangiogenesis inhibitors) in comparison with either a placebo or other chemotherapeutic
agent.
For question 2): different schedules or doses of the same chemotherapy regimens (including
dose-dense chemotherapy).
For question 3): different modes of administration of the same chemotherapy regimens
(including intravenous, intraperitoneal, oral administration).
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
4
For question 4): neoadjuvant chemotherapy compared with adjuvant chemotherapy.
For question 5): various chemotherapy regimens/schedules stratified or compared by
population/subset.
For question 6): different doses or schedules of the same chemotherapy regimens.
2.1.3
Outcome measures
Outcome measures of interest were:
2.1.4
overall survival
disease/progression-free survival
treatment compliance
response to chemotherapy (clinical/pathological)
adverse events
quality of life.
Additional issues of interest
The following topics were considered as additional issues of interest, and although they were
not specifically searched for in the literature review, any information on these topics
identified was recorded:
2.2
Any other women with specific chemotherapy requirements/issues for example
rural/remote, Aboriginal and Torres Strait Islander women.
Resources specification, for example resources required for intraperitoneal
chemotherapy.
Patient selection criteria.
Literature search
A systematic literature search was conducted in March 2012 to identify relevant studies
which addressed the inclusion criteria. The search was conducted using several databases
(see Appendix B), including:
Medline
Embase
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 chemotherapy (see
Appendix C). The primary search was limited to randomised controlled trials (RCTs)
conducted in humans which were published from January 2003 to March 2012 in the English
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
5
language. In addition, a supplementary search was conducted to identify articles
specifically for research question 5; this search was not limited to RCTs.
After the removal of duplicates and the addition of further citations sourced, a total of 963
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 previously. 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. Clinical trials sites searched included clinical trials.gov (USA), controlled
trials.com (UK) and the WHO International Clinical Trials Registry Platform (which includes the
Australian New Zealand Clinical Trials Registry (ANZCTR)). Further information on sites
searched can be found in Appendix D.
The following conference websites were searched from January 2008 to March 2012 to
identify recently presented abstracts about first line chemotherapy for ovarian cancer:
American Society of Clinical Oncology (ASCO) annual meeting
International Gynecologic Cancer Society (IGCS) biennial meeting
Note: Due to the breadth of the topic, the Society of Gynecologic Oncologists (SGO)
meeting & European Society of Gynaecological Oncology (ESGO) international meeting
were not searched as these meetings did not have a searchable electronic index for
abstracts.
In October 2012 the multidisciplinary working group re-prioritised the other issue of obese
patients to be a research question. The new research question ‘What are the specific
chemotherapy requirements for women with epithelial ovarian cancer who are obese?’ was
systematically searched for in November 2012. The search was limited to articles published
between January 2003 and November 2012. The search was not limited to RCTs.
2.2.1
Exclusion criteria
Papers were excluded if they met any of the following criteria:
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 in a population other than as defined in the
inclusion criteria. Studies investigating patients with recurrent ovarian cancer were
excluded.
inappropriate interventions—studies not investigating chemotherapy regimens as
defined in the inclusion criteria. Studies investigating immunotherapy/biological
therapies were excluded.
inappropriate outcomes—studies not reporting on the effect of chemotherapy.
not published in the English language
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
6
published prior to 2003
Based on these criteria, 753 articles were excluded. The full texts of the remaining 210
citations were retrieved and assessed to identify which met the inclusion criteria for the
review. Non-systematic overview papers were sourced and reference lists were checked for
further articles of interest. After full text assessment, 63 citations and one abstract were
identified as eligible for the current review (see Appendix E). Two additional studies (one
published article and one conference abstract) identified after the search were also
included.
Thirty five randomised controlled trials were included in the review for the primary research
questions. Ten studies that were not randomised controlled trials were included for the
subgroup question. Seven previously published systematic reviews, including six Cochrane
reviews were also used as primary references.
For the additional search to identify evidence for the research question ‘what are the
specific chemotherapy requirements for women with epithelial ovarian cancer who are
obese?, a total of 582 unique citations were identified. 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 previously. After review, 540 citations were
excluded. The full texts of the remaining 42 citations were retrieved and assessed to identify
which met the inclusion criteria for the review. After full text assessment 11 citations were
identified as eligible for the current review.
In total, 76 eligible articles and one conference abstract were included (see appendix E).
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.
Outcome data extracted from the studies included overall survival, progression-free survival,
treatment compliance, response to chemotherapy, adverse events and quality of life.
2.4
Quality assessment
Primary studies and systematic reviews were assessed for quality based on guidance from
the National Health and Medical Research Council (NHMRC).7 The following were
considered:
For randomised controlled trials:
Was an appropriate method used for treatment assignment?
Was there control of selection bias after treatment assignment (such as intention to
treat analysis, minimal patients lost to follow-up)
Was the study blinded?
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
7
Was there standardised outcome assessment (if blinding was not possible)?
Were groups well matched at baseline?
Was the study powered to detect a difference in primary outcome?
For systematic reviews:
Was the search strategy adequate?
Were the inclusion criteria appropriate?
Did the review perform quality assessment on included papers?
Was there appropriate summarisation?
What methods were used for pooling data?
Was heterogeneity explored?
Quality for each study/review was then assigned as high/moderate/low.
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
8
3
Results
3.1
International guidelines & recommendations
Various international guidelines were identified either through the literature search or from
health technology assessment and guidelines websites (see Appendix D).
Five international guidelines regarding the management of ovarian cancer in general were
identified. Recommendations with regard to chemotherapy are provided in Appendix F.
3.2
Research questions
3.2.1 What is the most effective chemotherapy regimen for first line adjuvant
treatment of epithelial ovarian cancer?
While all stages of invasive ovarian cancer were included, for this research question early
and advanced ovarian cancer are reported separately, where possible.
Early stage ovarian cancer (stage I-IIa)
Systematic reviews
One high quality Cochrane review on adjuvant chemotherapy for early stage epithelial
ovarian cancer was published in 2012 and includes RCTs published up to August 2011.8 The
review defined early stage as FIGO stage I/IIa and included trials which compared
chemotherapy following surgery to observation following surgery. The review includes five
RCTs which enrolled a total of 1277 women. The chemotherapy regimen in four trials was
cisplatin-based chemotherapy, one trial used melphalan. Four trials were included in metaanalyses and considered at low risk of bias. Some sub-group analyses were performed for
surgical staging and histological subtype. The review noted that only two trials, ACTION and
ICON1, were designed to have the power to detect treatment effect.
Randomised controlled trials
Two randomised controlled trials on adjuvant chemotherapy for early stage ovarian cancer
were identified in the Cancer Australia literature search (ACTION and ICON1).9,10 However,
both were included in the Cochrane systematic review, and therefore are not reported in
any further detail.
Outcomes
Overall survival
The Cochrane review on adjuvant chemotherapy for early stage ovarian cancer reported
that chemotherapy was associated with improved overall survival (OS) compared with
observation. 8 Meta-analysis of five-year data from three trials and of ten-year data from two
trials indicated that women who received adjuvant platinum-based chemotherapy had
better overall survival (OS) than those who did not (Table 1). Subgroup analysis suggested
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
9
that women who had optimal surgical staging of their disease were unlikely to benefit from
adjuvant chemotherapy, whereas those who had sub-optimal staging did (Table 1).8
Table 1
Adjuvant chemotherapy following surgery compared with observation following surgery for
early stage ovarian cancer: overall survival
Patient or population: women with stage I/IIa epithelial ovarian cancer
Settings: hospital and outpatient
Intervention: chemotherapy following surgery
Comparison: observation following surgery
Outcome
Hazard ratio (95%
CI)
Chemotherapy vs.
observation
HR 0.71 (0.53 to 0.93)
p=0.01
Number of
participants
(studies)
1006 women
(three studies)
High quality
Homogeneous data
Overall 5-yr
survival:
sub-optimal
staging*
HR 0.63 (0.46 to 0.85
p=0.003)
772 women
(two studies)
High quality
Homogeneous data
Overall 5-yr
survival: optimal
staging*
HR 1.22 (0.63 to 2.37)
p=0.56
234 women
(two studies)
Moderate quality; small
subgroup size
Overall 10-yr
survival
HR 0.74 (0.58 to 0.95)
p=0.02
925 women
(two studies)
High quality
Homogeneous data
Overall 5-year
survival
Quality of evidence
CI: confidence interval; HR: hazard ratio
*Tests for subgroup differences between optimal and sub-optimal subgroups for the 5-year OS outcome
were Chi² = 3.14, df = 1 (P= 0.08) and I² = 68.1%. This was considered to be a significant difference.
One trial included in the Cochrane review reported overall survival grouped by level of risk
(ICON 1): Low/medium risk was defined as stage Ia, tumour grade 1 and 2, stage Ib or Ic,
grade 1; high risk was defined as stage Ia, grade 3, stage Ib or Ic grade 2 or 3, any clear cell
tumours. The 10 year overall survival between adjuvant chemotherapy compared with
observation was not significantly different among women at low and medium risk, however
in women at high risk, adjuvant chemotherapy improved survival HR 0.48 (95% CI 0.32 to 0.72)
p=0.00039.8
In addition, the Cochrane review also reported on deaths from ovarian cancer. 8 No
significant difference was reported in deaths from ovarian cancer at 5 years, between
chemotherapy and observation groups (RR 0.76 (95% CI 0.52 to 1.11); data from 3 trials, 693
women). Only one study reported 10 year follow-up for this outcome (ACTION), with no
significant difference in deaths from ovarian cancer between the two groups overall.
Significantly fewer deaths occurred in the chemotherapy arm of the sub-optimally staged
subgroup however, there was no difference for those in the optimally staged subgroup.
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
10
Progression-free survival
Meta-analysis showed significantly better PFS at both five years and 10 years in women who
received chemotherapy compared to those who did not (Table 2). 8 Among optimally
staged women, analysis showed no significant difference in 5-year PFS between those who
did and did not receive adjuvant chemotherapy (two trials, 234 women; HR 0.67; 95% CI 0.36
to 1.22), however, in sub-optimally staged women, those who received adjuvant
chemotherapy had significantly better PFS than those who did not (three trials, 934 women;
HR 0.64; 95%CI 0.50 to 0.82) (Table 2).8 Note this analysis assumed progression-free survival
(reported in 1 trial), recurrence-free survival (reported in 2 trials) and disease-free survival
(reported in 2 trials) referred to the same outcome.
Table 2
Adjuvant chemotherapy following surgery compared with observation following surgery for
early stage ovarian cancer: progression free survival
Patient or population: women with stage I/IIa epithelial ovarian cancer
Settings: hospital and outpatient
Intervention: chemotherapy following surgery
Comparison: observation following surgery
Outcome
Hazard ratio (95%
CI)
Chemotherapy vs.
observation
HR 0.67 (0.53 to 0.84)
p=0.0005
Number of
participants
(studies)
1170 women
(four studies)
High quality
Homogeneous data
Progression-free
5-yr survival: suboptimal
staging*
HR 0.64 (0.50 to 0.82)
p=0.0004
934 women
(three studies)
High quality
Homogeneous data
Progression-free
5-yr survival:
optimal staging*
HR 0.67 (0.36 to 1.22)
p=0.19
234 women
(two studies)
Moderate quality; small
subgroup size
Progression-free
10-yr survival
HR 0.67 (0.54 to 0.84)
p=0.0005
925 women
(two studies)
High quality
Homogeneous data
Progression-free
5-yr survival
Quality of evidence
CI: confidence interval; HR: hazard ratio
*Tests for subgroup differences between optimal and sub-optimal subgroups for the 5-year PFS
outcome showed that the subgroups were not different with respect to this outcome (P = 0.91; I² = 0%).
One trial included in the Cochrane review reported progression-free survival grouped by
level of risk (ICON 1): Low/medium risk was defined as Ia, tumour grade 1 and 2, Ib or Ic,
grade 1; high risk was defined as Ia, grade 3, Ib or Ic grade 2 or 3, any clear cell. The 10-year
progression-free survival between adjuvant chemotherapy compared with observation was
not significantly different among women at low and medium risk (HR 0.96; 95% CI: 0.50 to
1.38), however in women at high risk, adjuvant chemotherapy improved survival; HR 0.52
(95% CI 0.33 to 0.82) p=0.0049.8
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
11
Treatment compliance
Treatment compliance was not a reported outcome in the Cochrane review.
Response to chemotherapy
Response to chemotherapy was not a reported outcome in the Cochrane review.
Adverse events
The Cochrane review on adjuvant chemotherapy for early stage ovarian cancer did not
report on adverse events, as none of the primary studies reported adverse events among
women who did not receive chemotherapy, therefore comparisons of risk of adverse events
could not be provided.8
Quality of life
The Cochrane review on adjuvant chemotherapy for early stage ovarian cancer noted that
none of the trials assessed the impact of adjuvant chemotherapy on quality of life.8
Ovarian cancer (stage I-IV) Chemotherapy
Systematic reviews
Four systematic reviews were identified which investigated the effectiveness of various
chemotherapy regimens for the treatment of epithelial ovarian cancer.
Three Cochrane reviews were identified which included first and second/subsequent lines of
treatment for ovarian cancer on the following topics:
DNA-repair pathway inhibitors for the treatment of ovarian cancer11
Topotecan for ovarian cancer12
Epidermal growth factor receptor blockers for the treatment of ovarian cancer.13
However, in each of these three reviews, no randomised controlled trials investigating first line
adjuvant treatment were identified. Therefore these reviews will not be discussed in any
further detail as results pertaining to first line treatment are unavailable.
An additional modelling meta-analysis reported survival benefits with diverse chemotherapy
regimens.14 The meta-analysis identified 82 RCTs comparing different types of treatment, of
which 60 RCTs provided usable survival information, including 51trials in the first line setting.
Only three of the first line studies were published after 2003. Some separate survival analyses
were provided regarding effectiveness of chemotherapy in the first-line setting.
Randomised controlled trials
Eighteen phase III trials investigating various chemotherapy regiments for first line adjuvant
treatment of ovarian cancer were identified (17 reported in full text publications, one has
been reported in an abstract only). Seven phase II trials have also been identified.
Two additional RCTs were identified which investigated complex chemotherapy regimens
which could be considered for both Question 1 and Question 2 therefore are reported
separately in Section 3.2.3.
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
12
Quality
The quality of each of the included trials was considered moderate to high. All trials were
randomised, with the methods of randomisation as described, usually of a high quality. In
some trials it was unclear how randomisation was performed. The majority of trials reported
survival outcomes by intention-to-treat analysis and limited numbers of patients were lost to
follow-up (usually less than 5%). Trials were either open label or blinding was not stated. All
trials had standardised assessment of outcomes and almost every trial had well matched
population characteristics between treatment arms at baseline. Most of the phase III trials
were powered to detect a significant difference in primary outcomes.
Study characteristics
The trial populations included in each study varied by which stage of ovarian cancer was
included. Some studies included stage Ic-IV, many studies included only advanced ovarian
cancer and enrolled stage IIb-IV, or some enrolled just stage III and/or IV. Throughout all of
the trials, the majority of patients in each trial were identified as stage III (usually >60%).
The median age for most trials was between 55 and 60 years, with some trials excluding
patients more than 75 years old.
Two trials enrolled specific populations:
Reed et al (2006)15 enrolled only patients who were considered unfit to receive
cisplatin
Takakura et al (2010)16 included clear cell carcinoma only.
Each individual trial size varied from less than 50 to over 4000 patients. Median follow-up for
trials ranged from less than two years to almost 15 years.
Interventions investigated
A range of regimens have been investigated, see Table 3. Most have been compared with
the combination of carboplatin and paclitaxel (considered as standard first line
chemotherapy).
All trials investigated combination chemotherapy, except for a trial by Reed et al which
compared single agent treosulfan with carboplatin for patients unfit to receive cisplatin.15
The type of comparison was usually a substitution of different agents or the addition of a third
agent. Various platinum/taxane combinations have been compared. Additional agents
investigated include anthracyclines (doxorubicin, epirubicin), antimetabolites (gemcitabine)
and topoisomerase inhibitors (topotecan, irinotecan).
