First-line chemotherapy for women with epithelial ovarian cancer

Transcription

1 First-line chemotherapy for women with epithelial ovarian cancer A systematic review July 2013

2 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: Fax: Website: Cancer Australia (2013) Online ISBN: Recommended citation Cancer Australia. First line chemotherapy for women with epithelial ovarian cancer: a systematic review. Cancer Australia, Surry Hills, NSW, Copyright statements: Internet sites This work is copyright. You may download, display, print and reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given the specific written permission from Cancer Australia to do so. Requests and inquiries concerning reproduction and rights are to be sent to the Publications and Copyright contact officer, Cancer Australia, Locked Bag 3, Strawberry Hills, NSW 2012 Copies of First line chemotherapy for women with epithelial ovarian cancer: a systematic review can be downloaded from the Cancer Australia website: First-line chemotherapy for women with epithelial ovarian cancer-a systematic review i

3 Contents Acknowledgments... iv Executive summary...v 1 Background Ovarian cancer in Australia Use of chemotherapy for the treatment of ovarian cancer Australian clinical practice guidelines Methods Inclusion criteria Literature search Data extraction Quality assessment Results International guidelines & recommendations Research questions Other issues Ongoing trials Discussion 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

4 Appendix K ASCO clinical practice guideline recommendations for chemotherapy dosing for obese adults with cancer Appendix L Ongoing trials...72 Abbreviations...79 References...81 Tables Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Adjuvant chemotherapy following surgery compared with observation following surgery for early stage ovarian cancer: overall survival Adjuvant chemotherapy following surgery compared with observation following surgery for early stage ovarian cancer: progression free survival Chemotherapy regimens investigated for first line adjuvant treatment of ovarian cancer Chemotherapy schedules investigated for first line adjuvant treatment of ovarian cancer Additional chemotherapy regimens and schedules investigated for first line adjuvant treatment of ovarian cancer Study characteristics of studies reporting the outcomes of chemotherapy in obese patients Table 7 Study characteristics of studies reporting adverse event outcomes only Table 8 Chemotherapy characteristics of Suh Table 9 Cumulative grade 3 and 4 toxicity based on BMI in Wright et al Table 10 Treatment modifications based on BMI in Wright et al First-line chemotherapy for women with epithelial ovarian cancer-a systematic review iii

5 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

6 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 to 43.3% in 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 The recommendations for treatment with chemotherapy include 3 : 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 (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 , 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 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

7 supplementary search was conducted to identify articles on subsets of the defined population that have specific chemotherapy requirements; this search was not limited to RCTs and included additional search terms related to the subpopulations. In October 2012 the multidisciplinary working group re-prioritised the other issue of obese patients to be a research question. A systematic search was undertaken in November 2012 to identify evidence for the new research question What are the specific chemotherapy requirements for women with epithelial ovarian cancer who are obese? Overall 75 articles and two conference abstracts were included in the systematic review. Of the included citations, 35 were phase III randomised controlled trials (RCTs) addressing the primary research questions, 10 were non-randomised controlled trials included in the subgroup question and six were Cochrane reviews used as primary references. Summary of results Chemotherapy regimens for first line adjuvant treatment of epithelial ovarian cancer Five systematic reviews were identified which investigated various chemotherapy regimens for epithelial ovarian cancer. One of these reviews included only patients with early stage ovarian cancer (stage I-IIa). Some sub-group analyses were performed for surgical staging and histological subtype. This Cochrane review found that overall and progression-free survival was improved in early stage ovarian cancer patients who had chemotherapy compared with those on observation. Subgroup analysis suggested that women who had optimal surgical staging of their disease were unlikely to benefit from adjuvant chemotherapy, whereas those who had sub-optimal staging did. The remaining reviews included ovarian cancer patients of all stages, however provided little to no information on chemotherapy in the first line setting. Eighteen phase III and seven phase II randomised controlled trials were identified which investigated different chemotherapy regimens in populations with a majority of advanced stage ovarian cancer patients. While a range of regimens have been investigated, including addition of chemotherapy agents to standard regimens or substitution of different agents, almost all failed to demonstrate an overall or progressionfree survival benefit compared with standard chemotherapy (most often platinum/taxane combination). Trials which did show survival differences were either in specific patient populations or compared older chemotherapy regimens no longer considered standard. Biological therapies for first line adjuvant treatment of epithelial ovarian cancer Two randomised controlled trials have shown improved progression-free survival for the biological therapy bevacizumab used in addition to carboplatin and. 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

8 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 compared with standard and reported improved overall survival and progression-free survival in the dose-dense 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

9 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 2m 2 and BMI >30kg/m 2 to be predictors of reduced planned relative dose intensity (RDI) <85% and reduced delivered RDI <85%. In both univariate analysis and multivariate analysis, delivered RDI <85% was negatively associated with overall survival. Adverse events reported and any differences between BMI groups varied between studies. First-line chemotherapy for women with epithelial ovarian cancer-a systematic review viii

10 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 to 43.3% in 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 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 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, 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

11 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 (175 mg/m 2 ) given every three weeks. In patients unsuitable for combination therapy (on the basis of either concurrent medical conditions, performance status or by patient preference) single agent carboplatin is an effective and acceptable treatment for advanced ovarian cancer. Intraperitoneal chemotherapy Although intraperitoneal chemotherapy is not recommended as standard therapy its use may be considered on an individual patient basis at a designated cancer centre. High-dose chemotherapy with stem cell support The use of chemotherapy protocols utilising high dose therapy should only be offered as part of an appropriately designed clinical trial. In , 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 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

12 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: 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- 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

13 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 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 Intervention/Comparison For question 1): various chemotherapy regimens (including platinum agents, taxanes, antiangiogenesis inhibitors) in comparison with either a placebo or other chemotherapeutic agent. For question 2): different schedules or doses of the same chemotherapy regimens (including dose-dense chemotherapy). For question 3): different modes of administration of the same chemotherapy regimens (including intravenous, intraperitoneal, oral administration). First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 4

14 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 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 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

15 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 The search was limited to articles published between January 2003 and November The search was not limited to RCTs 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

16 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

17 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

18 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 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 The review defined early stage as FIGO stage I/IIa and included trials which compared chemotherapy following surgery to observation following surgery. The review includes five RCTs which enrolled a total of 1277 women. The chemotherapy regimen in four trials was cisplatin-based chemotherapy, one trial used melphalan. Four trials were included in metaanalyses and considered at low risk of bias. Some sub-group analyses were performed for surgical staging and histological subtype. The review noted that only two trials, ACTION and ICON1, were designed to have the power to detect treatment effect. Randomised controlled trials Two randomised controlled trials on adjuvant chemotherapy for early stage ovarian cancer were identified in the Cancer Australia literature search (ACTION and ICON1). 9,10 However, both were included in the Cochrane systematic review, and therefore are not reported in any further detail. Outcomes Overall survival The Cochrane review on adjuvant chemotherapy for early stage ovarian cancer reported that chemotherapy was associated with improved overall survival (OS) compared with observation. 8 Meta-analysis of five-year data from three trials and of ten-year data from two trials indicated that women who received adjuvant platinum-based chemotherapy had better overall survival (OS) than those who did not (Table 1). Subgroup analysis suggested First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 9

19 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 Overall 5-year survival HR 0.71 (0.53 to 0.93) p=0.01 Number of participants (studies) 1006 women (three studies) Quality of evidence 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= women (two studies) Moderate quality; small subgroup size Overall 10-yr survival HR 0.74 (0.58 to 0.95) p= 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= 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

20 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 Progression-free 5-yr survival HR 0.67 (0.53 to 0.84) p= Number of participants (studies) 1170 women (four studies) Quality of evidence High quality Homogeneous data Progression-free 5-yr survival: suboptimal staging* HR 0.64 (0.50 to 0.82) p= women (three studies) High quality Homogeneous data Progression-free 5-yr survival: optimal staging* HR 0.67 (0.36 to 1.22) p= women (two studies) Moderate quality; small subgroup size Progression-free 10-yr survival HR 0.67 (0.54 to 0.84) p= 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= First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 11

21 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 cancer 11 Topotecan for ovarian cancer 12 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 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 First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 12

22 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 (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 (OVAR7; GOG182/ICON5; Bolis 2010; OV16) First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 13

23 The addition of doxorubicin to platinum and (HeCOG/Aravantinos 2008; GOG182/ICON5) Comparing 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 Epirubicin + carboplatin + OVAR 9, du Bois Gemcitabine + carboplatin + GOG 182 / ICON 5, i) Gemcitabine + Bookman carboplatin + ii) Doxorubicin + carboplatin + iii) Topotecan + carboplatin carboplatin + iv) Gemcitabine + carboplatin carboplatin + Bolis Topotecan + carboplatin + OVAR 7, Pfisterer Carboplatin + topotecan OV 16, Hoskins (abstract only) Cisplatin + topotecan x 4 cycles + carboplatin x 4 cycles Cisplatin + doxorubicin + Carboplatin + Carboplatin + Carboplatin + Carboplatin + Carboplatin + Carboplatin + x 8 cycles Addition Addition Addition Addition Addition Addition Substitution HeCOG, Aravantinos Carboplatin + Substitution Addition Lhomme Paclitaxel + carboplatin + Carboplatin + Addition valspodar (PSC 833) Trials which substituted the use of one chemotherapy agent with another chemotherapy agent GOCCNE, Nicoletto Cisplatin + Adriamycin + Substitution cyclophosphamide cyclophosphamide SGCTG, Reed Treosulfan Carboplatin Substitution MITO 2, Pignata Carboplatin + doxorubicin Carboplatin + Substitution SCOTROC, Vasey Docetaxel + carboplatin Carboplatin + Substitution GOG 158, Ozols Cisplatin + Carboplatin + Substitution OVAR 3, du Bois 2003, Greimel ,30 Cisplatin + Carboplatin + Substitution First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 14

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

25 Modelling estimated a 92% probability that combinations of platinum and taxane with intraperitoneal administration were the most effective regimens. 14 Nineteen of the primary randomised controlled trials reported overall survival as an outcome (including some phase III and phase II trials). Most of these reported no statistically significant survival differences between treatment groups. Note the phase II trials are not designed/powered to detect survival differences. See appendix G for overall survival for each trial. Two trials (both phase III) reported differences in overall survival. The trial by Reed et al (2006), which included patients unfit to receive cisplatin, reported improved survival in the carboplatin arm (median 15 months) compared with treosulfan (median 12 months) (p<0.026). 15 Long-term follow-up of the OV10 trial of of older chemotherapy regimens, reported that and cisplatin combination improved survival compared with cyclophosphamide and cisplatin (HR 0.75 (95% CI 0.63 to 0.90); p=0.001). 33 Progression-free survival Twenty-three of the primary randomised controlled trials reported on progression-free survival. One trial reported on disease-free survival rather than progression-free survival. 25 Most reported no statistically significant progression-free/disease-free survival differences between treatment groups. Note the phase II trials are not designed/powered to detect survival differences. Three trials (all phase III) reported differences in progression-free survival: Reed et al (2006), 15 OV10, 33 and OVAR9, 18. See Appendix G for progression free survival for each trial. In two trials, the standard chemotherapy arm reported longer progression-free survival than the intervention arm. The trial by Reed et al (2006) reported longer time to progression in the carboplatin arm (10 months) compared with treosulfan (5 months) (p<0.001). 15 The OVAR9 trial reported median progression-free survival in the standard /carboplatin arm as 19.3 months compared with 17.8 months for the /carboplatin/gemcitabine arm (p<0.01). 18 In the other trial, the intervention arm reported improved progression-free survival. OV10 reported better PFS in the /cisplatin arm compared with the older chemotherapy regimen cyclophosphamide/cisplatin (p<0.001). 33 Treatment compliance Most trials reported high treatment compliance, with many reporting that 80% or over received planned treatment 17,18,20,21,26-29 and some reporting more than 90%. 31,40,43 Two trials reported differences between treatment arms. Reed et al (2006) reported that only 35% completed 6 cycles of treosulfan compared with 68% in the carboplatin arm (statistical significance was not reported). 15 Lhomme et al (2008) reported that 76% of patients in the valspodar arm received at least 6 cycles of chemotherapy compared with 85% in the standard chemotherapy arm (p=0.0016). 24 First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 16

26 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 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= Lhomme 2008: ORR addition of valspodar 34% versus standard chemotherapy ( 175 mg/m2 and carboplatin AUC 6) 42%, p= OV16: ORR cisplatin plus topotecan followed by carboplatin plus 68% versus carboplatin plus 77%, p= 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 were more likely to report neurotoxicity compared to those without. 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/ chemotherapy. OVAR 3 compared carboplatin/ with cisplatin/ 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/ with carboplatin//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

27 Note an additional paper was identified which reported a retrospective analysis of data from OVAR 3, OVAR 5 and OVAR 7 which correlated common toxicity criteria (CTC) and patient-reported quality of life. 44 This paper found that correlations between toxicity grading and quality of life functioning scales were weak and symptom level agreement between clinician and patient reporting could differ. The authors conclude that clinicians should not rely on CTC grading to capture adverse events and information related to patient wellbeing, but should also consider patient reported symptoms or changes in QoL. Ovarian cancer (stage I-IV) - Biological therapies Randomised controlled trials Two trials were identified which investigated the addition of bevacizumab to carboplatin and (GOG ; OVAR11/ICON7 43 ). Study characteristics The ICON7, a phase III randomised study, compared standard chemotherapy (carboplatin AUC 5 or 6 and 175mg/m 2 every 3 weeks for 6 cycles) or standard chemotherapy plus bevacizumab (7.5mg per kilo body weight) given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 additional cycles or until progression of disease. GOG 218, a double-blind phase III randomised controlled trial compared three treatments. 45 Each of the three study regimens comprised 22 3-week cycles 175mg/m 2 plus carboplatin AUC 6. Control treatment was chemotherapy with placebo added in cycles 2 through 22; bevacizumab initiation treatment was chemotherapy with bevacizumab (15mg per kg body weight) added in cycles 2 through 6 and placebo added in cycles 7 through 22. Bevacizumab-throughout treatment was chemotherapy with bevacizumab added in cycles 2 through Outcomes Refer to Appendix H for summary table of outcomes. Overall survival The ICON7 trial reported improved survival in a subgroup of patients at high risk of progression in the bevacizumab and standard therapy (carboplatin + ) group, compared to the standard therapy alone group. 43 Patients at high risk of progression were those with stage IV disease or stage III disease and >1cm of residual disease following debulking surgery. While in the whole population the ICON7 trial reported no overall survival differences between treatment groups, in the updated analyses for patients at high risk for progression (n=465), patients in the bevacizumab arm had improved survival: Overall survival: median 36.6 months for intervention, 28.8 months or control, HR 0.64 (95% CI 0.48 to 0.85) p= Final overall survival results for the ICON7 trial are due in No significant differences in overall survival between the three groups (bezacizumabinitiation group, bevacizumab-throughout group and control group) have been reported by the GOG 218 trial. 45 First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 18

