UK Trial Shows Neoadjuvant Platinum-Based Chemotherapy Noninferior to Adjuvant Chemotherapy in Advanced Ovarian Cancer
In the UK phase III CHORUS trial reported in The Lancet, Kehoe et al found that a strategy of three cycles of platinum-based chemotherapy followed by delayed surgery and three additional cycles of chemotherapy was associated with overall survival noninferior to that achieved with surgery followed by six cycles of chemotherapy in patients with newly diagnosed stage III or IV ovarian cancer.
Study Details
In this open-label noninferiority trial, 550 women (539 of 552 total recruited from UK, 13 from New Zealand) were randomly assigned between March 2004 and August 2010 to receive three cycles of platinum-based chemotherapy followed by surgery and three additional cycles (n = 274) or surgery followed by six cycles of chemotherapy (n = 276). Chemotherapy consisted of carboplatin at AUC = 5 or AUC = 6 plus paclitaxel at 175 mg/m², an alternative carboplatin combination regimen, or carboplatin monotherapy. The primary endpoint was overall survival in the intent to treat population. To establish noninferiority, the upper bound of a one-sided 90% confidence interval (CI) for the hazard ratio (HR) had to be < 1.18.
The primary chemotherapy and primary surgery groups were generally balanced for age (median, 65 and 66 years), tumor size (median ≤ 2 cm in 5% in both, ≤ 5 cm in 22% and 21%, ≤ 10 cm in 40% in both, ≤ 20 cm in 29% in both, > 20% in 3% in both), International Federation of Gynecology and Obstetrics stage (III in 75% in both, IV in 25% in both), CA125:CEA ratio > 25 (98% and 99%), and prespecified chemotherapy regimen (carboplatin plus paclitaxel in 77% and 75%, carboplatin alone in 23% and 24%, carboplatin plus other chemotherapy agent in < 1% and 1%).
Noninferior Overall Survival
As of May 31, 2014, 451 deaths had occurred, consisting of 220 in the primary chemotherapy group and 231 in the primary surgery group; median follow-up in 99 survivors was 4.4 years. Median overall survival was 24.1 months in the primary chemotherapy group vs 22.6 months in the primary surgery group; the HR for death was 0.87 in favor of primary chemotherapy, with the upper bound of the one-sided 90% CI of 0.98 (95% CI = 0.72–1.05) excluding the predefined noninferiority boundary.
Median operation time was 120 minutes in both. Among patients with available data on residual disease, debulking to < 1 cm was achieved in 73% vs 41% (P = .0001) and to no macroscopic disease in 39% vs 17% (P = .0001).
Median progression-free survival was 12.0 vs 10.7 months (HR = 0.91, 95% CI = 0.76–1.09).
Adverse Events
Grade 3 or 4 postoperative adverse events occurred in 14% of the primary chemotherapy group vs 24% of the primary surgery group (P = .0007) and death within 28 days after surgery occurred in < 1% vs 6% (P = .001). The most common grade 3 or 4 postoperative adverse event was hemorrhage in both groups (6% vs 3%). Hospital discharge within 14 days after surgery was more common in the primary chemotherapy group (93% vs 80%, P < .0001). Chemotherapy-related grade 3 or 4 adverse events occurred in 40% vs 49% (P = .0654) and consisted mainly of uncomplicated neutropenia (20% vs 16%). One patient in the primary chemotherapy group had a fatal adverse event, consisting of neutropenic sepsis.
Global quality of life assessed by EORTC quality of life questionnaire core-36 and the ovarian cancer–specific quality of life questionnaire showed some improvement in the primary chemotherapy vs surgery group (P = .0438 at 6 months and P = .0515 at 12 months). Clinically significant improvements of ≥ 5 points occurred in 63% vs 55% at 6 months (P = .311) and in 61% vs 44% 12 months (P = .097).
The investigators concluded: “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.”
Matthew Nankivell, MSc, of MRC Clinical Trials Unit at University College London, is the corresponding author for The Lancet article.
The study was funded by Cancer Research UK and Royal College of Obstetricians and Gynaecologists. Jane Hook, MRCP, Matthew Nankivell, MSc, Selina Bannoom, MSc, Monica Mascarenhas, PhD, and Mahesh Parmar, DPhil, are employed by the Medical Research Council.
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