As most trials investigated different comparisons, it is difficult to group trials. Drug
combinations investigated by more than one trial are:
The addition of gemcitabine to carboplatin and taxane (OVAR9; GOG182/ICON5;
SCOTROC2A (phase II))
The addition of topotecan to carboplatin and paclitaxel (OVAR7; GOG182/ICON5;
Bolis 2010; OV16)
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
13
The addition of doxorubicin to platinum and paclitaxel (HeCOG/Aravantinos 2008;
GOG182/ICON5)
Comparing paclitaxel with cyclophosphamide both in combination with cisplatin
(Mouratidou 2007; OV10)
Comparing cisplatin with carboplatin both in combination with taxane
(HeCOG/Aravantinos 2008; HeCOG/Aravantinos 2005; GOG158; OVAR3; OV16;
Minagawa 2006 (phase II))
Table 3
Chemotherapy regimens investigated for first line adjuvant treatment of ovarian cancer
Study
Intervention
Comparator
Type of
comparison
Phase III trials
Trials which investigated the addition of agents to standard chemotherapy
OVAR 5, du Bois 200617
Epirubicin + carboplatin +
Carboplatin +
Addition
paclitaxel
paclitaxel
OVAR 9, du Bois 201018 Gemcitabine + carboplatin Carboplatin +
Addition
+ paclitaxel
paclitaxel
GOG 182 / ICON 5,
i) Gemcitabine +
Carboplatin +
Addition
Bookman 200919
carboplatin + paclitaxel
paclitaxel
ii) Doxorubicin +
carboplatin + paclitaxel
iii) Topotecan + carboplatin
→ carboplatin + paclitaxel
iv) Gemcitabine +
carboplatin → carboplatin
+ paclitaxel
Bolis 201020
Topotecan + carboplatin +
Carboplatin +
Addition
paclitaxel
paclitaxel
OVAR 7, Pfisterer 200621 Carboplatin + paclitaxel → Carboplatin +
Addition
topotecan
paclitaxel
OV 16, Hoskins 200822
Cisplatin + topotecan x 4
Carboplatin +
Addition
(abstract only)
cycles → paclitaxel +
paclitaxel x 8 cycles
Substitution
carboplatin x 4 cycles
HeCOG, Aravantinos
Cisplatin + doxorubicin +
Carboplatin +
Substitution
200823
paclitaxel
paclitaxel
Addition
Lhomme 200824
Paclitaxel + carboplatin +
Carboplatin +
Addition
valspodar (PSC 833)
paclitaxel
Trials which substituted the use of one chemotherapy agent with another chemotherapy
agent
GOCCNE, Nicoletto
Cisplatin +
Adriamycin +
Substitution
2007 25
cyclophosphamide
cyclophosphamide
SGCTG, Reed 200615
Treosulfan
Carboplatin
Substitution
MITO 2, Pignata 201126
Carboplatin + doxorubicin
Carboplatin +
Substitution
paclitaxel
SCOTROC, Vasey
Docetaxel + carboplatin
Carboplatin +
Substitution
200427
paclitaxel
GOG 158, Ozols 200328 Cisplatin + paclitaxel
Carboplatin +
Substitution
paclitaxel
OVAR 3, du Bois 2003,
Cisplatin + paclitaxel
Carboplatin +
Substitution
Greimel 200629,30
paclitaxel
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
14
Study
Intervention
Comparator
HeCOG, Aravantinos
200531
Mouratidou 200732
Paclitaxel + carboplatin ↔
cisplatin
Cisplatin + paclitaxel
OV10, Piccart 2003,
Bezjak 2004, Butler
200433-35
AOCSG, Dittrich 200336
Cisplatin + paclitaxel
Carboplatin +
paclitaxel
Cisplatin +
cyclophosphamide
Cisplatin +
cyclophosphamide
Cisplatin + carboplatin
Cisplatin +
cyclophosphamide
Type of
comparison
Substitution
Substitution
Substitution
Substitution
Phase II trials
Trials which investigated the addition of agents to standard chemotherapy
Muthuramalingam
Carboplatin + thalidomide
Carboplatin
Addition
201137
SCOTROC2A, Vasey
Carboplatin → docetaxel + Carboplatin →
Addition
200638
gemcitabine
docetaxel
SCOTROC2B, Clamp
Carboplatin → docetaxel + Carboplatin →
Addition
200639
irinotecan
docetaxel
Trials which substituted the use of one chemotherapy agent with another chemotherapy
agent
Minagawa 200640
Docetaxel + cisplatin
Carboplatin +
Substitution
docetaxel
Mori 200741
Docetaxel + carboplatin
Carboplatin +
Substitution
paclitaxel
JGOG3014, Takakura
Irinotecan + cisplatin
Carboplatin +
Substitution
201016
paclitaxel
Fruscio 200842
Cisplatin + paclitaxel +
Cisplatin + paclitaxel
Substitution
isosfamide
+ epirubicin
Outcomes
Refer to appendix G for summary table of outcomes.
Overall survival
The multiple-treatment modelling meta-analysis by Kyrgiou et al (2006)14 reported hazard
ratios for death for first line treatment, for each type of regimen as compared with
monotherapy with a nonplatinum, nontaxane agent, not administered intraperitoneally:
platinum monotherapy - HR 0.64 (95% CI 0.54 to 0.75)
platinum-based combination - HR 0.69 (95% CI 0.60 to 0.80)
platinum-based combination (IP) - HR 0.59 (95% CI 0.45 to 0.79)
taxane monotherapy - HR 0.73 (95% CI 0.51 to 1.05)
taxane-based combination - no data
platinum + taxane-based combination - HR 0.57 (95% CI 0.47 to 0.70)
platinum + taxane-based combination (IP)- HR 0.45 (95% CI 0.32 to 0.62)
non-platinum/non-taxane combination - HR 0.86 (95% CI 0.76 to 0.98).
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
15
Modelling estimated a 92% probability that combinations of platinum and taxane with
intraperitoneal administration were the most effective regimens.14
Nineteen of the primary randomised controlled trials reported overall survival as an outcome
(including some phase III and phase II trials). Most of these reported no statistically significant
survival differences between treatment groups. Note the phase II trials are not
designed/powered to detect survival differences. See appendix G for overall survival for
each trial.
Two trials (both phase III) reported differences in overall survival. The trial by Reed et al (2006),
which included patients unfit to receive cisplatin, reported improved survival in the
carboplatin arm (median 15 months) compared with treosulfan (median 12 months)
(p<0.026).15 Long-term follow-up of the OV10 trial of of older chemotherapy regimens,
reported that paclitaxel and cisplatin combination improved survival compared with
cyclophosphamide and cisplatin (HR 0.75 (95% CI 0.63 to 0.90); p=0.001).33
Progression-free survival
Twenty-three of the primary randomised controlled trials reported on progression-free
survival. One trial reported on disease-free survival rather than progression-free survival.25
Most reported no statistically significant progression-free/disease-free survival differences
between treatment groups. Note the phase II trials are not designed/powered to detect
survival differences.
Three trials (all phase III) reported differences in progression-free survival: Reed et al (2006),15
OV10,33 and OVAR9,18. See Appendix G for progression free survival for each trial.
In two trials, the standard chemotherapy arm reported longer progression-free survival than
the intervention arm. The trial by Reed et al (2006) reported longer time to progression in the
carboplatin arm (10 months) compared with treosulfan (5 months) (p<0.001). 15 The OVAR9
trial reported median progression-free survival in the standard paclitaxel/carboplatin arm as
19.3 months compared with 17.8 months for the paclitaxel/carboplatin/gemcitabine arm
(p<0.01).18
In the other trial, the intervention arm reported improved progression-free survival. OV10
reported better PFS in the paclitaxel/cisplatin arm compared with the older chemotherapy
regimen cyclophosphamide/cisplatin (p<0.001).33
Treatment compliance
Most trials reported high treatment compliance, with many reporting that 80% or over
received planned treatment17,18,20,21,26-29 and some reporting more than 90%.31,40,43
Two trials reported differences between treatment arms. Reed et al (2006) reported that only
35% completed 6 cycles of treosulfan compared with 68% in the carboplatin arm (statistical
significance was not reported).15 Lhomme et al (2008) reported that 76% of patients in the
valspodar arm received at least 6 cycles of chemotherapy compared with 85% in the
standard chemotherapy arm (p=0.0016).24
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
16
Response to chemotherapy
Most trials reported no differences in response to chemotherapy between treatment arms.
Overall response rates (complete response + partial response) ranged between trials from
25% to 90%, with most trials reporting rates more than 60%.
Four trials reported differences in overall response rates between treatment groups:
The OVAR9 trial reported that adding gemcitabine to carboplatin and paclitaxel improved
the objective response to chemotherapy (86% versus 78%, p=0.03).18
In the other three trials, overall response to chemotherapy was better in the standard
chemotherapy arm compared with intervention:
Reed 2006: ORR – treosulfan 29% versus carboplatin 49%, p=0.00815
Lhomme 2008: ORR – addition of valspodar 34% versus standard chemotherapy
(paclitaxel 175 mg/m2 and carboplatin AUC 6) 42%, p=0.0224
OV16: ORR – cisplatin plus topotecan followed by carboplatin plus paclitaxel 68%
versus carboplatin plus paclitaxel 77%, p=0.04.22
Adverse events
The adverse events reported varied between each trial. Within the trials, many reported
adverse events did not differ in prevalence or severity between treatment arms.
Overall, the addition of agents to standard chemotherapy tended to increase toxicity,
particularly haematological toxicity such as anaemia and neutropenia.
For trials which substituted different chemotherapy agents, the adverse event profile
reflected the substituted drug. For example, treatment arms including paclitaxel were more
likely to report neurotoxicity compared to those without paclitaxel.26,27,32 Similarly, treatment
arms containing cisplatin were more likely to report gastrointestinal toxicity such as nausea
and vomiting than arms containing carboplatin.28,29,31
Details about which adverse events were reported to be different in each individual trial are
presented in Appendix I.
Quality of life
Quality of life was assessed in 13 trials, with detailed data reported in 11 trials.
Most trials reported no significant differences in quality of life between treatment groups.
Two AGO-OVAR trials reported improved quality of life with carboplatin/paclitaxel
chemotherapy. OVAR 3 compared carboplatin/paclitaxel with cisplatin/paclitaxel and
found that the carboplatin arm showed better overall QoL, physical functioning, role
functioning, and cognitive functioning compared with the cisplatin arm after treatment.30
OVAR 5 compared carboplatin/paclitaxel with carboplatin/paclitaxel/epirubicin and found
that the standard arm performed better with respect to worst global health score over
time.17
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
17
Note – an additional paper was identified which reported a retrospective analysis of data
from OVAR 3, OVAR 5 and OVAR 7 which correlated common toxicity criteria (CTC) and
patient-reported quality of life.44 This paper found that correlations between toxicity grading
and quality of life functioning scales were weak and symptom level agreement between
clinician and patient reporting could differ. The authors conclude that clinicians should not
rely on CTC grading to capture adverse events and information related to patient wellbeing, but should also consider patient reported symptoms or changes in QoL.
Ovarian cancer (stage I-IV) - Biological therapies
Randomised controlled trials
Two trials were identified which investigated the addition of bevacizumab to carboplatin
and paclitaxel (GOG 21845; OVAR11/ICON743).
Study characteristics
The ICON7, a phase III randomised study, compared standard chemotherapy (carboplatin
AUC 5 or 6 and paclitaxel 175mg/m2 every 3 weeks for 6 cycles) or standard chemotherapy
plus bevacizumab (7.5mg per kilo body weight) given concurrently every 3 weeks for 5 or 6
cycles and continued for 12 additional cycles or until progression of disease.
GOG 218, a double-blind phase III randomised controlled trial compared three treatments.45
Each of the three study regimens comprised 22 3-week cycles paclitaxel 175mg/m2 plus
carboplatin AUC 6. Control treatment was chemotherapy with placebo added in cycles 2
through 22; bevacizumab initiation treatment was chemotherapy with bevacizumab (15mg
per kg body weight) added in cycles 2 through 6 and placebo added in cycles 7 through 22.
Bevacizumab-throughout treatment was chemotherapy with bevacizumab added in cycles
2 through 22.45
Outcomes
Refer to Appendix H for summary table of outcomes.
Overall survival
The ICON7 trial reported improved survival in a subgroup of patients at high risk of progression
in the bevacizumab and standard therapy (carboplatin + paclitaxel) group, compared to
the standard therapy alone group.43 Patients at high risk of progression were those with stage
IV disease or stage III disease and >1cm of residual disease following debulking surgery. While
in the whole population the ICON7 trial reported no overall survival differences between
treatment groups, in the updated analyses for patients at high risk for progression (n=465),
patients in the bevacizumab arm had improved survival:
Overall survival: median 36.6 months for intervention, 28.8 months or control, HR 0.64
(95% CI 0.48 to 0.85) p=0.002.43
Final overall survival results for the ICON7 trial are due in 2013.
No significant differences in overall survival between the three groups (bezacizumabinitiation group, bevacizumab-throughout group and control group) have been reported by
the GOG 218 trial.45
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
18
Progression free survival
The ICON7 trial reported improved PFS in the bevacizumab group compared with the
standard therapy, 19.8 months vs. 17.4 months (p=0.04) respectively, in the updated
analyses.43 The maximum improvement in progression-free survival was at 12 months,
coinciding with the end of planned bevacizumab treatment, and it diminished by 24 months.
In a subgroup of patients at high risk of progression, median PFS was improved in the
intervention group. Median PFS in the updated analyses, for patients at high risk of
progression, was 16 months in the bevacizumab group compared with 10.5 months in the
standard therapy group (p=0.002).43
In the GOG 218 trial, PFS was improved in the bevacizumab throughout arm (median 14.1
months) compared with control (median 10.3 months) (p<0.001), however this improvement
was not observed in the bevacizumab initiation arm (median 11.2 months) (p=0.16). Results
of updated analyses of PFS were consistent with those from the original analysis. 45
Response to treatment
The ICON7 trial reported that the addition of bevacizumab to carboplatin and paclitaxel
improved the overall response rate (complete or partial remission) compared with
carboplatin and paclitaxel alone (67% versus 48% respectively, p<0.001).43
Adverse events
Patients receiving bevacizumab were more likely to report hypertension than those in
standard chemotherapy arms.43,45
Details about which adverse events were reported to be different in each individual trial are
presented in Appendix J.
Quality of life
The ICON7 trial reported that global quality of life was marginally better in the control arm
compared with the bevacizumab arm at the end of chemotherapy and at completion of
the active treatment follow-up, however these differences were not considered to be
clinically significant (supplementary appendix43).
Summary
Five systematic reviews were identified which investigated various chemotherapy regimens
for epithelial ovarian cancer. One of these reviews included only patients with early stage
ovarian cancer (stage I-IIa). This review found that overall and progression-free survival was
improved in early stage ovarian cancer patients who had chemotherapy compared with
those on observation. Subgroup analysis suggested that women who had optimal surgical
staging of their disease were unlikely to benefit from adjuvant chemotherapy, whereas those
who had sub-optimal staging did. The remaining reviews included ovarian cancer patients of
all stages, however provided little to no information on chemotherapy in the first line setting.
Eighteen phase III and seven phase II randomised controlled trials were identified which
investigated different chemotherapy regimens in populations with a majority of advanced
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
19
stage ovarian cancer patients. While a range of regimens have been investigated, including
addition of chemotherapy agents to standard regimens or substitution of different agents,
almost all failed to demonstrate an overall or progression-free survival benefit compared with
standard chemotherapy (most often platinum/taxane combination). Trials which did show
survival differences were either in specific patient populations or compared older
chemotherapy regimens no longer considered standard.
Two randomised controlled trials have shown improved progression-free survival for the
biological therapy bevacizumab used in addition to carboplatin and paclitaxel. One of
these studies also indicated for patients at high risk of progression, overall survival benefit with
bevacizumab, and greater benefit in progression free survival than for patients at lower risk.
Adverse effect profiles reflected the various agents used however there were often limited
differences in toxicities between treatment arms. Similarly, most trials reported no significant
differences in quality of life between treatment arms investigated.
3.2.2 What is the most effective schedule (duration/dose/frequency) for
chemotherapy regimens for first line adjuvant treatment of epithelial
ovarian cancer?
Systematic reviews
No systematic reviews were identified which investigated different schedules
chemotherapy regimens for first line adjuvant treatment of epithelial ovarian cancer.
for
Randomised controlled trials
Six phase III and one phase II trials were identified which investigated different schedules for
chemotherapy regimens for first line adjuvant treatment of epithelial ovarian cancer.
Two additional RCTs were identified which investigated complex chemotherapy regimens
which could be considered for both Question 1 and Question 2 therefore are reported
separately in Section 3.2.3.
Study characteristics
One trial enrolled patients with early stage tumours only.46 In contrast the GOG trial enrolled
a majority of stage IV patients.47 The remaining studies included a majority of stage III patients
(usually IIIC). The median age across studies was between 50 and 60 years old and a high
percentage of patients had serous histology (usually >60%). The size of studies ranged from
16448 to 63749 patients and median follow-up ranged from 2.449 to 16.850 years.
Quality
Each of the included trials was considered to be of moderate to high quality. The trials were
all randomised, with methods used for randomisation considered high quality, though some
trials did not describe randomisation methods. The trials were either open label or blinding
was not stated. Survival outcomes by intention-to-treat analysis were reported by the majority
of trials. All trials had standardised assessment of outcomes and almost every trial had well
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
20
matched population characteristics between treatment arms at baseline. Most of the trials
were powered to detect a significant difference in primary outcomes.
Interventions investigated
A range of interventions have been investigated, see Table 4. Most have been compared
with the combination of carboplatin and paclitaxel (considered as standard first line
chemotherapy):
Table 4
Three dose-dense trials47,49,50 (dose-dense chemotherapy defined as a chemotherapy
treatment plan in which drugs are given with less time between treatments than in a
standard chemotherapy treatment plan51): JGOG 3016 Katsumata 2009, Fruscio 2011,
GOG 162. A conference abstract with long-term follow-up results of the Japanese
JGOG 3016 dose-dense trial has also been published.52
Two trials investigated different doses48,53: Bolis 2004, Ray-Coquard 2007
One trial investigated 3 cycles versus 6 cycles46: Bell 2006
Chemotherapy schedules investigated for first line adjuvant treatment of ovarian cancer
Study
Dose-dense trials
JGOG 3016
Katsumata 200949
Katsumata 201252
GOG 162, Spriggs
200747
Fruscio 201150
Different dose trials
Bolis 200453
RayCoquard/GINECO
200748
Different cycles
Bell 200646
Intervention
Comparator
Carboplatin + paclitaxel (80mg/m2)
(dose-dense)
Carboplatin (AUC 6 mg/mL per
min) + paclitaxel (180mg/m2)
(conventional)
Cisplatin (75mg/m2) and
paclitaxel (120mg/m2) during
96hrs x 6 cycles every 3 weeks
Cisplatin (75mg/m2) every 3
weeks x 6 cycles
Cisplatin (75mg/m2) and paclitaxel
(135mg/m2) during 24hrs x 6 cycles
every 3 weeks
Cisplatin (50mg/m2) weekly x 9
cycles
Carboplatin + paclitaxel (225mg/m2)
6 cycles every 21 days
Carboplatin + paclitaxel
(175mg/m2) 6 cycles every 21
days
Cyclophosphamide (1800mg/m2) +
epirubicin + cisplatin + filgrastim
(5µg/kg/day, sc, D2-11) x 6 cycles
every 3 weeks
Cyclophosphamide
(500mg/m2) + epirubicin +
cisplatin x 6 cycles every 3
weeks
Carboplatin + paclitaxel x 3 cycles
Carboplatin + paclitaxel x 6
cycles
AUC=area under the curve
Outcomes
Overall survival
The only trial which reported an overall survival difference between treatment groups was
JGOG 3016, reported by Katsumata et al (2009)49. Overall survival at 2 years and at 3 years
was significantly longer in the dose-dense paclitaxel arm compared with the standard dose
arm (2yr: 83.6% versus 77.7%, p=0.049; 3yr: 72.1% versus 65.1%, p=0.03). In long-term follow-up
results at 6.4 years of median follow-up, median survival had not yet been reached in the
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
21
dose-dense group. Overall survival at 5 years was higher in the dose-dense group than in the
conventional group (58.6% vs. 51.0%, HR 0.79, 95% CI 0.63-0.99, p=0.0448).52
The remaining trials showed no differences in overall survival between intervention and
comparator.
