First-line chemotherapy for women with epithelial ovarian cancer

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 i 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 Tel: +61 2 9357 9400 Fax: +61 2 9357 9477 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.

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First-line chemotherapy for women with epithelial ovarian cancer-a systematic review ii 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 iii 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 .

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First-line chemotherapy for women with epithelial ovarian cancer-a systematic review iv 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 v 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) † 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 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. * 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 vi 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 vii 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 viii 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)

First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 1 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 2 • 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 • 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.

) given every three weeks.

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 3 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 4 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 5 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 6 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 7 • 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 8 • 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 9 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 10 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 Number of participants (studies) Quality of evidence Overall 5-year survival HR 0.71 (0.53 to 0.93) p=0.01 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 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 11 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 Number of participants (studies) Quality of evidence Progression-free 5-yr survival HR 0.67 (0.53 to 0.84) p=0.0005 1170 women (four studies) • High quality • Homogeneous data Progression-free 5-yr survival: sub- optimal 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 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 12 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 13 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 14 • 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 + paclitaxel Carboplatin + paclitaxel Addition OVAR 9, du Bois 201018 Gemcitabine + carboplatin + paclitaxel Carboplatin + paclitaxel Addition GOG 182 / ICON 5, Bookman 200919 i) Gemcitabine + carboplatin + paclitaxel ii) Doxorubicin + carboplatin + paclitaxel iii) Topotecan + carboplatin → carboplatin + paclitaxel iv) Gemcitabine + carboplatin → carboplatin + paclitaxel Carboplatin + paclitaxel Addition Bolis 201020 Topotecan + carboplatin + paclitaxel Carboplatin + paclitaxel Addition OVAR 7, Pfisterer 200621 Carboplatin + paclitaxel → topotecan Carboplatin + paclitaxel Addition OV 16, Hoskins 200822 (abstract only) Cisplatin + topotecan x 4 cycles → paclitaxel + carboplatin x 4 cycles Carboplatin + paclitaxel x 8 cycles Addition Substitution HeCOG, Aravantinos 200823 Cisplatin + doxorubicin + paclitaxel Carboplatin + paclitaxel Substitution Addition Lhomme 200824 Paclitaxel + carboplatin + valspodar (PSC 833) Carboplatin + paclitaxel Addition Trials which substituted the use of one chemotherapy agent with another chemotherapy agent GOCCNE, Nicoletto 2007 25 Cisplatin + cyclophosphamide Adriamycin + cyclophosphamide Substitution SGCTG, Reed 200615 Treosulfan Carboplatin Substitution MITO 2, Pignata 201126 Carboplatin + doxorubicin Carboplatin + paclitaxel Substitution SCOTROC, Vasey 200427 Docetaxel + carboplatin Carboplatin + paclitaxel Substitution GOG 158, Ozols 200328 Cisplatin + paclitaxel Carboplatin + paclitaxel Substitution OVAR 3, du Bois 2003, Greimel 200629,30 Cisplatin + paclitaxel Carboplatin + paclitaxel Substitution

First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 15 Study Intervention Comparator Type of comparison HeCOG, Aravantinos 200531 Paclitaxel + carboplatin ↔ cisplatin Carboplatin + paclitaxel Substitution Mouratidou 200732 Cisplatin + paclitaxel Cisplatin + cyclophosphamide Substitution OV10, Piccart 2003, Bezjak 2004, Butler 200433-35 Cisplatin + paclitaxel Cisplatin + cyclophosphamide Substitution AOCSG, Dittrich 200336 Cisplatin + carboplatin Cisplatin + cyclophosphamide Substitution Phase II trials Trials which investigated the addition of agents to standard chemotherapy Muthuramalingam 201137 Carboplatin + thalidomide Carboplatin Addition SCOTROC2A, Vasey 200638 Carboplatin → docetaxel + gemcitabine Carboplatin → docetaxel Addition SCOTROC2B, Clamp 200639 Carboplatin → docetaxel + irinotecan Carboplatin → docetaxel Addition Trials which substituted the use of one chemotherapy agent with another chemotherapy agent Minagawa 200640 Docetaxel + cisplatin Carboplatin + docetaxel Substitution Mori 200741 Docetaxel + carboplatin Carboplatin + paclitaxel Substitution JGOG3014, Takakura 201016 Irinotecan + cisplatin Carboplatin + paclitaxel Substitution Fruscio 200842 Cisplatin + paclitaxel + isosfamide Cisplatin + paclitaxel + epirubicin Substitution 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).

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