28 Progression free survival The ICON7 trial reported improved PFS in the bevacizumab group compared with the standard therapy, 19.8 months vs months (p=0.04) respectively, in the updated analyses. 43 The maximum improvement in progression-free survival was at 12 months, coinciding with the end of planned bevacizumab treatment, and it diminished by 24 months. In a subgroup of patients at high risk of progression, median PFS was improved in the intervention group. Median PFS in the updated analyses, for patients at high risk of progression, was 16 months in the bevacizumab group compared with 10.5 months in the standard therapy group (p=0.002). 43 In the GOG 218 trial, PFS was improved in the bevacizumab throughout arm (median 14.1 months) compared with control (median 10.3 months) (p<0.001), however this improvement was not observed in the bevacizumab initiation arm (median 11.2 months) (p=0.16). Results of updated analyses of PFS were consistent with those from the original analysis. 45 Response to treatment The ICON7 trial reported that the addition of bevacizumab to carboplatin and improved the overall response rate (complete or partial remission) compared with carboplatin and alone (67% versus 48% respectively, p<0.001). 43 Adverse events Patients receiving bevacizumab were more likely to report hypertension than those in standard chemotherapy arms. 43,45 Details about which adverse events were reported to be different in each individual trial are presented in Appendix J. Quality of life The ICON7 trial reported that global quality of life was marginally better in the control arm compared with the bevacizumab arm at the end of chemotherapy and at completion of the active treatment follow-up, however these differences were not considered to be clinically significant (supplementary appendix 43 ). Summary Five systematic reviews were identified which investigated various chemotherapy regimens for epithelial ovarian cancer. One of these reviews included only patients with early stage ovarian cancer (stage I-IIa). This review found that overall and progression-free survival was improved in early stage ovarian cancer patients who had chemotherapy compared with those on observation. Subgroup analysis suggested that women who had optimal surgical staging of their disease were unlikely to benefit from adjuvant chemotherapy, whereas those who had sub-optimal staging did. The remaining reviews included ovarian cancer patients of all stages, however provided little to no information on chemotherapy in the first line setting. Eighteen phase III and seven phase II randomised controlled trials were identified which investigated different chemotherapy regimens in populations with a majority of advanced First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 19

29 stage ovarian cancer patients. While a range of regimens have been investigated, including addition of chemotherapy agents to standard regimens or substitution of different agents, almost all failed to demonstrate an overall or progression-free survival benefit compared with standard chemotherapy (most often platinum/taxane combination). Trials which did show survival differences were either in specific patient populations or compared older chemotherapy regimens no longer considered standard. Two randomised controlled trials have shown improved progression-free survival for the biological therapy bevacizumab used in addition to carboplatin and. One of these studies also indicated for patients at high risk of progression, overall survival benefit with bevacizumab, and greater benefit in progression free survival than for patients at lower risk. Adverse effect profiles reflected the various agents used however there were often limited differences in toxicities between treatment arms. Similarly, most trials reported no significant differences in quality of life between treatment arms investigated What is the most effective schedule (duration/dose/frequency) for chemotherapy regimens for first line adjuvant treatment of epithelial ovarian cancer? Systematic reviews No systematic reviews were identified which investigated different schedules for chemotherapy regimens for first line adjuvant treatment of epithelial ovarian cancer. Randomised controlled trials Six phase III and one phase II trials were identified which investigated different schedules for chemotherapy regimens for first line adjuvant treatment of epithelial ovarian cancer. Two additional RCTs were identified which investigated complex chemotherapy regimens which could be considered for both Question 1 and Question 2 therefore are reported separately in Section Study characteristics One trial enrolled patients with early stage tumours only. 46 In contrast the GOG trial enrolled a majority of stage IV patients. 47 The remaining studies included a majority of stage III patients (usually IIIC). The median age across studies was between 50 and 60 years old and a high percentage of patients had serous histology (usually >60%). The size of studies ranged from to patients and median follow-up ranged from to years. Quality Each of the included trials was considered to be of moderate to high quality. The trials were all randomised, with methods used for randomisation considered high quality, though some trials did not describe randomisation methods. The trials were either open label or blinding was not stated. Survival outcomes by intention-to-treat analysis were reported by the majority of trials. All trials had standardised assessment of outcomes and almost every trial had well First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 20

30 matched population characteristics between treatment arms at baseline. Most of the trials were powered to detect a significant difference in primary outcomes. Interventions investigated A range of interventions have been investigated, see Table 4. Most have been compared with the combination of carboplatin and (considered as standard first line chemotherapy): Three dose-dense trials 47,49,50 (dose-dense chemotherapy defined as a chemotherapy treatment plan in which drugs are given with less time between treatments than in a standard chemotherapy treatment plan 51 ): JGOG 3016 Katsumata 2009, Fruscio 2011, GOG 162. A conference abstract with long-term follow-up results of the Japanese JGOG 3016 dose-dense trial has also been published. 52 Two trials investigated different doses 48,53 : Bolis 2004, Ray-Coquard 2007 One trial investigated 3 cycles versus 6 cycles 46 : Bell 2006 Table 4 Chemotherapy schedules investigated for first line adjuvant treatment of ovarian cancer Study Intervention Comparator Dose-dense trials JGOG 3016 Katsumata Katsumata Carboplatin + (80mg/m 2 ) (dose-dense) Carboplatin (AUC 6 mg/ml per min) + (180mg/m 2 ) (conventional) GOG 162, Spriggs Cisplatin (75mg/m 2 ) and (135mg/m 2 ) during 24hrs x 6 cycles every 3 weeks Fruscio Cisplatin (50mg/m2) weekly x 9 cycles Different dose trials Bolis Carboplatin + (225mg/m 2 ) 6 cycles every 21 days Cisplatin (75mg/m 2 ) and (120mg/m 2 ) during 96hrs x 6 cycles every 3 weeks Cisplatin (75mg/m2) every 3 weeks x 6 cycles Carboplatin + (175mg/m 2 ) 6 cycles every 21 days Ray- Coquard/GINECO Cyclophosphamide (1800mg/m 2 ) + epirubicin + cisplatin + filgrastim (5µg/kg/day, sc, D2-11) x 6 cycles every 3 weeks Cyclophosphamide (500mg/m 2 ) + epirubicin + cisplatin x 6 cycles every 3 weeks Different cycles Bell Carboplatin + x 3 cycles Carboplatin + x 6 cycles AUC=area under the curve Outcomes Overall survival The only trial which reported an overall survival difference between treatment groups was JGOG 3016, reported by Katsumata et al (2009) 49. Overall survival at 2 years and at 3 years was significantly longer in the dose-dense arm compared with the standard dose arm (2yr: 83.6% versus 77.7%, p=0.049; 3yr: 72.1% versus 65.1%, p=0.03). In long-term follow-up results at 6.4 years of median follow-up, median survival had not yet been reached in the First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 21

31 dose-dense group. Overall survival at 5 years was higher in the dose-dense group than in the conventional group (58.6% vs. 51.0%, HR 0.79, 95% CI , p=0.0448). 52 The remaining trials showed no differences in overall survival between intervention and comparator. Progression-free survival Similarly, JGOG 3016 (Katsumata et al 2009) was the only trial to report a difference in progression-free survival. 49 Median progression-free survival was 28 months in the dose-dense arm compared with 17.2 months in the standard dose arm (adjusted HR % CI 0.53 to 0.80, p=0.0001). The authors noted that progression-free survival was longer in the dose-dense treatment group than in the conventional treatment group across all subgroups of patients, apart from those with clear-cell or mucinous tumours. In this subgroup of patients, the hazard ratio in the dose-dense treatment group was similar to that in the conventional treatment group. 49 In long-term follow-up results at 6.4 years of median follow-up, there continued to be statistically significant improvement in median progression-free survival in favour of the dosedense group compared to the conventional group (28.1 vs 17.5 months, HR 0.75, 95% CI , p=0.0037). 52 Treatment compliance Most trials reported that 80% or more of patients completed their planned treatment. Compliance was generally no different between treatment groups. Bell et al (2006) reported more patients in the 3 cycle group completed planned treatment (96%) than the 6 cycle group (83%). 46 Katsumata et al (2009) reported 62% of patients in the dose-dense arm received 6 or more cycles compared with 73% in the standard arm. 49 Response to chemotherapy No significant differences were reported between treatment groups with regards to response to chemotherapy. Overall response rate (complete + partial response) ranged from 53% 49 to 85%. 50 Adverse events Due to the range of adverse events reported and varied schedules investigated, each trial is reported separately. Bell et al (2006) reported that patients in the 6 cycle arm experienced worse/more neurotoxicity, granulocytopenia and anaemia than those in the 3 cycle arm. 46 One death in each arm was attributed to treatment. Bolis et al (2004) reported worse neurotoxicity in higher dose (225mg/m2) arm however worse alopecia in the lower dose (175mg/m2) arm. No other significant differences in adverse events were reported between treatment arms. 53 Fruscio et al (2011) reported worse leukopenia, thrombocytopenia and hepatotoxicity in the dose-dense cisplatin arm compared with the standard dose arm. 50 The GOG 162 trial partially attributed slightly more deaths to treatment in the intervention arm compared with control (6 versus 3). 47 Granulocytopenia was more common in the intervention arm, however anaemia was more common in the control arm. No significant First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 22

32 differences were observed between treatment arms for neurotoxicity, allergic reaction, infections or alopecia. The GINECO trial reported by Ray-Coquard et al (2007) reported two deaths from treatment in the intensive cyclophosphamide arm and one death in the standard arm. 48 Anaemia, thrombocytopenia, and infections were all significantly worse in the intensive arm compared with the standard arm. Katsumata et al (2009) reported worse anaemia in the dose-dense arm, however no significant differences were observed for other haematological toxicities such as neutropenia or thrombocytopenia. 49 Quality of life Quality of life outcomes were not assessed or reported in any of the trials. Summary Six phase III and one phase II trials were identified which investigated different schedules for chemotherapy regimens for first line adjuvant treatment of epithelial ovarian cancer. No systematic reviews in this topic were identified. A range of schedules were investigated including dose-dense chemotherapy, different doses of the same agent or different timing/cycles of the same regimen. Only one trial, JGOG 3016, showed survival benefits between treatment arms. This study investigated dose-dense compared with standard and reported improved overall survival and progression-free survival in the dose-dense group compared to the conventional group, at short-term followup (up to 3 years) and at long-term follow-up (median 6.4 years). While adverse events were often similar between treatments arms, some increased toxicity was observed in the higher dose, more intensive chemotherapy intervention arms compared with standard arms. Quality of life was not assessed in any of the trials Additional chemotherapy regimens and schedules investigated for first line adjuvant treatment of epithelial ovarian cancer Two phase III randomised controlled trials were identified which investigated complex chemotherapy regimens which could be considered for both Question 1) and Question 2) therefore they are reported separately here. Study characteristics Both trials enrolled advanced ovarian cancer patients, aged 65 or younger, and were relatively small, including only to patients. The HIDOC-EIS trial was originally two separate trials, however these were merged given they had a similar design. 55 Quality The quality of the two trials was considered to be moderate. Both trials were randomised however did not describe methods of randomisation. The FINOVA trial was an open-label trial, while HIDOC-EIS did not state if it was blinded. Both trials had standardised assessment First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 23

33 of outcomes and both were well matched for population characteristics between treatment arms at baseline. Interventions investigated The chemotherapy regimens used in these trials, summarised in table 5, were complex. In both trials chemotherapy was delivered at 3 weekly intervals, and the intervention arms received high-dose chemotherapy with peripheral blood stem cell support. Table 5 Additional chemotherapy regimens and schedules investigated for first line adjuvant treatment of ovarian cancer Study Intervention Comparator Phase III trials HIDOC- EIS 55 FINOVA, 54 Cyclophosphamide (3mg/m 2 )+ ( mg/m 2 ) x 2 cycles carboplatin (high dose: AUC 20) + ( mg/m 2 ) x 2 cycles carboplatin (high dose: AUC 20) + ( mg/m 2 ) + melphalan (140mg/m 2 ) x 1 cycle Cisplatin (75mg/m 2 ) + (135mg/m 2 ) x 3 cycles cyclophosphamide (3000mg/m 2 ) (175mg/m 2 ) high-dose chemotherapy (HDCT): carboplatin (1500mg/m 2 ) + cyclophosphamide (120mg/m 2 ) + mitoxantrone (75mg/m 2 ) x 1 cycle AUC=area under the curve Carboplatin (AUC 5) + (175mg/m 2 ) for 6 cycles ± epirubicin or doxorubicin Cisplatin (75mg/m 2 ) + (135mg/m 2 ) x 6 cycles Outcomes Overall survival No significant differences between treatments groups were observed for overall survival in either trial. Progression-free survival No significant differences between treatments groups were observed for progression-free survival in either trial. Treatment compliance The HIDOC-EIS trial reported a higher percentage of patients completed the planned treatment in the standard chemotherapy arm (90%) compared with the high-dose chemotherapy arm (76%), 55 however statistical significance was not reported. The FINOVA trial did not report on treatment compliance. Response to chemotherapy Response to chemotherapy was not reported in either trial. First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 24

34 Adverse events The FINOVA trial reported that the high-dose chemotherapy arm was more toxic than the standard chemotherapy arm. 54 One death due to treatment was reported in the HDCT arm. Anemia, thrombocytopenia, infections, mucositis and diarrhoea were worse in the HDCT arm. Patients in the HDCT arm spent more time in hospital and more days on IV antibiotics than those in the standard chemotherapy arm. Patients in the HDCT arm also required more red blood cell and platelet transfusions. The HIDOC-EIS trial reported toxicity within high-dose therapy but not compared with the control arm. Gastrointestinal toxicity showed a sharp increase in final high-dose cycle (containing melphalan). 55 Quality of life Quality of life outcomes were not assessed or reported in either trial. Summary Two trials were identified which investigated complex chemotherapy regimens including peripheral blood stem cell support. Neither of these trials reported any survival differences between intervention and standard treatment arms. Only one trial provided detailed data on adverse events, with higher toxicity experienced in the complex high-dose chemotherapy arm. Quality of life was not assessed in either trial What is the most effective mode of administration for chemotherapy regimens for first line adjuvant treatment of epithelial ovarian cancer? Systematic reviews Five systematic reviews were identified which investigated the effectiveness of intraperitoneal (IP) chemotherapy regimens for the treatment of epithelial ovarian cancer. No systematic reviews on other modes of administration for chemotherapy for ovarian cancer were identified. A Cochrane systematic review on IP chemotherapy was published in 2011 and includes RCTs published up to May The review identified nine RCTs including 2119 women receiving primary treatment for ovarian cancer, of which six trials were considered of high quality. Only one of the nine trials directly compared intravenous (IV) to IP (without additional IV) chemotherapy (Kirmani 1994 which included 87 patients); the remaining trials compared administering a certain component of chemotherapy via IV or IP along with IV chemotherapy in both arms. The chemotherapy component administered via IP always included a platinum agent, usually cisplatin, with or without additional agents. The IV chemotherapy given to both arms usually included or cyclophosphamide. 56 Four other systematic reviews on IP chemotherapy were identified which were published before These reviews are considered to be superseded by the Cochrane review and therefore are not reported in any further detail. First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 25

