Maintenance Therapy Does Not Improve Survival in Advanced Ovarian Cancer

Roxanne Nelson

August 28, 2009

August 28, 2009 — Maintenance chemotherapy does not appear to benefit patients with advanced ovarian cancer. A regimen of 6 cycles of paclitaxel did not improve progression-free or overall survival in women who had achieved a complete response following first-line treatment, according to a report published online August 24 in the Journal of Clinical Oncology.

The randomized phase 3 trial, known as After-6 Protocol 1, was conducted in 200 patients. The results showed a 2-year rate of progression-free survival of 59% in the group that received maintenance therapy with paclitaxel, and of 54% in the control group. The 2-year rate of overall survival was 87% in the maintenance group and 90% in the control group.

The role of maintenance chemotherapy in ovarian cancer remains controversial, and the authors point out that multiple studies using various types of therapy and regimens have produced "conflicting, inconclusive, and generally disappointing results." They note that the conclusions of the current After-6 Protocol 1 trial contradict those of a similar study conducted by the Southwest Oncology Group and Gynecologic Oncology Group (SWOG/GOG) in 2003 (J Clin Oncol. 2003;21:2460-2465).

Results Conflict With SWOG/GOG Study

Results of the 2003 SWOG/GOG study, also a randomized phase 3 trial, showed improved progression-free survival in patients with advanced disease who had achieved a complete clinical response with primary therapy. That study involved 277 patients randomized to receive either 3 or 12 cycles of single-agent paclitaxel administered every 28 days, and results showed a median progression-free survival of 21 and 28 months in the 3- and 12-cycle paclitaxel groups, respectively.

These findings led the SWOG data and safety monitoring committee to close the study; at the time of closure, no differences were observed in overall survival between the treatment groups.

Although there are several variables that may at least partly explain the conflicting results of these studies, "we are left with opposing conclusions regarding the effect of maintenance paclitaxel on progression-free survival in patients with complete response after primary therapy," says the author of an accompanying editorial, William Patrick McGuire, MD, from the Harry and Jeanette Weinberg Cancer Institute at Franklin Square Hospital Center in Baltimore, Maryland.

Dr. McGuire points out that neither of the 2 studies meets the criteria for "proof of benefit," since there is no "appreciable effect on overall survival and because quality of life was not formally assessed."

This leaves the question, he notes, of what the responsibility of the physician is to the patient who has just completed first-line therapy and is currently free of disease.

"Should physicians simply evaluate the opposing datasets and decide for the patients what to recommend, or should we fully disclose and possibly fully confuse the average patient with all the data?" he asks. "That would appear to be a personal decision for each practitioner."

An ongoing GOG trial will randomize complete responders to observation or 12 months of either paclitaxel or polyglumex, a paclitaxel congener. Although this study could possibly resolve the conflict generated by the After-6 Protocol 1 trial and the previous SWOG/GOG trial, writes Dr. McGuire, accrual has been slow.

It is also possible that it might "not definitively resolve an important question facing patients and their physicians about what is best to recommend for the patient with ovarian cancer in complete remission," he says.

No Benefit Noted From Maintenance Therapy

The After-6 Italian Cooperative Group designed the current trial to evaluate the efficacy of 6 courses of paclitaxel as consolidation treatment in patients with advanced epithelial ovarian cancer who achieved a complete response following first-line paclitaxel/platinum-based chemotherapy.

Sergio Pecorelli, MD, from the Division of Medical Oncology at the University of Modena and Reggio Emilia in Italy, and colleagues randomized 200 patients with stage IIb to IV disease, who had achieved complete clinical or pathologic response following primary therapy, to either maintenance treatment (6 courses of paclitaxel 175 mg/m2 every 3 weeks) or observation (control group).

At a median follow-up of 43.5 months, 107 patients (53%) had experienced relapse and 48 patients (24%) had died. As with the 2-year survival rates, the researchers did not observe any significant differences between the 2 groups for progression-free or overall survival in the per-protocol population. Median progression-free survival was 34 months in the maintenance group (95% confidence interval [CI], 20 to 43 months) and 30 months in the observation group (95% CI, 17 months to infinity).

For overall survival, the median was 77 months in the maintenance group (95% CI, 59 months to infinity), and was not reached in the observation group.

A Cox model showed that residual disease after initial surgery and International Federation of Gynecology and Obstetrics (FIGO) staging were independent prognostic factors for progression-free survival, and maintenance treatment vs observation had had no prognostic relevance.

Among patients receiving maintenance therapy, grades 3 and 4 neutropenia occurred in 21.3% and 3.4% of the cohort, respectively, and grades 2 and 3 motor neuropathy developed in 7.9% and 3.4%, respectively. In addition, grades 2 and 3 sensory neuropathy was detected in 21.3% and 6.7% of this group, respectively.

Overall, 525 courses of paclitaxel were administered to the maintenance group, and dose reductions were needed in 6.3% (4.8% due to toxicity) and treatment delays occurred in 5.5% (3.0% due to toxicity).

Still Experimental

The researchers conclude that even though 6 courses of maintenance therapy, given at 3-week intervals, is feasible and well tolerated, it does not appear to offer a survival benefit to the patient. "Until some definitive answers about maintenance chemotherapy are achieved, such treatment remains experimental and should only be evaluated in patients at high risk of recurrence," they write.

The researchers have disclosed no relevant financial relationships.

J Clin Oncol. Published online August 24, 2009.

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