Progression-free survival
Similarly, JGOG 3016 (Katsumata et al 2009) was the only trial to report a difference in
progression-free survival.49 Median progression-free survival was 28 months in the dose-dense
paclitaxel arm compared with 17.2 months in the standard dose arm (adjusted HR 0.65 95%
CI 0.53 to 0.80, p=0.0001). The authors noted that progression-free survival was longer in the
dose-dense treatment group than in the conventional treatment group across all subgroups
of patients, apart from those with clear-cell or mucinous tumours. In this subgroup of patients,
the hazard ratio in the dose-dense treatment group was similar to that in the conventional
treatment group. 49
In long-term follow-up results at 6.4 years of median follow-up, there continued to be
statistically significant improvement in median progression-free survival in favour of the dosedense group compared to the conventional group (28.1 vs 17.5 months, HR 0.75, 95% CI 0.620.91, p=0.0037).52
Treatment compliance
Most trials reported that 80% or more of patients completed their planned treatment.
Compliance was generally no different between treatment groups. Bell et al (2006) reported
more patients in the 3 cycle group completed planned treatment (96%) than the 6 cycle
group (83%).46 Katsumata et al (2009) reported 62% of patients in the dose-dense paclitaxel
arm received 6 or more cycles compared with 73% in the standard arm.49
Response to chemotherapy
No significant differences were reported between treatment groups with regards to response
to chemotherapy. Overall response rate (complete + partial response) ranged from 53%49 to
85%.50
Adverse events
Due to the range of adverse events reported and varied schedules investigated, each trial is
reported separately.
Bell et al (2006) reported that patients in the 6 cycle arm experienced worse/more
neurotoxicity, granulocytopenia and anaemia than those in the 3 cycle arm.46 One death in
each arm was attributed to treatment.
Bolis et al (2004) reported worse neurotoxicity in higher dose (225mg/m2) paclitaxel arm
however worse alopecia in the lower dose (175mg/m2) arm. No other significant differences
in adverse events were reported between treatment arms.53
Fruscio et al (2011) reported worse leukopenia, thrombocytopenia and hepatotoxicity in the
dose-dense cisplatin arm compared with the standard dose arm.50
The GOG 162 trial partially attributed slightly more deaths to treatment in the intervention
arm compared with control (6 versus 3).47 Granulocytopenia was more common in the
intervention arm, however anaemia was more common in the control arm. No significant
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
22
differences were observed between treatment arms for neurotoxicity, allergic reaction,
infections or alopecia.
The GINECO trial reported by Ray-Coquard et al (2007) reported two deaths from treatment
in the intensive cyclophosphamide arm and one death in the standard arm. 48 Anaemia,
thrombocytopenia, and infections were all significantly worse in the intensive arm compared
with the standard arm.
Katsumata et al (2009) reported worse anaemia in the dose-dense arm, however no
significant differences were observed for other haematological toxicities such as neutropenia
or thrombocytopenia.49
Quality of life
Quality of life outcomes were not assessed or reported in any of the trials.
Summary
Six phase III and one phase II trials were identified which investigated different schedules for
chemotherapy regimens for first line adjuvant treatment of epithelial ovarian cancer. No
systematic reviews in this topic were identified. A range of schedules were investigated
including dose-dense chemotherapy, different doses of the same agent or different
timing/cycles of the same regimen. Only one trial, JGOG 3016, showed survival benefits
between treatment arms. This study investigated dose-dense paclitaxel compared with
standard paclitaxel and reported improved overall survival and progression-free survival in
the dose-dense paclitaxel group compared to the conventional group, at short-term followup (up to 3 years) and at long-term follow-up (median 6.4 years). While adverse events were
often similar between treatments arms, some increased toxicity was observed in the higher
dose, more intensive chemotherapy intervention arms compared with standard arms. Quality
of life was not assessed in any of the trials.
3.2.3 Additional chemotherapy regimens and schedules investigated for first
line adjuvant treatment of epithelial ovarian cancer
Two phase III randomised controlled trials were identified which investigated complex
chemotherapy regimens which could be considered for both Question 1) and Question 2)
therefore they are reported separately here.
Study characteristics
Both trials enrolled advanced ovarian cancer patients, aged 65 or younger, and were
relatively small, including only 4254 to 14955 patients.
The HIDOC-EIS trial was originally two separate trials, however these were merged given they
had a similar design.55
Quality
The quality of the two trials was considered to be moderate. Both trials were randomised
however did not describe methods of randomisation. The FINOVA trial was an open-label
trial, while HIDOC-EIS did not state if it was blinded. Both trials had standardised assessment
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
23
of outcomes and both were well matched for population characteristics between treatment
arms at baseline.
Interventions investigated
The chemotherapy regimens used in these trials, summarised in table 5, were complex. In
both trials chemotherapy was delivered at 3 weekly intervals, and the intervention arms
received high-dose chemotherapy with peripheral blood stem cell support.
Table 5
Additional chemotherapy regimens and schedules investigated for first line adjuvant
treatment of ovarian cancer
Study
Intervention
Phase III trials
HIDOCCyclophosphamide (3mg/m2)+ paclitaxel (20055
EIS
250mg/m2) x 2 cycles →
carboplatin (high dose: AUC 20) + paclitaxel
(200-250mg/m2) x 2 cycles →
carboplatin (high dose: AUC 20) + paclitaxel
(200-250mg/m2) + melphalan (140mg/m2) x 1
cycle
FINOVA,
Cisplatin (75mg/m2) + paclitaxel (135mg/m2) x 3
54
cycles →
cyclophosphamide (3000mg/m2) →
paclitaxel (175mg/m2) →
high-dose chemotherapy (HDCT): carboplatin
(1500mg/m2) + cyclophosphamide (120mg/m2)
+ mitoxantrone (75mg/m2) x 1 cycle
AUC=area under the curve
Comparator
Carboplatin
(AUC
5)
+
paclitaxel (175mg/m2) for 6
cycles
±
epirubicin
or
doxorubicin
Cisplatin
paclitaxel
cycles
(75mg/m2)
(135mg/m2) x
+
6
Outcomes
Overall survival
No significant differences between treatments groups were observed for overall survival in
either trial.
Progression-free survival
No significant differences between treatments groups were observed for progression-free
survival in either trial.
Treatment compliance
The HIDOC-EIS trial reported a higher percentage of patients completed the planned
treatment in the standard chemotherapy arm (90%) compared with the high-dose
chemotherapy arm (76%),55 however statistical significance was not reported.
The FINOVA trial did not report on treatment compliance.
Response to chemotherapy
Response to chemotherapy was not reported in either trial.
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
24
Adverse events
The FINOVA trial reported that the high-dose chemotherapy arm was more toxic than the
standard chemotherapy arm.54 One death due to treatment was reported in the HDCT arm.
Anemia, thrombocytopenia, infections, mucositis and diarrhoea were worse in the HDCT arm.
Patients in the HDCT arm spent more time in hospital and more days on IV antibiotics than
those in the standard chemotherapy arm. Patients in the HDCT arm also required more red
blood cell and platelet transfusions.
The HIDOC-EIS trial reported toxicity within high-dose therapy but not compared with the
control arm. Gastrointestinal toxicity showed a sharp increase in final high-dose cycle
(containing melphalan).55
Quality of life
Quality of life outcomes were not assessed or reported in either trial.
Summary
Two trials were identified which investigated complex chemotherapy regimens including
peripheral blood stem cell support. Neither of these trials reported any survival differences
between intervention and standard treatment arms. Only one trial provided detailed data
on adverse events, with higher toxicity experienced in the complex high-dose chemotherapy
arm. Quality of life was not assessed in either trial.
3.2.4 What is the most effective mode of administration for chemotherapy
regimens for first line adjuvant treatment of epithelial ovarian cancer?
Systematic reviews
Five systematic reviews were identified which investigated the effectiveness of
intraperitoneal (IP) chemotherapy regimens for the treatment of epithelial ovarian cancer.
No systematic reviews on other modes of administration for chemotherapy for ovarian
cancer were identified.
A Cochrane systematic review on IP chemotherapy was published in 2011 and includes RCTs
published up to May 2011.56 The review identified nine RCTs including 2119 women receiving
primary treatment for ovarian cancer, of which six trials were considered of high quality. Only
one of the nine trials directly compared intravenous (IV) to IP (without additional IV)
chemotherapy (Kirmani 1994 which included 87 patients); the remaining trials compared
administering a certain component of chemotherapy via IV or IP along with IV
chemotherapy in both arms. The chemotherapy component administered via IP always
included a platinum agent, usually cisplatin, with or without additional agents. The IV
chemotherapy given to both arms usually included paclitaxel or cyclophosphamide.56
Four other systematic reviews on IP chemotherapy were identified which were published
before 2011.57-60 These reviews are considered to be superseded by the Cochrane review
and therefore are not reported in any further detail.
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
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Randomised controlled trials
All randomised controlled trials on IP chemotherapy identified in the Cancer Australia
literature search were included in the Cochrane systematic review, therefore are not
reported in any further detail.
No other trials which compared different modes of administration were identified.
Additional study of interest
An additional paper was identified in the Cancer Australia literature review which
investigated factors affecting the completion of IP chemotherapy in women with ovarian
cancer.61 While this study is not a randomised controlled trial, it is included here as it was
considered of interest to the research question. The study includes data from patients
enrolled in a US centre and includes some of the patients who were part of the GOG 172 trial
as well as other IP chemotherapy trials. Results of this paper are reported under the outcome
‘treatment compliance’.
Outcomes
Overall survival
The Cochrane review reported significantly improved overall survival for women who
received an IP component of chemotherapy.56 Data from a meta-analysis of data from eight
studies (2026 women) for overall survival the hazard ratio was 0.81 (95% CI 0.72 to 0.90)
p=0.0002 for women who received an IP component to chemotherapy compared to IV
chemotherapy. Results were similar when data only from the six high quality trials was used:
HR 0.80 (95% CI 0.72 to 0.90) p=0.0001. The data was reported to be homogenous.
The overall survival results were similar when the analysis was restricted to trials that used the
same chemotherapy regimens in each arm (data from 3 studies: HR 0.79 (95% CI 0.67 to
0.92)).56
Progression-free survival
The Cochrane review reported significantly improved progression free survival for women
who received an IP component of chemotherapy.56 From meta-analysis of data from five
studies (1311 women) the hazard ratio was 0.78 (95% CI 0.70 to 0.86) p<0.00001. The data was
reported to be homogenous.
Treatment compliance
Treatment compliance was not assessed as an outcome for the Cochrane review. 56 It was
mentioned that in the GOG 172 trial, 58% of women in the IP arm did not complete 6 cycles
of IP therapy.
The additional paper which investigated factors affecting the completion of IP
chemotherapy in women with ovarian cancer included 140 patients who received IP
chemotherapy as initial treatment.61 Of these patients, 95 (68%) completed all 6 planned
cycles of treatment. The reasons for non-completion of the planned regimen included:
Occlusion of the port (28 patients, 20%)
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
26
Progression of disease (7 patients, 5%)
Refusal by the patient to accept further IP treatment (6 patients, 4%)
Infection of the port/port site (3 patients, 2%)
Rupture of the port tubing (1 patient, <1%).61
Response to chemotherapy
Response to chemotherapy was not an outcome reported in the Cochrane review.
Adverse events
The Cochrane review undertook meta-analysis of several adverse events; data for each
event ranged from two to five trials.56
Women in the IP chemotherapy groups were significantly more likely to experience the
following severe adverse effects (grade 3/4): fever (RR 1.64), fatigue (RR 2.32),
gastrointestinal adverse events (RR 1.70), infection (RR 3.34), metabolic adverse events (RR
4.45) and pain (RR 7.47).56
Hearing loss was more common in the IV chemotherapy groups (RR 0.67).56
There were no significant differences between interventions for haematological adverse
events (such as anaemia, thromocytopenia and leukopenia), renal, neurological and
pulmonary adverse events.56 However substantial heterogeneity was noted in these metaanalyses.
The Cochrane review also mentioned that catheter-related complications of IP drug
administration (including infection, blockage and discontinuation of therapy) were discussed
in the trials however, data available was insufficient for meta-analysis.56
Quality of life
The Cochrane review noted that only one study assessed QoL as an outcome measure
(GOG 172).56 Women who received higher dose IP therapy experienced more QoL disruption
compared to those who received IV therapy. The IP arm reported worse QoL and pain prior
to the fourth chemotherapy cycle and worse QoL 3 to 6 weeks post-treatment, however
there were no significant QOL or PAIN score differences between arms at one year posttreatment.
Additional outcomes
The Cochrane review56 reported data from a modelling study which suggested that the aim
should be 5 cycles of IP chemotherapy (due to better survival compared with 1 to 3 cycles),
and that harms from IP chemotherapy exceed the benefits for elderly women with clear cell
tumours, especially those who have not been optimally debulked.
Summary
One recent high quality systematic review was identified which reported on the effectiveness
of IP chemotherapy in treating ovarian cancer. The review found that the inclusion of an IP
component of chemotherapy improved overall and progression-free survival. However,
women receiving IP chemotherapy reported more adverse events than those on standard
chemotherapy. Limited data on quality of life have been reported.
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
27
3.2.5 When is the most effective time to administer chemotherapy for first line
treatment of epithelial ovarian cancer?
Systematic reviews
One Cochrane review was identified which compared chemotherapy versus surgery for
initial treatment in advanced ovarian cancer. 62 This review was published in 2007 and
contains only one small randomised controlled trial which compared standard debulking
surgery followed by chemotherapy with pre-operative intra-arterial platinum-based
chemotherapy and ovarian artery embolisation followed by debulking surgery and further
chemotherapy. The study included in the Cochrane review was not considered of high
quality and due to the study design it is not possible to determine whether any effect was
due to pre-surgical ovarian artery embolisation or neoadjuvant chemotherapy, therefore the
results will not be discussed in any further detail.
Randomised controlled trials
One randomised controlled trial was identified which compared
chemotherapy with primary surgery followed by adjuvant chemotherapy.63
neoadjuvant
Study characteristics
The International EORTC 55971 trial included 670 women from 59 institutions with stage IIIC or
IV invasive epithelial ovarian cancer, primary peritoneal or fallopian tube cancer.63 Most of
the included patients had stage IIIC ovarian cancer. The median age was 62-63 (range 2586) and the majority of patients had serous histology (58-66%).
The trial randomised women to either:63
i.
3 courses of neoadjuvant platinum-based chemotherapy followed by debulking
surgery in all patients with a response or stable disease, followed in turn by at least 3
courses of platinum-based chemotherapy (n=334)
or
ii.
primary debulking surgery followed by
chemotherapy (n=336).
at least 6 courses of platinum-based
The most common chemotherapy regimen was paclitaxel (175mg/m2) plus carboplatin
(AUC6). The trial assessed overall survival, progression free survival, adverse events and
quality of life. Median follow-up was 4.7 years.
This RCT was considered of high quality.
Overall survival
The trial reported no difference in the median overall survival between the two groups
(median 30 months in neoadjuvant chemotherapy group compared with 29 months in
primary surgery group, HR 0.98 (90% CI 0.84 to 1.13)).63
Subgroup analyses by age, FIGO stage, WHO performance status, histologic type, and
presence or absence of pleural fluid showed no survival differences between the treatment
groups. The only difference reported was that neoadjuvant chemotherapy appeared to
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
28
improve survival among patients with metastatic tumours that were less than 5 cm in
diameter at randomisation (HR 0.64 (95% CI 0.45-0.93)).
Progression-free survival
The trial reported no difference in the median progression free survival between the two
groups (median 12 months in neoadjuvant chemotherapy group compared with 12 months
in primary surgery group, HR 1.01 (90% CI 0.89 to 1.15)).63
Treatment compliance
Eighty-six per cent of patients in the neoadjuvant chemotherapy group received at least 6
cycles of chemotherapy compared with 82% in the primary surgery group. Around 7% of
patients in the primary surgery group received no chemotherapy, mainly due to post-surgery
complications or the diagnosis of another primary tumour (Supplementary appendix).63
Response to chemotherapy
Response to chemotherapy was not an outcome reported in the trial.
Adverse events
There was a higher percentage of post-operative deaths (defined as death <28 days after
surgery) in the primary surgery group (2.5%) compared with neoadjuvant chemotherapy
(0.7%) (statistical significance not reported).63
Grade 3 or 4 haemorrhage, infections and venous complications were worse in the primary
surgery group compared with the neoadjuvant chemotherapy group (statistical significance
not reported).63
Analyses comparing the perioperative and postoperative characteristics of the two groups
were not performed because not all patients who were randomly assigned to primary
debulking underwent primary debulking surgery, and not all patients assigned to
neoadjuvant chemotherapy underwent interval debulking surgery.63
Quality of life
Quality of life was assessed using the EORTC QLQ-C30. The trial reported no significant
differences between groups in the QLQ-C30 global health scores at any of the assessment
times. The overall test for a treatment effect on global health was also not significant. 63
Additional study of interest
In addition to the EORTC trial, one phase II trial PRIMOVAR investigated 3 cycles versus 2
cycles of neoadjuvant chemotherapy.64 While this trial does not address the specific question
of neoadjuvant chemotherapy compared with primary surgery, it is included here as it was
considered of interest to the research question. This study enrolled 83 patients with stage IIIC
or IV ovarian cancer and an ascites volume of ≥500ml.
Outcomes
The phase II trial reported no overall or progression-free survival differences between 3 cycles
versus 2 cycles of neoadjuvant chemotherapy. There were also no significant differences
between groups in results of cytoreductive surgery.
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
29
Summary
One randomised controlled trial has been published comparing neoadjuvant chemotherapy
with primary surgery. No survival differences between treatment arms were observed. More
adverse events were observed in the primary surgery group than the neoadjuvant group,
however whether this was statistically significant was not reported. There were no differences
in quality of life between treatment arms.
A small phase II trial reported no differences in outcomes between patients who had 3 cycles
versus 2 cycles of neoadjuvant chemotherapy.
3.2.6 Are there subsets of the defined population for first line adjuvant
treatment of epithelial ovarian cancer that have specific
chemotherapy requirements?
Due to the limited information available for this question, the included papers were not
limited to RCTs. Comparisons between effectiveness of chemotherapy in general were
reported for:
women with ovarian cancer with or without BRCA mutations
older compared with younger patients
various histological subtypes.
However, limited information was identified on specific chemotherapy requirements for any
of these groups.
Systematic reviews
A Cochrane review on adjuvant chemotherapy for early stage EOC was published in 20128
and is reported in Section 3.2.1. No other systematic reviews on particular subgroups were
identified.
Individual studies
Some of the RCTs identified in Section 3.2.1 reported subgroup analyses for prognostic factors
such as age and histologic subtype. These analyses did not show any survival differences in
treatment effects across prognostic subgroups.18-20,25,26,45 However these analyses are
considered exploratory rather than definitive given the trials were not designed to detect
differences between these subgroups.