35 Randomised controlled trials All randomised controlled trials on IP chemotherapy identified in the Cancer Australia literature search were included in the Cochrane systematic review, therefore are not reported in any further detail. No other trials which compared different modes of administration were identified. Additional study of interest An additional paper was identified in the Cancer Australia literature review which investigated factors affecting the completion of IP chemotherapy in women with ovarian cancer. 61 While this study is not a randomised controlled trial, it is included here as it was considered of interest to the research question. The study includes data from patients enrolled in a US centre and includes some of the patients who were part of the GOG 172 trial as well as other IP chemotherapy trials. Results of this paper are reported under the outcome treatment compliance. Outcomes Overall survival The Cochrane review reported significantly improved overall survival for women who received an IP component of chemotherapy. 56 Data from a meta-analysis of data from eight studies (2026 women) for overall survival the hazard ratio was 0.81 (95% CI 0.72 to 0.90) p= for women who received an IP component to chemotherapy compared to IV chemotherapy. Results were similar when data only from the six high quality trials was used: HR 0.80 (95% CI 0.72 to 0.90) p= The data was reported to be homogenous. The overall survival results were similar when the analysis was restricted to trials that used the same chemotherapy regimens in each arm (data from 3 studies: HR 0.79 (95% CI 0.67 to 0.92)). 56 Progression-free survival The Cochrane review reported significantly improved progression free survival for women who received an IP component of chemotherapy. 56 From meta-analysis of data from five studies (1311 women) the hazard ratio was 0.78 (95% CI 0.70 to 0.86) p< The data was reported to be homogenous. Treatment compliance Treatment compliance was not assessed as an outcome for the Cochrane review. 56 It was mentioned that in the GOG 172 trial, 58% of women in the IP arm did not complete 6 cycles of IP therapy. The additional paper which investigated factors affecting the completion of IP chemotherapy in women with ovarian cancer included 140 patients who received IP chemotherapy as initial treatment. 61 Of these patients, 95 (68%) completed all 6 planned cycles of treatment. The reasons for non-completion of the planned regimen included: Occlusion of the port (28 patients, 20%) First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 26

36 Progression of disease (7 patients, 5%) Refusal by the patient to accept further IP treatment (6 patients, 4%) Infection of the port/port site (3 patients, 2%) Rupture of the port tubing (1 patient, <1%). 61 Response to chemotherapy Response to chemotherapy was not an outcome reported in the Cochrane review. Adverse events The Cochrane review undertook meta-analysis of several adverse events; data for each event ranged from two to five trials. 56 Women in the IP chemotherapy groups were significantly more likely to experience the following severe adverse effects (grade 3/4): fever (RR 1.64), fatigue (RR 2.32), gastrointestinal adverse events (RR 1.70), infection (RR 3.34), metabolic adverse events (RR 4.45) and pain (RR 7.47). 56 Hearing loss was more common in the IV chemotherapy groups (RR 0.67). 56 There were no significant differences between interventions for haematological adverse events (such as anaemia, thromocytopenia and leukopenia), renal, neurological and pulmonary adverse events. 56 However substantial heterogeneity was noted in these metaanalyses. The Cochrane review also mentioned that catheter-related complications of IP drug administration (including infection, blockage and discontinuation of therapy) were discussed in the trials however, data available was insufficient for meta-analysis. 56 Quality of life The Cochrane review noted that only one study assessed QoL as an outcome measure (GOG 172). 56 Women who received higher dose IP therapy experienced more QoL disruption compared to those who received IV therapy. The IP arm reported worse QoL and pain prior to the fourth chemotherapy cycle and worse QoL 3 to 6 weeks post-treatment, however there were no significant QOL or PAIN score differences between arms at one year posttreatment. Additional outcomes The Cochrane review 56 reported data from a modelling study which suggested that the aim should be 5 cycles of IP chemotherapy (due to better survival compared with 1 to 3 cycles), and that harms from IP chemotherapy exceed the benefits for elderly women with clear cell tumours, especially those who have not been optimally debulked. Summary One recent high quality systematic review was identified which reported on the effectiveness of IP chemotherapy in treating ovarian cancer. The review found that the inclusion of an IP component of chemotherapy improved overall and progression-free survival. However, women receiving IP chemotherapy reported more adverse events than those on standard chemotherapy. Limited data on quality of life have been reported. First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 27

37 3.2.5 When is the most effective time to administer chemotherapy for first line treatment of epithelial ovarian cancer? Systematic reviews One Cochrane review was identified which compared chemotherapy versus surgery for initial treatment in advanced ovarian cancer. 62 This review was published in 2007 and contains only one small randomised controlled trial which compared standard debulking surgery followed by chemotherapy with pre-operative intra-arterial platinum-based chemotherapy and ovarian artery embolisation followed by debulking surgery and further chemotherapy. The study included in the Cochrane review was not considered of high quality and due to the study design it is not possible to determine whether any effect was due to pre-surgical ovarian artery embolisation or neoadjuvant chemotherapy, therefore the results will not be discussed in any further detail. Randomised controlled trials One randomised controlled trial was identified which compared neoadjuvant chemotherapy with primary surgery followed by adjuvant chemotherapy. 63 Study characteristics The International EORTC trial included 670 women from 59 institutions with stage IIIC or IV invasive epithelial ovarian cancer, primary peritoneal or fallopian tube cancer. 63 Most of the included patients had stage IIIC ovarian cancer. The median age was (range 25-86) and the majority of patients had serous histology (58-66%). The trial randomised women to either: 63 i. 3 courses of neoadjuvant platinum-based chemotherapy followed by debulking surgery in all patients with a response or stable disease, followed in turn by at least 3 courses of platinum-based chemotherapy (n=334) or ii. primary debulking surgery followed by at least 6 courses of platinum-based chemotherapy (n=336). The most common chemotherapy regimen was (175mg/m2) plus carboplatin (AUC6). The trial assessed overall survival, progression free survival, adverse events and quality of life. Median follow-up was 4.7 years. This RCT was considered of high quality. Overall survival The trial reported no difference in the median overall survival between the two groups (median 30 months in neoadjuvant chemotherapy group compared with 29 months in primary surgery group, HR 0.98 (90% CI 0.84 to 1.13)). 63 Subgroup analyses by age, FIGO stage, WHO performance status, histologic type, and presence or absence of pleural fluid showed no survival differences between the treatment groups. The only difference reported was that neoadjuvant chemotherapy appeared to First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 28

38 improve survival among patients with metastatic tumours that were less than 5 cm in diameter at randomisation (HR 0.64 (95% CI )). Progression-free survival The trial reported no difference in the median progression free survival between the two groups (median 12 months in neoadjuvant chemotherapy group compared with 12 months in primary surgery group, HR 1.01 (90% CI 0.89 to 1.15)). 63 Treatment compliance Eighty-six per cent of patients in the neoadjuvant chemotherapy group received at least 6 cycles of chemotherapy compared with 82% in the primary surgery group. Around 7% of patients in the primary surgery group received no chemotherapy, mainly due to post-surgery complications or the diagnosis of another primary tumour (Supplementary appendix). 63 Response to chemotherapy Response to chemotherapy was not an outcome reported in the trial. Adverse events There was a higher percentage of post-operative deaths (defined as death <28 days after surgery) in the primary surgery group (2.5%) compared with neoadjuvant chemotherapy (0.7%) (statistical significance not reported). 63 Grade 3 or 4 haemorrhage, infections and venous complications were worse in the primary surgery group compared with the neoadjuvant chemotherapy group (statistical significance not reported). 63 Analyses comparing the perioperative and postoperative characteristics of the two groups were not performed because not all patients who were randomly assigned to primary debulking underwent primary debulking surgery, and not all patients assigned to neoadjuvant chemotherapy underwent interval debulking surgery. 63 Quality of life Quality of life was assessed using the EORTC QLQ-C30. The trial reported no significant differences between groups in the QLQ-C30 global health scores at any of the assessment times. The overall test for a treatment effect on global health was also not significant. 63 Additional study of interest In addition to the EORTC trial, one phase II trial PRIMOVAR investigated 3 cycles versus 2 cycles of neoadjuvant chemotherapy. 64 While this trial does not address the specific question of neoadjuvant chemotherapy compared with primary surgery, it is included here as it was considered of interest to the research question. This study enrolled 83 patients with stage IIIC or IV ovarian cancer and an ascites volume of 500ml. Outcomes The phase II trial reported no overall or progression-free survival differences between 3 cycles versus 2 cycles of neoadjuvant chemotherapy. There were also no significant differences between groups in results of cytoreductive surgery. First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 29

39 Summary One randomised controlled trial has been published comparing neoadjuvant chemotherapy with primary surgery. No survival differences between treatment arms were observed. More adverse events were observed in the primary surgery group than the neoadjuvant group, however whether this was statistically significant was not reported. There were no differences in quality of life between treatment arms. A small phase II trial reported no differences in outcomes between patients who had 3 cycles versus 2 cycles of neoadjuvant chemotherapy Are there subsets of the defined population for first line adjuvant treatment of epithelial ovarian cancer that have specific chemotherapy requirements? Due to the limited information available for this question, the included papers were not limited to RCTs. Comparisons between effectiveness of chemotherapy in general were reported for: women with ovarian cancer with or without BRCA mutations older compared with younger patients various histological subtypes. However, limited information was identified on specific chemotherapy requirements for any of these groups. Systematic reviews A Cochrane review on adjuvant chemotherapy for early stage EOC was published in and is reported in Section No other systematic reviews on particular subgroups were identified. Individual studies Some of the RCTs identified in Section reported subgroup analyses for prognostic factors such as age and histologic subtype. These analyses did not show any survival differences in treatment effects across prognostic subgroups ,25,26,45 However these analyses are considered exploratory rather than definitive given the trials were not designed to detect differences between these subgroups. A phase III RCT in Section enrolled patients who were unfit to receive cisplatin, the population in this trial consisted of an older population (median age 73, range 67-76). 15 One phase II RCT in Section specifically investigated patients with clear cell carcinoma. 16 Nine additional papers were identified as relevant for this question. Three reported on the association of BRCA1/2 mutation and chemotherapy sensitivity, two reported on the effects of chemotherapy in the elderly population (one a retrospective analysis of data from the RCT First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 30

40 OVAR 3 included in Section 3.2.1), three reported on various histological subtypes and effectiveness of chemotherapy, and one paper reported on subgroup analyses including age and histology subtypes. Quality As the papers included in this section had a range of study designs, formal quality assessment was not performed. BRCA mutations Study characteristics Three studies investigated the relationship between BRCA status and effectiveness of chemotherapy. An observational study was conducted of 316 high-grade serous ovarian cancer cases (219 BRCA wild-type, 35 BRCA1 mutation, 27 BRCA2 mutation, 33 BRCA1 methylation). 65 All patients received a platinum agent, 94% received a taxane. In this study, patients with BRCA1 mutations were younger at diagnosis than those with wild-type BRCA or BRCA2 mutation. A case-control study compared BRCA1- (n=99) or BRCA2-associated (n=13) epithelial ovarian cancer patients with matched sporadic epithelial ovarian cancer patients (n=222). 66 Patients with BRCA1 or BRCA2 mutations were more likely to have residual tumour <1cm after surgery than sporadic patients. There were no significant differences in the type of chemotherapy between the three groups. Another case-control study also compared patients with BRCA 1 or BRCA2 mutations (n=22) with non-hereditary epithelial ovarian cancer controls (n=44). 67 All patients received platinum-based chemotherapy. A study published after the systematic search, investigated the frequency of BRCA mutations and patterns of treatment response in a prospectively ascertained population-based cohort of 1001 Australian women with newly diagnosed nonmucinous ovarian cancer. Germline pathogenic BRCA1 or 2 mutations were identified in 141 (14.1%) of the women. 68 Outcomes Overall survival While the papers on BRCA mutations report on overall survival outcomes, the results do not relate to the impact of chemotherapy on survival therefore are not reported here. Progression-free survival While the papers on BRCA mutations reported on progression-free survival outcomes, the results do not relate to the impact of chemotherapy on progression-free survival, therefore are not reported here. Treatment compliance Treatment compliance was not reported in the BRCA mutation papers. First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 31

41 Response to chemotherapy In the observational study by Yang et al (2011), % of BRCA2 mutation carriers had a complete or partial response to platinum-based chemotherapy, compared with 85% of wild type BRCA cases (p=0.05) and only 80% of BRCA1 mutation carriers (p=0.02). Similarly, BRCA2 mutation carriers had significantly longer platinum-free duration than those with BRCA1 mutations (longer platinum-free duration, indicates less response to platinum).there were no significant differences with primary chemotherapy sensitivity or platinum-free survival between BRCA1 mutation carriers and wild-type BRCA cases. In the case-control study by Vencken et al (2011), 66 87% of BRCA1 mutation carriers obtained a complete response or no evidence of disease compared with 71% of the sporadic patients (p=0.002). Response to chemotherapy was improved in the BRCA2 group as well, however this was not statistically significant due to the low numbers of BRCA2 patients. In patients treated with a platinum-based regimen, no BRCA1 or BRCA2 patients had progressive disease compared with 15% of sporadic patients (p<0.001). In the case-control study by Tan et al (2008), % of patients with BRCA1 or BRCA2 mutations responded to first-line platinum based chemotherapy, compared with 59.1% of non-hereditary ovarian cancer patients (p=0.002). Patients with BRCA 1 or BRCA2 mutations were also more likely to achieve a complete response to chemotherapy than non-hereditary patients (81.8% versus 43.2%, p=0.004). The study by Alsop et al reported that of the 837 patients who received chemotherapy during primary treatment, 835 (99.8%) received a platin-based regimen and 642 (76.9%) received carboplatin/. Patients with BRCA1/2 mutations were less likely to have disease progression within 6 months of the end of primary treatment compared with those not carrying mutations (14.9% vs. 31.7% respectively, p<0.001). Disease progression within 6 months of completing primary platin-based chemotherapy has conventionally been associated with platinum resistance. 68 Adverse events Adverse events were not reported in the BRCA mutation papers. Quality of life Quality of life was not reported in the BRCA mutation papers. Elderly patients Study characteristics A phase III RCT in Section enrolled patients who were unfit to receive cisplatin, the population in this trial consisted of an older population (median age 73, range 67-76). 15 Two non-randomised studies analysed effectiveness of chemotherapy in elderly patients. One was a retrospective analysis of data from the RCT OVAR 3 69 comparing those younger than 70 years with those aged 70 or older, the other was a cohort study of stage III or IV ovarian cancer patients, who survived more than 120 days beyond their diagnosis and were aged 65 years or older. 70 First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 32

