Early initiation of chemotherapy following complete resection of advanced ovarian cancer associated with improved survival: NRG Oncology/Gynecologic Oncology Group study

Abstract

Background: To determine whether time from surgery to initiation of chemotherapy impacts survival in advanced ovarian carcinoma.

Patients and methods: This is a post-trial ad hoc analysis of Gynecologic Oncology Group protocol 218, a phase III randomized, double-blind, placebo-controlled trial designed to study the antiangiogenesis agent, bevacizumab, in primary and maintenance therapy for patients with newly diagnosed advanced ovarian carcinoma. Maximum attempt at debulking was an eligibility criterion. Stage III patients, not stage IV, were required to have gross macroscopic or palpable residual disease following surgery. The survival impact of time from surgery to initiation of chemotherapy was studied using Cox regression models and stratified by treatment arm, residual disease and other clinical and pathologic factors.

Results: One thousand seven hundred eighteen assessable patients were randomized (stage III (n = 1237); stage IV (n = 477), including those with complete resection (stage IV only, n = 81), low-volume residual (≤1 cm, n = 701), and suboptimal (>1 cm, n = 932). On multivariate analysis, time to chemotherapy initiation was predictive of overall survival (P < 0.001), with the complete resection group (i.e. stage IV) encountering an increased risk of death when time to initiation of chemotherapy exceeded 25 days (95% confidence interval 16.6-49.9 days).

Conclusion: Survival for women with advanced ovarian cancer may be adversely affected when initiation of chemotherapy occurs >25 days following surgery. Our analysis applies to stage IV only as women with stage III who underwent complete resection were not eligible for this trial. These results, however, are consistent with Gompertzian first-order kinetics where patients with microscopic residual are most vulnerable.

Clinical trials identifier: NCT00262847.

Keywords: NRG Oncology/GOG; chemotherapy initiation; complete resection; ovarian cancer.

Figure 1.

Association of time from surgery to initiation of chemotherapy with overall survival (OS). (A) This restricted cubic spline shows the impact of the interval from surgery to initiation of chemotherapy on the log hazard of death in the OS model. Note that the risk of death increases after 25 days. (B) Relationship between the interval between surgery and initiation of chemotherapy and log hazard ratio for each disease residual group. The lighter lines around each partial effects curve represent point-wise 95% confidence intervals. The figure suggests that the complete resection group is most affected by a longer interval from surgery to chemotherapy, whereas the other groups are affected very little. Importantly, this observation applies only to stage IV patients (81 of 477 had undergone complete resection); patients with stage III disease were required to have macroscopic visible/palpable residual disease following surgery. Note that the associated risk of time from surgery to initiation of chemotherapy is flat (15 days) or increasing (40 days, specifically for microscopic patients).

Figure 2.

Adjusted overall survival (OS) curves modeled for surgical outcome. (A) Adjusted survival curves for OS model for patients with large-volume residual disease (>1 cm) by various surgical intervals. Note that, although survival decreases with lengthening surgical interval, the differences are not profound. (B) Adjusted survival curves for OS model of patients with optimal cytoreduction (≤1 cm) for various surgical intervals. (C) Adjusted survival curves for OS model of patients with complete resection by various surgical intervals. Note that survival significantly decreases with lengthening surgical interval. Importantly, this observation applies only to stage IV patients (81 of 477 had undergone complete resection); patients with stage III disease were required to have macroscopic visible/palpable residual disease following surgery.