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First-line chemotherapy for the treatment of women with epithelial ovarian cancer

Recommendations for the use of first-line chemotherapy for the treatment of women with epithelial ovarian cancer

A CLINICAL PRACTICE GUIDELINE DEVELOPED BY CANCER AUSTRALIA

This document supplements information about use of chemotherapy for women with epithelial ovarian cancer (Chapter 11) contained in the Clinical practice guidelines for the management of women with epithelial ovarian cancer, 2004.1

This guideline includes statements and recommendations based on available, high-level evidence about the use of first-line chemotherapy for the treatment of women with epithelial ovarian cancer. The guideline provides health professionals with information designed to assist in making management recommendations for improved patient outcomes. Cancer Australia also develops information specifically for consumers about ovarian cancer and treatment options.

978-1-74127-282-6
Australia New Zealand Gynaecological Oncology Group
Australian Society of Gynaecologic Oncologists
Medical Oncology Group of Australia Incorporated
The Royal Australian and New Zealand College of Obstetricians and Gynaecologists
Current

Background

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.

Recommendations and practice points

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

RECOMMENDATION
TUMOURS OF LOW MALIGNANT POTENTIAL		 LEVEL OF EVIDENCE11 REFERENCE

Adjuvant chemotherapy is not indicated in patients with tumours of low malignant potential (borderline or proliferating), unless invasive peritoneal implants are histologically confirmed.

II

Siedman and Kurman 200012

 

RECOMMENDATIONS 
EARLY STAGE OVARIAN CANCER (I-IIA) 		LEVEL OF EVIDENCE11 REFERENCE

Adjuvant chemotherapy with a platinum compound is recommended for women with high-grade or clear-cell histology as these are known to have a higher recurrence rate.

I

Winter-Roach 201213

Adjuvant chemotherapy is not recommended for patients with comprehensively staged IA or IB well or moderately differentiated tumours, as their risk of relapse is low and the toxicity is not justified.

I

 

Winter-Roach 201213

 

PRACTICE POINT
EARLY STAGE OVARIAN CANCER (I-IIA)		 REFERENCE

If comprehensive surgical staging has not been undertaken by a certified gynaecological oncologist, the case should be referred for discussion at a multidisciplinary team meeting, for consideration of the option of surgical staging or chemotherapy.

Winter-Roach 201213

 

RECOMMENDATION
ADVANCED OVARIAN CANCER (IIB-IV) - CHEMOTHERAPY		 LEVEL OF EVIDENCE11 REFERENCE

Standard first-line treatment of advanced epithelial ovarian cancer should contain a platinum compound, either in combination or as a single agent, unless specifically contraindicated.

II

OVAR 11/ ICON714
GOG 21815
OVAR 516
OVAR 917
GOG 182/ ICON518
Bolis 201019
OVAR 720
OV 1621
HeCOG22
Lhomme 200823
GOCCNE24
SGCTG25
MITO 226
SCOTROC27
GOG 15828
OVAR 329, 30
HeCOG31
Mouratidou32
OV 1033-35
AOCSG36
Muthuramalingam37
SCOTROC2A38
SCOTROC2B39
Minagawa 200640
Mori 200741
JGOG301442
Fruscio 200843

 

RECOMMENDATION
ADVANCED OVARIAN CANCER (IIB-IV) -SCHEDULING - NEOADJUVANT CHEMOTHERAPY		 LEVEL OF EVIDENCE11 REFERENCE

While primary debulking is the usual treatment, neoadjuvant chemotherapy may be considered for selected patients with stage III or IV cancers.

II

Vergote 201044

 

RECOMMENDATION
ADVANCED OVARIAN CANCER (IIB-IV) -SCHEDULING – INTRAPERITONEAL CHEMOTHERAPY		 LEVEL OF EVIDENCE11 REFERENCE

Women with stage III ovarian cancer who are optimally debulked at primary surgery should be considered for intraperitoneal (IP) chemotherapy. 

IP chemotherapy should be provided in a centre with appropriate expertise and potential toxicities fully explained.

 

I

Jaaback 201145

Armstrong 200646

 

PRACTICE POINT
ADVANCED OVARIAN CANCER (IIB-IV) – BIOLOGICAL THERAPIES		 REFERENCE

Based on data from ICON7, bevacizumab can be considered for first-line treatment of women at high risk (stage IV disease or stage III and >1 cm residual disease), taking into account quality of life issues.   

Perren 201114

 

PRACTICE POINT
SCHEDULING- DOSE DENSE CHEMOTHERAPY		 REFERENCE

Dose-dense paclitaxel (where time between the administration of chemotherapy drugs is reduced), in combination with 3-weekly carboplatin, can be considered as an option for first-line treatment of advanced epithelial ovarian cancer.

Katsumata, 200947
Katsumata 201248
Harano 201449

 

PRACTICE POINT
OLDER WOMEN		 REFERENCE

Treatment should be considered on an individual basis, and age alone should not be used as a criterion for modifying standard treatment.  Adequate geriatric assessment is important to guide appropriate treatment.

 

Eisenhauer 200750

 

PRACTICE POINT
OBESE PATIENTS		 REFERENCE

When treating obese women with epithelial ovarian cancer, clinicians should consider the ASCO guidelines on chemotherapy dosing for obese adult cancer patients. 

http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2011.39.9436

Griggs 201251

 

PRACTICE POINT
CLINICAL TRIALS		 REFERENCE

Clinical trials have an unquestioned role in improving treatment for future patients and results of several clinical studies have prompted significant changes in practice. It is appropriate for clinicians to discuss participation in clinical trials with women who have ovarian cancer. 

Robinson 200952

Peppercorn 200453

 

Statements of evidence

Tumours of low malignant potential

STATEMENTS LEVEL OF EVIDENCE11 REFERENCE

Patients with tumours of low malignant potential (borderline or proliferating), even with documented metastases, have an excellent prognosis.  In the absence of documented invasive peritoneal implants, adjuvant chemotherapy is not indicated.

II

Siedman and Kurman 200012

 

 

Women with early stage ovarian cancer, Stage I-IIA

STATEMENTS LEVEL OF EVIDENCE11 REFERENCE

There is evidence from a meta-analysis that indicates that some women with early stage (I-IIA) epithelial ovarian cancer who received adjuvant platinum-based chemotherapy had better 5-year overall survival (HR 0.71; p=0.01) and 5-year progression-free survival (HR 0.67, P=0.0005) than women who did not.

Improved overall and progression-free survival for women who received adjuvant platinum-based chemotherapy was maintained at 10 years.  OS: HR 0.74, p=0.02. PFS: HR 0.67, p=0.0005

I

Winter-Roach 201213

Sub-group analysis:

For women with early stage epithelial ovarian cancer who had comprehensive surgical staging, there was no significant difference in overall survival (two trials) or in progression-free survival (two trials) between those who did and did not receive adjuvant chemotherapy. OS: HR 1.22 (95% CI 0.63 to 2.37), p=0.56. PFS: HR 0.67 (95% CI 0.36 to 1.22), p=0.19.