42 In the OVAR 3 trial, 103 patients were 70 years or older. 69 These patients were more likely to have ECOG performance status 2 and have measurable residual disease than those younger than 70. All patients received either carboplatin/ or cisplatin/. The cohort study included 1759 women 65 or older, of which 84% had received chemotherapy and 53% received platinum-based chemotherapy specifically (15% received platinum and ). 70 Women who were 80 years or older were less likely to be treated with chemotherapy than those aged 65 to 79. In addition, a subset analysis from RCT GOG 157 including women with early stage high risk epithelial ovarian cancer was performed to explore differences between 3 cycles and 6 cycles of chemotherapy. 71 Comparisons were made for subgroups including age 55 ( years versus >55years). An additional study by Tew et al (2010), presented as a conference abstract was identified after the systematic search. 72 The study was a review of outcomes and toxicity differences seen in patients 70 years and older (n=620) enrolled in the GOG 182 trial, a phase II RCT of adjuvant combination platinum therapy. Older patients had poorer performance status (p= <0.001), higher tumour grade differentiation (p=0.001), higher rates of serous histology (86% vs. 82%). Outcomes Overall survival The RCT by Reed et al (2006) reported improved survival in the carboplatin arm (median 15 months) compared with treosulfan (median 12 months) (p<0.026). 15 In a US cohort of patients aged 65 or older, 70 those who received chemotherapy had improved survival compared with those who had no chemotherapy, the mortality reduction was greatest for those who received a combination of platinum and (RR 0.59, 95% CI 0.5 to 0.7). In the analysis of the GOG 182 RCT, older patients had a significantly shorter survival (median overall survival 37 months vs. 45 months, p=<0.001), consistent across all regimens and adjusted for major prognostic factors. Older patients also had lower median survival after recurrence (19 vs. 22 months, p=0.022). 72 Progression-free survival The RCT by Reed et al (2006) reported longer time to progression in the carboplatin arm (10 months) compared with treosulfan (5 months) (p<0.001). 15 In the subset analysis from the GOG 157, the hazard ratio for recurrence for 6 versus 3 cycles of chemotherapy was no different based on age. 71 Treatment compliance In the OVAR 3 trial, early discontinuation of treatment occurred more frequently in the elderly patients compared with those less than 70 (26% versus 13%, p=0.001). 69 The reasons for discontinuation were more likely to be for toxicity and patient s withdrawal in the elderly population. There were no significant differences between the elderly or younger populations for discontinuation due to progressive disease or death. First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 33

43 In the analysis of the GOG 182 RCT, older patients had lower completion rates of all 8 cycles (72% vs. 82%, p=<0.001). 72 Response to chemotherapy Reed et al (2006) reported that only 35% completed 6 cycles of treosulfan compared with 68% in the carboplatin arm (statistical significance was not reported). 15 Adverse events In the OVAR 3 trial, most haematological toxicity did not differ between the age groups, however febrile neutropenia was more frequent in the elderly patients than in younger patients (5% versus <1% respectively, p<0.001). 69 There were no significant differences in nonhaematological toxic effects between age groups except that elderly patients were more likely to get grade 3/4 infections and younger patients were more likely to have grade 3/4 myalgia. In the analysis of the GOG 182 RCT, older patients had increased toxicities: grade 3-4 thrombocytopenia (51% vs. 43%), grade 3-4 neutropenia (70% vs. 64%), grade 3-4 pain (7.4% vs. 4.9%) and grade 2-4 hepatic (7.2% vs. 4.2%). 72 Quality of life In the OVAR 3 trial, no significant difference between the age groups was observed for the global health status/qol scale during the treatment period. Histological subtypes Study characteristics One phase II RCT in Section specifically investigated patients with clear cell carcinoma and compared Irinotecan and cisplatin to carboplatin and. 16 Three papers reported on comparisons between histological subtypes and effectiveness of chemotherapy. As each paper investigated different subtypes, each is described separately. These studies were not designed to investigate the effectiveness of different chemotherapy regimens in histological subtypes. A subset analysis of RCT data from the ACTION trial compares clear cell carcinoma (n=63) with serous carcinoma (n=156) in early ovarian cancer. 73 Data from a range of GINECO first line chemotherapy RCTs were retrospectively analysed to compare mucinous (n=54) with serous (n=786) ovarian cancer. 74 A phase II trial compared extraovarian peritoneal serous papillary carcinoma (n=36) with papillary serous ovarian carcinoma (n=130). 75 Patients were sourced from two different GOG trials with identical treatment protocols (cisplatin + cyclophosphamide). In addition, a subset analysis from GOG 157 including women with early stage high risk epithelial ovarian cancer was performed to explore differences between 3 cycles and 6 cycles of chemotherapy. 71 Comparisons were made for subgroups including histology subtype (serous versus non-serous). First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 34

44 Outcomes Overall survival In the subset analysis of the ACTION trial, while the overall survival rate for the serous and clear cell carcinoma groups was not significantly different, within the chemotherapy arm patients with serous carcinoma had improved survival compared with those with clear cell carcinoma (p=0.04). 73 However, survival benefits disappeared when only optimally staged patients were analysed. In the GINECO analysis, patients with mucinous ovarian cancer who had carboplatin based chemotherapy had shorter overall survival compared with serous ovarian cancer patients. 74 In the phase II trial comparing extraovarian peritoneal serous papillary carcinoma with papillary serous ovarian carcinoma, overall survival did not differ between the two groups. 75 Progression-free survival In the study of clear cell carcinoma, there was no significant difference in progression-free survival. 16 In the subset analysis from the GOG 157, 5-year recurrence-free survival for 6 versus 3 cycles of chemotherapy was significantly higher in serous tumours. 71 This benefit was not observed for non-serous tumours. In the subset analysis of the ACTION trial, within the chemotherapy arm, disease-free survival was not significantly different between patients with clear cell carcinoma and those with serous carcinoma (p=0.1). 73 Adjuvant chemotherapy significantly improved disease-free survival in patients with serous carcinoma (p=0.01) but there was no significant improvement for those with clear cell carcinoma (p=0.4). In the GINECO analysis, patients with mucinous ovarian cancer who had carboplatin based chemotherapy had shorter progression-free survival compared with serous ovarian cancer patients. 74 Treatment compliance In the study of clear cell carcinoma, 70.8% of patients in the plus carboplatin arm and 72% in the Irinotecan plus cisplatin arm received the planned 6 cycles of chemotherapy; this was not significantly different. 16 Response to chemotherapy In the study of clear cell carcinoma, there were no significant difference in overall response rate; 25% in Irinotecan plus cisplatin arm and 40% in plus carboplatin arm. Complete response rate in Irinotecan plus cisplatin arm and in plus carboplatin arm was 25% and 20% respectively. 16 In the GINECO analysis, the overall (complete and partial) response rate was significantly lower for mucinous ovarian cancer than those with serous ovarian cancer (p<0.001). 74 Progressive disease was more frequently observed in mucinous patients. First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 35

45 In the phase II trial comparing extraovarian peritoneal serous papillary carcinoma with papillary serous ovarian carcinoma, no differences were observed for overall, complete or partial response to chemotherapy. 75 Adverse events Adverse was not reported in the histological subtype papers. Quality of life Quality of life was not reported in the histological subtype papers. Summary Limited information was identified to suggest that there are specific chemotherapy requirements for particular subgroups such as BRCA mutation carriers, elderly patients or different histological subgroups. Trials were not designed to investigate the effectiveness of different chemotherapy regimens across different subgroups What are the specific chemotherapy requirements for women with epithelial ovarian cancer who are obese? Clinical practice guidelines The American Society of Clinical Oncology (ASCO) published clinical practice guidelines on the appropriate chemotherapy dosing for obese adult patients with cancer in These guidelines were not specific to ovarian cancer, however the guidelines noted that a majority of studies identified in the systematic review for the guidelines involved breast, ovarian, colon and lung cancers. The clinical practice guidelines address six clinical questions and make seven recommendations that are presented in Appendix K. The ASCO guidelines also highlight four key recommendations on appropriate chemotherapy dosing: 1. Panel recommends that full-weight-based chemotherapy doses be used in the treatment of the obese patient with cancer, particularly when the goal of treatment is cure Clinicians should respond to all treatment-related toxicities in obese patients with cancer in the same ways they do for non-obese patients If a dose reduction is employed in response to toxicity, consideration should be given to the resumption of full weight-based doses for subsequent cycles, especially if a possible cause of toxicity (e.g. impaired renal, hepatic function) has been resolved; there is no evidence to support the need for greater dose reductions for obese patients compared with non-obese patients The use of fixed-dose cytotoxic chemotherapy is rarely justified (except for a few select agents). 76 The ASCO guidelines recommend consideration of fixed dosing only with selected cytotoxic agents, e.g. carboplatin and bleomycin. The guidelines supporting text states that First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 36

46 carboplatin clearance depends on glomerular filtration rate (GFR) and doses are calculated best using the Calvert formula to achieve a targeted area under the curve (AUC). Because carboplatin clearance is dictated by renal filtration, and GFR correlates with BSA, dosing of carboplatin in the obese patient with cancer based on GFR may be most reasonable. 76 Systematic reviews One systematic review and meta-analysis on obesity and ovarian cancer survival, was published in The review by Protani et al (2012) aimed to examine the association between obesity and survival and as a second objective, to explore potential sources of variability, such as the timing of BMI assessment and the different cut off points used to categorise BMI. The systematic review was not specific to studies of chemotherapy among obese patients with ovarian cancer. The systematic review included 20 studies of women diagnosed with ovarian cancer. All studies used BMI as a measure of obesity, however, the time point when BMI was measured, as well as the cut off points used to categorise BMI for analysis varied between the studies. The meta-analysis, which included 14 studies, demonstrated slightly poorer survival among the obese group compared with non-obese women with ovarian cancer (pooled HR 1.17; 95% CI ). The meta-analysis reported a slightly stronger association in studies that only included women with a BMI 30 in their obese group (pooled HR 1.20; 95% CI )) than in studies that also included overweight women (BMI 25; pooled HR 1.14; 95% CI ) or analysed results per 5-unit increase in BMI (pooled HR 1.15; 95% CI ). 77 Studies No studies were identified which specifically compared different doses or schedules of chemotherapy among obese patients with epithelial ovarian cancer. Nine studies were identified which included obese patient populations and compared outcomes by BMI or by obesity. In most of the studies, chemotherapy dosing was based on actual body weight, whereas in some studies the formula used did not include body weight or body surface areas (BSA). Six of the studies examined the impact of BMI on outcomes including survival and adverse events Three of the studies reported on adverse events and BMI only Study characteristics Pavelka et al (2006) undertook a retrospective review to determine the influence of excess body weight on ovarian cancer survival, disease progression and clinicopathologic factors. 80 The study included 216 patients: 8% underweight (body mass index (BMI) <18.5), 50% ideal body weight (18.5 BMI <25), 25% overweight (25 BMI<30) and 16% obese (BMI 30). A secondary subgroup analysis was undertaken of 146 advanced ovarian cancer patients (stage III or IV) who had primary cytoreductive surgery followed by platinum- and taxanebased chemotherapy. The methods used for calculating doses were not reported. Wright et al (2008) investigated carboplatin dosing in obese women with ovarian cancer. 82 This paper reported a retrospective analysis of 387 patients from the RCT trial GOG 158 (included in Section 3.2.1), stratified by body mass index (BMI). Three groups were compared: normal weight (BMI<25, 50%), overweight (BMI , 32%) and obese (BMI 30, 18%). The dose of carboplatin for patients in this study was based on an area under the curve of 7.5 First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 37

47 and a glomerular filtration rate (GFR) derived from the Jelliffe formula that does not adjust for body weight. Barrett et al (2008) examined the association between BMI and overall survival and progression-free survival in 1067 ovarian cancer patients participating in the Scottish Randomised Trial in Ovarian Cancer I trial (SCOTROC I). 78 Patients were categorised into four groups: underweight (BMI <18.5, n=59), ideal weight (BMI , n=582), overweight (BMI , n=305) or obese (BMI >30, n=129). The dose of carboplatin for patients was determined by a measured GFR ensuring accurate dosing in all categories of BMI and the dose of taxane was not capped. Matthews et al (2009) undertook a retrospective review that evaluated the effect of obesity on surgical and chemotherapy outcomes in patients with epithelial ovarian cancer. 79 All patients underwent primary cytoreductive surgery followed by taxane/platinum based chemotherapy. Three-hundred and four patients were compared based on BMI: non-obese (BMI<30, n=233) and obese (BMI 30, n=71) and BMI strata (underweight BMI 1 8.4; normal weight BMI ; overweight BMI ; obese BMI ; and morbidly obese BMI 35.0). Drug dosages of and docetaxel were calculated with an actual body weight but the BSA was capped at 2.0. The Calvert formula was used to calculated the dosage of carboplatin using an AUC of A retrospective study by Suh et al (2012) examined the impact of obesity on the treatment and survival outcomes in 486 patients with epithelial ovarian cancer. 81 Based on the Asian BMI criteria for Koreans, 31(6.4%), 224 (46.1%), 179 (36.8%) and 52 (10.3%) of the patients were underweight BMI<18.5; normal weight 18.5 BMI <23; overweight 23 BMI <27.5; and obese BMI 27.5, respectively. The patients were also divided into two groups for the comparison based on a BMI above or below For chemotherapy dose calculation, Cockcroft-Gault formula was used to calculate the GFR and the carboplatin dose was calculated using the targeted area under the plasma carboplatin concentration-time curve from the Calvert formula. Hanna et al (2012) evaluated the prognostic significance of relative dose intensity (RDI) and predictors of reduced RDI in women with newly diagnosed advanced stage epithelial ovarian cancer treated with platinum-based chemotherapy. 83 Three-hundred and twentyfive patients were included, 69.5% had a BMI of less than 30 while 20.6% were obese or morbidly obese. Ninety per cent (n=291) of the study population had a body surface area (BSA) less than 2.0m 2 while the BSA for the remaining 10.2% was greater than 2.0m 2. Calculation of RDI required comparison to a standard regimen. Carboplatin AUC 6 was considered standard. Experimental therapies administered on clinical trials in addition to standard chemotherapy agents were not incorporated into RDI calculations, as there were no available standard regimens on which to base such calculations. If no literature-derived standard could be identified for a chemotherapy regimen and the subject was not enrolled on a research protocol, RDI was not calculated. After standard regimens had been determined, a standard dose of each agent was determined for each subject. In calculating the standard dose, the BSA calculation was based on actual body weight with no capping of BSA value; the Cockcroft/Gault formula was used for creatinine clearance calculation and the Calvert formula for carboplatin dosage calculation. In addition to dosing, the temporal delivery of the agents is also taken into account when calculating RDI, such that treatment delays result in reductions in delivered RDI. Reduced RDI was defined as <85% of standard over the four cycles studied. First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 38

48 Table 6 Study characteristics of studies reporting the outcomes of chemotherapy in obese patients Study Patient characteristics BMI categories n (%) Chemotherapy characteristics Pavelka 2006 Epithelial ovarian cancer patients n=216 Subgroup analysis of stage III and IV patients (n=146) <18.5kg/m 2 : 17(8) kg/m 2 : 108(50) kg/m 2 : 56(26) 30kg/m 2 : 35(16) Platinum- and taxane-based chemotherapy. The methods used for calculating doses were not reported, however a lower median dose of relative to BSA for obese patients compared to those of ideal body weight was reported. Carboplatin in combination with. Paclitaxel 175 mg/m 2 The dose of carboplatin for patients based on an AUC of 7.5 and a glomerular filtration rate (GFR) derived from the Jelliffe formula that does not adjust for body weight. Docetaxel-carboplatin or -carboplatin. Carboplatin dose was determined by a measured GFR. Carboplatin dose was derived using the Calvert formula. Taxane dose was calculated using BSA (docetaxel 75 mg/m 2, ; 175 mg/m 2 ) with no dose capping carried out. Platinum- and taxane-based chemotherapy. Drug dosages of and docetaxel were calculated with an actual body weight but the BSA was capped at 2.0. The Calvert formula was used to calculated the dosage of carboplatin based using an AUC of Paclitaxel-carboplatin; docetaxelcarboplatin; -cisplatin; and a combination of one of them with gemcitabine-carboplatin or topotecan. Cockcroft-Gault formula was used to calculate the GFR and the carboplatin dose was calculated using the targeted area under the plasma carboplatin concentrationtime curve from the Calvert formula Wright 2008 Epithelial ovarian cancer patients n=387 BMI <25: 194(50.1) BMI : 122(31.5) BMI 30: 71(18.4) Barrett 2008 Epithelial ovarian cancer patients n=1067 BMI <18.5: 59(5.5) BMI : 582(54) BMI : 305(28) BMI >30: 129(12) Matthews 2009 Epithelial ovarian cancer patients n=304 BMI <30: 233(77) BMI 30: 71(23) AND BMI 18.4: 12(3.9) BMI : 126(41.4) BMI : 95(31.2) BMI : 43(14.1) BMI 35.0: 28(9.2) Suh 2012 Epithelial ovarian cancer patients n=486 BMI<18.5: 31(6.4) 18.5 BMI <23: 224(46.1) 23 BMI <27.5: 179(36.8) BMI 27.5: 52(10.3) First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 39

