Statements of evidence

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

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

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

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

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

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

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 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

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

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