LOS ANGELES -- Women with advanced ovarian cancer had significantly worse survival when they started chemotherapy more than 25 days after surgery, according to a study reported here.
Within the range of 15 to 40 days, the risk of death increased 25% and continued to rise with a longer interval from surgery to initiation of chemotherapy, reported Ramez Eskander, MD, and colleagues, at the Society of Gynecologic Oncology meeting.
Patients with microscopic residual disease after surgery faced a greater mortality risk compared with the overall population of women with ovarian cancer. Across the range from 15 to 80 days, patients with microscopic residual disease had a survival hazard seven times greater compared with the overall patient population, said Eskander of the University of California Irvine.
"Our research indicates that there may be an optimal window for therapy to administer to patients who have had an exhaustive effort at cytoreductive surgical resection of their disease, and that approximates 25 days," he explained. "Delays beyond this window translate into adverse oncologic outcomes within this exploratory study."
However, Eskander cautioned that "these findings do not appear to hold for patients with bulky or macroscopic residual disease."
Several clinical factors have well established prognostic implications for advanced ovarian cancer, the strongest of these being disease stage, extent of residual disease after cytoreductive surgery, and response to systemic chemotherapy. The impact of the interval from surgery to initiation of chemotherapy on outcome has remained undefined.
Investigation of the association between time for surgery to chemotherapy has yielded inconsistent results. Three large studies based on cross-sectional data from the NCI Surveillance, Epidemiology, and End Results program have shown worse outcomes in ovarian, breast, and colorectal cancer, when chemotherapy is delayed by 2 to 3 months.
However, seven different studies in ovarian cancer have failed to demonstrate an adverse impact of delay in chemotherapy or to determine the optimal timing for initiation of chemotherapy, Eskander said
To address the uncertainty arising from inconsistent results, his group analyzed data from a contemporary Gynecologic Oncology Group (GOG) trial of chemotherapy in ovarian cancer. Data came from GOG 218, which showed significant improvement in progression-free survival with the addition of bevacizumab (Avastin) maintenance to first-line chemotherapy.
The analysis comprised 1,718 patients, and the interval from surgery to chemotherapy averaged 31 days in all three treatment groups.
However, examination of survival by interval to chemotherapy and residual disease revealed a significant impact of delay to chemotherapy. Patients with microscopic residual tumor started chemotherapy a median of 35 days after surgery, compared with 33 days for optimally debulked (≤1 cm) patients and 29 days after suboptimal (>1 cm) debulking (P<0.001).
Investigators found that 450 patients (>25%) started chemotherapy more than 40 days after surgery.
Comparison of the interval to chemotherapy and log hazard ratio for survival showed that the hazard began to increase after 25 days.
"Patients with microscopic residual disease were most affected by delay in the initiation of chemotherapy after surgical cytoreduction," Eskander said. "Specifically, there is an approximately 5% per day increase in the risk of death in microscopic patients when the interval between surgery and treatment exceeds 40 days."
For the subgroup of patients with microscopic residual disease, the hazard ratio for survival increased by 3.44 across the range of 15 to 60 days in the interval from surgery to treatment and by 7.22 when the range was extended to 80 days.
Also, the authors found that the Asian patients appeared to be negatively affected by increasing time from surgery to chemotherapy initiation (P=0.004).
The findings related to patient microscopic residual disease are consistent with preclinical data. In vivo animal models have shown worse outcomes when chemotherapy is delayed after removal of a primary tumor, followed by rapid regrowth of the tumor.
The explanation might lie in Gompertzian principles of cell kinetics, which posit that a decrease in tumor size translates into an increase in the growth rate fraction. In turn, the rapid regrowth may translate into increased susceptibility to early initiation of chemotherapy drugs, Eskander said
Previous studies of the relationship between delay to chemotherapy and survival in ovarian cancer involved retrospective data, single institutions, and heterogeneous patient populations and treatment. The analysis of GOG 218 used prospectively collected data from a large population of patients who received standardized care and contemporary therapy, including a targeted agent, Eskander noted.
During the discussion that followed, a SGO attendee referred to studies reported more than 20 years ago, documenting rapid regrowth of ovarian cancer cells during the first 4 to 7 days after cytoreductive surgery.
The European Organization for Treatment and Research in Cancer (EORTC) tried without success to develop a study of early chemotherapy, within 4 days after surgery. The EORTC subsequently did identify day 20 after surgery as the "D Day" for chemotherapy.
"After that, everything is going to be worse," the commenter said. "We have known this for 20 years, but nothing has happened, probably because of our hospitals and systems. We have to keep in mind that science is more important, sometimes, than the system itself."
Eskander and colleagues reported no conflicts of interest.
- Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner
Society of Gynecologic OncologySource Reference: Eskander R, et al "Negative survival impact associated with >25 day interval from surgical cytoredution to initiation of systemic therapy in advanced ovarian carcinoma: A Gynecologic Oncology Group ancillary data study" SGO 2013; Abstract 56.