49 Study Hanna 2013 Patient characteristics Epithelial ovarian cancer patients, stage III-IV, n=325 BMI categories n (%) BMI <30kg/m 2 : 226(69.5) BMI 30kg/m 2 : 67(20.6) N/A: 32(9.9) Chemotherapy characteristics Multi-agent chemotherapy (platinum-based). The most common regimen was carboplatin (AUC=6) and (175 mg/m 2 ). Calculation of RDI required comparison to a standard regimen. Carboplatin AUC 6 was considered standard. In calculating the standard dose, the BSA calculation was based on actual body weight with no capping of BSA value; the Cockcroft/Gault formula was used for creatinine clearance calculation and the Calvert formula for carboplatin dosage calculation. AUC=area under the curve; BMI=Body Mass Index; BSA=body surface area; GFR=Glomerular filtration rate; RDI=relative dose intensity Three studies only included adverse event outcomes, study details are presented in table 6 below. Table 7 Study characteristics of studies reporting adverse event outcomes only Study Patient characteristics Sendo 2005 N=105 Asian ovarian cancer patients who received carboplatin combination chemotherapy Mereu 2009 N=203 Epithelial ovarian cancer patients who underwent ambulatory first-line chemotherapy Outcomes Incidence of hypersensitivity reaction and risk factors including obesity Venous thromboembolism (VTE) risk including BMI Chemotherapy dosing Paclitaxel 180mg/m 2 infused intravenously over 3hr, followed by IV carboplatin infusion over 1hr at an AUC of 5mg/ml minute, according to the Calvert equation The first-line chemotherapy schedules: cysplatinum (CDDP50 mg/mq weekly); cysplatinum + other drugs (CDDP50 mg/mq + cyclophosphamide 600mg/mq±adriamycin 45mg/mq every 3-4 weeks); carboplatin (JM8 AUC6 every 3-4 weeks); carboplatin + other drugs (JM8 AUC mg/mq every 3 weeks, First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 40

50 Study Patient characteristics Outcomes Chemotherapy dosing JM8 AUC6 + epirubicin 120 mg/mq every 4 weeks, JM8 AUC mg/mq + topotecam 1mg/mq per 3 days every 3 weeks). Laskey 2012 N=326 Stage III-IV epithelial ovarian cancer patients treated postoperatively with multi-agent intravenous chemotherapy Predictors of severe and febrile neutropenia including BMI Dose intensity was calculated as the dose for each individual subject per unit time (week). Actual body weight was used to calculate the BSA for the standard dose with no capping of BSA values. The Cockcroft/Gault formula was used for creatinine clearance calculation and the Calvert formula for carboplatin dosage calculation. AUC=area under the curve; BMI=Body Mass Index; BSA=body surface area; RDI=relative dose intensity Outcomes Overall survival Pavelka et al (2006) noted in the analysis of stage III and IV patients, that increasing BMI classification was a negative predictor of overall survival. Median overall survival was 70 months, 79 months and 33 months for ideal body weight, overweight, and obese groups respectively(p=0.02). Median overall survival was not reached for underweight group. 80 Cox proportional hazards model including BMI as a continuous variable confirmed the negative prognostic impact of increasing BMI on overall survival (HR 1.050; 95% CI ; p=0.03). Wright et al (2008) reported no statistically significant differences in overall survival across BMI strata (p=0.41). 82 There was no statistically significant association between BMI category and overall survival (p=0.10) in the SCOTROC I trial (Barrett et al 2008). 78 Median overall survival was 32.9 months (95% CI ) in the underweight group, median survival not attained in the ideal weight group, 30.1 months (95% CI ) in the overweight group and 34.3 months (95% ) in the obese group. Matthews et al (2009) reported no statistical difference in overall survival between obese and non-obese patients (48 vs. 40 months, p=0.37) or when patients were stratified by BMI (underweight 38 months; normal weight 40 months; overweight 33 months; obese 47 months; morbid obesity 48 months; p=0.60). 79 Suh et al (2012) reported similar five-year overall survival rates across BMI categories; 73% in underweight, 58.4% in normal weight, 56.1% in overweight and 65.3% months in obese (p=0.67). 81 Overall survival was also similar across BMI categories in subgroup of patients who received one of the three regimens -carboplatin, docetaxel-carboplatin or -cisplatin, as the first chemotherapy session (p=0.99). In a sub-cohort of stage III-IV patients, overall survival was similar across the four BMI groups (p=0.70). When comparing the two BMI groups, <23 vs. 23 there was no significant differences in overall survival (p=0.83). First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 41

51 Hanna et al (2013) undertook univariate and multivariate analyses to demonstrate factors associated with poor overall survival. Median follow up was 34 months. 83 Death was recorded in 55.1% of patients; median time to death was 34 months. In both univariate analysis and multivariate analysis, delivered RDI <85% was negatively associated with overall survival; HR=1.59, 95% CI , p=0.007 and HR=1.71, 95% CI , p=0.003, respectively. Kaplan-Meier curves demonstrated that reduced delivered RDI <85% was associated with poorer overall survival; p= Progression free survival (PFS) Wright et al (2008) reported no significant differences in PFS across BMI strata (p=0.12). 82 However, after adjustment for age, performance status, histology and residual disease there was an increased relative risk of progression in obese women compared with normal weight women (RR=1.25; 95% CI ; p=0.14). Barrett et al (2008) reported no statistically significant association between BMI category and PFS (p=0.51). 78 Median PFS was 14.7 months (CI 95% ) in the underweight group, 14.7 months (95% CI ) in the ideal weight group, 14.7 months (95% CI ) in the overweight group and 16.6 months (95% CI ) in the obese group. Matthews et al (2009) reported that compared to non-obese patients (BMI <30), obese patients (BMI 30 ) had a lower recurrence rate (68% vs. 79%, p=0.04), but no statistical difference in PFS (17 vs. 11 months, p=0.14). 79 There was no statistically significant difference in PFS across the BMI categories: 9 months underweight, 11 months normal weight, 10 months overweight, 18 months obese and 15 months morbid obesity (p=0.26). Suh et al (2012) reported similar PFS rates across BMI categories; 24 months in underweight, 20 months in normal weight, 22 months in overweight and 25 months in obese (p=0.35). 81 Similar recurrence rates were also reported across the groups: 48.4% in underweight, 45.9% in normal weight, 53.1% in overweight and 42.9% in obese (p=0.43). PFS was also similar across BMI categories in subgroup of patients who received one of the three regimens carboplatin, docetaxel-carboplatin or -cisplatin, as the first chemotherapy session (p=0.28). In a sub-cohort of stage III-IV patients, PFS was similar across the four BMI groups (p=0.68). When comparing the two BMI groups, <23 23 vs. there was no significant differences in PFS (p=0.77). Hanna et al (2013) undertook univariate and multivariate analyses to demonstrate factors associated with reduced PFS. 83 Median follow up was 34 months. Progression or recurrence was recorded in 74.2% of patients; median time to recurrence or progression was 13 months. In multivariate analysis, there were no independent predictors of PFS. Disease free survival (DFS) Pavelka et al (2006) reported in the analysis of stage III and IV patients that BMI >25 was associated with decreased DFS compared with BMI <25 (17 vs. 25 months, respectively, p=0.04). 80 Increasing BMI classification was an independent negative predictor of DFS (p=0.02). Cox proportional hazards model confirmed the negative prognostic impact of each 1-unit increase in BMI on DFS (HR 1.042, 95% CI , p=0.01). First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 42

52 Dosing In the study by Pavelka et al (2006), for advanced stage patients, only 6/146 patients were unable to complete prescribed chemotherapy due to toxicity and these were not associated with BMI grouping. 80 Chemotherapy dose data for 83 patients demonstrated a significant difference in the median dose of per square metre of body surface area between the ideal body weight and obese groups (average 167mg/m 2 vs. 155mg/m 2, respectively, p=0.01). It was stated that given the multiple variables affecting carboplatin doses, this comparison was not undertaken. Wright et al (2008) reported that over the entire treatment course, the average dose of carboplatin received during treatment did not differ across BMI strata. 82 Barrett et al (2008) reported for the SCOTROC I trial overall, no statistically significant differences between the two arms for dose intensity or cumulative dose. In the current study of 1067 patients who received taxane treatment and had recorded BMI, there was neither a statistically significant difference in taxane dose intensity (p=0.120) or carboplatin dose intensity (p=0.578) between the BMI categories. 78 There was also no statistically significant difference between total intended taxane dose (p=0.217) or total intended carboplatin dose (p=0.722) between BMI. Based on the findings of no significant differences in survival between BMI categories from this study in which chemotherapy dose was based on measured GFR, the authors suggested accurate measurement of GFR before commencing chemotherapy and chemotherapy doses based on actual body weight. Matthews et al (2009) reported similar numbers of lines (p=0.83), courses (p=0.87), number of platinum-based regimens (p=0.42), and complication rates of chemotherapy (p=0.39) between obese and non-obese patients. 79 In the study by Suh et al (2012), there were no significant differences across BMI categories for the number of lines of chemotherapy used, the number of courses of chemotherapy or the number of courses before recurrence. 81 The level of neutropenia and platinum sensitivity rate were also similar in BMI groups. Hanna et al (2013) reported predictors of reduced planned RDI or delivered RDI <85% in a multivariate logistic analysis. BSA >2m 2 was reported to be a predictor of reduced planned RDI <85% (OR=6.14, 95% CI , p=<0.001) and BMI >30kg/m 2 was demonstrated to be a predictor of reduced delivered RDI (OR=2.35, 95% CI , p=<0.008). 83 Table 8 Chemotherapy characteristics of Suh 2011 Underweight Normal weight Overweight Obese P value (n=31) (n=224) (n=179) (n=52) Lines of chemotherapy 1.9 ± ± ± ± (mean ± SD) Total courses of 13.9 ± ± ± ± chemotherapy (mean ± SD) Courses of chemotherapy 7.1 ± ± ± ± before recurrence (mean ± SD) Neutropenia (%) 4 (13.3) 39 (19.7) 30 (17.9) 5 (11.1) 0.52 First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 43

53 Underweight Normal weight Overweight Obese P value (n=31) (n=224) (n=179) (n=52) Platinum sensitivity (%) Sensitive (%) 22 (78.6) 142 (76.3) 113 (72.4) 31 (77.5) 0.79 Resistant (%) 6 (21.4) 44 (23.7) 43 (27.6) 9 (22.5) Adverse events Wright et al (2008) reported obese women were less likely to experience moderate to severe thrombocytopenia, leukopenia and granulocytopenia over the entire treatment course compared with normal weight subjects. 82 Schedule delays and dose reductions were more common in the normal weight women than in obese women. Table 9 Cumulative grade 3 and 4 toxicity based on BMI in Wright et al 2008 Grade 3 or 4 toxicity (%) BMI group All < P value Thrombocytopenia Leukopenia < Granulocytopenia Gastrointestinal Genitourinary Neurologic Metabolic Table 10 Treatment modifications based on BMI in Wright et al 2008 Treatment adjustment (%) BMI group All < P value Dose reduction (any course Treatment delay (any course) < Received <6 cycles Matthews et al (2009) reported similar rates of neutropenia for obese and non-obese patients (52% and 46%, p=0.39). In the Japanese study by Sendo et al (2005) a multivariate analysis demonstrated that obesity (BMI >25) significantly affected the incidence of hypersensitivity reactions to (OR 8.47, 95% CI , p=0.017). 86 A retrospective study by Mereu et al (2009) demonstrated an association between increasing BMI and increased risk of venous thromboembolism (VTE) (HR 1.67, 95% CI , p=0.017). 85 BMI comparison was >24.5 vs or less. This association was confirmed in multivariate analysis; HR 1.62, 95% CI , p= First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 44

54 Laskey et al (2012) reported that BMI <30 and BSA <2.0 m 2 were significant predictors of severe neutropenia in women with stage III and IV epithelial ovarian cancer 84 by univariate analysis (p=<0.01 and p=0.03). Multivariate analysis indicated a trend to an association between severe neutropenia and BMI <30 (HR 1.60, p=0.06). Summary ASCO clinical practice guidelines on appropriate chemotherapy dosing for obese adult patients with cancer (not ovarian cancer specific) recommend that full weightbased cytotoxic chemotherapy doses be used to treat obese patients with cancer, particularly when the goal of treatment is cure. No studies were identified which specifically compared different doses of chemotherapy among obese patients for survival outcomes. No prospective studies comparing different doses or schedules of chemotherapy among obese patients with epithelial ovarian cancer were identified. Studies identified were retrospective, and analysed outcomes of chemotherapy between groups stratified by BMI, or for obese compared to non-obese patients. In most of the studies, chemotherapy dosing was based on actual body weight, whereas in some studies (such as carboplatin dosing, for GOG 158 patients by Wright et al, 2008) the formula used did not include body weight or body surface area (BSA). No significant differences in overall, progression-free or disease-free survival were reported between obese and non-obese patients in most of the studies. One study (Pavelka et al, 2006) reported a negative prognostic impact of increasing BMI on overall and disease-free survival in stage III and IV ovarian cancer patients. While the dosing calculations used for these patients were not described, a lower median dose of relative to BSA for obese patients compared to those of ideal body weight was reported. One study (SCOTROC I trial, Barrett et al, 2008) which did not find a link between obesity and poorer prognosis noted this finding to be because of more accurate dose calculations in that study. The authors recommended accurate measurement of GFR and chemotherapy doses based on actual body weight rather than ideal body weight. The majority of studies reported similar numbers of lines, courses, number of platinumbased regimens of chemotherapy between obese and non-obese patients. One study (Hanna et al 2013) determined BSA greater than 2m 2 and BMI >30kg/m 2 to be predictors of reduced planned relative dose intensity (RDI) <85% and reduced delivered RDI <85%. In both univariate analysis and multivariate analysis, delivered RDI <85% was negatively associated with overall survival. Adverse events reported and any differences between BMI groups varied between studies. In the study by Wright et al, in which the carboplatin dose calculation did not adjust for body weight, obese women were reported to experience less treatmentrelated toxicity compared with normal weight subjects. The authors suggested that as obese women were less likely to experience treatment-related toxicity, these women First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 45

