Chemotherapy for Advanced Stage Epithelial Ovarian Cancer

Systemic chemotherapy is the standard treatment for metastatic epithelial ovarian cancer. Early studies utilized single alkylating agents such as melphalan or combinations of alkylating agents and antimetabolites. After the introduction of cisplatin in the latter half of the 1970s, platinum-based combination chemotherapy became the most frequently used treatment regimen in the United States. Cisplatin was initially used in combination with cyclophosphamide and doxorubicin, but the modest contribution of doxorubicin to the efficacy of the combination prompted simplification of the standard regimen to cyclophosphamide and cisplatin. By the early 1990s a combination of carboplatin and cyclophosphamide was found to be as effective as cisplatin and cyclophosphamide, but substantially less toxic, with less nausea, renal toxicity and neurotoxicity. Paclitaxel was incorporated into combination chemotherapy in the 1990s. Over the last decade, a substantial amount of clinical investigation has centered on (1) whether a combination of a platinum compound and a taxane is superior to an optimal dose of a platinum compound alone, (2) the choice of the optimal platinum compound and taxane, and (3) the most convenient and effective schedule for taxane administration. Recent studies have focused on the introduction of a other compounds into a "triplet" or a "sequential doublet" to eliminate drug resistant cancer cells.

Single Alkylating Agents
For many years, oral single-agent alkylating therapy was used. The standard dose for the single alkylating agent, melphalan, is 0.2 mg/kg/day given orally for 5 consecutive days every 28 days. In three separate GOG studies of suboptimal stage III ovarian cancer, 193 patients were treated with this regimen. Sixty-two patients (33%) had a clinical response; with a 16% complete response rate and a 17% partial response rate. However, the median duration of response was only 7 months and median survival was 12 months. The use of single-agent chemotherapy for metastatic epithelial ovarian cancer is generally reserved for patients whose overall physical condition precludes the use of more toxic therapy.

A variety of regimens containing combinations of cytotoxic drugs have been tested in the treatment of advanced epithelial ovarian cancer. Combination chemotherapy has been shown to be superior to single-agent therapy in most patients with advanced epithelial ovarian cancer.

Platinum Compounds
For the last two decades, platinum compounds have been the most active agents against ovarian cancer. In early studies from England, cisplatin was found superior to cyclophosphamide as a single agent. Concurrently, cisplatin was tested in combination with a variety of different drugs. Platinum-containing regimens have proven superior to regimens that lacked platinum compounds. In a meta-analysis performed on 37 randomized studies involving 5,667 patients with advanced-stage disease, those patients given cisplatin-containing combination chemotherapy were compared with those treated with regimens that did not include cisplatin. Platinum based chemotherapy was superior to non-platinum based chemotherapy. A trend favored platinum combinations over single agent platinum. In studies of cisplatinum containing regimens, several trials have compared cyclophosphamide and cisplatin (CP) with cisplatin, doxorubicin and cyclophosphamide (PAC). No study showed a significant difference in survival between treatment arms. The GOG's randomized prospective comparison of equitoxic doses of PAC versus PC showed no benefit to the inclusion of doxorubicin in the combination. While a meta-analysis of the combined data from these four trials showed a 7% survival advantage at 6 years for those patients treated with the doxorubicin-containing regimen, the survival curves converge at 8 years. Consequently, in recent years doxorubicin has not been incorporated in regimens for epithelial ovarian cancer in the United States. It is, however, possible that a small subset of ovarian cancer patients benefit substantially from treatment with anthracyclines. In the future, new technologies may permit the identification of those patients and permit individualization of their treatment.