Western Regional Blog – BC, YK, AB, NWT and Nunavut
To combat the toxicities associated with paclitaxel plus cisplatin therapy in patients with platinum-resistant epithelial ovarian cancer, researchers are experimenting with a new combination—paclitaxel plus carboplatin (Paraplatin, Bristol-Myers Squibb)—and early results are promising.
In a study published online in December 2012 by the European Journal of Cancer, researchers identified 108 patients with epithelial ovarian cancer, of whom 43 were platinum resistant. Treatment consisted of six weekly induction cycles of 90 mg/m2 of paclitaxel plus area under the curve (AUC) 4 of carboplatin, both administered by one-hour infusion on days 1, 8, 15, 29, 36 and 43. Patients who demonstrated clinical benefit on the study regimen (stable disease, partial response and complete response) continued treatment with six maintenance cycles of 175 mg/m2 of paclitaxel in three-hour infusions plus AUC 6 carboplatin in one-hour infusions administered every three weeks. The study end points included progression-free survival (PFS), overall survival (OS), response rate (RR) and toxicity.
Both the weekly and the three-weekly cycles of the study regimen were well tolerated. Treatment delay (median seven days) was required in 16% of the 633 weekly cycles administered (these occurred mainly after the third or the fourth cycle) and in 29% of the 448 three-weekly cycles. Dose reduction was needed in only 2% and 15% of the cycles, respectively. During the 633 weekly cycles, reported grade 3/4 toxicities included thrombocytopenia (8%), neutropenia (30%) and febrile neutropenia (0.5%).
Among platinum-resistant patients, the RR for the paclitaxel plus carboplatin regimen was 58%. Median PFS and OS were eight and 15 months, respectively. Among platinum-sensitive patients, the RR was 76%, whereas PFS and OS were 13 and 26 months, respectively. Among 13 platinum-resistant patients who were started on weekly paclitaxel plus carboplatin less than six months after progression had significantly shorter PFS (four months) and OS (nine months).
Paul Haluska, MD, PhD, Oncologist, and Associate Professor of Oncology, Assistant Professor of Pharmacology, Mayo ClinicPlatinum-based chemotherapy is not only the standard front-line treatment for ovarian cancer, it is disease defining. Indeed, sensitivity to platinum is a powerful prognostic tool, with platinum-resistant patients carrying a poor prognosis. Platinum-resistant ovarian cancer can be defined as cancer that has progressed within six months of prior platinum-based chemotherapy.
Although such patients may have a low RR, resistance is not absolute and may be overcome to varying degrees with combination chemotherapy, such as paclitaxel, or by varying the schedule. This study published by van der Berg et al in the most recent issue of the European Journal of Cancer investigates weekly induction chemotherapy with paclitaxel (90 mg/m2) and carboplatin (AUC 4) for six cycles, followed by six cycles of every three-weekly paclitaxel (175 mg/m2)/carboplatin (AUC 6).
In summary, the authors conclude that given a 58% RR, eight-month PFS and 15-month OS for platinum-resistant patients, the treatment was effective therapy for this patient population. Additionally, there were no reported grade 4, nonhematologic toxicities and a low incidence of grade 3 toxicities, leading the authors to conclude that the toxicity profile of the regimen was reasonably tolerable.
The seemingly paradoxical sensitivity of platinum-resistant ovarian cancer to platinum is not a new area of investigation. Indeed, the authors draw comparisons to several prior studies, which identify the current study as having the largest platinum-resistant cohort yet investigated. It confirms that longer platinum-free intervals increase sensitivity to platinum therapy and outcomes.
Technically, the study was conducted soundly and demonstrated that there is a high RR, including 16% complete responses, in platinum-resistant ovarian cancer. However, this comes at a price—26 weeks worth of chemotherapy, including an initial six weeks of intensive treatment, for approximately 32 weeks of PFS.
Although the nonhematologic toxicities were very reasonable, as expected, grade 3 or worse neutropenia was nearly universal. Thus, a quality-of-life assessment may have been useful to determine if patients themselves felt combination chemotherapy would be worth it to them at this point in the treatment of their disease. As these agents are clinically available for use in ovarian cancer, this work does remind us that platinum combinations are a potential option for patients with platinum-resistant disease.
In addition to assessing quality of life, future studies could stand to perform correlative molecular analyses on tumor tissue to identify which patients are most likely to benefit from platinum, such that we could better individualize treatment for this group of patients in dire need of better therapies.