In women who had sub-optimal staging, those who received adjuvant chemotherapy had statistically significantly better overall survival (two trials) and progression-free survival (three trials). OS: HR 0.63 (95% CI 0.46 to 0.85), p= 0.003. PFS: HR 0.64 (95% CI 0.50 to 0.82), p=0.0004

In one trial that reported survival grouped by level of risk, adjuvant chemotherapy improved 10-year overall and progression-free survival in high risk women, but not in those at low/medium risk.  OS: HR 0.48 (95% CI 0.32 to 0.72), p=0.00039. PFS: HR 0.52 (95% CI 0.33 to 0.82) p=0.0049

I

Winter-Roach 201213

 

Advanced ovarian cancer (IIB-IV)- Chemotherapy

STATEMENTS LEVEL OF EVIDENCE11 REFERENCE

Almost all regimens which investigated the addition or substitution of a range of agents to the standard regimen of combination carboplatin and paclitaxel, in populations with a majority of advanced stage ovarian cancer patients, failed to demonstrate an overall or progression-free survival advantage.

 

 

II

 OVAR 11/ ICON714
GOG 21815
OVAR 516
OVAR 917
GOG 182/ ICON518
Bolis 201019
OVAR 720
OV 1621
HeCOG22
Lhomme 200823
GOCCNE24
SGCTG25
MITO 226
SCOTROC27
GOG 15828
OVAR 329, 30
HeCOG31
Mouratidou32
OV 1033-35
AOCSG36
Muthuramalingam37
SCOTROC2A38
SCOTROC2B39
Minagawa 200640
Mori 200741
JGOG301442
Fruscio 200843

 

 

Advanced ovarian cancer (IIB-IV) – Biological therapies

STATEMENTS LEVEL OF EVIDENCE11 REFERENCE

In ICON7, improved progression-free survival was reported in the group receiving bevacizumab compared with standard therapy; HR=0.81 p=0.04.  The maximum improvement was at 12 months, co-inciding with the end of planned bevacizumab treatment, and diminished by 24 months. 

II

Perren 201114

 In ICON7, improved overall survival was reported in a sub-group of patients at high risk of progression when bevacizumab was used in addition to carboplatin and paclitaxel; HR=0.64, p=0.002.

II

Perren 201114

In ICON7, bevacizumab treatment was associated with a small but clinically significant decrease in quality of life compared to standard chemotherapy.

II

Stark 201354

In the GOG 218 trial, progression-free survival was improved in the bevacizumab throughout arm (chemotherapy plus bevacizumab cycles 2 to 22) (p= <0.001), but not in the bevacizumab initiation arm (chemotherapy plus bevacizumab cycles 2 to 6), compared to the chemotherapy control group. 

II

Burger 201115

In GOG 218, in both arms concurrent bevacizumab compared to control without bevacizumab, doubled the odds of a gastrointestinal adverse event (odds ratio 2.15, 95% CI 1.05-4.40, p=0.032), after controlling for history of treatment for irritable bowel disease, small bowel resection at primary surgery and bowel resection at primary surgery, however was not appreciably increased by continuation of bevacizumab beyond chemotherapy.

II

Burger 201455

Scheduling – Dose-dense chemotherapy

STATEMENTS LEVEL OF EVIDENCE11 REFERENCE

In one trial (JGOG 3016), dose-dense paclitaxel improved overall survival at 5 years (58.6% vs. 51.0%, HR 0.79, p=0.0448) and median progression-free survival at median 6.4 years follow-up (28.1 vs. 17.5 months, HR 0.75, p=0.0037) in women with advanced ovarian cancer compared with standard treatment. 

Anaemia was worse in the dose-dense arm but no significant differences were reported for other toxicities.

II

Katsumata 200947

Katsumata 201248

 

 

In two trials that investigated complex, high-dose chemotherapy regimens including peripheral blood stem cell support, no overall or progression-free survival differences were reported between intervention and standard treatment arms.

II

Grenman 200656

Mobus 200757

Scheduling – Intraperitoneal Chemotherapy

STATEMENTS LEVEL OF EVIDENCE11 REFERENCE

A meta-analysis has indicated that women with epithelial ovarian cancer who received an intraperitoneal component of chemotherapy had significantly better overall survival HR 0.81, p=0.0002 and progression-free survival HR 0.78, p<0.00001, than women who did not.

 

 I

Jaaback 201145

 

Women receiving intraperitoneal chemotherapy were significantly more likely to experience a range of adverse events, including gastrointestinal effects, pain, fever and infection.

 I

Jaaback 201145

 

Scheduling – Neoadjuvant Chemotherapy

STATEMENTS LEVEL OF EVIDENCE11 REFERENCE

One randomised trial has indicated no differences in median overall survival between treatment arms for women receiving neoadjuvant chemotherapy compared with primary surgery.

II

Vergote 201044

Subgroup analyses by age, FIGO stage, WHO performance status, histologic type and presence or absence of pleural fluid demonstrated no survival differences between neoadjuvant chemotherapy and primary surgery arms.

II

Vergote 201044

More adverse events were observed in the primary surgery arm compared with women receiving neoadjuvant chemotherapy.

II

Vergote 201044

 

 

BRCA mutations

STATEMENTS LEVEL OF EVIDENCE11 REFERENCE

BRCA mutation carriers were more likely to have a complete or partial response to platinum-based chemotherapy than non-carriers or sporadic cases.

III-2

Yang 201158

Vencken 201159

Tan 200960

Women with a BRCA1/2 mutation receiving a platinum-based regimen were less likely to have disease progression within 6 months of the end of primary treatment compared with those who did not carry a BRCA1/2 mutation; 14.9% vs. 31.7%, p<0.001.

III-2

Alsop 201261

 

Older women

STATEMENTS LEVEL OF EVIDENCE11 REFERENCE

Improved survival was reported in women aged 65 years and older who received chemotherapy compared with those who had no chemotherapy (RR 0.59).  

III-2

Hershman 200462

In a study of women with median age 73 years, overall survival and progression-free survival were improved in women receiving carboplatin or a combination of platinum and paclitaxel compared with those receiving a non-platinum regimen.

II

Reed 200625

 

Women aged 70 years and over discontinued their treatment earlier than those aged under 70 years (p=0.001).

III-3

 

 Hilpert 200763

In the OVAR trial, most haematological toxicity did not differ between age groups; however, febrile neutropenia was more frequent in older patients than in younger patients (p <0.001). 

There were no significant differences in non-haematological toxicity between age groups, except that older patients were more likely to get grade 3/4 infections.

III-3

 

 Hilpert 200763

 

Obese patients

STATEMENTS LEVEL OF EVIDENCE11 REFERENCE

While the evidence indicates that obese women are under dosed and have inferior survival, the available evidence is limited. No studies were identified which specifically compared different doses of chemotherapy among obese patients for survival outcomes. 

  • In four studies there were no statistically significant differences in overall survival, progression-free survival or disease free survival across the BMI strata.

III-3

 

Wright 200864

Barrett 200865

Matthews  200966

Suh 201267
  • In only one study (SCOTROC) the taxane dosage was not capped.

III-3

 

Barrett 200865
  • One study reported that, compared to non-obese patients, obese patients had a lower recurrence rate (68% vs. 79%, p=0.04) but no statistically significant difference in progression-free survival. Dosage was based on their current body weight and BSA (Body surface area) capped at 2.0 m2. 

III-3

 

Matthews  200966
  • One retrospective study demonstrated delivered relative dose intensity (RDI) <85% to be negatively associated with overall survival; multivariate analysis: HR=1.71, p=0.003. BSA greater than 2m2 and BMI >30 kg/m2 were reported to be predictors of reduced planned RDI <85% and reduced delivered RDI <85%.

III-3

 

Hanna 201368
  • In one retrospective study, in which patients who were obese were more likely to receive a lower median dose of paclitaxel relative to BSA compared to those of ideal body weight, increasing BMI was associated with lower overall survival.

