Clear survival benefit is achieved if all or most (< 1 cm remaining) of the tumour after primary surgical treatment for advanced epithelial ovarian cancer is removed

Ovarian cancer is a cancerous growth arising from different parts of the ovary. It is the sixth most common cancer among women. Most ovarian cancers are classified as epithelial. Ovarian epithelial cancer is a disease in which malignant (cancer) cells form in the tissue covering the ovary and most cases are epithelial. Primary surgery is performed to achieve optimal cytoreduction (surgical efforts aiming at removing the bulk of the tumour) as the amount of tumour that remains after surgery (residual disease) is one of the most important factors that is taken into account when determining a prognosis (prognostic factor) for survival of epithelial ovarian cancer. Optimal cytoreductive surgery remains a subject of controversy to many practising obstetric gynaecologists who specialise in the diagnosis and treatment of women with cancer of the reproductive organs (gynae-oncologists). The Gynaecologic Oncology Group (GOG) currently defines 'optimal' as having a small aggregation of remaining cancer cells after surgery (residual tumour nodules) each measuring 1 cm or less in maximum diameter, with complete cytoreduction (microscopic disease) being the ideal surgical outcome. Although the size of residual tumour masses after surgery has been shown to be an important prognostic factor for advanced ovarian cancer, there is limited evidence to support the conclusion that the surgical procedure is directly responsible for the superior outcome associated with less residual disease. This review assessed overall and progression-free survival of optimal primary cytoreductive surgery for women with advanced epithelial ovarian cancer (stages III and IV). We found 11 retrospective studies that included more than 100 women and used a multivariate analysis (used statistical adjustment for important prognostic factors) and met our inclusion criteria. Analyses showed the prognostic importance of complete cytoreduction, where the residual disease is microscopic with no visible disease, as overall (OS) and progression-free survival (PFS) were significantly prolonged in these groups of women. PFS was not reported in all of the studies but was sufficiently documented to allow firm conclusions to be drawn. When we compared suboptimal (> 1 cm) versus optimal (< 1 cm) cytoreduction the survival estimates were attenuated but remained statistically significant in favour of the lower volume disease group, but there was no significant difference in OS and only a borderline difference in PFS when residual disease of > 2 cm and < 2 cm were compared. There was a high risk of bias due to the retrospective nature of these studies. Adverse events, quality of life (QoL) and cost-effectiveness were not reported by treatment arm or to a satisfactory level in any of the studies. During primary surgery for advanced stage epithelial ovarian cancer, all attempts should be made to achieve complete cytoreduction. When this is not achievable, the surgical goal should be optimal (< 1 cm) residual disease. Due to the high risk of bias in the current evidence, randomised controlled trials should be performed to determine whether it is the surgical intervention or patient-related and disease-related factors that are associated with the improved survival in these groups of women.

Authors' conclusions: 

During primary surgery for advanced stage epithelial ovarian cancer all attempts should be made to achieve complete cytoreduction. When this is not achievable, the surgical goal should be optimal (< 1 cm) residual disease. Due to the high risk of bias in the current evidence, randomised controlled trials should be performed to determine whether it is the surgical intervention or patient-related and disease-related factors that are associated with the improved survival in these groups of women. The findings of this review that women with residual disease < 1 cm still do better than women with residual disease > 1 cm should prompt the surgical community to retain this category and consider re-defining it as 'near optimal' cytoreduction, reserving the term 'suboptimal' cytoreduction to cases where the residual disease is > 1 cm (optimal/near optimal/suboptimal instead of complete/optimal/suboptimal).

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Background: 

Ovarian cancer is the sixth most common cancer among women. In addition to diagnosis and staging, primary surgery is performed to achieve optimal cytoreduction (surgical efforts aimed at removing the bulk of the tumour) as the amount of residual tumour is one of the most important prognostic factors for survival of women with epithelial ovarian cancer. An optimal outcome of cytoreductive surgery remains a subject of controversy to many practising gynae-oncologists. The Gynaecologic Oncology group (GOG) currently defines 'optimal' as having residual tumour nodules each measuring 1 cm or less in maximum diameter, with complete cytoreduction (microscopic disease) being the ideal surgical outcome. Although the size of residual tumour masses after surgery has been shown to be an important prognostic factor for advanced ovarian cancer, it is unclear whether it is the surgical procedure that is directly responsible for the superior outcome that is associated with less residual disease.

Objectives: 

To evaluate the effectiveness and safety of optimal primary cytoreductive surgery for women with surgically staged advanced epithelial ovarian cancer (stages III and IV).

To assess the impact of various residual tumour sizes, over a range between zero and 2 cm, on overall survival.

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 3) and the Cochrane Gynaecological Cancer Review Group Trials Register, MEDLINE and EMBASE (up to August 2010). We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field.

Selection criteria: 

Retrospective data on residual disease from randomised controlled trials (RCTs) or prospective and retrospective observational studies which included a multivariate analysis of 100 or more adult women with surgically staged advanced epithelial ovarian cancer and who underwent primary cytoreductive surgery followed by adjuvant platinum-based chemotherapy. We only included studies that defined optimal cytoreduction as surgery leading to residual tumours with a maximum diameter of any threshold up to 2 cm.

Data collection and analysis: 

Two review authors independently abstracted data and assessed risk of bias. Where possible, the data were synthesised in a meta-analysis.

Main results: 

There were no RCTs or prospective non-RCTs identified that were designed to evaluate the effectiveness of surgery when performed as a primary procedure in advanced stage ovarian cancer.

We found 11 retrospective studies that included a multivariate analysis that met our inclusion criteria. Analyses showed the prognostic importance of complete cytoreduction, where the residual disease was microscopic that is no visible disease, as overall (OS) and progression-free survival (PFS) were significantly prolonged in these groups of women. PFS was not reported in all of the studies but was sufficiently documented to allow firm conclusions to be drawn.

When we compared suboptimal (> 1 cm) versus optimal (< 1 cm) cytoreduction the survival estimates were attenuated but remained statistically significant in favour of the lower volume disease group There was no significant difference in OS and only a borderline difference in PFS when residual disease of > 2 cm and < 2 cm were compared (hazard ratio (HR) 1.65, 95% CI 0.82 to 3.31; and HR 1.27, 95% CI 1.00 to 1.61, P = 0.05 for OS and PFS respectively).

There was a high risk of bias due to the retrospective nature of these studies where, despite statistical adjustment for important prognostic factors, selection bias was still likely to be of particular concern.

Adverse events, quality of life (QoL) and cost-effectiveness were not reported by treatment arm or to a satisfactory level in any of the studies.

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