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Swing and Miss?!? Efforts in Front-line Ovarian Cancer Chemotherapy Development
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 is a retained consultant for GlaxoSmithKline, Eli Lilly Co., Abbott Laboratories, Sanofi-Aventis, and Pfizer; and serves on the speakers bureau for OrthoBiotech.
Data from the Surveillance Epidemiology and End Results (SEER) registry have consistently demonstrated improved life expectancy for women with epithelial ovarian cancer every year since 1973.1 The modest gains in this parameter can be attributed to several important programmatic developments, including establishment of a sub-specialty devoted to the science and treatment of women with gynecological malignancies (Society of Gynecologic Oncologists, SGO); the identification of efficacious chemotherapy, such as platinum and its analogues, as well the taxanes (e.g., paclitaxel); better pre-, intra- and post-operative care; higher rates of optimal surgery; specialized nursing and support services; development of supporting medications (e.g., 5-HT3 antagonists) to enhance the therapeutic:toxicity ratio of the chemotherapy; development of new delivery methodologies of therapy (e.g., intraperitoneal chemotherapy); and continued novel agent discovery. A closer look at the components of these positively sloped survival curves demonstrates that most of the benefit afforded women is in life gained in the presence of disease, rather than cure. Indeed, the cure rates from ovarian cancer have remained relatively flat over these 3 decades, adding no more than approximately 2 weeks per year in the overall gain of life expectancy. This is clearly due to the unmovable percentage of advanced stage cases still indicative of the most common clinical presentation (stage III/IV), and underscores the immense impact even a slight stage migration could have on the overall clinical performance of women with this disease.
However, until that strategy is elucidated, the burden is to rationally develop new agents in hopes that better primary and recurrent disease control will continue to extend the lives of these patients. There have been many important milestones in this effort. Gynecologic Oncology Group (GOG) protocol #111 established the current standard in this disease in 1996, when the combination of paclitaxel and cisplatin was found to be superior in nearly every parameter studied (e.g., complete response [CR] rate, negative second-look rate, progression-free survival [PFS], and overall survival [OS]).2 While the regimen was quickly adopted to an outpatient regimen by shortening the infusion of paclitaxel and substituting cisplatin with carboplatin,3 the regimen has essentially been unaltered over the last 13 years. Intraperitoneal chemotherapy (using these same agents) appears to offer somewhat of a greater benefit over IV in selected (optimally cytoreduced) patients.4 Yet, definitive new agents in primary disease have been slow to come.
The genesis of most new therapeutics tested in the front-line setting come from promising clinical investigation in the recurrent setting. The benchmarks are not standardized, but "positive" clinical observations, combined with rational preclinical data and substantial financial support, can make a good case to compete with the current standard in an effort to move the survival "line in the sand." Recently, one such effort, meeting each of these criteria, was published.5 The study (GOG 182) tested 4 experimental arms against paclitaxel and carboplatin. Each of the arms was based on provocative preclinical and clinical information that was felt to add substantively to the taxane and platinum backbone. Two of the arms addressed the hypothesis that a non-cross-resistant agent added to paclitaxel and carboplatin (as a triplet) would increase efficacy by attacking different growth mechanisms in the known heterogeneous tumor microenvironment of bulky ovarian cancers. Two other arms were constructed to capitalize on drug-drug synergy seen in preclinical models of the disease and delivered as sequential doublets.6,7 To make the trial robust and relevant to a broad audience of ovarian cancer patients, eligibility included all women with stage III and IV disease. To sufficiently evaluate the treatment arms against paclitaxel and carboplatin, 4000 patients were required. This was approximately 3 times the size of any prior chemotherapeutic study conducted in the worldwide gynecologic oncology community. While a daunting effort, the GOG, in collaboration with the Gynecologic Cancer Intergroup (GCIG) recruited nearly 1200 patients per year, ultimately accruing 4312 patients to the study and providing an unprecedented look at the power of cooperative groups working collaboratively to address a singular hypothesis. Global randomization ensured the 860 or so patients per arm were well balanced in terms of age, percent stage III (vs IV), measurable (vs evaluable), and primary ovarian cancer (vs peritoneal). There was also balance in the stratification factors of those undergoing interval surgery and those left with tumor residuum following primary surgery.
Unfortunately, the immense success in accrual was not matched in the evaluation of its primary and secondary endpoints. Each experimental arm was individually compared to the control arm; in each case, no statistical difference was observed in either OS or PFS. Among strata and subgroups, no modification in this conclusion was reached. The arms had different toxicity profiles: The triplets were associated with more neurotoxicity, the gemcitabine arms with more thrombocytopenia, but equal numbers of patients completed intended therapy.
In all, while this important phase III clinical study missed its endpoints, it provided convincing evidence that novel hypotheses could be addressed with appropriate power in the global community. Given the rapidity of new agents being developed, particularly those addressing growth signaling, survival, and proliferation in the microenvironment, this coordinated effort of our committed global investigators and patients will have the palpable opportunity to deftly respond with new trials incorporating innovative designs. Currently, 5 large phase III clinical studies are under way, 2 in front-line and 3 in recurrence, which are evaluating the impact anti-angiogenesis therapy (e.g., bevacizumab and cediranib) has on chemotherapy for women with ovarian cancer. This direction was again chosen based on promising preclinical and clinical data of the response of ovarian cancer models and patients to this modality of therapy. Indeed, the clinical activity of single-agent bevacizumab in ovarian cancer (see Table, below), is nearly 2-3 times the rate observed in the disease where the agent is now FDA approved.8-10 The apparent "addiction" of ovarian cancer cells to an angiogenic milieu has prompted many to have great optimism in this strategy.
It is once again hoped that these rationally constructed novel treatment arms will move the bar of expected outcome in this disease. Fortunately, the investigational infrastructure is in place and being exercised to enable an answerable hypothesis.