III-3

 

Pavelka 200669
  • One retrospective study reported there was no significant difference between BMI groups for overall or progression-free survival. However, patients receiving RDI <85% for carboplatin had worse progression-free survival; univariate analysis HR 1.29, p=0.04. Multivariate analysis was not significant. 

III-3

 

Au-Yeung 201470

In one retrospective analysis, where the average dose of carboplatin received did not differ across the BMI strata, obese women were less likely to experience treatment-related toxicity. 

III-3

Wright 200864

 

A retrospective study of adverse events reported that a BMI<30 and BSA <2.0m2 were univariate predictors of severe neutropenia in women with stage III and IV undergoing a multi-agent intravenous chemotherapy (p=<0.01 and p=0.03). 

III-3

Laskey 201271

 

One study reported similar rates of neutropenia for obese and non-obese patients.

III-3

Matthews  200966

 

Summary of evidence

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.

 

Summary of study results

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.

Ovarian cancer (stage I-IV) - Chemotherapy

A range of regimens have been investigated, most of which were compared with the combination of carboplatin and paclitaxel (considered as standard first-line chemotherapy). The type of comparison was usually a substitution of different agents or the addition of a third agent. Various platinum/taxane combinations were compared. Additional agents investigated included anthracyclines (doxorubicin, epirubicin), antimetabolites (gemcitabine), and topoisomerase inhibitors (topotecan, irinotecan.)14-43, 72

Almost all the regimens 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.

Overall survival

A multiple-treatment modelling meta-analysis reported hazard ratios for death for first-line treatment, for each type of regimen compared with monotherapy with a non-platinum, non-taxane agent, not administered intraperitoneally.  Modelling estimated a 92% probability that combinations of platinum and taxane with intraperitoneal administration were the most effective regimens.72

Two phase III trials 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).25  Long-term follow-up of the OV10 trial of older chemotherapy regimens, reported that paclitaxel and cisplatin combination improved survival compared with cyclophosphamide and cisplatin HR 0.75 (95% CI 0.63 to 0.90), p=0.001.35

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.24  Most reported no statistically significant progression-free/disease-free survival differences between treatment groups however, the phase II trials were not designed/powered to detect survival differences.

Three phase III trials reported differences in progression-free survival: Reed et al (2006), OV1035 and OVAR9.17   In two trials, those in the standard chemotherapy arm had longer progression-free survival than those in 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).25  The OVAR9 trial reported median progression-free survival in the standard paclitaxel/carboplatin arm as 19.3 months compared with 17.8 months for the paclitaxel/carboplatin/gemcitabine arm (p<0.01).17

In the other trial, improved progression-free survival, was reported in the intervention arm. OV10 reported better PFS in the paclitaxel/cisplatin arm compared with the older chemotherapy regimen cyclophosphamide/cisplatin (p<0.001).35

Adverse events

The adverse events reported varied between each trial. Overall, the addition of agents to standard chemotherapy tended to increase toxicity, particularly haematological toxicity such as anaemia and neutropenia. Adverse effect profiles reflected the various agents used. However, there were often limited differences in toxicities between treatment arms.

Quality of life

Quality of life (QoL) was assessed in 13 trials, with detailed data reported in 11 trials. Most trials reported no significant differences in quality of life between treatment arms investigated.28, 29, 31 OVAR 3 found that those in the carboplatin/paclitaxel arm showed better overall QoL, physical functioning, role functioning, and cognitive functioning compared with those in the cisplatin/paclitaxel arm after treatment.30 However, an additional paper which reported a retrospective analysis of data from OVAR 3, OVAR 5 and OVAR 7 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.30

Ovarian cancer (stage I-IV) - Biological therapies

Based on a study of molecular pathways involved in tumour growth, a number of potential anti-angiogenic agents have been identified.  Bevazicumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), has been studied in the first-line treatment of ovarian cancer.73

The ICON7, a phase III randomised study, compared standard chemotherapy (carboplatin AUC 5 or 6 and paclitaxel 175 mg/m2 every 3 weeks for 6 cycles) or standard chemotherapy plus bevacizumab (7.5 mg 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.14

GOG 218, a double-blind phase III randomised controlled trial compared three treatments. Each of the three study regimens comprised 22 3-week cycles paclitaxel 175 mg/m2 plus carboplatin AUC 6. Control treatment was chemotherapy with placebo added in cycles 2 through 22; bevacizumab initiation treatment was chemotherapy with bevacizumab (15 mg per kg body weight) added in cycles 2 through 6 and placebo added in cycles 7 through 22. Bevacizumab-throughout treatment was chemotherapy with bevacizumab added in cycles 2 through 22. 15

 

Overall survival

The ICON7 trial reported that there were no overall survival differences between treatment groups.  However, improved survival was reported in a subgroup of patients (n=465) at high risk of progression (stage IV disease or stage III and >1 cm residual disease) in the bevacizumab (7.5 mg/kg body weight) plus standard therapy (carboplatin + paclitaxel) group, compared to the standard therapy alone group.14   Patients in the bevacizumab arm had improved survival OS median 36.6 months in intervention group, 28.8 months in control group, HR 0.64 (95% CI 0.48 to 0.85), p=0.002.14

In the GOG 218 trial, bevacizumab (15 mg/kg body weight) was given every three weeks, in addition to the standard carboplatin/paclitaxel regimen. No significant differences in overall survival were reported between the three groups (bezacizumab-initiation group, bezacizumab-throughout group and control group).15

Progression-free survival

In the updated analyses from ICON7, improved progression-free survival, (19.8 months vs. 17.4 months; p=0.04), was reported in the group receiving bevazicumab (7.5 mg/kg of body weight), compared with standard therapy.14  The maximum improvement was at 12 months, co-inciding with the end of planned bevacizumab treatment, and diminished by 24 months.   Median PFS in the updated analyses was 16 months in the bevacizumab group compared with 10.5 months in the standard therapy group (p=0.002).14

In GOG2018, progression-free survival 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).15

Adverse events

In GOG 218, in both arms concurrent bevacizumab compared to control group without bevacizumab, doubled the odds of a gastrointestinal adverse event (odds ratio 2.15, 95% CI 1.05-4.40, p=0.032), after controlling for history of treatment for irritable bowel disease, small bowel resection at primary surgery and bowel resection at primary surgery, however was not appreciably increased by continuation of bevacizumab beyond chemotherapy.55

Quality of life

In ICON7, bevacizumab treatment was associated with a small but clinically significant decrease in quality of life compared to standard chemotherapy.54

Scheduling

Dose-dense therapy

Dose-dense chemotherapy, where the interval between chemotherapy cycles is reduced, has been considered to improve the activity of drugs used to treat ovarian cancer.73 Dose-dense chemotherapy reduces the time for tumour re-growth between cycles.74  The cumulative drug dose remains constant but the same amount of drug is administered over a shorter period of time.74

In an RCT conducted in Japan (JGOG 3016) 637 patients with FIGO stage II-IV disease were randomly assigned to receive paclitaxel (80 mg/m2) once weekly and carboplatin every three weeks (dose-dense therapy) or carboplatin (AUC6)and paclitaxel 180 mg/m2 given every three weeks (standard therapy).48

Overall survival

Dose-dense paclitaxel improved overall and progression-free survival compared to the standard treatment.  Overall survival at two and three years was significantly better in the dose-dense paclitaxel arm compared to the standard dose arm (2 yrs: 83.6% vs. 77.7%, p=0.049; 3 yrs: 72.1% vs. 65.1%, p= 0.03).  At five years, OS was higher in the dose-dense group 58.6% vs. 51.0%, HR 0.79, 95% CI 0.63-0.99, p=0.0448).  At 6.4 years of median follow up, median survival had not been reached in the dose-dense group.47

Progression-free survival

JGOG 3016 also reported improved progression-free survival.  Median progression-free survival was 28 months in the dose-dense paclitaxel arm, compared with 17.2 months in the standard arm, adjusted HR 0.65, (95% CI 0.53 to 0.80), p = 0.0001.  PFS was longer in the dose-dense arm across all sub-groups, except amongst women with clear-cell or mucinous tumours. 

