- © 2000 by American Society of Clinical Oncology
Maintenance Chemotherapy in Advanced Ovarian Cancer
To the Editor:
With the beginning of a new millennium, I would suggest that it is time to consider a major paradigm shift in the chemotherapy management of women with advanced-stage epithelial ovarian cancer whose initial surgery is suboptimal (>1 cm residual disease). That is, that epithelial ovarian cancer is a chronic disease requiring (for now) lifelong therapy, much as insulin is required for insulin-dependent diabetes mellitus. The Gynecologic Oncology Group Protocol 1321 prescribed six cycles of chemotherapy over approximately 126 days (18 weeks), and treatment was stopped or changed depending on the outcome of therapy. At the time of the analysis, only 9%, or 55, of the 614 eligible patients had not developed progression of their ovarian cancer. With longer follow-up, regrettably, most of these 55 women will most likely develop recurrent ovarian cancer and die of the disease, leaving very few women initially enrolled onto this trial alive without ovarian cancer. Although everyone is hopeful that “the magic bullet” for ovarian cancer will someday be developed, it seems that since the initial report in 1976 by Wiltshaw and Kroner2 of the effectiveness of cisplatin in epithelial ovarian cancer, not much has changed. The results of Muggia et al’s well-conducted trial1 demonstrate that cisplatin alone remains as effective as any combination chemotherapy and produces progression-free survival (16.4 months) similar to cisplatin plus paclitaxel (14.1 months)—regrettably, less than one would have hoped for over this past quarter of a century.
Although progression-free survival and overall survival were not improved by the addition of paclitaxel to cisplatin, Muggia et al rightly conclude that, because of the “better toxicity profile,” the combination of cisplatin and paclitaxel “remains the preferred initial treatment option.” They state that “the preliminary results from three more recent trials indicate that carboplatinum and paclitaxel is as effective as cisplatin and paclitaxel and better tolerated.” Patients and their oncologists are eagerly awaiting the results of the next phase III trial in this subset of patients. However, currently, for those patients with suboptimal resected ovarian cancer in complete remission after six cycles of platinum chemotherapy plus paclitaxel, it may be time to consider long-term, every-other-month maintenance therapy with the combination of carboplatinum and paclitaxel.3,4 Informed consent should be obtained before maintenance chemotherapy is initiated because of a possible “relatively small excess risk of secondary leukemia.”5
References
Response
In Reply:
With 25,000 women in the United States diagnosed with ovarian cancer per year, there is urgency to answer questions on the treatment of this disease. When Gynecologic Oncology Group Protocol 132 was initiated,1 there was considerable hope that single-agent paclitaxel would prove as effective as cisplatin and that it would prove to be more suitable than the platinum compound for maintenance treatment. However, as this and additional trials reviewed in our Discussion have shown, the role of paclitaxel in the treatment of ovarian cancer may be more complex than initially conceived. For example, its effects on overall survival are disproportionate to its effect on progression-free survival. Moreover, agents such as topotecan, doxorubicin liposome injection, and gemcitabine now capture attention for their possible contributions in modifying the unsatisfactory outcome. In fact, the Gynecologic Oncology Group together with international collaborators, is planning to mount a five-arm study to explore additional therapy to the current standard platinum-paclitaxel treatment. Concepts such as sequential doublets combining these promising agents with carboplatin, before administering paclitaxel plus carboplatin, or triplets that include an agent such as gemcitabine without attenuating the combination of paclitaxel plus carboplatin will be tested in such a large study.
Important therapeutic questions in ovarian cancer include the following: (1) are there more effective upfront therapies (this is being addressed by the above projected trial)? and (2) are there effective consolidation (or maintenance) strategies, including established or novel therapies directed by molecular markers, secondary cytoreductive surgery, and intraperitoneal chemotherapy? Although platinum-based therapies provide dramatic and sometimes durable clinical responses, relapses in the majority of patients have led to disappointment. Most large-scale clinical trials using such regimens have included six to eight courses of therapy as the standard regimen. There is, however, no supporting evidence from randomized trials that a longer duration of therapy is beneficial.2 Nevertheless, a recent workshop of clinical trialists concurred that the question of duration of front-line therapy deserves more attention.3 Therefore, although we agree that consolidation trials are important, we believe other options may be preferable to extending paclitaxel/carboplatin therapy. Piver himself cites one reason why this option may not be as attractive as others (ie, secondary leukemia). The challenge is to identify well-tolerated consolidation therapies (chemotherapy or others) that prolong remission and improve overall survival. The most convincing evidence supporting the benefits of a consolidation strategy will come from randomized controlled clinical trials.
