Early Detection and Treatment of Ovarian Cancer Improves Outcome: Right?

Abstract & Commentary

By Robert L. Coleman, MD, Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.

Dr. Coleman reports no financial relationship to this field of study.

Synopsis: In this randomized phase III trial of early vs delayed treatment based on CA125 surveillance, no benefit to overall survival was observed for early treatment. Further, patients undergoing early initiation of therapy had more rapid deterioration in global health quality-of-life measures.

Source: Rustin GJS, et al. Early vs delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): A randomised trial. Lancet 2010;376:1155-1163.

Patients with advanced ovarian cancer frequently have corresponding CA125 values that pace tumor response and progression during therapy. This has supported the common practice of monitoring patients with serial CA125 in complete remission following primary chemotherapy. The supposition is that earlier identification of recurrent disease can be better controlled by earlier initiation of therapy. To formally address this hypothesis, the EORTC conducted a randomized phase III trial in which women in complete clinical remission following primary surgery and chemotherapy were enrolled into a blind surveillance program. Follow-up visits were scheduled every 3 months during which an exam was performed and blood was taken for CA125 assessment. All registrants were blind to their CA125 values during this time. However, when an individual's CA125 rose to twice the upper limit of normal, they were randomized 1:1 to unblinding of the result (early) or continued blinded surveillance (delayed). In this latter group, intervention was determined by the development of clinical or symptomatic relapse. Post-progression therapy was determined by local standards of care. The primary endpoint of the study was overall survival. In all, 1442 patients were registered, of whom 529 were randomly assigned to the treatment groups. Patients unblinded and made aware of their rising CA125 values generally started treatment immediately, and on the median, 4.8 months before those in the delayed group. After a median follow-up of nearly 57 months from randomization and 370 deaths, there was no difference in overall survival between the arms (hazard rate, 0.98; 95% confidence interval, 0.8-1.2). Median survival in the early treatment group was 25.7 months compared to 27.1 months in the delayed group. For patients receiving third-line therapy, the time differential to initiation was nearly the same as the time differential to initiation of second-line therapy (median, 4.6 months). Interestingly, first deterioration in Global Health score occurred significantly sooner in the early treatment group. The authors conclude no benefit in survival is gained by treatment dictated solely by asymptomatic rise in CA125 and challenge the practice of routine biomarkers surveillance in this setting.

Commentary

This extremely provocative study was no doubt as difficult to conduct as the results are to accept. It is remarkable that such a large cohort of patients accepted follow-up care without one of the staples of reassurance — their CA125. However, the investigators are to be congratulated in tackling a mantra of care that is absolutely pervasive in clinical management. Patients and clinicians alike are "addicted" to CA125, particularly in those where the biomarker follows clinical disease regression. Since it's usually obtained with every course of therapy during primary management, it frequently serves as a surrogate for the unseen and positive reinforcement to endure the unpleasantries of chemotherapy. However, the results suggest our dependence on, and clinical response to, the biomarker does not help our patients live longer.

Since these data became public in 2009, we have struggled with counseling patients who are concerned that complacency in surveillance will harm their chances at lasting survival. In this regard, it is important to synthesize the message the trial brings. First, the analysis follows a cohort of women destined to recur and, in this regard, the results are not that surprising. Nearly every randomized clinical treatment study conducted to date regarding management of recurrent disease has failed to extend overall survival. The difference in detection of disease in this study is likely too short to make a difference even if all the post-progression treatment is the same. Second, patients with early recurrence are good candidates for treatment trials including ones of biomarker-only recurrence. Biological and immunological therapies are hypothesized to be most efficacious in this setting and are under active investigation. So candidate selection would be a reasonable indication to follow CA125 closely. Third, and maybe most importantly, patients can be reassured that they have time to process, contemplate, and initiate therapy when recurrence is suspected or documented. This is particularly important in those with lasting adverse events from their previous treatment.

It would be of great value to repeat this study with tighter regulation of post-progression management strategies, such as higher utilization of platinum-based combination therapies and secondary surgery, and in the context of newer validated biomarkers. However, based on responses from patients aware of this study's findings, I'm not optimistic.