A phase III RCT in Section 3.2.1 enrolled patients who were unfit to receive cisplatin, the
population in this trial consisted of an older population (median age 73, range 67 - 76).15
One phase II RCT in Section 3.2.1 specifically investigated patients with clear cell
carcinoma.16
Nine additional papers were identified as relevant for this question. Three reported on the
association of BRCA1/2 mutation and chemotherapy sensitivity, two reported on the effects
of chemotherapy in the elderly population (one a retrospective analysis of data from the RCT
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
30
OVAR 3 included in Section 3.2.1), three reported on various histological subtypes and
effectiveness of chemotherapy, and one paper reported on subgroup analyses including
age and histology subtypes.
Quality
As the papers included in this section had a range of study designs, formal quality assessment
was not performed.
BRCA mutations
Study characteristics
Three studies investigated the relationship between BRCA status and effectiveness of
chemotherapy.
An observational study was conducted of 316 high-grade serous ovarian cancer cases (219
BRCA wild-type, 35 BRCA1 mutation, 27 BRCA2 mutation, 33 BRCA1 methylation).65 All
patients received a platinum agent, 94% received a taxane. In this study, patients with
BRCA1 mutations were younger at diagnosis than those with wild-type BRCA or BRCA2
mutation.
A case-control study compared BRCA1- (n=99) or BRCA2-associated (n=13) epithelial
ovarian cancer patients with matched sporadic epithelial ovarian cancer patients (n=222). 66
Patients with BRCA1 or BRCA2 mutations were more likely to have residual tumour <1cm after
surgery than sporadic patients. There were no significant differences in the type of
chemotherapy between the three groups.
Another case-control study also compared patients with BRCA 1 or BRCA2 mutations (n=22)
with non-hereditary epithelial ovarian cancer controls (n=44). 67 All patients received
platinum-based chemotherapy.
A study published after the systematic search, investigated the frequency of BRCA mutations
and patterns of treatment response in a prospectively ascertained population-based cohort
of 1001 Australian women with newly diagnosed nonmucinous ovarian cancer. Germline
pathogenic BRCA1 or 2 mutations were identified in 141 (14.1%) of the women.68
Outcomes
Overall survival
While the papers on BRCA mutations report on overall survival outcomes, the results do not
relate to the impact of chemotherapy on survival therefore are not reported here.
Progression-free survival
While the papers on BRCA mutations reported on progression-free survival outcomes, the
results do not relate to the impact of chemotherapy on progression-free survival, therefore
are not reported here.
Treatment compliance
Treatment compliance was not reported in the BRCA mutation papers.
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
31
Response to chemotherapy
In the observational study by Yang et al (2011),65 100% of BRCA2 mutation carriers had a
complete or partial response to platinum-based chemotherapy, compared with 85% of wild
type BRCA cases (p=0.05) and only 80% of BRCA1 mutation carriers (p=0.02). Similarly, BRCA2
mutation carriers had significantly longer platinum-free duration than those with BRCA1
mutations (longer platinum-free duration, indicates less response to platinum).There were no
significant differences with primary chemotherapy sensitivity or platinum-free survival
between BRCA1 mutation carriers and wild-type BRCA cases.
In the case-control study by Vencken et al (2011),66 87% of BRCA1 mutation carriers
obtained a complete response or no evidence of disease compared with 71% of the
sporadic patients (p=0.002). Response to chemotherapy was improved in the BRCA2 group
as well, however this was not statistically significant due to the low numbers of BRCA2
patients. In patients treated with a platinum-based regimen, no BRCA1 or BRCA2 patients
had progressive disease compared with 15% of sporadic patients (p<0.001).
In the case-control study by Tan et al (2008),67 95.5% of patients with BRCA1 or BRCA2
mutations responded to first-line platinum based chemotherapy, compared with 59.1% of
non-hereditary ovarian cancer patients (p=0.002). Patients with BRCA 1 or BRCA2 mutations
were also more likely to achieve a complete response to chemotherapy than non-hereditary
patients (81.8% versus 43.2%, p=0.004).
The study by Alsop et al reported that of the 837 patients who received chemotherapy
during primary treatment, 835 (99.8%) received a platin-based regimen and 642 (76.9%)
received carboplatin/paclitaxel. Patients with BRCA1/2 mutations were less likely to have
disease progression within 6 months of the end of primary treatment compared with those
not carrying mutations (14.9% vs. 31.7% respectively, p<0.001). Disease progression within 6
months of completing primary platin-based chemotherapy has conventionally been
associated with platinum resistance.68
Adverse events
Adverse events were not reported in the BRCA mutation papers.
Quality of life
Quality of life was not reported in the BRCA mutation papers.
Elderly patients
Study characteristics
A phase III RCT in Section 3.2.1 enrolled patients who were unfit to receive cisplatin, the
population in this trial consisted of an older population (median age 73, range 67 - 76).15
Two non-randomised studies analysed effectiveness of chemotherapy in elderly patients.
One was a retrospective analysis of data from the RCT OVAR 3 69 comparing those younger
than 70 years with those aged 70 or older, the other was a cohort study of stage III or IV
ovarian cancer patients, who survived more than 120 days beyond their diagnosis and were
aged 65 years or older.70
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
32
In the OVAR 3 trial, 103 patients were 70 years or older.69 These patients were more likely to
have ECOG performance status 2 and have measurable residual disease than those
younger than 70. All patients received either carboplatin/paclitaxel or cisplatin/paclitaxel.
The cohort study included 1759 women 65 or older, of which 84% had received
chemotherapy and 53% received platinum-based chemotherapy specifically (15% received
platinum and paclitaxel).70 Women who were 80 years or older were less likely to be treated
with chemotherapy than those aged 65 to 79.
In addition, a subset analysis from RCT GOG 157 including women with early stage high risk
epithelial ovarian cancer was performed to explore differences between 3 cycles and 6
cycles of chemotherapy.71 Comparisons were made for subgroups including age (≤55years
versus >55years).
An additional study by Tew et al (2010), presented as a conference abstract was identified
after the systematic search.72 The study was a review of outcomes and toxicity differences
seen in patients 70 years and older (n=620) enrolled in the GOG 182 trial, a phase II RCT of
adjuvant combination platinum therapy. Older patients had poorer performance status (p=
<0.001), higher tumour grade differentiation (p=0.001), higher rates of serous histology (86%
vs. 82%).
Outcomes
Overall survival
The RCT by Reed et al (2006) reported improved survival in the carboplatin arm (median 15
months) compared with treosulfan (median 12 months) (p<0.026).15
In a US cohort of patients aged 65 or older,70 those who received chemotherapy had
improved survival compared with those who had no chemotherapy, the mortality reduction
was greatest for those who received a combination of platinum and paclitaxel (RR 0.59, 95%
CI 0.5 to 0.7).
In the analysis of the GOG 182 RCT, older patients had a significantly shorter survival (median
overall survival 37 months vs. 45 months, p=<0.001), consistent across all regimens and
adjusted for major prognostic factors. Older patients also had lower median survival after
recurrence (19 vs. 22 months, p=0.022).72
Progression-free survival
The RCT by Reed et al (2006) reported longer time to progression in the carboplatin arm (10
months) compared with treosulfan (5 months) (p<0.001).15
In the subset analysis from the GOG 157, the hazard ratio for recurrence for 6 versus 3 cycles
of chemotherapy was no different based on age.71
Treatment compliance
In the OVAR 3 trial, early discontinuation of treatment occurred more frequently in the elderly
patients compared with those less than 70 (26% versus 13%, p=0.001). 69 The reasons for
discontinuation were more likely to be for toxicity and patient’s withdrawal in the elderly
population. There were no significant differences between the elderly or younger
populations for discontinuation due to progressive disease or death.
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
33
In the analysis of the GOG 182 RCT, older patients had lower completion rates of all 8 cycles
(72% vs. 82%, p=<0.001).72
Response to chemotherapy
Reed et al (2006) reported that only 35% completed 6 cycles of treosulfan compared with
68% in the carboplatin arm (statistical significance was not reported).15
Adverse events
In the OVAR 3 trial, most haematological toxicity did not differ between the age groups,
however febrile neutropenia was more frequent in the elderly patients than in younger
patients (5% versus <1% respectively, p<0.001).69 There were no significant differences in nonhaematological toxic effects between age groups except that elderly patients were more
likely to get grade 3/4 infections and younger patients were more likely to have grade 3/4
myalgia.
In the analysis of the GOG 182 RCT, older patients had increased toxicities: grade 3-4
thrombocytopenia (51% vs. 43%), grade 3-4 neutropenia (70% vs. 64%), grade 3-4 pain (7.4%
vs. 4.9%) and grade 2-4 hepatic (7.2% vs. 4.2%).72
Quality of life
In the OVAR 3 trial, no significant difference between the age groups was observed for the
global health status/QoL scale during the treatment period.
Histological subtypes
Study characteristics
One phase II RCT in Section 3.2.1 specifically investigated patients with clear cell carcinoma
and compared Irinotecan and cisplatin to carboplatin and paclitaxel.16
Three papers reported on comparisons between histological subtypes and effectiveness of
chemotherapy. As each paper investigated different subtypes, each is described separately.
These studies were not designed to investigate the effectiveness of different chemotherapy
regimens in histological subtypes.
A subset analysis of RCT data from the ACTION trial compares clear cell carcinoma (n=63)
with serous carcinoma (n=156) in early ovarian cancer.73
Data from a range of GINECO first line chemotherapy RCTs were retrospectively analysed to
compare mucinous (n=54) with serous (n=786) ovarian cancer.74
A phase II trial compared extraovarian peritoneal serous papillary carcinoma (n=36) with
papillary serous ovarian carcinoma (n=130).75 Patients were sourced from two different GOG
trials with identical treatment protocols (cisplatin + cyclophosphamide).
In addition, a subset analysis from GOG 157 including women with early stage high risk
epithelial ovarian cancer was performed to explore differences between 3 cycles and 6
cycles of chemotherapy.71 Comparisons were made for subgroups including histology
subtype (serous versus non-serous).
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
34
Outcomes
Overall survival
In the subset analysis of the ACTION trial, while the overall survival rate for the serous and
clear cell carcinoma groups was not significantly different, within the chemotherapy arm
patients with serous carcinoma had improved survival compared with those with clear cell
carcinoma (p=0.04).73 However, survival benefits disappeared when only optimally staged
patients were analysed.
In the GINECO analysis, patients with mucinous ovarian cancer who had carboplatinpaclitaxel based chemotherapy had shorter overall survival compared with serous ovarian
cancer patients.74
In the phase II trial comparing extraovarian peritoneal serous papillary carcinoma with
papillary serous ovarian carcinoma, overall survival did not differ between the two groups.75
Progression-free survival
In the study of clear cell carcinoma, there was no significant difference in progression-free
survival.16
In the subset analysis from the GOG 157, 5-year recurrence-free survival for 6 versus 3 cycles
of chemotherapy was significantly higher in serous tumours.71 This benefit was not observed
for non-serous tumours.
In the subset analysis of the ACTION trial, within the chemotherapy arm, disease-free survival
was not significantly different between patients with clear cell carcinoma and those with
serous carcinoma (p=0.1).73 Adjuvant chemotherapy significantly improved disease-free
survival in patients with serous carcinoma (p=0.01) but there was no significant improvement
for those with clear cell carcinoma (p=0.4).
In the GINECO analysis, patients with mucinous ovarian cancer who had carboplatinpaclitaxel based chemotherapy had shorter progression-free survival compared with serous
ovarian cancer patients.74
Treatment compliance
In the study of clear cell carcinoma, 70.8% of patients in the paclitaxel plus carboplatin arm
and 72% in the Irinotecan plus cisplatin arm received the planned 6 cycles of chemotherapy;
this was not significantly different.16
Response to chemotherapy
In the study of clear cell carcinoma, there were no significant difference in overall response
rate; 25% in Irinotecan plus cisplatin arm and 40% in paclitaxel plus carboplatin arm.
Complete response rate in Irinotecan plus cisplatin arm and in paclitaxel plus carboplatin
arm was 25% and 20% respectively.16
In the GINECO analysis, the overall (complete and partial) response rate was significantly
lower for mucinous ovarian cancer than those with serous ovarian cancer (p<0.001).74
Progressive disease was more frequently observed in mucinous patients.
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
35
In the phase II trial comparing extraovarian peritoneal serous papillary carcinoma with
papillary serous ovarian carcinoma, no differences were observed for overall, complete or
partial response to chemotherapy.75
Adverse events
Adverse was not reported in the histological subtype papers.
Quality of life
Quality of life was not reported in the histological subtype papers.
Summary
Limited information was identified to suggest that there are specific chemotherapy
requirements for particular subgroups such as BRCA mutation carriers, elderly patients or
different histological subgroups. Trials were not designed to investigate the effectiveness of
different chemotherapy regimens across different subgroups.
3.2.7
What are the specific chemotherapy requirements for women with
epithelial ovarian cancer who are obese?
Clinical practice guidelines
The American Society of Clinical Oncology (ASCO) published clinical practice guidelines on
the appropriate chemotherapy dosing for obese adult patients with cancer in 2012.76 These
guidelines were not specific to ovarian cancer, however the guidelines noted that a majority
of studies identified in the systematic review for the guidelines involved breast, ovarian, colon
and lung cancers. The clinical practice guidelines address six clinical questions and make
seven recommendations that are presented in Appendix K. The ASCO guidelines also
highlight four key recommendations on appropriate chemotherapy dosing:
1. Panel recommends that full-weight-based chemotherapy doses be used in the
treatment of the obese patient with cancer, particularly when the goal of treatment
is cure.76
2. Clinicians should respond to all treatment-related toxicities in obese patients with
cancer in the same ways they do for non-obese patients.76
3. If a dose reduction is employed in response to toxicity, consideration should be given
to the resumption of full weight-based doses for subsequent cycles, especially if a
possible cause of toxicity (e.g. impaired renal, hepatic function) has been resolved;
there is no evidence to support the need for greater dose reductions for obese
patients compared with non-obese patients.76
4. The use of fixed-dose cytotoxic chemotherapy is rarely justified (except for a few
select agents).76
The ASCO guidelines recommend consideration of fixed dosing only with selected cytotoxic
agents, e.g. carboplatin and bleomycin. The guidelines supporting text states that
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
36
carboplatin clearance depends on glomerular filtration rate (GFR) and doses are calculated
best using the Calvert formula to achieve a targeted area under the curve (AUC). Because
carboplatin clearance is dictated by renal filtration, and GFR correlates with BSA, dosing of
carboplatin in the obese patient with cancer based on GFR may be most reasonable. 76
Systematic reviews
One systematic review and meta-analysis on obesity and ovarian cancer survival, was
published in 2012.77 The review by Protani et al (2012) aimed to examine the association
between obesity and survival and as a second objective, to explore potential sources of
variability, such as the timing of BMI assessment and the different cut off points used to
categorise BMI. The systematic review was not specific to studies of chemotherapy among
obese patients with ovarian cancer. The systematic review included 20 studies of women
diagnosed with ovarian cancer. All studies used BMI as a measure of obesity, however, the
time point when BMI was measured, as well as the cut off points used to categorise BMI for
analysis varied between the studies. The meta-analysis, which included 14 studies,
demonstrated slightly poorer survival among the obese group compared with non-obese
women with ovarian cancer (pooled HR 1.17; 95% CI 1.03-1.34). The meta-analysis reported a
slightly stronger association in studies that only included women with a BMI ≥30 in their obese
group (pooled HR 1.20; 95% CI 0.94-1.53)) than in studies that also included overweight
women (BMI ≥25; pooled HR 1.14; 95% CI 0.92-1.41) or analysed results per 5-unit increase in
BMI (pooled HR 1.15; 95% CI 0.95-1.39).77
Studies
No studies were identified which specifically compared different doses or schedules of
chemotherapy among obese patients with epithelial ovarian cancer.
Nine studies were identified which included obese patient populations and compared
outcomes by BMI or by obesity. In most of the studies, chemotherapy dosing was based on
actual body weight, whereas in some studies the formula used did not include body weight
or body surface areas (BSA). Six of the studies examined the impact of BMI on outcomes
including survival and adverse events.78-83 Three of the studies reported on adverse events
and BMI only.84-86
Study characteristics
Pavelka et al (2006) undertook a retrospective review to determine the influence of excess
body weight on ovarian cancer survival, disease progression and clinicopathologic factors.80
The study included 216 patients: 8% underweight (body mass index (BMI) <18.5), 50% ideal
body weight (18.5 ≤BMI <25), 25% overweight (25≤BMI<30) and 16% obese (BMI ≥30). A
secondary subgroup analysis was undertaken of 146 advanced ovarian cancer patients
(stage III or IV) who had primary cytoreductive surgery followed by platinum- and taxanebased chemotherapy. The methods used for calculating doses were not reported.
Wright et al (2008) investigated carboplatin dosing in obese women with ovarian cancer.82
This paper reported a retrospective analysis of 387 patients from the RCT trial GOG 158
(included in Section 3.2.1), stratified by body mass index (BMI). Three groups were compared:
normal weight (BMI<25, 50%), overweight (BMI 25-29.9, 32%) and obese (BMI≥30, 18%). The
dose of carboplatin for patients in this study was based on an area under the curve of 7.5
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
37
and a glomerular filtration rate (GFR) derived from the Jelliffe formula that does not adjust for
body weight.
Barrett et al (2008) examined the association between BMI and overall survival and
progression-free survival in 1067 ovarian cancer patients participating in the Scottish
Randomised Trial in Ovarian Cancer I trial (SCOTROC I).78 Patients were categorised into four
groups: underweight (BMI <18.5, n=59), ideal weight (BMI 18.5-24.9, n=582), overweight (BMI
25-29.9, n=305) or obese (BMI >30, n=129). The dose of carboplatin for patients was
determined by a measured GFR ensuring accurate dosing in all categories of BMI and the
dose of taxane was not capped.
