In 2010, ovarian cancer was the second most commonly diagnosed gynaecological cancer in Australia, with a total of 1,305 ovarian cancer cases diagnosed.² It is the most common cause of gynaecological cancer death, representing over half (56%) of such deaths.³ The five-year relative survival rate for Australian women with ovarian cancer has increased significantly, from 32.4% in 1982-1987 to 43.3% in 2006-2010.⁴

Most women diagnosed with epithelial ovarian cancer are treated with surgery and chemotherapy with the aim of eliminating detectable disease.  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  maximal diameter, with complete cytoreduction (microscopic disease) being the ideal surgical outcome.⁵ Ovarian cancer is surgically staged, based on the extent of the disease, using the guidelines established by FIGO (International Federation of Gynecology and Obstetrics).⁶ All women with a suspected or diagnosed gynaecological cancer should have access to a comprehensive multi-disciplinary team led by a gynaecological oncologist to provide high quality management tailored to their needs to achieve the best outcome for each woman.⁷ Epithelial ovarian cancer (EOC) is a highly chemosensitive tumour, but most women with advanced EOC initially responding to first-line chemotherapy will eventually relapse.⁸

This guideline represents an update of the 2004 guidelines Clinical practice guidelines for the management of women with epithelial ovarian cancer for first-line chemotherapy for treatment of women with epithelial ovarian cancer. ¹

A systematic review on first-line chemotherapy for women with epithelial ovarian cancer was undertaken to identify areas requiring revision in relation to the 2004 guideline recommendations.⁹ Details on the literature search including research questions are provided in the Summary of evidence and Summary of study results.

The recommendations are based on the statements of evidence for the use of first-line chemotherapy for women with epithelial ovarian cancer. The level of evidence assigned to recommendations is based on the NHMRC Evidence Intervention Hierarchy (Appendix 1). Practice points are also provided to help guide clinical decisions for the use of first-line chemotherapy for women with epithelial ovarian cancer. Practice points are based on expert opinion when the evidence to make a recommendation is insufficient or where the evidence is outside the scope of the systematic review.

Recommendations to individual patients should be based on their circumstances, the absolute benefits and harms of the treatment, other treatments used, quality of life issues and their personal preferences.  These factors should be discussed with the woman and her family and carer(s), tailored to her preferences for information and decision-making involvement.

The recommendations for the use of first-line chemotherapy for the treatment of women with epithelial ovarian cancer should be considered within a multidisciplinary team setting.

Multidisciplinary care is the best-practice approach to providing evidence-based cancer care.¹⁰ Multidisciplinary care is an integrated team-based approach to cancer care where medical and allied health care professionals consider all relevant treatment options and collaboratively develop an individual treatment and care plan for each patient.¹⁰

Tumours of low malignant potential

Women with early stage ovarian cancer, Stage I-IIA

Advanced ovarian cancer (IIB-IV)- Chemotherapy

Advanced ovarian cancer (IIB-IV) – Biological therapies

Scheduling – Dose-dense chemotherapy

Scheduling – Intraperitoneal Chemotherapy

Scheduling – Neoadjuvant Chemotherapy

BRCA mutations

Older women

Obese patients

The statements of evidence and recommendations about the use of first-line chemotherapy for epithelial ovarian cancer are based on a Cancer Australia systematic review of available evidence published between January 2003 and November 2012.⁹

This systematic review was undertaken by Cancer Australia 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, given differing treatment modalities and heterogeneous needs of women with recurrent disease.       

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 (RCTs) conducted in humans published in the English language. A 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 sub-populations. In October 2012 the multidisciplinary working group re-prioritised the other issue of obese patients to be a research question. The new research question was systematically searched for in November 2012.

Overall, 75 articles and two conference abstracts were included in the systematic review. Of the included citations, 35 were phase III (RCTs) addressing the primary research questions, 10 were non-randomised controlled trials included in the sub-group question and six were Cochrane reviews used as primary references.

The systematic review addressed six research questions which were developed with input from the 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 (such as women with BRCA mutations) that have specific chemotherapy requirements?
6. What are the specific chemotherapy requirements for women with epithelial ovarian cancer who are obese?

The following topics were considered as additional issues of interest, and although they were not specifically searched for in the systematic 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.

For detailed evidence from studies on the use of first-line chemotherapy for epithelial ovarian cancer refer to the Cancer Australia systematic review⁹.

Chemotherapy regimens for first-line adjuvant treatment

Early stage ovarian cancer (FIGO stage I-IIa)

Overall survival

While 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, subgroup analysis suggested that women who had comprehensive surgical staging of their disease were unlikely to benefit from adjuvant chemotherapy, whereas those who had sub-optimal staging did.¹³

One trial included in the Cochrane Review (ICON 1) reported overall survival grouped by level of risk, with low/medium risk, defined as stage 1a, tumour grade 1 and 2, stage 1b or 1c, grade 1; high risk was defined as stage 1a, grade 3, stage 1b or 1c grade 2 or 3, any clear cell tumours.  In the low and medium risk group, there was no significant difference in 10-year overall survival between those who received adjuvant chemotherapy and those who received surgery alone. However, among women at high risk, adjuvant chemotherapy improved survival HR 0.48 (95% CI 0.32 to 0.72), p=0.00039.¹³

Analysis of data from 693 women in three trials, showed no significant difference in deaths from ovarian cancer at five years, between the chemotherapy and observation groups (RR 0.76, 95% CI 0.52 to 1.11).  Only one RCT (ACTION) reported 10-year follow-up for this outcome, 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 comprehensively staged subgroup.¹³

Progression-free survival

Among comprehensively staged women, analysis showed no significant difference in progression-free survival (PFS) between those who did and did not receive adjuvant chemotherapy. However, in sub-optimally staged women, those receiving adjuvant chemotherapy had significantly better PFS than those who did not.¹³

ICON 1 reported progression-free survival grouped by level of risk.  The 10-year progression-free 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 PFS HR 0.52 (95% CI 0.33 to 0.82), p=0.0049.¹³

None of the trials reported on treatment compliance, response to chemotherapy, adverse events or quality of life.

