First-line chemotherapy for women with epithelial ovarian cancer

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
produced by:

Cancer Australia
Locked Bag 3 Strawberry Hills NSW 2012 Australia
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Website: www.canceraustralia.gov.au

© 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          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

2          Methods .....................................................................................................................................4

           2.1         Inclusion criteria ............................................................................................................... 4
           2.2         Literature search ............................................................................................................. 5
           2.3         Data extraction ............................................................................................................... 7
           2.4         Quality assessment.......................................................................................................... 7

3          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.

      −2011, National Breast and Ovarian Cancer Centre (NBOCC) † and the
In 2009
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 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.

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)
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 –              including     intraperitoneal      therapy,     dose
        intense/dose dense, stem cell support

    •   Monitoring and duration

    •   Maintenance chemotherapy


                    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/m2) 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 carboplatin-
paclitaxel:

   •   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     Inclusion criteria

2.1.1      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, anti-
angiogenesis 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:

   •    overall survival
   •    disease/progression-free survival
   •    treatment compliance
   •    response to chemotherapy (clinical/pathological)
   •    adverse events
   •    quality of life.


2.1.4      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:

   •    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.



2.2     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 meta-
analyses 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%          Number of             Quality of evidence
                    CI)                        participants
                    Chemotherapy vs.           (studies)
                    observation
Overall 5-year      HR 0.71 (0.53 to 0.93)     1006 women                 •   High quality
survival            p=0.01                     (three studies)            •   Homogeneous data

Overall 5-yr        HR 0.63 (0.46 to 0.85      772 women                  •   High quality
survival:           p=0.003)                   (two studies)              •   Homogeneous data
sub-optimal
staging*

Overall 5-yr        HR 1.22 (0.63 to 2.37)     234 women                  •   Moderate quality; small
survival: optimal   p=0.56                     (two studies)                  subgroup size
staging*

Overall 10-yr       HR 0.74 (0.58 to 0.95)     925 women                  •   High quality
survival            p=0.02                     (two studies)              •   Homogeneous data

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%           Number of            Quality of evidence
                       CI)                         participants
                       Chemotherapy vs.            (studies)
                       observation
Progression-free       HR 0.67 (0.53 to 0.84)      1170 women               •    High quality
5-yr survival          p=0.0005                    (four studies)           •    Homogeneous data

Progression-free       HR 0.64 (0.50 to 0.82)      934 women                 •   High quality
5-yr survival: sub-    p=0.0004                    (three studies)           •   Homogeneous data
optimal
staging*

Progression-free       HR 0.67 (0.36 to 1.22)      234 women                •    Moderate quality; small
5-yr survival:         p=0.19                      (two studies)                 subgroup size
optimal staging*

Progression-free       HR 0.67 (0.54 to 0.84)      925 women                •    High quality
10-yr survival         p=0.0005                    (two studies)            •    Homogeneous data

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                    Type of
                                                                                              comparison
HeCOG, Aravantinos         Paclitaxel + carboplatin ↔           Carboplatin +                 Substitution
200531                     cisplatin                            paclitaxel
Mouratidou 200732          Cisplatin + paclitaxel               Cisplatin +                   Substitution
                                                                cyclophosphamide
OV10, Piccart 2003,        Cisplatin + paclitaxel               Cisplatin +                   Substitution
Bezjak 2004, Butler                                             cyclophosphamide
200433-35
AOCSG, Dittrich 200336     Cisplatin + carboplatin              Cisplatin +                   Substitution
                                                                cyclophosphamide
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
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
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