Matthews et al (2009) undertook a retrospective review that evaluated the effect of obesity
on surgical and chemotherapy outcomes in patients with epithelial ovarian cancer.79 All
patients underwent primary cytoreductive surgery followed by taxane/platinum based
chemotherapy. Three-hundred and four patients were compared based on BMI: non-obese
(BMI<30, n=233) and obese (BMI≥30, n=71) and BMI strata (underweight BMI ≤18.4; normal
weight BMI 18.5-24.9; overweight BMI 25.0-29.9; obese BMI 30.0-34.9; and morbidly obese BMI
≥35.0). Drug dosages of paclitaxel and docetaxel were calculated with an actual body weight
but the BSA was capped at 2.0. The Calvert formula was used to calculated the dosage of
carboplatin using an AUC of 6-7.5
A retrospective study by Suh et al (2012) examined the impact of obesity on the treatment
and survival outcomes in 486 patients with epithelial ovarian cancer.81 Based on the Asian
BMI criteria for Koreans, 31(6.4%), 224 (46.1%), 179 (36.8%) and 52 (10.3%) of the patients were
underweight BMI<18.5; normal weight 18.5≤ BMI <23; overweight 23≤ BMI <27.5; and obese BMI
≥27.5, respectively. The patients were also divided into two groups for the comparison based
on a BMI above or below 23.0. For chemotherapy dose calculation, Cockcroft-Gault formula
was used to calculate the GFR and the carboplatin dose was calculated using the targeted area
under the plasma carboplatin concentration-time curve from the Calvert formula.
Hanna et al (2012) evaluated the prognostic significance of relative dose intensity (RDI) and
predictors of reduced RDI in women with newly diagnosed advanced stage epithelial
ovarian cancer treated with platinum-based chemotherapy.83 Three-hundred and twentyfive patients were included, 69.5% had a BMI of less than 30 while 20.6% were obese or
morbidly obese. Ninety per cent (n=291) of the study population had a body surface area
(BSA) less than 2.0m2 while the BSA for the remaining 10.2% was greater than 2.0m 2.
Calculation of RDI required comparison to a standard regimen. Carboplatin AUC 6 was
considered standard. Experimental therapies administered on clinical trials in addition to
standard chemotherapy agents were not incorporated into RDI calculations, as there were
no available standard regimens on which to base such calculations. If no literature-derived
standard could be identified for a chemotherapy regimen and the subject was not enrolled
on a research protocol, RDI was not calculated. After standard regimens had been
determined, a standard dose of each agent was determined for each subject. In calculating
the standard dose, the BSA calculation was based on actual body weight with no capping
of BSA value; the Cockcroft/Gault formula was used for creatinine clearance calculation
and the Calvert formula for carboplatin dosage calculation. In addition to dosing, the
temporal delivery of the agents is also taken into account when calculating RDI, such that
treatment delays result in reductions in delivered RDI. Reduced RDI was defined as <85% of
standard over the four cycles studied.
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
38
Table 6
Study
Study characteristics of studies reporting the outcomes of chemotherapy in obese patients
Patient
characteristics
Epithelial ovarian
cancer patients
n=216
Subgroup analysis
of stage III and IV
patients (n=146)
BMI categories n (%)
Chemotherapy characteristics
<18.5kg/m2: 17(8)
18.5-24.9kg/m2: 108(50)
25-29.9kg/m2: 56(26)
≥30kg/m2: 35(16)
Platinum- and taxane-based
chemotherapy.
Wright
2008
Epithelial ovarian
cancer patients
n=387
BMI <25: 194(50.1)
BMI 25-29.9: 122(31.5)
BMI ≥30: 71(18.4)
Barrett
2008
Epithelial ovarian
cancer patients
n=1067
BMI <18.5: 59(5.5)
BMI 18.5-24.9: 582(54)
BMI 25-29.9: 305(28)
BMI >30: 129(12)
Matthews
2009
Epithelial ovarian
cancer patients
n=304
BMI <30: 233(77)
BMI ≥30: 71(23) AND
BMI ≤18.4: 12(3.9)
BMI 18.5-24.9: 126(41.4)
BMI 25.0-29.9: 95(31.2)
BMI 30.0-34.9: 43(14.1)
BMI ≥35.0: 28(9.2)
Suh 2012
Epithelial ovarian
cancer patients
n=486
BMI<18.5: 31(6.4)
18.5≤ BMI <23: 224(46.1)
23≤ BMI <27.5: 179(36.8)
BMI ≥27.5: 52(10.3)
Pavelka
2006
The methods used for calculating
doses were not reported,
however a lower median dose of
paclitaxel relative to BSA for
obese patients compared to
those of ideal body weight was
reported.
Carboplatin in combination with
paclitaxel.
Paclitaxel 175 mg/m2
The dose of carboplatin for
patients based on an AUC of 7.5
and a glomerular filtration rate
(GFR) derived from the Jelliffe
formula that does not adjust for
body weight.
Docetaxel-carboplatin or
paclitaxel-carboplatin.
Carboplatin dose was determined
by a measured GFR. Carboplatin
dose was derived using the Calvert
formula. Taxane dose was
calculated using BSA (docetaxel
75 mg/m2,; paclitaxel 175 mg/m2)
with no dose capping carried out.
Platinum- and taxane-based
chemotherapy.
Drug dosages of paclitaxel and
docetaxel were calculated with
an actual body weight but the BSA
was capped at 2.0. The Calvert
formula was used to calculated
the dosage of carboplatin based
using an AUC of 6-7.5
Paclitaxel-carboplatin; docetaxelcarboplatin; paclitaxel-cisplatin;
and a combination of one of them
with gemcitabine-carboplatin or
topotecan.
Cockcroft-Gault formula was used
to calculate the GFR and the
carboplatin dose was calculated
using the targeted area under the
plasma carboplatin concentrationtime curve from the Calvert
formula
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
39
Study
Hanna
2013
Patient
characteristics
Epithelial ovarian
cancer patients,
stage III-IV, n=325
BMI categories n (%)
Chemotherapy characteristics
BMI <30kg/m2: 226(69.5)
BMI ≥30kg/m2: 67(20.6)
N/A: 32(9.9)
Multi-agent chemotherapy
(platinum-based). The most
common regimen was carboplatin
(AUC=6) and paclitaxel (175
mg/m2).
Calculation of RDI required
comparison to a standard
regimen. Carboplatin AUC 6 was
considered standard. In
calculating the standard dose, the
BSA calculation was based on
actual body weight with no
capping of BSA value; the
Cockcroft/Gault formula was used
for creatinine clearance
calculation and the Calvert
formula for carboplatin dosage
calculation.
AUC=area under the curve; BMI=Body Mass Index; BSA=body surface area; GFR=Glomerular
filtration rate; RDI=relative dose intensity
Three studies only included adverse event outcomes, study details are presented in table 6
below.
Table 7
Study
Sendo 2005
Mereu 2009
Study characteristics of studies reporting adverse event outcomes only
Patient
characteristics
N=105
Asian ovarian
cancer patients
who received
paclitaxelcarboplatin
combination
chemotherapy
N=203
Epithelial ovarian
cancer patients
who underwent
ambulatory first-line
chemotherapy
Outcomes
Chemotherapy dosing
Incidence of
hypersensitivity
reaction and risk
factors including
obesity
Paclitaxel 180mg/m2 infused
intravenously over 3hr, followed
by IV carboplatin infusion over
1hr at an AUC of 5mg/ml
minute, according to the
Calvert equation
Venous
thromboembolism
(VTE) risk including BMI
The first-line chemotherapy
schedules: cysplatinum
(CDDP50 mg/mq weekly);
cysplatinum + other drugs
(CDDP50 mg/mq +
cyclophosphamide
600mg/mq±adriamycin
45mg/mq every 3-4 weeks);
carboplatin (JM8 AUC6 every 34 weeks); carboplatin + other
drugs (JM8 AUC6 + paclitaxel
175-225mg/mq every 3 weeks,
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
40
Study
Laskey 2012
Patient
characteristics
N=326
Stage III-IV epithelial
ovarian cancer
patients treated
postoperatively with
multi-agent
intravenous
chemotherapy
Outcomes
Predictors of severe
and febrile
neutropenia including
BMI
Chemotherapy dosing
JM8 AUC6 + epirubicin 120
mg/mq every 4 weeks, JM8
AUC5 + paclitaxel 175mg/mq +
topotecam 1mg/mq per 3 days
every 3 weeks).
Dose intensity was calculated
as the dose for each individual
subject per unit time (week).
Actual body weight was used
to calculate the BSA for the
standard dose with no capping
of BSA values. The
Cockcroft/Gault formula was
used for creatinine clearance
calculation and the Calvert
formula for carboplatin dosage
calculation.
AUC=area under the curve; BMI=Body Mass Index; BSA=body surface area; RDI=relative dose
intensity
Outcomes
Overall survival
Pavelka et al (2006) noted in the analysis of stage III and IV patients, that increasing BMI
classification was a negative predictor of overall survival. Median overall survival was 70
months, 79 months and 33 months for ideal body weight, overweight, and obese groups
respectively(p=0.02). Median overall survival was not reached for underweight group.80 Cox
proportional hazards model including BMI as a continuous variable confirmed the negative
prognostic impact of increasing BMI on overall survival (HR 1.050; 95% CI 1.005-1.097; p=0.03).
Wright et al (2008) reported no statistically significant differences in overall survival across BMI
strata (p=0.41).82
There was no statistically significant association between BMI category and overall survival
(p=0.10) in the SCOTROC I trial (Barrett et al 2008). 78 Median overall survival was 32.9 months
(95% CI 23.5-42.4) in the underweight group, median survival not attained in the ideal weight
group, 30.1 months (95% CI 25.4-34.7) in the overweight group and 34.3 months (95% 26.941.7) in the obese group.
Matthews et al (2009) reported no statistical difference in overall survival between obese and
non-obese patients (48 vs. 40 months, p=0.37) or when patients were stratified by BMI
(underweight 38 months; normal weight 40 months; overweight 33 months; obese 47 months;
morbid obesity 48 months; p=0.60).79
Suh et al (2012) reported similar five-year overall survival rates across BMI categories; 73% in
underweight, 58.4% in normal weight, 56.1% in overweight and 65.3% months in obese
(p=0.67).81 Overall survival was also similar across BMI categories in subgroup of patients who
received one of the three regimens paclitaxel-carboplatin, docetaxel-carboplatin or
paclitaxel-cisplatin, as the first chemotherapy session (p=0.99). In a sub-cohort of stage III-IV
patients, overall survival was similar across the four BMI groups (p=0.70). When comparing the
two BMI groups, <23 vs. ≥23 there was no significant differences in overall survival (p=0.83).
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
41
Hanna et al (2013) undertook univariate and multivariate analyses to demonstrate factors
associated with poor overall survival. Median follow up was 34 months.83 Death was
recorded in 55.1% of patients; median time to death was 34 months. In both univariate
analysis and multivariate analysis, delivered RDI <85% was negatively associated with overall
survival; HR=1.59, 95% CI 1.14-2.21, p=0.007 and HR=1.71, 95% CI 1.19-2.45, p=0.003,
respectively.
Kaplan-Meier curves demonstrated that reduced delivered RDI <85% was associated with
poorer overall survival; p=0.006.
Progression free survival (PFS)
Wright et al (2008) reported no significant differences in PFS across BMI strata (p=0.12).82
However, after adjustment for age, performance status, histology and residual disease there
was an increased relative risk of progression in obese women compared with normal weight
women (RR=1.25; 95% CI 0.93-1.69; p=0.14).
Barrett et al (2008) reported no statistically significant association between BMI category and
PFS (p=0.51).78 Median PFS was 14.7 months (CI 95% 11.6-17.9) in the underweight group, 14.7
months (95% CI 13.3-16.1) in the ideal weight group, 14.7 months (95% CI 12.6-16.8) in the
overweight group and 16.6 months (95% CI 11.8-21.4) in the obese group.
Matthews et al (2009) reported that compared to non-obese patients (BMI <30), obese
patients (BMI ≥30) had a lower recurrence rate (68% vs. 79%, p=0.04), but no statistical
difference in PFS (17 vs. 11 months, p=0.14).79 There was no statistically significant difference
in PFS across the BMI categories: 9 months underweight, 11 months normal weight, 10 months
overweight, 18 months obese and 15 months morbid obesity (p=0.26).
Suh et al (2012) reported similar PFS rates across BMI categories; 24 months in underweight, 20
months in normal weight, 22 months in overweight and 25 months in obese (p=0.35). 81 Similar
recurrence rates were also reported across the groups: 48.4% in underweight, 45.9% in normal
weight, 53.1% in overweight and 42.9% in obese (p=0.43). PFS was also similar across BMI
categories in subgroup of patients who received one of the three regimens paclitaxelcarboplatin, docetaxel-carboplatin or paclitaxel-cisplatin, as the first chemotherapy session
(p=0.28). In a sub-cohort of stage III-IV patients, PFS was similar across the four BMI groups
(p=0.68). When comparing the two BMI groups, <23 vs. ≥23 there was no significant
differences in PFS (p=0.77).
Hanna et al (2013) undertook univariate and multivariate analyses to demonstrate factors
associated with reduced PFS.83 Median follow up was 34 months. Progression or recurrence
was recorded in 74.2% of patients; median time to recurrence or progression was 13 months.
In multivariate analysis, there were no independent predictors of PFS.
Disease free survival (DFS)
Pavelka et al (2006) reported in the analysis of stage III and IV patients that BMI >25 was
associated with decreased DFS compared with BMI <25 (17 vs. 25 months, respectively,
p=0.04).80 Increasing BMI classification was an independent negative predictor of DFS
(p=0.02). Cox proportional hazards model confirmed the negative prognostic impact of
each 1-unit increase in BMI on DFS (HR 1.042, 95% CI 1.009-1.076, p=0.01).
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
42
Dosing
In the study by Pavelka et al (2006), for advanced stage patients, only 6/146 patients were
unable to complete prescribed chemotherapy due to toxicity and these were not
associated with BMI grouping.80 Chemotherapy dose data for 83 patients demonstrated a
significant difference in the median dose of paclitaxel per square metre of body surface
area between the ideal body weight and obese groups (average 167mg/m 2 vs. 155mg/m2,
respectively, p=0.01). It was stated that given the multiple variables affecting carboplatin
doses, this comparison was not undertaken.
Wright et al (2008) reported that over the entire treatment course, the average dose of
carboplatin received during treatment did not differ across BMI strata.82
Barrett et al (2008) reported for the SCOTROC I trial overall, no statistically significant
differences between the two arms for dose intensity or cumulative dose. In the current study
of 1067 patients who received taxane treatment and had recorded BMI, there was neither a
statistically significant difference in taxane dose intensity (p=0.120) or carboplatin dose
intensity (p=0.578) between the BMI categories.78 There was also no statistically significant
difference between total intended taxane dose (p=0.217) or total intended carboplatin dose
(p=0.722) between BMI. Based on the findings of no significant differences in survival
between BMI categories from this study in which chemotherapy dose was based on
measured GFR, the authors suggested accurate measurement of GFR before commencing
chemotherapy and chemotherapy doses based on actual body weight.
Matthews et al (2009) reported similar numbers of lines (p=0.83), courses (p=0.87), number of
platinum-based regimens (p=0.42), and complication rates of chemotherapy (p=0.39)
between obese and non-obese patients.79
In the study by Suh et al (2012), there were no significant differences across BMI categories
for the number of lines of chemotherapy used, the number of courses of chemotherapy or
the number of courses before recurrence.81 The level of neutropenia and platinum sensitivity
rate were also similar in BMI groups.
Hanna et al (2013) reported predictors of reduced planned RDI or delivered RDI <85% in a
multivariate logistic analysis. BSA >2m2 was reported to be a predictor of reduced planned
RDI <85% (OR=6.14, 95% CI 2.32-16.20, p=<0.001) and BMI >30kg/m2 was demonstrated to be
a predictor of reduced delivered RDI (OR=2.35, 95% CI 1.25-4.41, p=<0.008).83
Table 8
Chemotherapy characteristics of Suh 2011
Lines of chemotherapy
Underweight
Normal weight
Overweight
Obese
P value
(n=31)
(n=224)
(n=179)
(n=52)
1.9 ± 1.3
2.1 ± 1.6
2.4 ± 1.9
2.1 ± 1.5
0.38
13.9 ± 10.6
12.4 ± 9.1
14.8 ± 11.5
12.5 ± 8.8
0.18
7.1 ± 3.6
7.3 ± 2.2
7.2 ± 2.3
6.7 ± 2.0
0.69
4 (13.3)
39 (19.7)
30 (17.9)
5 (11.1)
0.52
(mean ± SD)
Total courses of
chemotherapy
(mean ± SD)
Courses of chemotherapy
before recurrence
(mean ± SD)
Neutropenia (%)
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
43
Underweight
Normal weight
Overweight
Obese
(n=31)
(n=224)
(n=179)
(n=52)
P value
Sensitive (%)
22 (78.6)
142 (76.3)
113 (72.4)
31 (77.5)
Resistant (%)
6 (21.4)
44 (23.7)
43 (27.6)
9 (22.5)
Platinum sensitivity (%)
0.79
Adverse events
Wright et al (2008) reported obese women were less likely to experience moderate to severe
thrombocytopenia, leukopenia and granulocytopenia over the entire treatment course
compared with normal weight subjects.82 Schedule delays and dose reductions were more
common in the normal weight women than in obese women.
Table 9
Cumulative grade 3 and 4 toxicity based on BMI in Wright et al 2008
Thrombocytopenia
Leukopenia
Granulocytopenia
Gastrointestinal
Genitourinary
Neurologic
Metabolic
Table 10
All
39.8
59.4
90.7
9.8
0.8
7.0
2.3
Grade 3 or 4 toxicity (%)
BMI group
<25.0
25.0-29.9
49.5
32.0
70.1
51.6
93.3
91.8
10.3
8.2
1.0
0.0
4.6
7.4
2.6
2.5
≥30.0
26.8
43.7
81.7
11.3
1.4
12.7
1.4
P value
0.0004
<0.0001
0.01
0.75
0.48
0.07
0.85
Treatment modifications based on BMI in Wright et al 2008
Dose reduction (any course
Treatment delay (any course)
Received <6 cycles
Treatment adjustment (%)
BMI group
All
<25.0
25.6
34.0
59.2
69.1
11.6
10.3
25.0-29.9
14.8
54.1
10.7
≥30.0
21.1
40.9
16.9
P value
0.004
<0.0001
0.31
Matthews et al (2009) reported similar rates of neutropenia for obese and non-obese patients
(52% and 46%, p=0.39).