55 received a lower effective dose of carboplatin and that body weight should be taken into consideration when calculating carboplatin dose Other issues Other issues to be considered, but not specifically searched for, within this systematic review included: Any other women with specific chemotherapy requirements/issues for example rural/remote, Aboriginal and Torres Strait Islander women Resources specification, for example resources required for intraperitoneal chemotherapy Patient selection criteria While some information was identified on patient selection criteria for included chemotherapy trials, no information was identified on specific chemotherapy requirements or rural/remote/aboriginal and Torres Strait Islander women with ovarian cancer or any papers specifically on resources specification for providing chemotherapy such as requirements for performing intraperitoneal chemotherapy. Patient selection criteria For each of the trials included in this systematic review, details on the patient inclusion/exclusion criteria were recorded. While the majority of trials did not impose an age limit, the median age was most often between 55 and 60 years. Of those which did impose an age limit, two trials included patients up to 65 years, one trial up to 70 years, five trials up to 75 years and one trial up to 80 years. The majority of trials required patients to have a performance status (WHO or ECOG) of 0 to 2. Patients in the trials were also required to have adequate cardiac, bone marrow, hepatic and renal function. Trials excluded patients with borderline or low malignant potential tumours or other concurrent malignancies 3.4 Ongoing trials Clinical trials registries were searched to identify any additional studies investigating various chemotherapy regimens for treatment of ovarian cancer which have not yet reported. Please see Appendix L for details of ongoing trials identified. First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 46

56 4 Discussion In this systematic review of first line chemotherapy for women with epithelial ovarian cancer, 75 citations and two conference abstracts were identified as eligible from a search of the literature published between January 2003 and November Thirty five RCTs were included in the review for the primary research questions, and ten studies that were not RCTs were included for examination of subgroups. Six Cochrane reviews were also used as primary references. The included RCTs were considered to be moderate to high quality and the previously published systematic reviews to be high quality. A recent Cochrane systematic review investigated chemotherapy regimens for patients with early stage ovarian cancer (stage I-IIa). 8 This high quality review found that overall and progression-free survival was improved in early stage ovarian cancer patients who had chemotherapy after surgery compared with those on observation after surgery. Subgroup analysis suggested that women who had optimal surgical staging of their disease were unlikely to benefit from adjuvant chemotherapy, whereas those who had sub-optimal staging did. The authors of the Cochrane review suggested the following approaches for adjuvant chemotherapy for early stage ovarian cancer: 8 1. unilateral, encapsulated, well-differentiated serous and endometrioid carcinoma (stage Ia grade 1, non-optimally staged) may be managed without adjuvant chemotherapy 2. stage Ia, and Ib that has been comprehensively staged, well or moderately differentiated (grade I/2) may be managed without adjuvant chemotherapy 3. poorly or undifferentiated (grade 3) stage Ia/IIb disease should be offered adjuvant chemotherapy 4. non serous histotypes, mucinous and clear cell, should be offered adjuvant chemotherapy. The review of the literature on different chemotherapy regimens for first line treatment of women with epithelial ovarian cancer was limited in the comparisons of trial results that were possible, due to the many different regimens reported. Twenty phase III and seven phase II randomised controlled trials were included which investigated different chemotherapy regimens in populations with a majority of advanced stage ovarian cancer patients. While many regimens have been trialled, including addition of chemotherapy agents to standard regimens or substitution of different agents, almost all failed to demonstrate an overall or progression-free survival benefit compared with standard chemotherapy (most often platinum/taxane combination). Trials which did show survival differences were either in specific patient populations or compared older chemotherapy regimens no longer considered standard. Two randomised controlled trials have shown improved progression-free survival for the biological therapy bevacizumab used in addition to carboplatin and. One of First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 47

57 these studies also indicated for patients at high risk of progression, overall survival benefit with bevacizumab, and greater benefit in progression free survival than for patients at lower risk. Adverse effect profiles reflected the various agents used however there were often limited differences in toxicities between treatment arms. Similarly, most trials reported no significant differences in quality of life between the treatment arms investigated. Similarly, the review of different schedules for chemotherapy regimens for first line adjuvant treatment of epithelial ovarian cancer was limited in the comparisons of trial results that were possible, due to the differences in the schedules investigated between trials. Six phase III and one phase II trials were included which investigated different schedules including dosedense chemotherapy, different doses of the same agent or different timing/cycles of the same regimen. Only one trial, JGOG 3016, showed survival benefits between treatment arms. This study investigated dose-dense compared with standard and reported improved overall survival and progression-free survival in the dose-dense group compared to the conventional group, at short-term follow-up (up to 3 years) and at long-term follow-up (median 6.4 years). While adverse events were often similar between treatments arms, some increased toxicity was observed in the higher dose, more intensive chemotherapy intervention arms compared with standard arms. Quality of life was not assessed in any of the trials. The recent high quality Cochrane systematic review on the effectiveness of IP chemotherapy in treating ovarian cancer found that the inclusion of an IP component of chemotherapy improved overall and progression-free survival. IP chemotherapy however was associated with significantly more pain, fever, infection, metabolic complications and gastrointestinal adverse effects than IV chemotherapy. 56 Quality of life was reported in one trial only. More disruption in quality of life was noted in the IP arm during and shortly after treatment, but it then improved over time in both arms. It was noted in the review that current standard therapy is carboplatin with or without a taxane and that ongoing trials are investigating IP carboplatin rather than cisplatin which was mainly used in the older trials included in the review. 56 The authors of this Cochrane review concluded that their review supports the use of IP chemotherapy, however the potential for catheter related complications and toxicity needs to be considered when deciding on the most appropriate treatment for each individual woman. 56 Currently only one randomised controlled trial has been published comparing neoadjuvant chemotherapy with primary surgery, although further studies are ongoing. In this high quality trial, no survival differences between treatment arms were observed. 63 More adverse events were observed in the primary surgery group than the neoadjuvant group, however whether this was statistically significant was not reported. There were no differences in quality of life between treatment arms. Limited information was identified on subsets, such as such as BRCA mutation carriers, elderly patients or different histological subgroups, which may have specific chemotherapy requirements for first line adjuvant treatment of epithelial ovarian cancer. While some data on subgroups was identified, in general the studies were not designed to investigate the effectiveness of different chemotherapy regimens across different subgroups. No studies were identified which specifically compared different doses of chemotherapy among obese patients for survival outcomes. In most of the studies, chemotherapy dosing was based on actual body weight, whereas in some studies the formula used did not include First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 48

58 body weight or body surface area (BSA). No significant differences in overall, progressionfree or disease-free survival were reported between obese and non-obese patients in most of the studies. The majority of studies reported similar numbers of lines, courses, number of platinum-based regimens of chemotherapy between obese and non-obese patients. One study (Hanna et al 2013) determined BSA greater than 2m 2 and BMI >30kg/m 2 to be predictors of reduced planned relative dose intensity (RDI) <85% and reduced delivered RDI <85%. In both univariate analysis and multivariate analysis, delivered RDI <85% was negatively associated with overall survival. Adverse events varied between studies. In the study by Wright et al, in which the carboplatin dose calculation did not adjust for body weight, obese women were reported to experience less treatment-related toxicity compared with normal weight subjects. The authors suggested that as obese women were less likely to experience treatment-related toxicity, these women received a lower effective dose of carboplatin and that body weight should be taken into consideration when calculating carboplatin dose. 82 First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 49

59 5 Conclusion This systematic review considered the evidence on different regimens, schedules, mode of administration and time of administration of chemotherapy regimens, and on subsets with specific chemotherapy requirements, for first line adjuvant treatment of epithelial ovarian cancer. For early stage ovarian cancer patients who had chemotherapy following surgery, overall and progression-free survival was improved compared with women on observation following surgery. However subgroup analysis suggested that women who had optimal surgical staging of their disease were unlikely to benefit from adjuvant chemotherapy, whereas those who had sub-optimal staging did. Standard first line chemotherapy for advanced epithelial ovarian cancer is currently a platinum agent combined with a taxane. While many different regimens have been investigated, including addition or substitution of chemotherapy agents and different schedules of treatment, almost all failed to demonstrate an overall or progression-free survival benefit compared with standard chemotherapy. Some improvements in progressionfree survival have been reported for bevacizumab used in addition to carboplatin and. Inclusion of an intraperitoneal component of chemotherapy improved overall and progression-free survival, however women receiving intraperitoneal chemotherapy reported more adverse events than those on standard chemotherapy. One randomised controlled trial has compared neoadjuvant chemotherapy with primary surgery and no survival differences between treatment arms were observed. Limited information was identified on subsets, for first line adjuvant treatment of epithelial ovarian cancer. While some data were identified on subsets that may have specific chemotherapy requirements, such as BRCA mutation carriers, elderly patients or different histological subgroups, in general trials were not designed to investigate the effectiveness of different chemotherapy regimens across different subgroups. No prospective studies comparing different doses or schedules of chemotherapy among obese patients with epithelial ovarian cancer were identified. Studies identified were retrospective, and analysed outcomes of chemotherapy between groups stratified by BMI, or for obese compared to non-obese patients. Based on the evidence from this systematic review, updates to existing clinical practice recommendations are required for first line adjuvant treatment of epithelial ovarian cancer, as well as new clinical practice recommendations, such as for the use of dose-dense chemotherapy. The current evidence is inadequate to support clinical practice recommendations for the use of bevacizumab. First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 50

60 Appendix A Contributors The following Cancer Australia staff were involved in the development of First line chemotherapy for the treatment of women with epithelial ovarian cancer: a systematic review Ms Katrina Anderson Senior Project Officer, Evidence Review Mr Paul Cramer General Manager, Programs, Project Sponsor Ms Jane Francis Manager, Gynaecological Cancers Ms Emma Hanks Senior Project Officer Ms Charmaine Larment Senior Project Officer Dr Anne Nelson Manager, Evidence Review Ms Lara Matkovic Senior Project Officer Ms Angela Pearce Senior Project Officer, Research Ms Sue Sinclair General Manager, Service Delivery and Clinical Practice Ms Rosemary Wade Senior Project Officer, Research First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 51

61 Appendix B Literature databases searched Source Medline (OVID) Embase Pubmed Results/Retrievals 412 (86 subgroup search and 119 obesity search) 567 (128 subgroup search and 271 obesity search) 774 (167 subgroup search and 399 obesity search) First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 52

62 Appendix C Search strategy Ovarian cancer Ovarian Neoplasms/ ovarian neoplasms ovarian and (cancer or carcinoma or tumour or tumor) First line Chemotherapy Antineoplastic agents/ Drug therapy/ (("first line" or first-line or "1st line" or "primary treatment" or newly diagnosed ) and (chemotherapy or systemic therapy ) RCTs Meta-analysis/systematic review Randomized controlled trials/ or randomized controlled trials or randomized controlled trial or randomised controlled trials or randomised controlled trial or random allocation or double blind method or single blind method or controlled trial$ Meta-analysis/ meta-analysis or meta analysis or systematic review or pooled analysis Obesity Obese or obesity or body weight or overweight or over weight or BMI or body mass index or adiposity or fat or body surface First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 53

63 Appendix D Health technology assessment, guidelines and clinical trials websites searched Acronym Organisation Website Canada CCO Cancer Care Ontario International HTAi Health Technology Assessment International Scotland SIGN Scottish Intercollegiate Guidelines Network UK CCT Current Controlled Trials NICE National Institute for Health and Clinical Excellence NRR National Research Register US ClinicalTrials.gov NCI National Cancer Institute Clinical Trials NGC National Guideline Clearinghouse First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 54

64 Appendix E Flowchart-inclusion/exclusion of articles First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 55

65 Appendix F International guidelines and recommendations 1. Ovarian Cancer Guidelines National Comprehensive Cancer Network (NCCN) (US) version NCCN provides flow-charts with management pathways for epithelial ovarian cancer. Chemotherapy information is provided on: Principles of chemotherapy Primary chemotherapy/primary adjuvant therapy for stage I-IV o This section includes guidance on intraperitoneal (IP) chemotherapy as well as suggested drug regimens used for ovarian cancer Recurrent disease 2. The recognition and initial management of ovarian cancer (CG122) National Institute for Health and Clinical Excellence (NICE) (UK) 2011 Recommendations are provided regarding the following areas: Adjuvant systemic chemotherapy for stage I disease o Recommendations: IP chemotherapy o Do not offer adjuvant chemotherapy to women who have had optimal surgical staging and have low risk stage I disease (grade I or 2, stage Ia or Ib) Offer women with high-risk stage I disease (grade 3 or stage Ic) adjuvant chemotherapy consisting of six cycles of carboplatin Discuss the possible benefits and side effects of adjuvant chemotherapy with women who have had suboptimal surgical staging and appear to have stage I disease Recommendation: Do not offer intraperitoneal chemotherapy to women with ovarian cancer except as part of a clinical trial Chemotherapy regimens first line o refers to NICE technology appraisal on use of recommendations from this technology appraisal are below It is recommended that in combination with a platinum based compound or platinum-based therapy alone (cisplatin or carboplatin) are offered as alternatives for first line chemotherapy (usually following surgery) in the treatment of ovarian cancer. The choice of treatment for first line chemotherapy for ovarian cancer should be made after discussion between the responsible clinician and the patient about the risks and benefits of the options available. In choosing between treatment with a platinum-based compound alone or in combination with a platinum-based compound, this discussion should cover the side-effect profiles of the alternative First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 56

66 therapies, the stage of the woman s disease, the extent of surgical treatment of the tumour, and disease-related performance status. 3. Epithelial ovarian cancer. A national clinical guideline Scottish Intercollegiate Guidelines Network (SIGN) 2003 (reaffirmed 2007). Given these guidelines are older than the current ACN/NBCC guidelines, further information is not provided here. 4. Ovarian carcinoma Association of Comprehensive Cancer Centres - The Netherlands 2009 Includes the following recommendations for chemotherapy: Treatment of low-stage carcinoma (I-IIa) o Recommendations for chemotherapy The committee advises that a complete surgical (re)staging is performed in patients with a clinical low-stage ovarian carcinoma. When a complete (re)staging cannot be performed, the committee advises adjuvant chemotherapy. Because of a substantial chance of micrometastasis in the case of incomplete staging (NCS), it is advised to treat these patients as a stage III tumour with sic courses of carboplatin. After complete staging (CS), the committee recommends an expectative policy (surgery only). Specifically in relation to grade 3 tumours, the committee could not reach an agreement. A number of members were supporters of providing additional chemotherapy in this situation, but there is no scientific data to support this statement. Treatment of high-stage carcinoma (IIb-IV) o o Current standard chemotherapy for stage FIGO IIb-IV consists of combination therapy with: Taxol 175 mg/m2 (in a 3-hour infusion) Carboplatin with an area-under-the-curve (AUC) of 6 (creatinine clearance calculated using the Cockcroft-Gault formula and the dosage carboplatin via the Calvert formula) or Taxol 175 mg/m2 (in a 3-hour infusion) Cisplatin 75 mg/m2. A minimum of six three-weekly courses are administered (more extensive information on this can be found on 'SIB op maat.' (SIB op maat is a website with patient information on adverse events related to drugs used in the treatment of cancer). o IP chemo Recommendations It has been shown that the addition of intraperitoneal (IP) chemotherapy to intravenous chemotherapy for patients with a FIGO stage III ovarian carcinoma that have had a complete or optimal debulking (residual intraperitoneal lesions, <1 cm) First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 57