Adverse events

Sixty-two percent (62%) of patients in the dose-dense arm received six or more cycles compared to 73% in the standard arm. The most common adverse event was neutropenia (dose-dense regimen, 286 [92%] of 312; conventional regimen, 276 [88%] of 314). The frequency of grade 3 and 4 anaemia was higher in the dose-dense treatment group (214 [69%]) than in the conventional treatment group (137 [44%]; p<0.001). The frequencies of other toxic effects were similar between groups.

Quality of life

A 2014 publication of the JGOG 3016 trial by Harano et al, reported QoL outcomes. QoL was assessed at baseline, 6 months and 12 months using FACT-general scale, FACT-taxane subscale and FACT-ovary subscale. The authors reported no significant difference in QoL between the two treatment groups up to 12 months after randomisation (p=0.46). However, QoL was significant lower in the dose-dense group according to the FACT-taxane subscale, compared with the conventional chemotherapy group (p=0.02).49

Dose-dense chemotherapy has been adopted in some centres. However, given that JGOG 3016 involved patients recruited only in Japan (mostly stage III) and that patients who had treatment delays or neutropenic complications received granulocyte-colony stimulating factor (G-CSF), a number of international trials  (including the Italian trial MITO7, ICON8 AND GOG 262) are in progress to further assess the applicability of dose-dense regimens for other populations.73

Complex high-dose chemotherapy regimens

In two trials that investigated complex high-dose chemotherapy regimens including peripheral blood stem cell support, no overall or progression-free survival differences were reported between the intervention and standard treatment arms.56, 57

 

Intraperitoneal (IP) chemotherapy

A Cochrane systematic review published in 2011, included RCTs published up to May 2011 on IP chemotherapy.45  Only one of the nine trials (Kirmani 1994) directly compared intravenous (IV) to IP (without additional IV) chemotherapy; the remaining trials compared administered a certain component of chemotherapy via IV or IP, along with IV chemotherapy in both arms. The chemotherapy component administered IP always included a platinum agent, usually cisplatin, with or without additional agents. The IV chemotherapy given to both arms usually included paclitaxel or cyclophosphamide.45

Overall survival

The Cochrane review reported significantly improved overall survival for women who received an IP component of chemotherapy.45 From meta-analysis of data from eight studies (2026 women) for overall survival, the hazard ratio was 0.81 (95% CI 0.72 to 0.90), p=0.0002 for women who received an IP component of chemotherapy compared to only IV chemotherapy. Results were similar when only data from the six high quality trials was used: HR 0.80 (95% CI 0.72 to 0.90), p=0.0001 and 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)).45   

Progression-free survival

The Cochrane review reported significantly improved progression-free survival for women who received an IP component of chemotherapy.45 From meta-analysis of five studies (1311 women) the hazard ratio was 0.78 (95% CI 0.70 to 0.86), p<0.00001. The data were reported to be homogenous.

Adverse events

The Cochrane review reported that women in the IP chemotherapy groups were significantly more likely to experience 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).45  Hearing loss was more common in the IV chemotherapy groups (RR 0.67).  There were no significant differences between interventions for haematological adverse events (such as anaemia, thrombocytopenia and leukopenia), renal, neurological and pulmonary adverse events.45 However, substantial heterogeneity was noted in these meta-analyses.

Insufficient data were available for meta-analysis of catheter-related complications of IP drug administration, including infection, blockage and discontinuation of therapy.

Treatment compliance

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.75  The study included 140 patients from one US centre who received IP chemotherapy as initial treatment; some of these  were part of the GOG 172 trial as well as other IP chemotherapy trials.

Of these 140 patients, 95 (68%) completed all six planned cycles of treatment.

The reasons for non-completion of the planned regimen included:

  • Occlusion of the port (28 patients, 20%)
  • 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%).75

Quality of life

Only GOG 172 assessed quality of life (QoL) as an outcome measure. Women who received higher dose IP therapy experienced more QoL disruption compared to those who received IV therapy. Those in the IP arm reported worse QoL and pain prior to the fourth chemotherapy cycle and worse QoL three to six weeks post-treatment. However, there were no significant QoL or PAIN score differences between arms at one year post-treatment.

 

Neoadjuvant chemotherapy

One randomised controlled trial (EORTC 55971) was identified that compared neoadjuvant chemotherapy with primary surgery followed by adjuvant chemotherapy.44  The trial included 670 women from 59 institutions with stage IIIC or IV invasive epithelial ovarian cancer, primary peritoneal or fallopian tube cancer, with extensive disease (61% metastases >10 cm at primary debulking).44, 76 Most (76%) of the included patients had stage IIIC ovarian cancer. The median age range was 62-63 (range 25-86) and the majority of patients had serous histology (62%).

The trial randomised women to either:

  1. Three 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 three courses of platinum-based chemotherapy (n=334)

or

  1. primary debulking surgery followed by at least six courses of platinum-based chemotherapy (n=336).44

Optimal resection with no macroscopic residual tumour was achieved in 19% of cases after primary debulking and in 51% after interval debulking. However, debulking rates differed from country to country in this international trial.76

The most common chemotherapy regimen was paclitaxel (175mg/m2) plus carboplatin (AUC6). Eighty-six per cent of patients in the neoadjuvant chemotherapy group received at least six 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, while 88% of patients in the neoadjuvant group underwent interval debulking surgery.44

Overall survival

The trial found no difference in the median overall survival between the two groups (median 30 months in the neoadjuvant chemotherapy group compared with 29 months in the primary surgery group, HR 0.98 (90% CI 0.84 to 1.13)).44  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 improve survival among patients with metastatic tumours that were less than 5 cm in diameter at randomisation (HR 0.64 (95% CI 0.45-0.93)).44

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)).44

Adverse events

There was a higher percentage of post-operative deaths (<28 days after surgery) in the primary surgery group (2.5%) compared with neoadjuvant chemotherapy (0.7%) (statistical significance not reported).44  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).44 Direct statistical comparison was not possible as post-operative morbidity and mortality in the primary chemotherapy group could only be analysed in the 92% of patients who underwent interval debulking; the remaining 8% either died or had disease progression and may have selected out poor-risk patients who were included in the post-operative analysis after primary cytoreduction.76

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.44

 

Additional studies of interest

The CHORUS trial (CRUK 07/009), a randomised controlled trial investigating neoadjuvant chemotherapy, has reported outcomes in a conference abstract.77 Patients with clinical FIGO stage III-IV ovarian cancer were randomised to standard treatment (n= 276; primary surgery followed by six cycles of platinum-based chemotherapy) or neoadjuvant chemotherapy (n= 274; three cycles platinum-based chemotherapy either side of surgery). The median age was 65 years, median tumour size was 80mm and 25% of patients were FIGO stage IV.