In the Japanese study by Sendo et al (2005) a multivariate analysis demonstrated that
obesity (BMI >25) significantly affected the incidence of hypersensitivity reactions to
paclitaxel (OR 8.47, 95% CI 1.48-48.57, p=0.017).86
A retrospective study by Mereu et al (2009) demonstrated an association between
increasing BMI and increased risk of venous thromboembolism (VTE) (HR 1.67, 95% CI 1.172.38, p=0.017).85 BMI comparison was >24.5 vs. 24.5 or less. This association was confirmed in
multivariate analysis; HR 1.62, 95% CI 1.08-2.42, p=0.019.
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
44
Laskey et al (2012) reported that BMI <30 and BSA <2.0 m2 were significant predictors of
severe neutropenia in women with stage III and IV epithelial ovarian cancer 84 by univariate
analysis (p=<0.01 and p=0.03). Multivariate analysis indicated a trend to an association
between severe neutropenia and BMI <30 (HR 1.60, p=0.06).
Summary
ASCO clinical practice guidelines on appropriate chemotherapy dosing for obese
adult patients with cancer (not ovarian cancer specific) recommend that full weightbased cytotoxic chemotherapy doses be used to treat obese patients with cancer,
particularly when the goal of treatment is cure.
No studies were identified which specifically compared different doses of
chemotherapy among obese patients for survival outcomes.
No prospective studies comparing different doses or schedules of chemotherapy
among obese patients with epithelial ovarian cancer were identified. Studies
identified were retrospective, and analysed outcomes of chemotherapy between
groups stratified by BMI, or for obese compared to non-obese patients.
In most of the studies, chemotherapy dosing was based on actual body weight,
whereas in some studies (such as carboplatin dosing, for GOG 158 patients by Wright
et al, 2008) the formula used did not include body weight or body surface area (BSA).
No significant differences in overall, progression-free or disease-free survival were
reported between obese and non-obese patients in most of the studies.
One study (Pavelka et al, 2006) reported a negative prognostic impact of increasing
BMI on overall and disease-free survival in stage III and IV ovarian cancer patients.
While the dosing calculations used for these patients were not described, a lower
median dose of paclitaxel relative to BSA for obese patients compared to those of
ideal body weight was reported.
One study (SCOTROC I trial, Barrett et al, 2008) which did not find a link between
obesity and poorer prognosis noted this finding to be because of more accurate
dose calculations in that study. The authors recommended accurate measurement
of GFR and chemotherapy doses based on actual body weight rather than ideal
body weight.
The majority of studies reported similar numbers of lines, courses, number of platinumbased regimens of chemotherapy between obese and non-obese patients.
One study (Hanna et al 2013) determined BSA greater than 2m2 and BMI >30kg/m2 to
be predictors of reduced planned relative dose intensity (RDI) <85% and reduced
delivered RDI <85%. In both univariate analysis and multivariate analysis, delivered RDI
<85% was negatively associated with overall survival.
Adverse events reported and any differences between BMI groups varied between
studies. In the study by Wright et al, in which the carboplatin dose calculation did not
adjust for body weight, obese women were reported to experience less treatmentrelated toxicity compared with normal weight subjects. The authors suggested that as
obese women were less likely to experience treatment-related toxicity, these women
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
45
received a lower effective dose of carboplatin and that body weight should be
taken into consideration when calculating carboplatin dose.82
3.3
Other issues
Other issues to be considered, but not specifically searched for, within this systematic review
included:
Any other women with specific chemotherapy requirements/issues for example
rural/remote, Aboriginal and Torres Strait Islander women
Resources specification, for example resources required for intraperitoneal
chemotherapy
Patient selection criteria
While some information was identified on patient selection criteria for included
chemotherapy trials, no information was identified on specific chemotherapy requirements
or rural/remote/Aboriginal and Torres Strait Islander women with ovarian cancer or any
papers specifically on resources specification for providing chemotherapy such as
requirements for performing intraperitoneal chemotherapy.
Patient selection criteria
For each of the trials included in this systematic review, details on the patient
inclusion/exclusion criteria were recorded.
While the majority of trials did not impose an age limit, the median age was most often
between 55 and 60 years. Of those which did impose an age limit, two trials included
patients up to 65 years, one trial up to 70 years, five trials up to 75 years and one trial up to 80
years.
The majority of trials required patients to have a performance status (WHO or ECOG) of 0 to
2. Patients in the trials were also required to have adequate cardiac, bone marrow, hepatic
and renal function.
Trials excluded patients with borderline or low malignant potential tumours or other
concurrent malignancies
3.4
Ongoing trials
Clinical trials registries were searched to identify any additional studies investigating various
chemotherapy regimens for treatment of ovarian cancer which have not yet reported.
Please see Appendix L for details of ongoing trials identified.
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
46
4
Discussion
In this systematic review of first line chemotherapy for women with epithelial ovarian cancer,
75 citations and two conference abstracts were identified as eligible from a search of the
literature published between January 2003 and November 2012. Thirty five RCTs were
included in the review for the primary research questions, and ten studies that were not RCTs
were included for examination of subgroups. Six Cochrane reviews were also used as primary
references. The included RCTs were considered to be moderate to high quality and the
previously published systematic reviews to be high quality.
A recent Cochrane systematic review investigated chemotherapy regimens for patients with
early stage ovarian cancer (stage I-IIa). 8 This high quality review found that overall and
progression-free survival was improved in early stage ovarian cancer patients who had
chemotherapy after surgery compared with those on observation after surgery. Subgroup
analysis suggested that women who had optimal surgical staging of their disease were
unlikely to benefit from adjuvant chemotherapy, whereas those who had sub-optimal
staging did.
The authors of the Cochrane review suggested the following approaches for adjuvant
chemotherapy for early stage ovarian cancer:8
1. unilateral, encapsulated, well-differentiated serous and endometrioid carcinoma
(stage Ia grade 1, non-optimally staged) may be managed without adjuvant
chemotherapy
2. stage Ia, and Ib that has been comprehensively staged, well or moderately
differentiated (grade I/2) may be managed without adjuvant chemotherapy
3. poorly or undifferentiated (grade 3) stage Ia/IIb disease should be offered adjuvant
chemotherapy
4. non serous histotypes, mucinous and clear cell, should be offered adjuvant
chemotherapy.
The review of the literature on different chemotherapy regimens for first line treatment of
women with epithelial ovarian cancer was limited in the comparisons of trial results that were
possible, due to the many different regimens reported. Twenty phase III and seven phase II
randomised controlled trials were included which investigated different chemotherapy
regimens in populations with a majority of advanced stage ovarian cancer patients.
While many regimens have been trialled, including addition of chemotherapy agents to
standard regimens or substitution of different agents, almost all failed to demonstrate an
overall or progression-free survival benefit compared with standard chemotherapy (most
often platinum/taxane combination). Trials which did show survival differences were either in
specific patient populations or compared older chemotherapy regimens no longer
considered standard.
Two randomised controlled trials have shown improved progression-free survival for the
biological therapy bevacizumab used in addition to carboplatin and paclitaxel. One of
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
47
these studies also indicated for patients at high risk of progression, overall survival benefit with
bevacizumab, and greater benefit in progression free survival than for patients at lower risk.
Adverse effect profiles reflected the various agents used however there were often limited
differences in toxicities between treatment arms. Similarly, most trials reported no significant
differences in quality of life between the treatment arms investigated.
Similarly, the review of different schedules for chemotherapy regimens for first line adjuvant
treatment of epithelial ovarian cancer was limited in the comparisons of trial results that were
possible, due to the differences in the schedules investigated between trials. Six phase III and
one phase II trials were included which investigated different schedules including dosedense chemotherapy, different doses of the same agent or different timing/cycles of the
same regimen. Only one trial, JGOG 3016, showed survival benefits between treatment arms.
This study investigated dose-dense paclitaxel compared with standard paclitaxel and
reported improved overall survival and progression-free survival in the dose-dense paclitaxel
group compared to the conventional group, at short-term follow-up (up to 3 years) and at
long-term follow-up (median 6.4 years). While adverse events were often similar between
treatments arms, some increased toxicity was observed in the higher dose, more intensive
chemotherapy intervention arms compared with standard arms. Quality of life was not
assessed in any of the trials.
The recent high quality Cochrane systematic review on the effectiveness of IP chemotherapy
in treating ovarian cancer found that the inclusion of an IP component of chemotherapy
improved overall and progression-free survival. IP chemotherapy however was associated
with significantly more pain, fever, infection, metabolic complications and gastrointestinal
adverse effects than IV chemotherapy. 56 Quality of life was reported in one trial only. More
disruption in quality of life was noted in the IP arm during and shortly after treatment, but it
then improved over time in both arms. It was noted in the review that current standard
therapy is carboplatin with or without a taxane and that ongoing trials are investigating IP
carboplatin rather than cisplatin which was mainly used in the older trials included in the
review.56 The authors of this Cochrane review concluded that their review supports the use of
IP chemotherapy, however the potential for catheter related complications and toxicity
needs to be considered when deciding on the most appropriate treatment for each
individual woman. 56
Currently only one randomised controlled trial has been published comparing neoadjuvant
chemotherapy with primary surgery, although further studies are ongoing. In this high quality
trial, no survival differences between treatment arms were observed. 63 More adverse events
were observed in the primary surgery group than the neoadjuvant group, however whether
this was statistically significant was not reported. There were no differences in quality of life
between treatment arms.
Limited information was identified on subsets, such as such as BRCA mutation carriers, elderly
patients or different histological subgroups, which may have specific chemotherapy
requirements for first line adjuvant treatment of epithelial ovarian cancer. While some data
on subgroups was identified, in general the studies were not designed to investigate the
effectiveness of different chemotherapy regimens across different subgroups.
No studies were identified which specifically compared different doses of chemotherapy
among obese patients for survival outcomes. In most of the studies, chemotherapy dosing
was based on actual body weight, whereas in some studies the formula used did not include
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
48
body weight or body surface area (BSA). No significant differences in overall, progressionfree or disease-free survival were reported between obese and non-obese patients in most
of the studies. The majority of studies reported similar numbers of lines, courses, number of
platinum-based regimens of chemotherapy between obese and non-obese patients. One
study (Hanna et al 2013) determined BSA greater than 2m 2 and BMI >30kg/m2 to be
predictors of reduced planned relative dose intensity (RDI) <85% and reduced delivered RDI
<85%. In both univariate analysis and multivariate analysis, delivered RDI <85% was negatively
associated with overall survival. Adverse events varied between studies. In the study by
Wright et al, in which the carboplatin dose calculation did not adjust for body weight, obese
women were reported to experience less treatment-related toxicity compared with normal
weight subjects. The authors suggested that as obese women were less likely to experience
treatment-related toxicity, these women received a lower effective dose of carboplatin and
that body weight should be taken into consideration when calculating carboplatin dose. 82
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
49
5
Conclusion
This systematic review considered the evidence on different regimens, schedules, mode of
administration and time of administration of chemotherapy regimens, and on subsets with
specific chemotherapy requirements, for first line adjuvant treatment of epithelial ovarian
cancer.
For early stage ovarian cancer patients who had chemotherapy following surgery, overall
and progression-free survival was improved compared with women on observation following
surgery. However subgroup analysis suggested that women who had optimal surgical
staging of their disease were unlikely to benefit from adjuvant chemotherapy, whereas those
who had sub-optimal staging did.
Standard first line chemotherapy for advanced epithelial ovarian cancer is currently a
platinum agent combined with a taxane. While many different regimens have been
investigated, including addition or substitution of chemotherapy agents and different
schedules of treatment, almost all failed to demonstrate an overall or progression-free
survival benefit compared with standard chemotherapy. Some improvements in progressionfree survival have been reported for bevacizumab used in addition to carboplatin and
paclitaxel. Inclusion of an intraperitoneal component of chemotherapy improved overall
and progression-free survival, however women receiving intraperitoneal chemotherapy
reported more adverse events than those on standard chemotherapy. One randomised
controlled trial has compared neoadjuvant chemotherapy with primary surgery and no
survival differences between treatment arms were observed. Limited information was
identified on subsets, for first line adjuvant treatment of epithelial ovarian cancer. While
some data were identified on subsets that may have specific chemotherapy requirements,
such as BRCA mutation carriers, elderly patients or different histological subgroups, in general
trials were not designed to investigate the effectiveness of different chemotherapy regimens
across different subgroups. No prospective studies comparing different doses or schedules of
chemotherapy among obese patients with epithelial ovarian cancer were identified. Studies
identified were retrospective, and analysed outcomes of chemotherapy between groups
stratified by BMI, or for obese compared to non-obese patients.
Based on the evidence from this systematic review, updates to existing clinical practice
recommendations are required for first line adjuvant treatment of epithelial ovarian cancer,
as well as new clinical practice recommendations, such as for the use of dose-dense
chemotherapy. The current evidence is inadequate to support clinical practice
recommendations for the use of bevacizumab.
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
50
Appendix A
Contributors
The following Cancer Australia staff were involved in the development of First line
chemotherapy for the treatment of women with epithelial ovarian cancer: a systematic
review
Ms Katrina Anderson
Senior Project Officer, Evidence Review
Mr Paul Cramer
General Manager, Programs, Project Sponsor
Ms Jane Francis
Manager, Gynaecological Cancers
Ms Emma Hanks
Senior Project Officer
Ms Charmaine Larment
Senior Project Officer
Dr Anne Nelson
Manager, Evidence Review
Ms Lara Matkovic
Senior Project Officer
Ms Angela Pearce
Senior Project Officer, Research
Ms Sue Sinclair
General
Practice
Ms Rosemary Wade
Senior Project Officer, Research
Manager,
Service
Delivery
and
Clinical
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
51
Appendix B
Literature databases searched
Source
Results/Retrievals
Medline (OVID)
412 (86 subgroup search and 119 obesity
search)
Embase
567 (128 subgroup search and 271 obesity
search)
Pubmed
774 (167 subgroup search and 399 obesity
search)
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
52
Appendix C
Search strategy
Ovarian cancer
Ovarian Neoplasms/
“ovarian neoplasms”
ovarian and (cancer or carcinoma or
tumour or tumor)
First line Chemotherapy
Antineoplastic agents/
Drug therapy/
(("first line" or first-line or "1st line" or "primary
treatment" or “newly diagnosed”) and
(chemotherapy or “systemic therapy”)
RCTs
Randomized controlled trials/ or randomized
controlled trials or randomized controlled
trial or randomised controlled trials or
randomised controlled trial or random
allocation or double blind method or single
blind method or controlled trial$
Meta-analysis/systematic review
Meta-analysis/
meta-analysis or “meta analysis” or
“systematic review” or “pooled analysis”
Obesity
Obese or obesity or “body weight” or
overweight or “over weight” or BMI or “body
mass index” or adiposity or fat or “body
surface”
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
53
Appendix D
Health technology assessment, guidelines
and clinical trials websites searched
Acronym
Canada
Organisation
Website
CCO
Cancer
Ontario
http://www.cancercare.on.ca/
International
HTAi
Scotland
SIGN
UK
CCT
NICE
NRR
Care
Health
Technology
Assessment
International
http://www.htai.org/
Scottish
Intercollegiate
Guidelines
Network
http://www.sign.ac.uk/
Current
Controlled Trials
National Institute
for Health and
Clinical
Excellence
National
Research
Register
http://www.controlled-trials.com/
ClinicalTrials.gov
National Cancer
Institute Clinical
Trials
National
Guideline
Clearinghouse
http://www.clinicaltrials.gov/
http://www.cancer.gov/clinicaltrials
http://www.nice.org.uk/
http://www.nrr.nhs.uk/
US
NCI
NGC
http://www.guideline.gov/
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
54
Appendix E
Flowchart-inclusion/exclusion of articles
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
55
Appendix F
International guidelines and
recommendations
1. Ovarian Cancer Guidelines National Comprehensive Cancer Network (NCCN) (US) version
3.2012
NCCN provides flow-charts with management pathways for epithelial ovarian cancer.
Chemotherapy information is provided on:
Principles of chemotherapy
Primary chemotherapy/Primary adjuvant therapy for stage I-IV
o
This section includes guidance on intraperitoneal (IP) chemotherapy as well as
suggested drug regimens used for ovarian cancer
Recurrent disease
2. The recognition and initial management of ovarian cancer (CG122) National Institute for
Health and Clinical Excellence (NICE) (UK) 2011
Recommendations are provided regarding the following areas:
Adjuvant systemic chemotherapy for stage I disease
o
Recommendations:
Do not offer adjuvant chemotherapy to women who have had
optimal surgical staging and have low risk stage I disease (grade I or 2,
stage Ia or Ib)
Offer women with high-risk stage I disease (grade 3 or stage Ic)
adjuvant chemotherapy consisting of six cycles of carboplatin
Discuss the possible benefits and side effects of adjuvant
chemotherapy with women who have had suboptimal surgical
staging and appear to have stage I disease
IP chemotherapy
o
Recommendation:
Do not offer intraperitoneal chemotherapy to women with ovarian
cancer except as part of a clinical trial
Chemotherapy regimens – first line
o
refers to NICE technology appraisal on use of paclitaxel – recommendations
from this technology appraisal are below
It is recommended that paclitaxel in combination with a platinum
based compound or platinum-based therapy alone (cisplatin or
carboplatin) are offered as alternatives for first line chemotherapy
(usually following surgery) in the treatment of ovarian cancer.
The choice of treatment for first line chemotherapy for ovarian cancer
should be made after discussion between the responsible clinician
and the patient about the risks and benefits of the options available. In
choosing between treatment with a platinum-based compound alone
or paclitaxel in combination with a platinum-based compound, this
discussion should cover the side-effect profiles of the alternative
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
56
therapies, the stage of the woman’s disease, the extent of surgical
treatment of the tumour, and disease-related performance status.
3. Epithelial ovarian cancer. A national clinical guideline Scottish Intercollegiate Guidelines
Network (SIGN) 2003 (reaffirmed 2007).
Given these guidelines are older than the current ACN/NBCC guidelines, further information
is not provided here.
4. Ovarian carcinoma Association of Comprehensive Cancer Centres - The Netherlands 2009
Includes the following recommendations for chemotherapy:
Treatment of low-stage carcinoma (I-IIa)
o
Recommendations for chemotherapy
The committee advises that a complete surgical (re)staging is
performed in patients with a clinical low-stage ovarian carcinoma.
When a complete (re)staging cannot be performed, the committee
advises adjuvant chemotherapy. Because of a substantial chance of
micrometastasis in the case of incomplete staging (NCS), it is advised
to treat these patients as a stage III tumour with sic courses of
paclitaxel carboplatin.
After complete staging (CS), the committee recommends an
expectative policy (surgery only). Specifically in relation to grade 3
tumours, the committee could not reach an agreement. A number of
members were supporters of providing additional chemotherapy in this
situation, but there is no scientific data to support this statement.
