First-Line Therapy for Ovarian Carcinoma: What Next?
Faculty Disclosure: Tate Thigpen, MD
This presentation by Dr. Thigpen discusses the use of cetuximab, bevacizumab, and PSC 833 for the treatment of ovarian cancer which has not been approved by the FDA. Also discussed are off label uses of trastuzumab, gefitinib, and gemcitabine for the treatment of ovarian cancer.
The current standard of care for FIGO stage III/IV ovarian cancer is as follows: First, optimal surgical debulking is performed. This is supported by retrospective data showing improved survival and chemotherapy response rates with optimal debulking. Interval cytoreduction for patients undergoing sub-optimal initial surgery may be beneficial, though some controversy surrounds this issue. Carboplatin/paclitaxel chemotherapy has recently been adopted as the standard adjuvant regimen, supported by the recently reported GOG 158 trial showing equivalent efficacy of carbo/paclitaxel and cisplatin/paclitaxel but reduced toxicity with the carbo/paclitaxel arm. With this standard of care, overall survival in these patients remains poor: 30 - 50 months median for small and large volume disease, respectively.
Several recent attempts have been made to further improve outcomes. Three recent studies have evaluated intra-peritoneal (IP) chemotherapy, GOG 104, GOG 114 and GOG 172. All three reported improved progression free survival (PFS) while the first two also showed improved overall survival (survival data for GOG 172 still pending). Unfortunately, unacceptable toxicity with IP chemotherapy has led to this treatment modality not being accepted into general practice. Plans exist for new phase I-II trials to identify better tolerated IP chemotherapy regimens.
The addition or substitution of 3rd cytotoxic agents is currently being tested in a GOG trial. Carboplatin/paclitaxel chemotherapy with or without liposomal doxorubicin (Doxil), topotecan and gemcitabine are being investigated in this trial. Planned accrual is 4000 patients. Results will likely not be reported until 2005 at the earliest.
Targeted therapies are currently being explored. The EGFR tyrosine kinase inhibitor Iressa, the anti-EGFR receptor antibody, C225 and the anti-VEGF antibody, bevacizumab(Avastin) are all currently being investigated in the phase I/II setting. The GOG 160 trial of trastuzumab recently showed a low overall response rate of 7% in patients overexpressing the receptor (only 11% of the total ovarian cancer population). The resistance modulator PSC 833 has been shown to add toxicity but no survival advantage in early trials. The small Austrian trial of interferon-gamma showed benefit when added to conventional chemotherapy. We await results of the randomized confirmatory trial of carbo/taxol +/- interferon-gamma.
Given that 75% of patients in remission ultimately relapse, maintenance therapy has been investigated in GOG 178. Twelve cycles vs. 3 cycles of maintenance paclitaxel were compared. PFS was improved by 33% with 12 cycles prompting early closure of the study. No survival data will be reported due to crossover into the 12 cycle arm. A confirmatory GOG trial is currently underway to evaluate potential survival benefit. Based on the GOG 178 data alone, maintenance therapy cannot yet be considered the standard of care.
For high risk FIGO stage I-II ovarian cancer, adjuvant chemotherapy has been investigated in the ICON I/ACTION trial. This showed an 8% OS benefit with adjuvant chemotherapy vs. none. The GOG 157 trial compared 3 vs. 6 cycles of adjuvant carbo/paclitaxel chemotherapy in these patients. There appeared to be no benfit to 6 cycles. The standard of care is therefore 3 cycles of adjuvant carbo/paclitaxel chemotherapy in high risk stage I/II patients.
Future directions in ovarian cancer clinical research will involve continued investigation of targeted biologic agents and enhanced cytotoxic therapies with improved toxicity profiles. These studies will hopefully lead to increased survival in what remains a very difficult disease.