At median follow-up of  three years, intention to treat analysis showed a median overall survival of 22.8 months for primary surgery vs 24.5 months for neoadjuvant chemotherapy (hazard ratio (HR) 0.87 in favor of neoadjuvant chemotherapy, 80% CI 0.76 – 0.98) and median progression free survival of 10.2 vs 11.7 months (HR 0.91, 0.81 – 1.02). The 12-month survival rates were 70% for primary surgery and 76% for neoadjuvant chemotherapy. For patients treated with primary surgery, 15% were debulked to 0cm residual disease, compared to 35% for neoadjuvant chemotherapy.77

A small, phase II trial of 83 women (PRIMOVAR) reported no differences in outcomes between women receiving three cycles of neoadjuvant chemotherapy versus two cycles prior to surgery.78

BRCA mutations

Limited information was identified to suggest that there are specific chemotherapy requirements for BRCA carriers.  Three studies that investigated the relationship between BRCA status and the effectiveness of chemotherapy, did not report on the impact of chemotherapy on overall or progression-free survival, treatment compliance, adverse events or quality of life, but did report on response to chemotherapy.

The study by Alsop et al 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 non mucinous ovarian cancer.61 Germ-line pathogenic BRCA1 or BRCA2 mutations were identified in 141 (14.1%) of the women. Of the 837 patients who received chemotherapy during primary treatment, 835 (99.8%) received a platinum-based regimen and 642 (76.9%) received carboplatin/paclitaxel.  Patients with BRCA1 and BRCA2 mutations were less likely to have disease progression within six 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 six months of completing primary platinum-based chemotherapy has conventionally been associated with platinum resistance.61

Older Women

There is a lack of prospective randomised trial data specifically in older populations.

While the majority of trials in the systematic review did not impose an age limit, the median age was most often between 55 and 60 years.  Of those trials that did impose an age limit, two trials included patients up to 65 years, one up to 70 years and one up to 80 years. 

It is recognised that older women with ovarian cancer have more aggressive tumours, more advanced stage at diagnosis, increased risk of death from their cancer and more comorbidities than younger patients.79 Data from an Australian population-based study also indicate that patients over the age of 70 years are less likely to receive standard chemotherapy.80

The current standard chemotherapy regimen of three weekly carboplatin and paclitaxel is generally well tolerated and has established efficacy in older patients.50 Despite this, alternative strategies such as using single agent carboplatin, reducing the dose and weekly scheduling are used in an attempt to preserve efficacy and reduce toxicity. These therapeutic manoeuvres are based on small phase II trials or retrospective analyses.

In a retrospective analysis of a large prospective trial (GOG182) it was shown that older patients (age > 70 years) were less likely to complete the prescribed 8 cycles of chemotherapy, had a shorter survival and increased toxicity; particularly peripheral neuropathy and bone marrow suppression. These data are published in abstract form only, but this is currently the largest age-specific subgroup analysis of a prospective trial.81 Unfortunately, this subgroup is probably not representative of the wider population of elderly women requiring treatment for ovarian cancer. Prospective trials of chemotherapy in older women are required particularly in patients who are frail or have comorbidities.

The National Comprehensive Cancer Network (NCCN) guidelines for management of cancer in the senior adult contain a specific section on the management of ovarian cancer.82 These guidelines also stress the importance of adequate geriatric assessment that then informs appropriate treatment decisions and guides supportive care for both the patients and their carers. Assessment tools based on factors including functional status, comorbidities, cognitive function and nutritional status can assist a comprehensive geriatric assessment. 82

Histological sub-types

The majority of ovarian cancer patients are diagnosed with serous carcinomas (80-85%) and these tumours have a high response rate to platinum-based chemotherapy.73 While one sub-set analysis in the ACTION trial showed improved overall survival for women with early-stage ovarian cancer within the chemotherapy arm, for those with serous carcinoma compared with clear-cell carcinoma (p= 0.04), the differences disappeared when optimal staging was taken into account.83   The sub-set analysis also showed adjuvant chemotherapy significantly improved disease-free survival for women with serous ovarian cancer but there was no significant improvement for women with clear-cell ovarian cancer.  

Analysis of data from four randomised phase III and one phase II first-line trials (GINECO database) indicated that women with mucinous ovarian cancer receiving carboplatin-paclitaxel based chemotherapy had significantly lower overall response (complete and partial) (p<0.001), shorter overall survival and shorter progression-free survival than women who had serous ovarian cancer.84    

Obese patients

The American Society of Clinical Oncology (ASCO) published clinical practice guidelines on the appropriate chemotherapy dosing for obese adult patients with cancer in 2012.51 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 ASCO guidelines recommend that full weight-based cytotoxic chemotherapy doses be used to treat obese patients with cancer, particularly when the goal of treatment is cure.(ASCO: http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2011.39.9436)

No studies were identified which specifically compared different doses of chemotherapy among obese patients for survival outcomes.

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.64-69 Three of the studies reported on adverse events and BMI only.71, 85, 86

Hourdequin et al (2013) published a systematic review and meta-analysis of studies comparing toxic effect and survival outcomes between obese and normal weight cancer patients. Patients in the studies were from various tumour groups.  Both obese and normal weight patients received chemotherapy dosed using actual body weight, without dose reductions. The authors concluded that obese patients receiving chemotherapy based on actual body weight experienced similar or lower rates of toxic effects as normal weight patients, and survival outcomes do not differ.87

An additional study published in 2014 was also identified. Au-Yeung et al (2014) published a retrospective study from the Australian Ovarian Cancer Study (AOCS) to evaluate the relationship between BMI, dose intensity of chemotherapy received, overall survival and progression-free survival. Doses were calculated based on standard treatment regimen.70

Survival

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 SCOTROC I, (Barrett et al, 2008) did not find a link between obesity and poorer prognosis, with the authors noting this finding was due to more accurate dose calculations in that study.65 The authors recommended accurate measurement of GFR and chemotherapy doses based on actual body weight rather than ideal body weight.

Au-Yeung et al (2014) reported no significant association between BMI groups and overall or progression-free survival. Patients who received less than 85% RDI for carboplatin had significantly worse progression-free survival (univariate analysis: median PFS 11 vs. 15mths; p=0.04). In multivariate analysis, the difference in progression-free survival for RDI of carboplatin trended in the same direction but no longer reached statistical significance (p=0.06).\

Dosing

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 2m2 and BMI >30 kg/m2 to be predictors of reduced planned relative dose intensity (RDI) <85% and reduced delivered RDI <85%.68

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.64

Data from the SCOTROC I trial, showed no statistically significant differences overall 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) nor carboplatin dose intensity (p=0.578) between the BMI categories.65 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 categories. 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.65

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.67 The level of neutropenia and platinum sensitivity rate were also similar in BMI groups.

Au-Yeung et al (2014) reported that obese patients were more likely to receive RDI <85% for carboplatin compared to non-obese patients (p<0.001). The RDI comparison for paclitaxel was not significantly different between BMI groups (p=0.76). For the average RDI for both carboplatin and paclitaxel, significantly more obese patients received an average RDI <85% (p=0.02).