67 o o leads to a better disease-free and overall survival. However, treatment is associated with substantial toxicity. Restraint should be exercised with IP chemotherapy if there is an increased risk of anastomotic leakage, such as after colon surgery. It is plausible to advise the schedule used by Armstrong, on the basis of the greatest advantage in survival. There are indications that less catheter obstructions are seen with a single lumen bard, a non-fenestrated 9.6 F catheter. It is the opinion of the committee that this treatment requires a particular expertise; as a result, it is advised that this treatment is performed in a centre that has gained experience in this area. All information relating to patients treated with IP chemotherapy should be registered, for a clear picture of the complications. Chemo in platinum-resistant tumours Platinum-resistant tumours can be treated with topotecan, liposomal doxorubicin, gemcitabine, oral etoposide or weekly platinum combination therapy. Approximately 12% to 15% of patients will respond to these agents, while around 30% of patients will have stable disease with a time to progression period between 12 to 22 weeks. Induction chemo with intervention surgery Recommendations Await the outcome of EORTC Until such time, continue using standard policy: primary cytoreductive surgery followed by multichemotherapy. 5. Adjuvant Care for Stage 1 Ovarian Cancer Cancer Care Ontario 2004 This guidelines includes the following recommendations relating to chemotherapy: Women who have undergone optimal surgical staging, including pelvic and paraaortic lymph node sampling, and have stage I disease may or may not benefit from adjuvant platinum-based chemotherapy Women who have not undergone optimal surgical staging can be offered two options. The first option is that they undergo re-operation to optimally define the tumour stage and then be offered adjuvant therapy based on the findings. The other option is that they be offered platinum-based chemotherapy to decrease the risk of recurrence and improve survival 6. Chemotherapy specific An additional two guidelines were identified specifically relating to the use of chemotherapy in ovarian cancer. Both guidelines were published by Cancer Care Ontario. 6.1 First-line Chemotherapy for Postoperative Patients with Stage II, III or IV Epithelial Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer Cancer Care Ontario 2004 Update The following recommendations are made in this guideline: First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 58

68 Intravenous carboplatin with or without or docetaxel is the recommended postoperative chemotherapy regimen for newly diagnosed stage II-IV epithelial ovarian cancer o Paclitaxel in combination with carboplatin is associated with greater neurotoxicity than docetaxel and carboplatin, however, the combination of docetaxel and carboplatin is associated with more myelosuppresion than and carboplatin. The differences in the toxicity profiles should be discussed with patients when choosing the most appropriate regimen Intravenous cisplatin plus may also be considered as a treatment option 6.2 The Role of Intraperitoneal Chemotherapy in the First-line Treatment of Women with Stage III Epithelial Ovarian Cancer Cancer Care Ontario 2006 The following recommendations on IP chemotherapy are made in this guideline: As front-line therapy, the intravenous administration of a platinum agent and a taxane remains a standard of care for this patient population. Cisplatin-containing intraperitoneal chemotherapy should be offered to patients on the basis of significant improvements in progression-free and overall survival when compared with cisplatincontaining intravenous chemotherapy alone. o o The survival benefits associated with intraperitoneal chemotherapy must be weighed against the statistically significant increases in toxicity and catheterrelated complications. For patients with residual tumour diameter 1 cm in any one area, significant survival benefits were detected with intraperitoneal chemotherapy. For patients with disease volumes > 1 cm in any one area, the role of intraperitoneal chemotherapy is yet to be defined. The optimal intraperitoneal chemotherapy regimen has yet to be defined. The greatest median survival benefits were detected with intraperitoneal cisplatin and ; however, only 42% of patients were able to complete all six cycles of the assigned treatment. First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 59

69 Appendix G Overall and progression free survival for studies investigating different chemotherapy regimens Study Intervention Comparator Survival Overall survival Progression-free survival Intervention Comparator pvalue Intervention Comparator pvalue Phase III trials Trials which investigated the addition of agents to standard chemotherapy OVAR 5, du Epirubicin + Carboplatin + median 45.8 median 41.0 Adjuste median median 17.9 HR 0.95 Bois carboplatin + months months d 18.4 months p=0.334 treatme months 2 nt effect 0.93; OVAR 9, du Gemcitabine + Carboplatin + median 49.5 median median median 19.3 p<0.01 Bois carboplatin + months months 17.8 months months GOG 182 / i) Gemcitabine + Carboplatin + median 44.1 months median 16.0 months ICON 5, carboplatin + Bookman ii) Doxorubicin + carboplatin + iii) Topotecan + carboplatin carboplatin + iv) Gemcitabine + carboplatin carboplatin + First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 60

70 Study Intervention Comparator Survival Overall survival Progression-free survival Intervention Comparator pvalue Intervention Comparator pvalue Bolis Topotecan + Carboplatin + carboplatin + 5yr: 32% 5yr: 32% NS NS OVAR 7, Pfisterer OV 16, Hoskins (abstract only) Carboplatin + topotecan Cisplatin + topotecan x 4 cycles + carboplatin x 4 cycles Cisplatin + doxorubicin + Carboplatin + Carboplatin + x 8 cycles median 43.1 months; 3yr: 55.7% median 44.5 months; 3yr: 58.5% HR 1.01 ; HeCOG, Carboplatin + median median p=0.53; Aravantinos months; 5yr OS months ; 5yr NR; rate: 40.6% OS rate: 38.9% multivar iate analysis HR 0.86 p=0.23 Lhomme Paclitaxel + Carboplatin + 32 months 28.9 months HR carboplatin , valspodar (PSC 833) p=0.94 Trials which substituted the use of one chemotherapy agent with another chemotherapy agent median 18.2 months median 14.6 months median months; 5yr PFS rate: 26.6% median 13.2 months median 18.5 months median 16.2 months median months; 5yr PFS rate: 22.2% median 13.5 months HR 0.97 p=0.688 HR 1.10 p= ; NR; multivari ate analysis HR p=0.009 HR 0.96, p=0.67 First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 61

71 Study Intervention Comparator Survival Overall survival Progression-free survival Intervention Comparator pvalue Intervention Comparator pvalue GOCCNE, Cisplatin + Adriamycin + median 39.4 median ; DFS DFS median DFS Nicoletto 2007 cyclophosphamide cyclophosphamide months; 5yr: 39%, , median months; ; 25 10yr: 31%, 15yr: months; , months; 5yr: 40%, 10yr: , 28% 5yr: 32%, 10yr: 23%, yr: 49%, 10yr: 31%, 37%, 15yr: 31% , yr: 16% 15yr: 31% SGCTG, Reed Treosulfan Carboplatin median 12 months median 15 months RR 1.77 p< months 10 months RR 1.77 p<0.001 MITO 2, Pignata Carboplatin + Carboplatin + median 61.6 median HR 0.89 median median 16.8 HR doxorubicin months 53.2 p= months p=0.58; months months multivari ate analysis HR 0.97 p=0.70 SCOTROC, Docetaxel + Carboplatin + 2yr: 64.2% 2yr: 68.9% HR 1.13 median 15 median 14.8 HR 0.97 Vasey carboplatin p=0.238 months months p=0.707 GOG 158, Cisplatin + Carboplatin + median 57.4 median RR 0.84 median median 19.4 NS; RR of Ozols months months treatme months months nt failure is 0.88 ( ) OVAR 3, du Cisplatin + Carboplatin + median 44.1 median HR Disease Disease NS; HR Bois 2003, months 43.3 progression progression at 1.05 Greimel ,30 months at 2yr: 60%; 2yr: 62.5%; median median months First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 62

72 Study Intervention Comparator Survival Overall survival Progression-free survival Intervention Comparator pvalue Intervention Comparator pvalue months HeCOG, Paclitaxel + Carboplatin + median 38.6 median median median 39 median 38 median Aravantinos carboplatin months; 5yr: 39% 40.6 p=0.79 months; months; 5 yr p= cisplatin months; 5 5yr: 28% 29% yr 35% Mouratidou Cisplatin + Cisplatin + median 24 median median 12 median cyclophosphamide months months months months OV10, Piccart Cisplatin + Cisplatin + 34% alive 23% alive HR 0.75); better 2003, Bezjak cyclophosphamide , Butler <0.001 AOCSG, Dittrich Cisplatin + carboplatin Cisplatin + cyclophosphamide median 43.0 months median 41.2 RR 1.05 p=0.75 median 23.1 median 29.7 months RR 1.03 months months p=0.88 Phase II trials Trials which investigated the addition of agents to standard chemotherapy Muthuramaling Carboplatin + Carboplatin am thalidomide SCOTROC2A, Carboplatin Carboplatin median ii) median i) Vasey docetaxel + docetaxel gemcitabine months, iii) months 13.7 months SCOTROC2B, Carboplatin Carboplatin median median Clamp docetaxel + docetaxel irinotecan months months Trials which substituted the use of one chemotherapy agent with another chemotherapy agent Minagawa Docetaxel + cisplatin Carboplatin + docetaxel First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 63

73 Study Intervention Comparator Survival Overall survival Progression-free survival Intervention Comparator pvalue Intervention Comparator pvalue Mori Docetaxel + Carboplatin + 2yr: 61.5% 2yr: 68.5% NS median median NS carboplatin months months JGOG3014, Irinotecan + Carboplatin + NS NS Takakura cisplatin Fruscio Cisplatin + Cisplatin + 51 months 65 months 25 months 23 months + isosfamide + epirubicin First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 64

74 Appendix H Overall and progression free survival for biological therapy studies Study Intervention Comparator Survival Overall survival Progression-free survival Intervention Comparator pvalue Intervention Comparator pvalue Phase III trials Trials which investigated the addition of agents to standard chemotherapy OVAR 11 / ICON 7, Perren GOG 218, Burger Bevacizumab + carboplatin + i) Bevacizumab + carboplatin + ii) Bevacizumab + carboplatin + bevacizumab Carboplatin + Carboplatin + 1yr 95%; updated analysis: 1 yr 92% median ii) 38.7 months, iii) 39.7 months 1yr 93%; updated analysis: 1 yr 86% i) median 39.3 months HR 0.81 p=0.098 ; update d analysis: HR 0.85 p=0.11 i) vs ii) HR p=0.76; i) vs iii) HR p=0.45 median 19.0 months; updated analysis: 19.8 months median ii) 11.2 months, iii) 14.1 months median 17.3 months; updated analysis: 17.4 months median i) 10.3 months HR 0.81 p=0.004; update d analysis: HR 0.87 p=0.04 i) vs ii) HR 0.908, p=0.16; i) vs iii) HR p<0.001 First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 65

75 Appendix I Adverse events reported in trials investigating different chemotherapy regimens (research question 1) Adverse events that were reported to be different between treatment arms are included in the Table, adverse events which were not significantly different between treatment arms are not reported here. Study Intervention Comparator Adverse events Worse on intervention Phase III trials Worse on comparator OVAR 5, du Bois OVAR 9, du Bois GOG 182 / ICON 5, Bookman Epirubicin + carboplatin + Gemcitabine + carboplatin + i) Gemcitabine + carboplatin + ii) Doxorubicin + carboplatin + iii) Topotecan + carboplatin carboplatin + iv) Gemcitabine + Carboplatin + Carboplatin + Carboplatin + Granulocytopenia (SS), Anaemia (SS), Neutropenia (SS), Febrile neutropenia (SS), Thrombocytopenia (SS), Infections (SS), Nausea and vomiting (SS), Stomatitis (SS), Days on IV antibiotics (SS), RBC transfusions (SS), G-CSF Granulocytopenia (SS), Anaemia (SS), Neutropenia (SS), Febrile Neutropenia (SS), Thrombocytopenia (SS), Fatigue, Days on IV antibiotics (SS), RBC transfusions (SS), G- CSF (SS) There was increased hematologic toxicity in the triplet regimens and increased thrombocytopenia in both arms with gemcitabine. Neuropathy was decreased in the doublet regimens, which included only four cycles of. Transient elevations of transaminases were more commonly observed in arms with gemcitabine, but they were generally without clinical impact. There was no significant increase in pulmonary toxicity Pain (other) (SS) Renal toxicity First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 66

76 Study Intervention Comparator Adverse events Worse on intervention carboplatin associated with gemcitabine. carboplatin + Bolis Topotecan + Carboplatin + Higher percentage experienced 1 life carboplatin + threatening adverse event (SNR), Leukopenia (SS), Anaemia (SS), Neutropenia (SS), Fatigue (BS), RBC transfusions (SS), G-CSF (SS) OVAR 7, Pfisterer OV 16, Hoskins (abstract only) HeCOG, Aravantinos Carboplatin + topotecan Cisplatin + topotecan x 4 cycles + carboplatin x 4 cycles Cisplatin + doxorubicin + Carboplatin + Carboplatin + x 8 cycles Carboplatin + Leukopenia (SS), Anaemia (SS), Neutropenia (SS), Thrombocytopenia (SS), Allergic reaction (SS), Infections (SS), Arrhythmia (SS), Constipation (SS), Days on IV antibiotics (SS), RBC transfusions (SS), G- CSF (SS) Febrile neutropenia (SNR), Hospitalisations (SNR) Deaths from treatment slightly higher (SNR) Febrile neutropenia (SS) Worse on comparator Neutropenia Lhomme Paclitaxel + carboplatin + valspodar (PSC 833) Carboplatin + Grade 3 or 4 adverse events (SS); serious adverse events (SS), Neurotoxicity (SNR), Grade 4 neutropenia (SS), Febrile neutropenia (SS), Grade 4 thrombocytopenia (SS), Hyperbilirubinemia (SNR), Ataxia (SS), Gastrointestinal toxicity Toxicity not reported GOCCNE, Nicoletto Cisplatin + cyclophosphamide Adriamycin + cyclophosphamide SGCTG, Reed Treosulfan Carboplatin Anaemia (SS), Neutropenia (SS) MITO 2, Pignata Carboplatin + Carboplatin + Anaemia (SS), Thrombocytopenia (SS), Neurotoxicity (SS), doxorubicin Cardiotoxicity (NS), Skin toxicity (SS), Neutropenia (NS), First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 67

77 Study Intervention Comparator Adverse events Worse on intervention Worse on comparator Stomatitis (any grade: SS, severe: NS) RBC transfusions (SS) Alopecia (SS), Diarrhoea (any grade: SS, severe: NS) SCOTROC, Vasey Docetaxel + carboplatin Carboplatin + Allergic reaction (SS), Neutropenia (SS), Febrile neutropenia (SS), Nausea (SS), Neurotoxicity (SS), Alopecia (SS), Myalgia (SS) Diarrhoea (SS), Stomatitis (SS) GOG 158, Ozols Cisplatin + Carboplatin + Leukopenia (SS), Gastrointestinal, renal and metabolic toxicity Thrombocytopenia (SS) OVAR 3, du Bois 2003, Greimel ,30 Cisplatin + Carboplatin + HeCOG, Aravantinos Paclitaxel + carboplatin cisplatin Carboplatin + Mouratidou Cisplatin + Cisplatin + cyclophosphamide OV10, Piccart 2003, Bezjak 2004, Butler AOCSG, Dittrich Phase II trials Cisplatin + Cisplatin + cyclophosphamide Cisplatin + carboplatin Cisplatin + cyclophosphamide Neuropathy (SS), Nausea and vomiting (SS) Nausea and vomiting (SS) Neurotoxicity (SNR); Neutropenia (SS), Thrombocytopenia (NS), Alopecia (SS), Myalgia (SS), Toxicity not reported Granulocytopenia (SS), Anaemia (SS), Thrombocytopenia (SS), Nausea and vomiting (SS), Ototoxicity (SS) Leukopenia (SS), Neutropenia (SS), Febrile neutropenia (SS), Thrombocytopenia (SS), Infections (SS), RBC transfusions (SS), G-CSF Deaths from treatment slightly higher (SNR) Nausea and vomiting (NS) Muthuramalingam SCOTROC2A, Vasey SCOTROC2B, Clamp Carboplatin + thalidomide Carboplatin docetaxel + gemcitabine Carboplatin docetaxel + irinotecan Carboplatin Carboplatin docetaxel Carboplatin docetaxel Constipation (SNR), Dizziness (SNR), Fatigue (SNR), Neurotoxicity (SNR) Anaemia (SS), Thrombocytopenia (SS), Dyspnoea (SS) Alopecia (SNR), Diarrhoea (SNR) Neutropenia (SS), Alopecia (SS) Neurotoxicity (SNR), Neutropenia (SNR), Febrile First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 68

