Elsevier

The Lancet

Volume 386, Issue 9990, 18–24 July 2015, Pages 249-257
The Lancet

Articles
Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial

https://doi.org/10.1016/S0140-6736(14)62223-6Get rights and content

Summary

Background

The international standard of care for women with suspected advanced ovarian cancer is surgical debulking followed by platinum-based chemotherapy. We aimed to establish whether use of platinum-based primary chemotherapy followed by delayed surgery was an effective and safe alternative treatment regimen.

Methods

In this phase 3, non-inferiority, randomised, controlled trial (CHORUS) undertaken in 87 hospitals in the UK and New Zealand, we enrolled women with suspected stage III or IV ovarian cancer. We randomly assigned women (1:1) either to undergo primary surgery followed by six cycles of chemotherapy, or to three cycles of primary chemotherapy, then surgery, followed by three more cycles of completion chemotherapy. Each 3-week cycle consisted of carboplatin AUC5 or AUC6 plus paclitaxel 175 mg/m2, or an alternative carboplatin combination regimen, or carboplatin monotherapy. We did the random assignment by use of a minimisation method with a random element, and stratified participants according to the randomising centre, largest radiological tumour size, clinical stage, and prespecified chemotherapy regimen. Patients and investigators were not masked to group assignment. The primary outcome measure was overall survival. Primary analyses were done in the intention-to-treat population. To establish non-inferiority, the upper bound of a one-sided 90% CI for the hazard ratio (HR) had to be less than 1·18. This trial is registered, number ISRCTN74802813, and is closed to new participants.

Findings

Between March 1, 2004, and Aug 30, 2010, we randomly assigned 552 women to treatment. Of the 550 women who were eligible, 276 were assigned to primary surgery and 274 to primary chemotherapy. All were included in the intention-to-treat analysis; 251 assigned to primary surgery and 253 to primary chemotherapy were included in the per-protocol analysis. As of May 31, 2014, 451 deaths had occurred: 231 in the primary-surgery group versus 220 in the primary-chemotherapy group. Median overall survival was 22·6 months in the primary-surgery group versus 24·1 months in primary chemotherapy. The HR for death was 0·87 in favour of primary chemotherapy, with the upper bound of the one-sided 90% CI 0·98 (95% CI 0·72–1·05). Grade 3 or 4 postoperative adverse events and deaths within 28 days after surgery were more common in the primary-surgery group than in the primary-chemotherapy group (60 [24%] of 252 women vs 30 [14%] of 209, p=0·0007, and 14 women [6%] vs 1 woman [<1%], p=0·001). The most common grade 3 or 4 postoperative adverse event was haemorrhage in both groups (8 women [3%] in the primary-surgery group vs 14 [6%] in the primary-chemotherapy group). 110 (49%) of 225 women receiving primary surgery and 102 (40%) of 253 receiving primary chemotherapy had a grade 3 or 4 chemotherapy related toxic effect (p=0·0654), mostly uncomplicated neutropenia (20% and 16%, respectively). One fatal toxic effect, neutropenic sepsis, occurred in the primary-chemotherapy group.

Interpretation

In women with stage III or IV ovarian cancer, survival with primary chemotherapy is non-inferior to primary surgery. In this study population, giving primary chemotherapy before surgery is an acceptable standard of care for women with advanced ovarian cancer.

Funding

Cancer Research UK and the Royal College of Obstetricians and Gynaecologists.

Introduction

Ovarian cancer is the leading cause of death from gynaecological cancer in developed countries.1 More than 75% of women have advanced disease (International Federation of Gynecology and Obstetrics [FIGO] stage IIIC or IV) at diagnosis, of whom a substantial proportion are unwell and unfit and have a 5-year survival rate of less than 25%.1 Primary cytoreductive surgery followed by platinum-based chemotherapy is the mainstay of treatment for advanced disease. Although no randomised trials of primary surgery exist, observational studies consistently report that a lower postoperative tumour residuum is associated with longer survival.2, 3, 4, 5, 6, 7, 8 Achievement of optimum debulking (defined in the study period as disease <1 cm in maximum diameter at completion of surgery) can need complex and widespread surgery, and is more likely to be achieved when done by specialist gynaecological oncologists.9, 10, 11 Even so, many women treated in specialist centres will have bulky residual tumour after surgery.

An alternative treatment strategy using primary chemotherapy with delayed surgery has been developed. This strategy is based on the high response rate to platinum-based chemotherapy and many women have had rapid symptomatic improvement and reduction in tumour burden with it. The primary-chemotherapy strategy seemed to increase optimum debulking rates and reduce surgery related complications in observational studies,12, 13 but two meta-analyses of non-randomised studies produced conflicting results on the effect of delaying surgery on survival.14, 15

We designed the CHORUS trial to test the hypothesis that giving primary chemotherapy with delayed surgery could result in survival similar to primary surgery, with reduced surgical morbidity. A non-inferiority design was chosen because we judged that a reduction in surgery related morbidity without detriment to survival would justify the use of this treatment strategy in clinical practice.

Section snippets

Study design and participants

We designed this trial as an investigator-designed and led multicentre, randomised phase 3 trial that took place in the UK and New Zealand (appendix). We obtained national ethical and regulatory approvals in both countries and local approvals at each centre. Trial conduct and progress were monitored by an independent data monitoring committee and overseen by the UK Medical Research Council Clinical Trials Unit (MRC CTU) Gynaecological Cancer Trial Steering Committee. All participating centres

Results

Between March 1, 2004, and Aug 30, 2010, 552 women were recruited: 539 from 74 UK trial centres and 13 from two centres in New Zealand. Surgery was done at 64 trial centres. Two women were randomly assigned in error and withdrawn from the trial immediately after; one woman because she was unable to give informed consent to participation and the other because of an administrative error. These women were excluded from all analyses, and 550 women were therefore included in the final analyses (

Discussion

Our study (CHORUS) showed that for women with stage III or IV ovarian cancer with a high tumour burden, survival after receiving primary chemotherapy followed by surgery was not inferior compared with receiving primary surgery, and surgical morbidity and mortality were significantly reduced (panel).

The median survival of 22–24 months was less than expected, but was similar in both groups. The explanation for the less-than-expected overall survival might be attributed to the older median age of

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