Treatment of high-stage carcinoma (IIb-IV)
o
Current standard chemotherapy for stage FIGO IIb-IV consists of combination
therapy with:
Taxol 175 mg/m2 (in a 3-hour infusion)
Carboplatin with an area-under-the-curve (AUC) of 6 (creatinine
clearance calculated using the Cockcroft-Gault formula and the
dosage carboplatin via the Calvert formula)
or
Taxol 175 mg/m2 (in a 3-hour infusion)
Cisplatin 75 mg/m2.
o
A minimum of six three-weekly courses are administered (more extensive
information on this can be found on 'SIB op maat.' (SIB op maat is a website
with patient information on adverse events related to drugs used in the
treatment of cancer).
o
IP chemo
Recommendations
It has been shown that the addition of intraperitoneal (IP)
chemotherapy to intravenous chemotherapy for patients with
a FIGO stage III ovarian carcinoma that have had a complete
or optimal debulking (residual intraperitoneal lesions, <1 cm)
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
57
leads to a better disease-free and overall survival. However,
treatment is associated with substantial toxicity.
o
Restraint should be exercised with IP chemotherapy if there is
an increased risk of anastomotic leakage, such as after colon
surgery.
It is plausible to advise the schedule used by Armstrong, on the
basis of the greatest advantage in survival.
There are indications that less catheter obstructions are seen
with a single lumen bard, a non-fenestrated 9.6 F catheter.
It is the opinion of the committee that this treatment requires a
particular expertise; as a result, it is advised that this treatment
is performed in a centre that has gained experience in this
area. All information relating to patients treated with IP
chemotherapy should be registered, for a clear picture of the
complications.
Chemo in platinum-resistant tumours
o
Platinum-resistant tumours can be treated with topotecan,
liposomal doxorubicin, gemcitabine, oral etoposide or weekly
platinum combination therapy. Approximately 12% to 15% of
patients will respond to these agents, while around 30% of
patients will have stable disease with a time to progression
period between 12 to 22 weeks.
Induction chemo with intervention surgery
Recommendations
Await the outcome of EORTC 55971. Until such time, continue
using standard policy: primary cytoreductive surgery followed
by multichemotherapy.
5. Adjuvant Care for Stage 1 Ovarian Cancer Cancer Care Ontario 2004
This guidelines includes the following recommendations relating to chemotherapy:
Women who have undergone optimal surgical staging, including pelvic and paraaortic lymph node sampling, and have stage I disease may or may not benefit from
adjuvant platinum-based chemotherapy
Women who have not undergone optimal surgical staging can be offered two
options. The first option is that they undergo re-operation to optimally define the
tumour stage and then be offered adjuvant therapy based on the findings. The other
option is that they be offered platinum-based chemotherapy to decrease the risk of
recurrence and improve survival
6. Chemotherapy specific
An additional two guidelines were identified specifically relating to the use of chemotherapy
in ovarian cancer. Both guidelines were published by Cancer Care Ontario.
6.1 First-line Chemotherapy for Postoperative Patients with Stage II, III or IV Epithelial Ovarian
Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer Cancer Care Ontario 2004
Update
The following recommendations are made in this guideline:
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
58
Intravenous carboplatin with or without paclitaxel or docetaxel is the recommended
postoperative chemotherapy regimen for newly diagnosed stage II-IV epithelial
ovarian cancer
o
Paclitaxel in combination with carboplatin is associated with greater
neurotoxicity than docetaxel and carboplatin, however, the combination of
docetaxel and carboplatin is associated with more myelosuppresion than
paclitaxel and carboplatin. The differences in the toxicity profiles should be
discussed with patients when choosing the most appropriate regimen
Intravenous cisplatin plus paclitaxel may also be considered as a treatment option
6.2 The Role of Intraperitoneal Chemotherapy in the First-line Treatment of Women with Stage
III Epithelial Ovarian Cancer Cancer Care Ontario 2006
The following recommendations on IP chemotherapy are made in this guideline:
As front-line therapy, the intravenous administration of a platinum agent and a
taxane remains a standard of care for this patient population. Cisplatin-containing
intraperitoneal chemotherapy should be offered to patients on the basis of significant
improvements in progression-free and overall survival when compared with cisplatincontaining intravenous chemotherapy alone.
o
o
The survival benefits associated with intraperitoneal chemotherapy must be
weighed against the statistically significant increases in toxicity and catheterrelated complications.
For patients with residual tumour diameter ≤ 1 cm in any one area,
significant survival benefits were detected with intraperitoneal
chemotherapy.
For patients with disease volumes > 1 cm in any one area, the role of
intraperitoneal chemotherapy is yet to be defined.
The optimal intraperitoneal chemotherapy regimen has yet to be defined. The
greatest median survival benefits were detected with intraperitoneal cisplatin
and paclitaxel; however, only 42% of patients were able to complete all six
cycles of the assigned treatment.
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
59
Appendix G
Study
Overall and progression free survival for studies investigating different
chemotherapy regimens
Intervention
Comparator
Survival
Intervention
Overall survival
Comparator
Phase III trials
Trials which investigated the addition of agents to standard chemotherapy
OVAR 5, du
Epirubicin +
Carboplatin +
median 45.8
Bois 200617
carboplatin +
paclitaxel
months
paclitaxel
OVAR 9, du
Bois 201018
Gemcitabine +
carboplatin +
paclitaxel
Carboplatin +
paclitaxel
median 49.5
months
GOG 182 /
ICON 5,
Bookman
200919
i) Gemcitabine +
carboplatin +
paclitaxel
ii) Doxorubicin +
carboplatin +
paclitaxel
iii) Topotecan +
carboplatin →
carboplatin +
paclitaxel
iv) Gemcitabine +
carboplatin →
carboplatin +
Carboplatin +
paclitaxel
median 44.1 months
pValue
Progression-free survival
Intervention
Comparator
pValue
median 41.0
months
Adjuste
d
treatme
nt
effect
0.93;
0.3652
median
18.4
months
median 17.9
months
HR 0.95
p=0.334
2
median 51.5
months
0.5106
median
17.8
months
median 19.3
months
p<0.01
median 16.0 months
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
60
Study
Intervention
Comparator
Survival
Intervention
Bolis 201020
OVAR 7,
Pfisterer 200621
OV 16, Hoskins
200822 (abstract
only)
HeCOG,
Aravantinos
200823
Lhomme 200824
paclitaxel
Topotecan +
carboplatin +
paclitaxel
Carboplatin +
paclitaxel →
topotecan
Overall survival
Comparator
pValue
Carboplatin +
paclitaxel
5yr: 32%
5yr: 32%
NS
Carboplatin +
paclitaxel
median 43.1
months; 3yr:
55.7%
median 44.5
months; 3yr:
58.5%
HR 1.01
; 0.885
Progression-free survival
Intervention
Comparator
pValue
NS
median
18.2
months
median 18.5
months
HR 0.97
p=0.688
median
14.6
months
median 16.2
months
HR 1.10
p=0.25
Cisplatin +
topotecan x 4 cycles
→ paclitaxel +
carboplatin x 4
cycles
Cisplatin +
doxorubicin +
paclitaxel
Carboplatin +
paclitaxel x 8 cycles
Carboplatin +
paclitaxel
median 44.33
months; 5yr OS
rate: 40.6%
median 37.97
months ; 5yr
OS rate: 38.9%
p=0.53;
NR;
multivar
iate
analysis
HR 0.86
p=0.23
median
18.13
months; 5yr
PFS rate:
26.6%
median 13.25
months; 5yr
PFS rate:
22.2%
0.07; NR;
multivari
ate
analysis
HR 0.745
p=0.009
Paclitaxel +
carboplatin +
valspodar (PSC 833)
Carboplatin +
paclitaxel
32 months
28.9 months
HR
0.994,
p=0.94
median
13.2
months
median 13.5
months
HR 0.96,
p=0.67
Trials which substituted the use of one chemotherapy agent with another chemotherapy agent
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
61
Study
Intervention
Comparator
Survival
Intervention
GOCCNE,
Nicoletto 2007
Overall survival
Comparator
pValue
Progression-free survival
Intervention
Comparator
pValue
Cisplatin +
cyclophosphamide
Adriamycin +
cyclophosphamide
median 39.4
months; 5yr: 39%,
10yr: 31%, 15yr:
28%
median
32.0
months;
5yr: 32%,
10yr: 23%,
15yr: 16%
0.8586;
0.3547,
0.2545,
0.0678
DFS
median 46
months;
5yr: 49%,
10yr: 31%,
15yr: 31%
DFS median
25 months;
5yr: 40%, 10yr:
37%, 15yr: 31%
DFS
0.44513;
0.4147,
0.5679,
0.9219
SGCTG, Reed
200615
Treosulfan
Carboplatin
median 12
months
median 15
months
5 months
10 months
RR 1.77
p<0.001
MITO 2, Pignata
201126
Carboplatin +
doxorubicin
Carboplatin +
paclitaxel
median 61.6
months
median
53.2
months
RR 1.77
p<0.026
HR 0.89
p=0.32
median
19.0
months
median 16.8
months
HR 0.95
p=0.58;
multivari
ate
analysis
HR 0.97
p=0.70
SCOTROC,
Vasey 200427
Docetaxel +
carboplatin
Carboplatin +
paclitaxel
2yr: 64.2%
2yr: 68.9%
HR 1.13
p=0.238
median 15
months
median 14.8
months
HR 0.97
p=0.707
GOG 158,
Ozols 200328
Cisplatin +
paclitaxel
Carboplatin +
paclitaxel
median 57.4
months
median
48.7
months
RR 0.84
median
20.7
months
median 19.4
months
NS; RR of
treatme
nt failure
is 0.88
(0.751.03)
OVAR 3, du
Bois 2003,
Greimel
200629,30
Cisplatin +
paclitaxel
Carboplatin +
paclitaxel
median 44.1
months
median
43.3
months
HR 1.045
Disease
progression
at 2yr: 60%;
median
19.1
Disease
progression at
2yr: 62.5%;
median 17.2
months
NS; HR
1.05
25
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
62
Study
Intervention
Comparator
Survival
Intervention
Overall survival
Comparator
pValue
Progression-free survival
Intervention
Comparator
pValue
months
HeCOG,
Aravantinos
200531
Paclitaxel +
carboplatin ↔
cisplatin
Carboplatin +
paclitaxel
median 38.6
months; 5yr: 39%
median
40.6
months; 5
yr 35%
median
p=0.79
median 39
months;
5yr: 28%
median 38
months; 5 yr
29%
median
p=0.95
Mouratidou
200732
Cisplatin +
paclitaxel
Cisplatin +
cyclophosphamide
median 24
months
median 20
months
0.35
median 12
months
median 9
months
0.215
OV10, Piccart
2003, Bezjak
2004, Butler
200433-35
AOCSG,
Dittrich 200336
Cisplatin +
paclitaxel
Cisplatin +
cyclophosphamide
34% alive
23% alive
HR 0.75);
0.001
better
Cisplatin +
carboplatin
Cisplatin +
cyclophosphamide
median 43.0
months
median
41.2
months
RR 1.05
p=0.75
median
23.1
months
median 29.7
months
median ii)
18.1
months, iii)
13.7
months
median i)
15.5
months
median
15.9
months
median
17.1
months
<0.001
Phase II trials
Trials which investigated the addition of agents to standard chemotherapy
Muthuramaling Carboplatin +
Carboplatin
am 201137
thalidomide
SCOTROC2A,
Carboplatin →
Carboplatin →
Vasey 200638
docetaxel +
docetaxel
gemcitabine
SCOTROC2B,
Clamp 200639
Carboplatin →
docetaxel +
irinotecan
Carboplatin →
docetaxel
RR 1.03
p=0.88
Trials which substituted the use of one chemotherapy agent with another chemotherapy agent
Minagawa
Docetaxel +
Carboplatin +
200640
cisplatin
docetaxel
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
63
Study
Intervention
Comparator
Survival
Intervention
Mori 200741
Docetaxel +
carboplatin
Carboplatin +
paclitaxel
JGOG3014,
Takakura 201016
Fruscio 200842
Irinotecan +
cisplatin
Cisplatin + paclitaxel
+ isosfamide
Carboplatin +
paclitaxel
Cisplatin + paclitaxel
+ epirubicin
2yr: 61.5%
Overall survival
Comparator
2yr: 68.5%
NS
pValue
Progression-free survival
Intervention
Comparator
pValue
median
17.9
months
median
21.1
months
NS
51 months
65 months
NS
NS
25 months
23 months
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
64
Appendix H
Study
Overall and progression free survival for biological therapy studies
Intervention
Comparator
Survival
Intervention
Overall survival
Comparator
Phase III trials
Trials which investigated the addition of agents to standard chemotherapy
OVAR 11 /
Bevacizumab +
Carboplatin +
1yr 95%; updated
ICON 7, Perren
carboplatin +
paclitaxel
analysis: 1 yr 92%
201143
paclitaxel
GOG 218,
Burger 201145
i) Bevacizumab +
carboplatin +
paclitaxel
ii) Bevacizumab +
carboplatin +
paclitaxel →
bevacizumab
Carboplatin +
paclitaxel
median ii) 38.7
months, iii) 39.7
months
pValue
Progression-free survival
Intervention
Comparator
pValue
1yr 93%;
updated
analysis: 1 yr
86%
HR 0.81
p=0.098
;
update
d
analysis:
HR 0.85
p=0.11
median
19.0
months;
updated
analysis:
19.8
months
median 17.3
months;
updated
analysis: 17.4
months
HR 0.81
p=0.004;
update
d
analysis:
HR 0.87
p=0.04
i) median
39.3 months
i) vs ii)
HR
1.036
p=0.76;
i) vs iii)
HR
0.915
p=0.45
median ii)
11.2
months, iii)
14.1
months
median i) 10.3
months
i) vs ii)
HR
0.908,
p=0.16;
i) vs iii)
HR 0.717
p<0.001
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
65
Appendix I
Adverse events reported in trials investigating different chemotherapy
regimens (research question 1)
Adverse events that were reported to be different between treatment arms are included in the Table, adverse events which were not
significantly different between treatment arms are not reported here.
Study
Intervention
Comparator
Adverse events
Worse on intervention
Worse on comparator
Granulocytopenia (SS), Anaemia (SS),
Neutropenia (SS), Febrile neutropenia (SS),
Thrombocytopenia (SS), Infections (SS),
Nausea and vomiting (SS), Stomatitis (SS),
Days on IV antibiotics (SS), RBC transfusions
(SS), G-CSF
Granulocytopenia (SS), Anaemia (SS),
Neutropenia (SS), Febrile Neutropenia (SS),
Thrombocytopenia (SS), Fatigue, Days on
IV antibiotics (SS), RBC transfusions (SS), GCSF (SS)
“There was increased hematologic toxicity
in the triplet regimens and increased
thrombocytopenia in both arms with
gemcitabine. Neuropathy was decreased
in the doublet regimens, which included
only four cycles of paclitaxel. Transient
elevations of transaminases were more
commonly observed in arms with
gemcitabine, but they were generally
without clinical impact. There was no
significant increase in pulmonary toxicity
Pain (other) (SS)
Phase III trials
OVAR 5, du Bois
200617
Epirubicin +
carboplatin +
paclitaxel
Carboplatin +
paclitaxel
OVAR 9, du Bois
201018
Gemcitabine +
carboplatin +
paclitaxel
Carboplatin +
paclitaxel
GOG 182 / ICON 5,
Bookman 200919
i) Gemcitabine +
carboplatin +
paclitaxel
ii) Doxorubicin +
carboplatin +
paclitaxel
iii) Topotecan +
carboplatin →
carboplatin +
paclitaxel
iv) Gemcitabine +
Carboplatin +
paclitaxel
Renal toxicity
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
66
Study
Bolis 201020
Intervention
carboplatin →
carboplatin +
paclitaxel
Topotecan +
carboplatin +
paclitaxel
Comparator
Adverse events
Worse on intervention
Worse on comparator
associated with gemcitabine.”