The evidence included in the systematic review was primarily based on randomised controlled trials. The quality of all included systematic reviews and randomised controlled trials was considered to be moderate to high.

Thirty-five randomised controlled trials were included in the systematic review for the primary research questions:

• Each of the included trials was considered to be of moderate to high quality.
• The trials were all randomised, though some trials did not describe randomisation method.  In trials that did specify method of randomisation, methods were considered high quality.
• The trials were either open label or blinding was not stated, with only GOG218 identified as double blind.
• 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 matched population characteristics between treatment arms at baseline.
• Most of the phase III trials were powered to detect a significant difference in primary outcomes.

Ten studies that were not randomised controlled trials were included for the research question assessing subgroups. As the papers included in this section had a range of study designs, formal quality assessment was not performed.

Nine studies that were not randomised controlled trials were included for the research question addressing specific chemotherapy requirements for women with epithelial ovarian cancer who are obese. These studies did not compare different doses or schedules of chemotherapy among obese patients.

Six Cochrane reviews were included in the systematic review. These were considered to be of high quality.

Important unanswered questions about the use of first-line chemotherapy for the treatment of women with epithelial ovarian cancer may be addressed in clinical trials investigating:

• Generalisability of dose-dense chemotherapy across a range of populations.
• Role of novel biological/molecular therapies in the first-line treatment of women with epithelial ovarian cancer.
• Chemotherapy regimens in older women, particularly in patients who are frail or have comorbidities.
• Specific chemotherapy requirements for women with epithelial ovarian cancer who are obese.

Five international guidelines regarding the management of ovarian cancer in general were identified. Recommendations with regards to chemotherapy are provided in the Cancer Australia systematic review, Appendix F.⁹

Clinical trials are an important way to improve treatment for people with cancer. The results of clinical trials today will help people with cancer in the future. Participating in a clinical trial may be of direct benefit to women with epithelial ovarian cancer.  For more information about clinical trials visit Australian Cancer Trials at http://www.australiancancertrials.gov.au/

There are a number of trials investigating the first-line chemotherapy for women with epithelial ovarian cancer. A summary of trials is outlined in the Cancer Australia systematic review, Appendix L.⁹

Areas for ongoing research for first-line adjuvant treatment of epithelial ovarian cancer include:

• Effective chemotherapy regimen
• Effective schedule for chemotherapy regimens
• Effective mode of administration of chemotherapy

A number of international trials are in progress to further assess the applicability of dose-dense regimens for use in other populations, including the Italian trial MITO7, ICON8 AND GOG 262.

Other international trials that are in progress which are of interest are GINECO and GOG 273.

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NHMRC Evidence Hierarchy: designations of ‘levels of evidence’ according to type of research question⁸⁸

Membership of Cancer Australia Review of clinical practice guidelines – chemotherapy for ovarian cancer Working Group

This guideline was developed by a multidisciplinary working group convened by Cancer Australia.

• Dr Christopher Steer (Chair) - Medical oncologist
• Mr Keith Cox OAM - Nurse Practitioner
• Dr Jeffery Goh - Medical oncologist
• Dr Susan Jordan - Epidemiologist
• Ms Eugenia Koussidis - Consumer
• Professor Yee Leung - Gynaecological Oncologist
• A/Professor Penny Webb - Epidemiologist
• Ms Nicole Wilton - Consumer representative

Cancer Australia Staff

• Ms Katrina Anderson - Senior Project Officer, Evidence Review
• Ms Jennifer Chynoweth - General Manager, Cancer Care, Project Sponsor
• 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
• Ms Lara Matkovic - Senior Project Officer  
• Dr Anne Nelson -  Manager, Evidence Review
• Ms Sue Sinclair - General Manager, Service Delivery and Clinical Practice, Project Sponsor
• Ms Rosemary Wade - Senior Project Officer, Research

External Review

Cancer Australia acknowledges those who gave their time to provide comment on the draft guideline recommendations as part of the external review process.

Topic-specific guideline development process

Priority topic areas for guideline development are determined in consultation with key stakeholders including experts in relevant disciplines and consumer representatives. A specific multidisciplinary Working Group, including consumers, is established for each topic identified and is involved in all aspects of guideline development. A systematic evidence review is undertaken for each guideline. All members are asked to declare any conflicts of interest and these declarations are recorded. The content of the guideline is not influenced by any external funding body. The guideline is reviewed externally by key stakeholders and the wider community and endorsement is sought from relevant professional colleges and groups in Australia.

Copyright statements

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Website:  www.canceraustralia.gov.au

ISBN online: 978-1-74127-282-6

© Cancer Australia 2014

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Copies of Recommendations for the use of first-line chemotherapy for the treatment of women with epithelial ovarian can be downloaded from the Cancer Australia website: www.canceraustralia.gov.au.