Adverse events

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 treatment-related toxicity compared with normal weight subjects.64 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.64

Matthews et al (2009) reported similar rates of neutropenia for obese and non-obese patients (52% and 46%, p=0.39).66

In the Japanese study by Sendo et al (2005) a multivariate analysis demonstrated that the incidence of hypersensitivity reactions to paclitaxel was significantly higher in obese patients (BMI >25)(OR 8.47, 95% CI 1.48-48.57, p=0.017).86

Laskey et al (2012) reported that BMI <30 and BSA <2.0 m2 were significant predictors of severe neutropenia in women with stage III and IV epithelial ovarian cancer by univariate analysis (p=<0.01 and p=0.03).71 Multivariate analysis indicated a trend to an association between severe neutropenia and BMI <30 (HR 1.60, p=0.06).

Additional issues of interest

Specific chemotherapy requirements/issues for women in rural/remote areas, Aboriginal and Torres Strait Islander women, resources specification, and patient selection criteria were considered as additional issues of interest.  No information about these issues was recorded from the search.

 

Strengths and weakness of the evidence

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.

Unanswered questions

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.

 

International clinical practice guidelines

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

Ongoing trials

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.

References

  1. The Australian Cancer Network and National Breast Cancer Centre. Clinical practice guidelines for the management of women with epithelial ovarian cancer. National Breast Cancer Centre, Camperdown, NSW, 2004
  2. Australian Institute of Health and Welfare (AIHW). Australian Cancer Incidence and Mortality (ACIM) Books – Ovarian cancer for Australia (ICD10 C56). http://www.aihw.gov.au. Accessed: May 2014
  3. Australian Insitute of Health and Welfare (AIHW) & Australasian Association of Cancer Registries (AACR). Cancer in Australia: an overview 2012. Cancer series no. 74. Cat. no. CAN 70. AIHW, Canberra, 2012
  4. Australian Institute of Health and Welfare. Cancer survival and prevalence in Australia: period estimates from 1982 to 2010. AIHW, Canberra, 2012
  5. Elattar A, Bryant A, Winter-Roach BA, et al. Optimal primary surgical treatment for advanced epithelial ovarian cancer. Cochrane Database Syst Rev. 2011; (8):CD007565
  6. Prat J and Oncology FCoG. Staging classification for cancer of the ovary, fallopian tube, and peritoneum. Int J Gynaecol Obstet. 2014; 124(1):1-5
  7. Cancer Australia and the Royal Australian College of Obstetricians and Gynaecologists. National gynaecological cancers service delivery and resource framework. Cancer Australia, Canberra, 2011
  8. Pospísková M, Spenerová M, Pilka R, et al. Repeated chemosensitivity testing in patients with epithelial ovarian carcinoma. Eur J Gynaecol Oncol. 2010; 31(3):295-98
  9. Cancer Australia. First line chemotherapy for women with epithelial ovarian cancer: a systematic review. Cancer Australia, Surry Hills, NSW, 2013
  10. NBOCC. Multidisciplinary care in Australia: a national demonstration project in breast cancer. NBOCC, Sydney, 2003
  11. National Health and Medical Research Council (NHMRC). How to review the evidence: systematic identification and review of the scientific literature. NHMRC, Canberra, 2000
  12. Seidman JD and Kurman RJ. Ovarian serous borderline tumors: a critical review of the literature with emphasis on prognostic indicators. Hum Pathol. 2000; 31(5):539-57
  13. Winter-Roach BA, Kitchener HC and Dickinson HO. Adjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer. Cochrane Database Syst Rev. 2012; CD004706
  14. Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011; 365(26):2484-96
  15. Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011; 365(26):2473-83
  16. du Bois A, Weber B, Rochon J, et al. Addition of epirubicin as a third drug to carboplatin-paclitaxel in first-line treatment of advanced ovarian cancer: a prospectively randomized gynecologic cancer intergroup trial by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group and the Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens. J Clin Oncol. 2006; 24(7):1127-35
  17. du Bois A, Herrstedt J, Hardy-Bessard AC, et al. Phase III trial of carboplatin plus paclitaxel with or without gemcitabine in first-line treatment of epithelial ovarian cancer. J Clin Oncol. 2010; 28(27):4162-9
  18. Bookman MA, Brady MF, McGuire WP, et al. Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a Phase III Trial of the Gynecologic Cancer Intergroup. J Clin Oncol. 2009; 27(9):1419-25
  19. Bolis G, Scarfone G, Raspagliesi F, et al. Paclitaxel/carboplatin versus topotecan/paclitaxel/carboplatin in patients with FIGO suboptimally resected stage III-IV epithelial ovarian cancer a multicenter, randomized study. Eur J Cancer. 2010; 46(16):2905-12
  20. Pfisterer J, Weber B, Reuss A, et al. Randomized phase III trial of topotecan following carboplatin and paclitaxel in first-line treatment of advanced ovarian cancer: a gynecologic cancer intergroup trial of the AGO-OVAR and GINECO. J Natl Cancer Inst. 2006; 98(15):1036-45
  21. Hoskins PJ, Vergote I, Stuart G, et al. A phase III trial of cisplatin plus topotecan followed by paclitaxel plus carboplatin versus standard carboplatin plus paclitaxel as first-line chemotherapy in women with newly diagnosed advanced epithelial ovarian cancer (EOC) (OV.16). A Gynecologic Cancer Intergroup Study of the NCIC CTG, EORTC GCG, and GEICO. J Clin Oncol, 2008
  22. Aravantinos G, Fountzilas G, Bamias A, et al. Carboplatin and paclitaxel versus cisplatin, paclitaxel and doxorubicin for first-line chemotherapy of advanced ovarian cancer: a Hellenic Cooperative Oncology Group (HeCOG) study. Eur J Cancer. 2008; 44(15):2169-77
  23. Lhomme C, Joly F, Walker JL, et al. Phase III study of valspodar (PSC 833) combined with paclitaxel and carboplatin compared with paclitaxel and carboplatin alone in patients with stage IV or suboptimally debulked stage III epithelial ovarian cancer or primary peritoneal cancer. J Clin Oncol. 2008; 26(16):2674-82
  24. Nicoletto MO, Tumolo S, Sorio R, et al. Long-term survival in a randomized study of nonplatinum therapy versus platinum in advanced epithelial ovarian cancer. Int J Gynecol Cancer. 2007; 17(5):986-92
  25. Reed NS, Poole CJ, Coleman R, et al. A randomised comparison of treosulfan and carboplatin in patients with ovarian cancer: a study by the Scottish Gynaecological Cancer Trials Group (SGCTG). Eur J Cancer. 2006; 42(2):179-85
  26. Pignata S, Scambia G, Ferrandina G, et al. Carboplatin plus paclitaxel versus carboplatin plus pegylated liposomal doxorubicin as first-line treatment for patients with ovarian cancer: the MITO-2 randomized phase III trial. J Clin Oncol. 2011; 29(27):3628-35
  27. Vasey PA, Jayson GC, Gordon A, et al. Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma. J Natl Cancer Inst. 2004; 96(22):1682-91
  28. Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2003; 21(17):3194-200
  29. du Bois A, Luck HJ, Meier W, et al. A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst. 2003; 95(17):1320-9
  30. Greimel ER, Bjelic-Radisic V, Pfisterer J, et al. Randomized study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group comparing quality of life in patients with ovarian cancer treated with cisplatin/paclitaxel versus carboplatin/paclitaxel. J Clin Oncol. 2006; 24(4):579-86
  31. Aravantinos G, Fountzilas G, Kosmidis P, et al. Paclitaxel plus carboplatin versus paclitaxel plus alternating carboplatin and cisplatin for initial treatment of advanced ovarian cancer: long-term efficacy results: a Hellenic Cooperative Oncology Group (HeCOG) study. Ann Oncol. 2005; 16(7):1116-22
  32. Mouratidou D, Gennatas C, Michalaki V, et al. A phase III randomized study comparing paclitaxel and cisplatin versus cyclophosphamide and cisplatin in patients with advanced ovarian cancer. Anticancer Res. 2007; 27(1B):681-5
  33. Bezjak A, Tu D, Bacon M, et al. Quality of life in ovarian cancer patients: comparison of paclitaxel plus cisplatin, with cyclophosphamide plus cisplatin in a randomized study. J Clin Oncol. 2004; 22(22):4595-603
  34. Butler L, Bacon M, Carey M, et al. Determining the relationship between toxicity and quality of life in an ovarian cancer chemotherapy clinical trial. J Clin Oncol. 2004; 22(12):2461-8
  35. Piccart MJ, Bertelsen K, Stuart G, et al. Long-term follow-up confirms a survival advantage of the paclitaxel-cisplatin regimen over the cyclophosphamide-cisplatin combination in advanced ovarian cancer. Int J Gynecol Cancer. 2003; 13 Suppl 2144-8
  36. Dittrich C, Sevelda P, Salzer H, et al. Lack of impact of platinum dose intensity on the outcome of ovarian cancer patients. 10-year results of a prospective randomised phase III study comparing carboplatin-cisplatin with cyclophosphamide-cisplatin. Eur J Cancer. 2003; 39(8):1129-40
  37. Muthuramalingam SR, Braybrooke JP, Blann AD, et al. A prospective randomised phase II trial of thalidomide with carboplatin compared with carboplatin alone as a first-line therapy in women with ovarian cancer, with evaluation of potential surrogate markers of angiogenesis. Eur J Gynaecol Oncol. 2011; 32(3):253-8
  38. Vasey PA, Atkinson R, Osborne R, et al. SCOTROC 2A: carboplatin followed by docetaxel or docetaxel-gemcitabine as first-line chemotherapy for ovarian cancer. Br J Cancer. 2006; 94(1):62-8
  39. Clamp AR, Maenpaa J, Cruickshank D, et al. SCOTROC 2B: feasibility of carboplatin followed by docetaxel or docetaxel-irinotecan as first-line therapy for ovarian cancer. Br J Cancer. 2006; 94(1):55-61