Carboplatin +
paclitaxel
OVAR 7, Pfisterer
200621
Carboplatin +
paclitaxel →
topotecan
Carboplatin +
paclitaxel
OV 16, Hoskins
200822 (abstract
only)
HeCOG,
Aravantinos 200823
Cisplatin + topotecan x
4 cycles → paclitaxel +
carboplatin x 4 cycles
Cisplatin + doxorubicin
+ paclitaxel
Carboplatin +
paclitaxel x 8 cycles
Higher percentage experienced ≥1 life
threatening adverse event (SNR),
Leukopenia (SS), Anaemia (SS),
Neutropenia (SS), Fatigue (BS), RBC
transfusions (SS), G-CSF (SS)
Leukopenia (SS), Anaemia (SS),
Neutropenia (SS), Thrombocytopenia (SS),
Allergic reaction (SS), Infections (SS),
Arrhythmia (SS), Constipation (SS), Days on
IV antibiotics (SS), RBC transfusions (SS), GCSF (SS)
Febrile neutropenia (SNR), Hospitalisations
(SNR)
Carboplatin +
paclitaxel
Deaths from treatment slightly higher (SNR)
Febrile neutropenia (SS)
Lhomme 200824
Paclitaxel +
carboplatin +
valspodar (PSC 833)
Carboplatin +
paclitaxel
GOCCNE, Nicoletto
2007 25
SGCTG, Reed 200615
Cisplatin +
cyclophosphamide
Treosulfan
Adriamycin +
cyclophosphamide
Carboplatin
Grade 3 or 4 adverse events (SS); serious
adverse events (SS), Neurotoxicity (SNR),
Grade 4 neutropenia (SS), Febrile
neutropenia (SS), Grade 4
thrombocytopenia (SS),
Hyperbilirubinemia (SNR), Ataxia (SS),
Gastrointestinal toxicity
Toxicity not reported
MITO 2, Pignata
201126
Carboplatin +
doxorubicin
Carboplatin +
paclitaxel
Anaemia (SS), Thrombocytopenia (SS),
Cardiotoxicity (NS), Skin toxicity (SS),
Neutropenia
Anaemia (SS), Neutropenia
(SS)
Neurotoxicity (SS),
Neutropenia (NS),
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
67
Study
Intervention
Comparator
Adverse events
Worse on intervention
Stomatitis (any grade: SS, severe: NS)
RBC transfusions (SS)
Allergic reaction (SS), Neutropenia (SS),
Febrile neutropenia (SS), Nausea (SS),
Diarrhoea (SS), Stomatitis (SS)
Leukopenia (SS), Gastrointestinal, renal
and metabolic toxicity
Neuropathy (SS), Nausea and vomiting
(SS)
SCOTROC, Vasey
200427
Docetaxel +
carboplatin
Carboplatin +
paclitaxel
GOG 158, Ozols
200328
OVAR 3, du Bois
2003, Greimel
200629,30
Cisplatin + paclitaxel
Carboplatin +
paclitaxel
Carboplatin +
paclitaxel
HeCOG,
Aravantinos 200531
Mouratidou 200732
Paclitaxel +
carboplatin ↔ cisplatin
Cisplatin + paclitaxel
Carboplatin +
paclitaxel
Cisplatin +
cyclophosphamide
OV10, Piccart 2003,
Bezjak 2004, Butler
200433-35
AOCSG, Dittrich
200336
Cisplatin + paclitaxel
Cisplatin +
cyclophosphamide
Cisplatin + carboplatin
Cisplatin +
cyclophosphamide
Granulocytopenia (SS), Anaemia (SS),
Thrombocytopenia (SS), Nausea and
vomiting (SS), Ototoxicity (SS)
Carboplatin +
thalidomide
Carboplatin →
docetaxel +
gemcitabine
Carboplatin →
docetaxel + irinotecan
Carboplatin
Constipation (SNR), Dizziness (SNR), Fatigue
(SNR), Neurotoxicity (SNR)
Anaemia (SS), Thrombocytopenia (SS),
Dyspnoea (SS)
Cisplatin + paclitaxel
Nausea and vomiting (SS)
Neurotoxicity (SNR); Neutropenia (SS),
Thrombocytopenia (NS), Alopecia (SS),
Myalgia (SS),
Toxicity not reported
Worse on comparator
Alopecia (SS), Diarrhoea
(any grade: SS, severe: NS)
Neurotoxicity (SS),
Alopecia (SS), Myalgia (SS)
Thrombocytopenia (SS)
Leukopenia (SS),
Neutropenia (SS), Febrile
neutropenia (SS),
Thrombocytopenia (SS),
Infections (SS), RBC
transfusions (SS), G-CSF
Deaths from treatment
slightly higher (SNR)
Nausea and vomiting (NS)
Phase II trials
Muthuramalingam
201137
SCOTROC2A, Vasey
200638
SCOTROC2B, Clamp
200639
Carboplatin →
docetaxel
Carboplatin →
docetaxel
Alopecia (SNR), Diarrhoea (SNR)
Neutropenia (SS), Alopecia
(SS)
Neurotoxicity (SNR),
Neutropenia (SNR), Febrile
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
68
Study
Intervention
Comparator
Adverse events
Worse on intervention
Minagawa 200640
Docetaxel + cisplatin
Mori 200741
Docetaxel +
carboplatin
Irinotecan + cisplatin
JGOG3014,
Takakura 201016
Fruscio 200842
Cisplatin + paclitaxel +
isosfamide
Carboplatin +
docetaxel
Carboplatin +
paclitaxel
Carboplatin +
paclitaxel
Cisplatin + paclitaxel
+ epirubicin
Worse on comparator
neutropenia (SNR)
Grade 4 neutropenia (SS),
Diarrhoea (SS), G-CSF (SS)
No significant differences reported
Gastrointestinal toxicities (NS)
Neurotoxicity (SS),
Thrombocytopenia (SS)
Leukopenia (SS), Anaemia (SS), Grade 3
febrile neutropenia (SS), Fever (SS),
Hospitalisations (SS), Transfusions (SS)
BS=borderline significance (p=0.05); G-CSF= ; NS=not significant; RBC=red blood cell; SNR=significance not reported; SS=statistically significant
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
69
Appendix J
Study
Adverse events reported in trials investigating biological therapies
Intervention
Comparator
Adverse events
Worse on intervention
Worse
on
comparator
Phase III trials
OVAR 11 /
ICON 7,
Perren 201143
GOG 218,
Burger 201145
Bevacizumab + carboplatin
+ paclitaxel
Carboplatin +
paclitaxel
Overall toxicity higher (SNR), Deaths from treatment slightly
higher (SNR), Hypertension higher (SNR)
i) Bevacizumab +
carboplatin + paclitaxel
ii) Bevacizumab +
carboplatin + paclitaxel →
bevacizumab
Carboplatin +
paclitaxel
Hypertension (SS), Deaths from treatment slightly higher,
particularly in intervention group (ii) (SNR)
“hypertension, proteinuria and pain were more commonly
reported in the extended therapy phase among patients in
the bevacizumab throughout group (iii).”
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
70
Appendix K
ASCO clinical practice guideline recommendations for chemotherapy dosing
for obese adults with cancer76
Clinical Question
1. Is there evidence that full weight–based
dosing increases toxicity in obese patients
with cancer?
2. Is there evidence that less than full
weight–based dosing compromises
efficacy in obese patients with cancer?
3. If an obese patient experiences
highgrade
toxicity, should chemotherapy
doses or schedules be modified
differently from modifications used for
non-obese patients with cancer?
4. Is the use of fixed-dose (dose prescribed
independently of weight or BSA) cytotoxic
chemotherapy ever justified? Are there
unique dosing considerations for certain
chemotherapeutic agents?
5. How should BSA be calculated?
Specifically, what is the best formula for
use with the obese patient with cancer?
6. What is the role of pharmacokinetic and/
or phamacogenetic factors when
determining optimal chemotherapy dose
and delivery (bolus, infusional, therapeutic
drug monitoring) for obese patients
with cancer?
Recommendation
Recommendation 1.1: The Panel recommends that actual body weight be used when selecting cytotoxic chemotherapy doses regardless of obesity
status. There is no evidence that short- or long-term toxicity is increased among obese patients receiving full weight–based chemotherapy doses. Most
data indicate that myelosuppression is the same or less pronounced among the obese than the non-obese administered full weight–based doses.
Recommendation 1.2: The Panel recommends full weight–based chemotherapy dosing for morbidly obese patients with cancer, subject to appropriate
consideration of other comorbid conditions. Data are extremely limited regarding optimal dose selection among the morbidly obese and other special
subgroups. More studies are needed to evaluate optimal agents and agent combinations for obese and morbidly obese patients with cancer; however,
based on available information, it seems likely that the same principles regarding dose selection for obese patients apply to the morbidly obese.
Recommendation 2.1: The Panel recommends that full weight–based chemotherapy doses (IV and oral) be used in the treatment of the obese patient
with cancer, particularly when the goal of treatment is cure. Selecting reduced doses in this setting may result in poorer disease-free and overall survival
rates. There are compelling data in patients with breast cancer that reduced dose-intensity chemotherapy is associated with increased disease
recurrence and mortality. Although data in other malignancies are more limited, based on improved survival observed with chemotherapy compared
with controls, a dose-response relationship exists for many responsive malignancies. Therefore, although data are not available to address this question for
all cancer types, in the absence of data demonstrating sustained efficacy for reduced dose chemotherapy, the Panel believes that the prudent
approach is to provide full weight–based hemotherapy dosing to obese patients with cancer, especially those receiving treatment with curative intent.
Most of the data in support of full weight–based dosing come from the treatment of early-stage disease. Data supporting the use of full weight– based
doses in the advanced disease setting are limited.
Recommendation 3.1: Clinicians should follow the same guidelines for dose reduction, regardless of obesity status, for all patients, depending on the type
and severity of toxicity, any comorbid conditions, and whether the treatment intention is cure or palliation. There is no evidence to support the need for
greater dose reductions for obese patients compared with non-obese patients. If a dose reduction is employed in response to toxicity, consideration
should be given to the resumption of full weight–based doses for subsequent cycles, especially if a possible cause of toxicity (eg, impaired renal, hepatic
function) has been resolved. The Panel recognizes the need for clinicians to exercise judgment when providing care for patients who have experienced
grade 3 or 4 chemotherapy toxicity. The presence of obesity alone should not alter such clinical judgment.
Recommendation 4.1: The Panel recommends consideration of fixed dosing only with select cytotoxic agents (eg, carboplatin and bleomycin). On the
basis primarily of neurotoxicity concerns, vincristine is capped at a maximum dose of 2.0 mg when used as part of the CHOP and CVP regimens. Several
other cytotoxic chemotherapeutic agents have been used in clinical trials at a fixed dose independent of patient weight or BSA. However, it is not clear
that fixed dosing is optimal for any of these other agents.
Recommendation 5.1: The Panel recommends that BSA be calculated using any of the standard formulae. There is no evidence to support one formula
for calculating BSA over another.
Recommendation 6.1: The Panel recommends further research into the role of pharmacokinetic and pharmacogenetic information for guiding the
dosing of IV and oral chemotherapeutic agents for adult patients with cancer who are obese. It should be emphasized that there is a paucity of
information on the influence of obesity on the pharmacokinetics of most anticancer drugs from properly powered trials. This is the result, inpart, of empiric
eligibility restrictions from the outset in clinical trials and a lack of pharmacokinetic analyses performed and published for this subpopulation. Overall, there
are insufficient pharmacokinetic data to reject the recommendation to use a full weight–based dosing strategy for chemotherapeutic agents in patients
with cancer who are obese, regardless of route of administration and/or infusion time.
Abbreviations: BSA, body surface area; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CVP, cyclophosphamide, vincristine, prednisone; IV, intravenous.
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
71
Appendix L
Ongoing trials
Research question 1
Trial name and
location
Study
design
Participants
Intervention
Control
Completion
status
NCT00838656
Phase 2
RCT,
openlabel
Stage IIIC or stage IV ovarian
cancer, fallopian tube cancer,
or primary peritoneal cancer
Neoadjuvant Carboplatin
surgery adjuvant Paclitaxel
and Gemcitabine
Neoadjuvant
Gemcitabine and
Carboplatin surgery
adjuvant Paclitaxel
Unknown
Phase 2
RCT,
doubleblind
Advanced ovarian cancer
ZD4054, Paclitaxel, Carboplatin
Placebo, Paclitaxel,
Carboplatin
Completed
Phase 2
RCT,
doubleblind
Adenocarcinoma of the ovary,
the fallopian tube, or serous
adenocarcinoma of the
peritoneum
Neo-adjuvant chemotherapy
(Carboplatin and Paclitaxel),
interval debulking surgery,
Vargatef® (Nintedanib)
Neo-adjuvant
chemotherapy
(Carboplatin and
Paclitaxel), interval
debulking surgery
Ongoing
UK
NCT00929162
Italy and
Germany
NCT01583322
France
n=88
n=120
n=188
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
72
Trial name and
location
Study
design
Participants
Intervention
Control
Completion
status
NCT00452985
Phase 2
RCT,
openlabel
Advanced or metastatic
ovarian cancer
Docetaxel, Cisplatin,
Cyclophosphamide
Docetaxel, Carboplatin
Completed
Carboplatin, Paclitaxel,
Placebo
Ongoing
Carboplatin, Paclitaxel
Completed
Bangladesh
n=30
NCT00391118
US, Belgium,
Germany
NCT00610714
International
NCT01081262
UK
Phase 2
RCT,
doubleblind
Advanced ovarian cancer,
fallopian tube neoplasms,
peritoneal neoplasm
Carboplatin, Paclitaxel,
n=149
1125 (LY317615)
Phase 2
RCT,
doubleblind
Advanced ovarian cancer
Carboplatin, Paclitaxel,
n=211
AZD0530
Phase 3
RCT,
openlabel
Stage II, stage III, stage IV, or
recurrent stage I epithelial
ovarian cancer or fallopian
tube cancer
Oxaliplatin and Capecitabine
+/- Bevacizumab
Carboplatin and
Paclitaxel +/Bevacizumab
Ongoing
Carboplatin, Paclitaxel, SCH
58500
Carboplatin, Paclitaxel
Completed
Enzastaurin
n=332
NCT00003880
USA
Phases 2/3
RCT
Stage III ovarian and primary
peritoneal cancers
n= 360
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
73
Trial name and
location
Study
design
Participants
Intervention
Control
Completion
status
ISRCTN52615671
Phase 3
RCT
Clear cell carcinoma of the
ovary
Irinotecan, Cisplatin
Paclitaxel, Carboplatin
Completed
Carboplatin, Paclitaxel, BIBF
1120
Carboplatin, Paclitaxel,
placebo
Ongoing
Docetaxel, Carboplatin,
Docetaxel, Carboplatin
Ongoing
Cisplatin, Topotecan, Paclitaxel,
Carboplatin
Cisplatin, Topotecan
Completed
Paclitaxel, Carboplatin,
Lonafarnib
Paclitaxel, Carboplatin
Completed
International
n=652
EUCTR2008006831-10
International
NTR1491
The Netherlands
Phase 3
RCT,
doubleblind
Advanced ovarian cancer,
fallopian tube cancer, or
primary peritoneal cancer
Phase 2
RCT,
Epithelial ovarian, fallopian
tube, or primary peritoneal
carcinomas
openlabel
NCT00005051
US
ISRCTN51315091
Germany
Phase 2
RCT
n=1300
Celecoxib
n=200
Advanced ovarian epithelial
cancer
n=30
Phase 2
RCT,
openlabel
Extra-ovarian papillary serous
tumors
n=100
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
74
Trial name and
location
Study
design
Participants
Intervention
Control
Completion
status
ISRCTN83438782
Phase 3
RCT,
openlabel
Mucinous carcinoma of the
ovary
Oxaliplatin and Capecitabine
+/- Bevacizumab
Carboplatin and
Paclitaxel +/Bevacizumab
Ongoing
Trial name and
location
Study
design
Participants
Intervention
Control
Completion
status
NCT00660842
Phase 3
RCT,
openlabel
Ovarian cancer
Weekly Carboplatin and
Paclitaxel
Every 3 weekly
Carboplatin and
Paclitaxel
Ongoing
Phase 3
RCT,
openlabel
Epithelial ovarian, fallopian
tube or peritoneal cancer
Bevacizumab continuously for
up to 15 months and
Carboplatin and Paclitaxel
Bevacizumab
continuously for up to 30
months and Carboplatin
and Paclitaxel
Ongoing
Phase 2
RCT,
openlabel
Epithelial ovarian cancer
International
n=330
Research question 2
Italy
NCT01462890
Germany
NCT00239980
Canada
n=800
n=800
One of 3 doses of a LMWH
Dalteparin (Fragmin: 50, 100,
and 150 IU/kg) in conjunction
with standard adjuvant taxaneand platinum-based
chemotherapy
Completed
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
75
Trial name and
location
Study
design
Participants
Intervention
Control
Completion
status
NCT00098878
Phase 3
RCT
Fallopian tube cancer, ovarian
cancer, peritoneal cavity
cancer
Intra-patient dose-escalated
Carboplatin on day 1
Flat dose of Carboplatin
on day 1
Unknown
Phase 3
RCT
Stage III or stage IV ovarian
cancer of primary peritoneal
cavity cancer (residual disease
after surgery)
Paclitaxel continuously over 96
hours Cisplatin over 2 hours
Paclitaxel continuously
over 24 hours Cisplatin
over 2 hours
Completed
Dose-fractionated CarboplatinPaclitaxel
Standard CarboplatinPaclitaxel
Ongoing
International
NCT00002717
US
n=324
EUCTR2010022209-16
International
Phase 3
RCT,
openlabel
High risk early stage (FIGO
stage IC/IIA, grade 3 or clear
cell histology only) or
advanced stage (FIGO stage
IIB-IV, all grades and all
histological types) epithelial
ovarian, fallopian tube, or
primary peritoneal carcinoma
n=1485
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
76
Research question 3
Trial name and
location
Study
design
Participants
Intervention
Control
Completion
status
NCT00993655
Phases 2/3
RCT,
openlabel
Stage IIB, stage IIC, stage III, or
stage IV ovarian epithelial
cancer, primary peritoneal
cancer, or fallopian tube
cancer
Intraperitoneal and intravenous
Intravenous Carboplatin
and Paclitaxel
Ongoing
Canada
chemotherapy
n=830
Phases 2/3
RCT,
singleblind
NCT01091636
Korea
Epithelial ovarian cancer
n=168
Intraoperative hyperthermic
intraperitoneal chemotherapy
followed by intravenous
chemotherapy
Ongoing
Research question 4
Trial name
and
location
Study
design
Participants
Intervention
Control
Completion
status
NCT007152
86
Phase
3
RCT, openlabel
Advanced epithelial ovarian
carcinoma
Neoadjuvant
chemotherapy
followed by interval debulking
surgery
Upfront surgery followed by
chemotherapy
Unknown
India
n=180
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
77
Research questions 1 and 3
Trial name
and
location
Study
design
Participants
Intervention
Control
Completion
status
NCT009514
96
Phase 3
RCT, openlabel
Fallopian tube cancer, ovarian
cancer, primary peritoneal
cavity cancer
Bevacizumab and
intraperitoneal chemotherapy
Bevacizumab with intravenous
chemotherapy
Ongoing
US
n=1500
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
78
Abbreviations
AUC
Area Under The Curve
ACN
Australian Cancer Network
ASCO
American Society Of Clinical Oncology
ANZCTR
Australian New Zealand Clinical Trials Registry
BMI
Body Mass Index
BRCA
Breast Cancer
BSA
Body Surface Area
CI
Confidence Interval
ESGO
European Society Of Gynaecological Oncology
FINOVA
Finnish Ovarian Cancer Study
GFR
Glomerular Filtration Rate
GIN
Guidelines International Network
GOG
Gynecologic Oncology Group
HeCOG
Hellenic Co-Operative Oncology Group
HDCT
High-Dose Chemotherapy
HIDOC-EIS
High-Dose Ovarian Cancer-European Intergroup Study
HR
Hazard Ratio
IGCS
International Gynecologic Cancer Society
IP
Intraperitoneal
IV
Intravenous
NBOCC
National Breast And Ovarian Cancer Centre
NBCC
National Breast Cancer Centre
NHMRC
National Health And Medical Research Council
ORR
Overall Response Rate
OS
Overall Survival
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
79
PFS
Progression-Free Survival
QoL
Quality Of Life
QIMR
Queensland Institute Of Medical Research
RCT
Randomised Controlled Trial
RR
Relative Risk
SGCTG
Scottish Gynaecological Clinical Trials Group
SS
Statistically Significant
First-line chemotherapy for women with epithelial ovarian cancer-a systematic review
80
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3. Australian Cancer Network & National Breast Cancer Centre. Clinical practice guidelines
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