78 Study Intervention Comparator Adverse events Worse on intervention Minagawa Docetaxel + cisplatin Carboplatin + docetaxel Mori Docetaxel + Carboplatin + carboplatin JGOG3014, Irinotecan + cisplatin Carboplatin + Takakura Fruscio Cisplatin + + Cisplatin + isosfamide + epirubicin No significant differences reported Gastrointestinal toxicities (NS) Leukopenia (SS), Anaemia (SS), Grade 3 febrile neutropenia (SS), Fever (SS), Hospitalisations (SS), Transfusions (SS) Worse on comparator neutropenia (SNR) Grade 4 neutropenia (SS), Diarrhoea (SS), G-CSF (SS) Neurotoxicity (SS), Thrombocytopenia (SS) BS=borderline significance (p=0.05); G-CSF= ; NS=not significant; RBC=red blood cell; SNR=significance not reported; SS=statistically significant First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 69

79 Appendix J Adverse events reported in trials investigating biological therapies Study Intervention Comparator Adverse events Worse on intervention Worse on comparator Phase III trials OVAR 11 / ICON 7, Perren GOG 218, Burger Bevacizumab + carboplatin + i) Bevacizumab + carboplatin + ii) Bevacizumab + carboplatin + bevacizumab Carboplatin + Carboplatin + Overall toxicity higher (SNR), Deaths from treatment slightly higher (SNR), Hypertension higher (SNR) Hypertension (SS), Deaths from treatment slightly higher, particularly in intervention group (ii) (SNR) hypertension, proteinuria and pain were more commonly reported in the extended therapy phase among patients in the bevacizumab throughout group (iii). First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 70

80 Appendix K ASCO clinical practice guideline recommendations for chemotherapy dosing for obese adults with cancer 76 Clinical Question 1. Is there evidence that full weight based dosing increases toxicity in obese patients with cancer? 2. Is there evidence that less than full weight based dosing compromises efficacy in obese patients with cancer? 3. If an obese patient experiences highgrade toxicity, should chemotherapy doses or schedules be modified differently from modifications used for non-obese patients with cancer? 4. Is the use of fixed-dose (dose prescribed independently of weight or BSA) cytotoxic chemotherapy ever justified? Are there unique dosing considerations for certain chemotherapeutic agents? 5. How should BSA be calculated? Specifically, what is the best formula for use with the obese patient with cancer? 6. What is the role of pharmacokinetic and/ or phamacogenetic factors when determining optimal chemotherapy dose and delivery (bolus, infusional, therapeutic drug monitoring) for obese patients with cancer? Recommendation Recommendation 1.1: The Panel recommends that actual body weight be used when selecting cytotoxic chemotherapy doses regardless of obesity status. There is no evidence that short- or long-term toxicity is increased among obese patients receiving full weight based chemotherapy doses. Most data indicate that myelosuppression is the same or less pronounced among the obese than the non-obese administered full weight based doses. Recommendation 1.2: The Panel recommends full weight based chemotherapy dosing for morbidly obese patients with cancer, subject to appropriate consideration of other comorbid conditions. Data are extremely limited regarding optimal dose selection among the morbidly obese and other special subgroups. More studies are needed to evaluate optimal agents and agent combinations for obese and morbidly obese patients with cancer; however, based on available information, it seems likely that the same principles regarding dose selection for obese patients apply to the morbidly obese. Recommendation 2.1: The Panel recommends that full weight based chemotherapy doses (IV and oral) be used in the treatment of the obese patient with cancer, particularly when the goal of treatment is cure. Selecting reduced doses in this setting may result in poorer disease-free and overall survival rates. There are compelling data in patients with breast cancer that reduced dose-intensity chemotherapy is associated with increased disease recurrence and mortality. Although data in other malignancies are more limited, based on improved survival observed with chemotherapy compared with controls, a dose-response relationship exists for many responsive malignancies. Therefore, although data are not available to address this question for all cancer types, in the absence of data demonstrating sustained efficacy for reduced dose chemotherapy, the Panel believes that the prudent approach is to provide full weight based hemotherapy dosing to obese patients with cancer, especially those receiving treatment with curative intent. Most of the data in support of full weight based dosing come from the treatment of early-stage disease. Data supporting the use of full weight based doses in the advanced disease setting are limited. Recommendation 3.1: Clinicians should follow the same guidelines for dose reduction, regardless of obesity status, for all patients, depending on the type and severity of toxicity, any comorbid conditions, and whether the treatment intention is cure or palliation. There is no evidence to support the need for greater dose reductions for obese patients compared with non-obese patients. If a dose reduction is employed in response to toxicity, consideration should be given to the resumption of full weight based doses for subsequent cycles, especially if a possible cause of toxicity (eg, impaired renal, hepatic function) has been resolved. The Panel recognizes the need for clinicians to exercise judgment when providing care for patients who have experienced grade 3 or 4 chemotherapy toxicity. The presence of obesity alone should not alter such clinical judgment. Recommendation 4.1: The Panel recommends consideration of fixed dosing only with select cytotoxic agents (eg, carboplatin and bleomycin). On the basis primarily of neurotoxicity concerns, vincristine is capped at a maximum dose of 2.0 mg when used as part of the CHOP and CVP regimens. Several other cytotoxic chemotherapeutic agents have been used in clinical trials at a fixed dose independent of patient weight or BSA. However, it is not clear that fixed dosing is optimal for any of these other agents. Recommendation 5.1: The Panel recommends that BSA be calculated using any of the standard formulae. There is no evidence to support one formula for calculating BSA over another. Recommendation 6.1: The Panel recommends further research into the role of pharmacokinetic and pharmacogenetic information for guiding the dosing of IV and oral chemotherapeutic agents for adult patients with cancer who are obese. It should be emphasized that there is a paucity of information on the influence of obesity on the pharmacokinetics of most anticancer drugs from properly powered trials. This is the result, inpart, of empiric eligibility restrictions from the outset in clinical trials and a lack of pharmacokinetic analyses performed and published for this subpopulation. Overall, there are insufficient pharmacokinetic data to reject the recommendation to use a full weight based dosing strategy for chemotherapeutic agents in patients with cancer who are obese, regardless of route of administration and/or infusion time. Abbreviations: BSA, body surface area; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CVP, cyclophosphamide, vincristine, prednisone; IV, intravenous. First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 71

81 Appendix L Ongoing trials Research question 1 Trial name and location Study design Participants Intervention Control Completion status NCT UK Phase 2 RCT, openlabel Stage IIIC or stage IV ovarian cancer, fallopian tube cancer, or primary peritoneal cancer n=88 Neoadjuvant Carboplatin surgery adjuvant Paclitaxel and Gemcitabine Neoadjuvant Gemcitabine and Carboplatin surgery adjuvant Paclitaxel Unknown NCT Italy and Germany Phase 2 RCT, doubleblind Advanced ovarian cancer n=120 ZD4054, Paclitaxel, Carboplatin Placebo, Paclitaxel, Carboplatin Completed NCT France Phase 2 RCT, doubleblind Adenocarcinoma of the ovary, the fallopian tube, or serous adenocarcinoma of the peritoneum n=188 Neo-adjuvant chemotherapy (Carboplatin and Paclitaxel), interval debulking surgery, Vargatef (Nintedanib) Neo-adjuvant chemotherapy (Carboplatin and Paclitaxel), interval debulking surgery Ongoing First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 72

82 Trial name and location Study design Participants Intervention Control Completion status NCT Bangladesh Phase 2 RCT, openlabel Advanced or metastatic ovarian cancer Docetaxel, Cisplatin, Cyclophosphamide Docetaxel, Carboplatin Completed n=30 NCT US, Belgium, Germany Phase 2 RCT, doubleblind Advanced ovarian cancer, fallopian tube neoplasms, peritoneal neoplasm n=149 Carboplatin, Paclitaxel, Enzastaurin 1125 (LY317615) Carboplatin, Paclitaxel, Placebo Ongoing NCT International Phase 2 RCT, doubleblind Advanced ovarian cancer n=211 Carboplatin, Paclitaxel, AZD0530 Carboplatin, Paclitaxel Completed NCT UK Phase 3 RCT, openlabel Stage II, stage III, stage IV, or recurrent stage I epithelial ovarian cancer or fallopian tube cancer Oxaliplatin and Capecitabine +/- Bevacizumab Carboplatin and Paclitaxel +/- Bevacizumab Ongoing n=332 NCT USA Phases 2/3 RCT Stage III ovarian and primary peritoneal cancers n= 360 Carboplatin, Paclitaxel, SCH Carboplatin, Paclitaxel Completed First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 73

83 Trial name and location Study design Participants Intervention Control Completion status ISRCTN International Phase 3 RCT Clear cell carcinoma of the ovary Irinotecan, Cisplatin Paclitaxel, Carboplatin Completed n=652 EUCTR International Phase 3 RCT, doubleblind Advanced ovarian cancer, fallopian tube cancer, or primary peritoneal cancer n=1300 Carboplatin, Paclitaxel, BIBF 1120 Carboplatin, Paclitaxel, placebo Ongoing NTR1491 The Netherlands Phase 2 RCT, openlabel Epithelial ovarian, fallopian tube, or primary peritoneal carcinomas n=200 Docetaxel, Carboplatin, Celecoxib Docetaxel, Carboplatin Ongoing NCT US Phase 2 RCT Advanced ovarian epithelial cancer n=30 Cisplatin, Topotecan, Paclitaxel, Carboplatin Cisplatin, Topotecan Completed ISRCTN Germany Phase 2 RCT, openlabel Extra-ovarian papillary serous tumors n=100 Paclitaxel, Carboplatin, Lonafarnib Paclitaxel, Carboplatin Completed First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 74

84 Trial name and location Study design Participants Intervention Control Completion status ISRCTN International Phase 3 RCT, openlabel Mucinous carcinoma of the ovary n=330 Oxaliplatin and Capecitabine +/- Bevacizumab Carboplatin and Paclitaxel +/- Bevacizumab Ongoing Research question 2 Trial name and location Study design Participants Intervention Control Completion status NCT Italy Phase 3 RCT, openlabel Ovarian cancer n=800 Weekly Carboplatin and Paclitaxel Every 3 weekly Carboplatin and Paclitaxel Ongoing NCT Germany Phase 3 RCT, openlabel Epithelial ovarian, fallopian tube or peritoneal cancer n=800 Bevacizumab continuously for up to 15 months and Carboplatin and Paclitaxel Bevacizumab continuously for up to 30 months and Carboplatin and Paclitaxel Ongoing NCT Canada Phase 2 RCT, openlabel Epithelial ovarian cancer One of 3 doses of a LMWH Dalteparin (Fragmin: 50, 100, and 150 IU/kg) in conjunction with standard adjuvant taxaneand platinum-based chemotherapy Completed First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 75

85 Trial name and location Study design Participants Intervention Control Completion status NCT International Phase 3 RCT Fallopian tube cancer, ovarian cancer, peritoneal cavity cancer Intra-patient dose-escalated Carboplatin on day 1 Flat dose of Carboplatin on day 1 Unknown NCT US Phase 3 RCT Stage III or stage IV ovarian cancer of primary peritoneal cavity cancer (residual disease after surgery) Paclitaxel continuously over 96 hours Cisplatin over 2 hours Paclitaxel continuously over 24 hours Cisplatin over 2 hours Completed n=324 EUCTR International Phase 3 RCT, openlabel High risk early stage (FIGO stage IC/IIA, grade 3 or clear cell histology only) or advanced stage (FIGO stage IIB-IV, all grades and all histological types) epithelial ovarian, fallopian tube, or primary peritoneal carcinoma Dose-fractionated Carboplatin- Paclitaxel Standard Carboplatin- Paclitaxel Ongoing n=1485 First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 76

86 Research question 3 Trial name and location Study design Participants Intervention Control Completion status NCT Canada Phases 2/3 RCT, openlabel Stage IIB, stage IIC, stage III, or stage IV ovarian epithelial cancer, primary peritoneal cancer, or fallopian tube cancer Intraperitoneal and intravenous chemotherapy Intravenous Carboplatin and Paclitaxel Ongoing n=830 NCT Korea Phases 2/3 RCT, singleblind Epithelial ovarian cancer n=168 Intraoperative hyperthermic intraperitoneal chemotherapy followed by intravenous chemotherapy Ongoing Research question 4 Trial name and location Study design Participants Intervention Control Completion status NCT India Phase 3 RCT, openlabel Advanced epithelial ovarian carcinoma n=180 Neoadjuvant chemotherapy followed by interval debulking surgery Upfront surgery followed by chemotherapy Unknown First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 77

87 Research questions 1 and 3 Trial name and location Study design Participants Intervention Control Completion status NCT US Phase 3 RCT, openlabel Fallopian tube cancer, ovarian cancer, primary peritoneal cavity cancer n=1500 Bevacizumab and intraperitoneal chemotherapy Bevacizumab with intravenous chemotherapy Ongoing First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 78

88 Abbreviations AUC ACN ASCO ANZCTR BMI BRCA BSA CI ESGO FINOVA GFR GIN GOG HeCOG HDCT HIDOC-EIS HR IGCS IP IV NBOCC NBCC NHMRC ORR OS Area Under The Curve Australian Cancer Network American Society Of Clinical Oncology Australian New Zealand Clinical Trials Registry Body Mass Index Breast Cancer Body Surface Area Confidence Interval European Society Of Gynaecological Oncology Finnish Ovarian Cancer Study Glomerular Filtration Rate Guidelines International Network Gynecologic Oncology Group Hellenic Co-Operative Oncology Group High-Dose Chemotherapy High-Dose Ovarian Cancer-European Intergroup Study Hazard Ratio International Gynecologic Cancer Society Intraperitoneal Intravenous National Breast And Ovarian Cancer Centre National Breast Cancer Centre National Health And Medical Research Council Overall Response Rate Overall Survival First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 79

89 PFS QoL QIMR RCT RR SGCTG SS Progression-Free Survival Quality Of Life Queensland Institute Of Medical Research Randomised Controlled Trial Relative Risk Scottish Gynaecological Clinical Trials Group Statistically Significant First-line chemotherapy for women with epithelial ovarian cancer-a systematic review 80

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