  40. Minagawa Y, Kigawa J, Kanamori Y, et al. Feasibility study comparing docetaxel-cisplatin versus docetaxel-carboplatin as first-line chemotherapy for ovarian cancer. Gynecol Oncol. 2006; 101(3):495-8
  41. Mori T, Hosokawa K, Kinoshita Y, et al. A pilot study of docetaxel-carboplatin versus paclitaxel-carboplatin in Japanese patients with epithelial ovarian cancer. Int J Clin Oncol. 2007; 12(3):205-11
  42. Takakura S, Takano M, Takahashi F, et al. Randomized phase II trial of paclitaxel plus carboplatin therapy versus irinotecan plus cisplatin therapy as first-line chemotherapy for clear cell adenocarcinoma of the ovary: a JGOG study. Int J Gynecol Cancer. 2010; 20(2):240-7
  43. Fruscio R, Colombo N, Lissoni AA, et al. A phase II randomised clinical trial comparing cisplatin, paclitaxel and ifosfamide with cisplatin, paclitaxel and epirubicin in newly diagnosed advanced epithelial ovarian cancer: long-term survival analysis. Br J Cancer. 2008; 98(4):720-7
  44. Vergote I, Trope CG, Amant F, et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med. 2010; 363(10):943-53
  45. Jaaback K and Johnson N. Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer. Cochrane Database Syst Rev. 2011; CD005340
  46. Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006; 354(1):34-43
  47. Katsumata N, Yasuda M, Takahashi F, et al. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet. 2009; 374(9698):1331-8
  48. Katsumata N, Yasuda M, Isonishi S, et al. Long-term follow-up of a randomized trial comparing conventional paclitaxel and carboplatin with dose-dense weekly paclitaxel and carboplatin in women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: JGOG 3016 trial. J Clin Oncol 30, 2012 (suppl; abstr 5003). 2012; 30(15 Supplement):Abstract 5003
  49. Harano K, Terauchi F, Katsumata N, et al. Quality-of-life outcomes from a randomized phase III trial of dose-dense weekly paclitaxel and carboplatin compared with conventional paclitaxel and carboplatin as a first-line treatment for stage II-IV ovarian cancer: Japanese Gynecologic Oncology Group Trial (JGOG3016). Ann Oncol. 2014; 25(1):251-7
  50. Eisenhauer EL, Tew WP, Levine DA, et al. Response and outcomes in elderly patients with stages IIIC-IV ovarian cancer receiving platinum-taxane chemotherapy. Gynecol Oncol. 2007; 106(2):381-7
  51. Griggs JJ, Mangu PB, Anderson H, et al. Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline. Journal of Clinical Oncology. 2012; 30(13):1553-1561
  52. Robinson WR, Ritter J, Rogers AS, et al. Clinical trial participation is associated with improved outcome in women with ovarian cancer. Int J Gynecol Cancer. 2009; 19(1):124-8
  53. Peppercorn JM, Weeks JC, Cook EF and Joffe S. Comparison of outcomes in cancer patients treated within and outside clinical trials: conceptual framework and structured review. Lancet. 2004; 363(9405):263-70
  54. Stark D, Nankivell M, Pujade-Lauraine E, et al. Standard chemotherapy with or without bevacizumab in advanced ovarian cancer: quality-of-life outcomes from the International Collaboration on Ovarian Neoplasms (ICON7) phase 3 randomised trial. Lancet Oncol. 2013; 14(3):236-43
  55. Burger RA, Brady MF, Bookman MA, et al. Risk Factors for GI Adverse Events in a Phase III Randomized Trial of Bevacizumab in First-Line Therapy of Advanced Ovarian Cancer: A Gynecologic Oncology Group Study. J Clin Oncol. 2014;
  56. Grenman S, Wiklund T, Jalkanen J, et al. A randomised phase III study comparing high-dose chemotherapy to conventionally dosed chemotherapy for stage III ovarian cancer: the Finnish Ovarian Cancer (FINOVA) study. Eur J Cancer. 2006; 42(14):2196-9
  57. Mobus V, Wandt H, Frickhofen N, et al. Phase III trial of high-dose sequential chemotherapy with peripheral blood stem cell support compared with standard dose chemotherapy for first-line treatment of advanced ovarian cancer: intergroup trial of the AGO-Ovar/AIO and EBMT. J Clin Oncol. 2007; 25(27):4187-93
  58. Yang D, Khan S, Sun Y, et al. Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA. 2011; 306(14):1557-65
  59. Vencken PM, Kriege M, Hoogwerf D, et al. Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after first-line chemotherapy compared with sporadic ovarian cancer patients. Ann Oncol. 2011; 22(6):1346-52
  60. Tan DS, Rothermundt C, Thomas K, et al. "BRCAness" syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol. 2008; 26(34):5530-6
  61. Alsop K, Fereday S, Meldrum C, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012; 30(21):2654-63
  62. Hershman D, Jacobson JS, McBride R, et al. Effectiveness of platinum-based chemotherapy among elderly patients with advanced ovarian cancer. Gynecol Oncol. 2004; 94(2):540-9
  63. Hilpert F, du Bois A, Greimel ER, et al. Feasibility, toxicity and quality of life of first-line chemotherapy with platinum/paclitaxel in elderly patients aged >or=70 years with advanced ovarian cancer--a study by the AGO OVAR Germany. Ann Oncol. 2007; 18(2):282-7
  64. Wright JD, Tian C, Mutch DG, et al. Carboplatin dosing in obese women with ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol. 2008; 109(3):353-8
  65. Barrett SV, Paul J, Hay A, et al. Does body mass index affect progression-free or overall survival in patients with ovarian cancer? Results from SCOTROC I trial. Annals of Oncology. 2008; 19(5):898-902
  66. Matthews KS, Straughn JM, Jr., Kemper MK, et al. The effect of obesity on survival in patients with ovarian cancer. Gynecol Oncol. 2009; 112(2):389-93
  67. Suh DH, Kim HS, Chung HH, et al. Body mass index and survival in patients with epithelial ovarian cancer. Journal of Obstetrics & Gynaecology Research. 2012; 38(1):70-6
  68. Hanna R, Poniwierski M, Laskey R, et al. Predictors and effects of reduced relative dose intensity in women receiving their primary course of chemotherapy for ovarian cancer. Gynecologic Oncology. 2011; 120S98
  69. Pavelka JC, Brown RS, Karlan BY, et al. Effect of obesity on survival in epithelial ovarian cancer. Cancer. 2006; 107(7):1520-4
  70. Au-Yeung G, Webb PM, DeFazio A, et al. Impact of obesity on chemotherapy dosing for women with advanced stage serous ovarian cancer in the Australian Ovarian Cancer Study (AOCS). Gynecol Oncol. 2014; 133(1):16-22
  71. Laskey RA, Poniewierski MS, Lopez MA, et al. Predictors of severe and febrile neutropenia during primary chemotherapy for ovarian cancer. Gynecologic Oncology. 2012; 125(3):625-630
  72. Kyrgiou M, Salanti G, Pavlidis N, et al. Survival benefits with diverse chemotherapy regimens for ovarian cancer: meta-analysis of multiple treatments. J Natl Cancer Inst. 2006; 98(22):1655-63
  73. Raja FA, Chopra N and Ledermann JA. Optimal first-line treatment in ovarian cancer. Ann Oncol. 2012; 23(Suppl 10):X118-27
  74. Katsumata N. Dose-dense therapy is of benefit in primary treatment of ovarian cancer? In favor. Ann Oncol. 2011; 22(Suppl 8):viii29-viii32
  75. Robinson WR and Beyer J. Factors affecting the completion of intraperitoneal chemotherapy in women with ovarian cancer. Int J Gynecol Cancer. 2010; 20(1):70-4
  76. Vergote I, du Bois A, Amant F, et al. Neoadjuvant chemotherapy in advanced ovarian cancer: On what do we agree and disagree? Gynecol Oncol. 2013; 128(1):6-11
  77. Kehoe. S, Hook. J, Nankivell. M, et al. Chemotherapy or upfront surgery for newly diagnosed advanced ovarian cancer: Results from the MRC CHORUS trial. J Clin Oncol 31, 2013 (suppl; abstr 5500) 2013;
  78. Polcher M, Mahner S, Ortmann O, et al. Neoadjuvant chemotherapy with carboplatin and docetaxel in advanced ovarian cancer--a prospective multicenter phase II trial (PRIMOVAR). Oncol Rep. 2009; 22(3):605-13
  79. Sundararajan V, Hershman D, Grann VR, et al. Variations in the use of chemotherapy for elderly patients with advanced ovarian cancer: a population-based study. J Clin Oncol. 2002; 20(1):173-8
  80. Jordan S, Steer C, DeFazio A, et al. Patterns of chemotherapy treatment for women with invasive epithelial ovarian cancer--a population-based study. Gynecol Oncol. 2013; 129(2):310-7
  81. Tew W, Java J, Chi D, et al. Treatment outcomes for older women with advanced ovarian cancer: results from a phase III clinical trial (GOG182). J Clin Oncol. 2010; 28(15S):Abstract 5030
  82. Hurria A, Browner IS, Cohen HJ, et al. Senior adult oncology. J Natl Compr Canc Netw. 2012; 10(2):162-209
  83. Timmers PJ, Zwinderman AH, Teodorovic I, et al. Clear cell carcinoma compared to serous carcinoma in early ovarian cancer: same prognosis in a large randomized trial. Int J Gynecol Cancer. 2009; 19(1):88-93
  84. Alexandre J, Ray-Coquard I, Selle F, et al. Mucinous advanced epithelial ovarian carcinoma: clinical presentation and sensitivity to platinum-paclitaxel-based chemotherapy, the GINECO experience. Annals of Oncology. 2010; 21(12):2377-81
  85. Mereu L, Tateo S, Klersy C, et al. Stratification of venous thromboembolism risk in ovarian cancer patients during chemotherapy. International Journal of Gynecological Cancer. 2009; 19(1):79-83
  86. Sendo T, Sakai N, Itoh Y, et al. Incidence and risk factors for paclitaxel hypersensitivity during ovarian cancer chemotherapy. Cancer Chemotherapy and Pharmacology. 2005; 56(1):91-96
  87. Hourdequin KC, Schpero WL, McKenna DR, et al. Toxic effect of chemotherapy dosing using actual body weight in obese versus normal-weight patients: a systematic review and meta-analysis. Ann Oncol. 2013; 24(12):2952-62
  88. National Health and Medical Research Council (NHMRC). NHMRC additional levels of evidence and grades for recommendations for developers of guidelines. Commonwealth of Australia, 2009

 

APPENDIX 1: NHMRC Evidence Hierarchy

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

Level Intervention Diagnostic accuracy Prognosis Aetiology Screening Intervention

I

A systematic review of level II studies

A systematic review of level II studies

A systematic review of level II studies

A systematic review of level II studies

A systematic review of level II studies

II

A randomised controlled trial

A study of test accuracy with:

  • an independent, blinded
  • comparison with a valid reference standard, among consecutive persons with a defined clinical presentation

A prospective cohort study

A prospective cohort study

A randomised controlled trial

III-1

A pseudorandomised controlled trial(i.e. alternate allocation or some other method)

A study of test accuracy with:

  • an independent, blinded comparison with a valid reference standard, among non-consecutive persons with
  • a defined clinical presentation

All or none

All or none

A pseudorandomised controlled trial (i.e. alternate allocation or some other method)

III-2

A comparative study with concurrent controls:

  • Non-randomised,
  • experimental trial
  • Cohort study
  • Case-control study
  • Interrupted time series with a control group

A comparison with reference standard that does not meet the criteria required for Level II and III-1 evidence

Analysis of prognostic factors amongst persons in a single arm of a randomised controlled trial

A retrospective cohort study

A comparative study with concurrent controls:

  • Non-randomised,
  • experimental trial
  • Cohort study
  • Case-control study

III-3

A comparative study without concurrent controls:

  • Historical control study
  • Two or more single arm
  • study
  • Interrupted time series without a parallel control group

Diagnostic case-control study

A retrospective cohort study

A case-control study

A comparative study without concurrent controls:

  • Historical control study
  • Two or more single arm study

IV

Case series with either post-test or pre-test/post-test outcomes

Study of diagnostic yield (no reference standard)

Case series, or cohort study of persons at different stages of disease

A cross-sectional study or case series

Case series

Acknowledgements

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.

Additional information

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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