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Platinum/taxane regimens induce high response rates and prolong survival in women with ovarian cancer. After recurrence, however, response to second-line chemotherapy is limited. Pegylated liposomal doxorubicin (Doxil/Caelyx [PLD]), is the only liposomal anthracycline indicated for second-line treatment of platinum- and paclitaxel-refractory ovarian cancer. Response rates ranged from 14% to 20% in nonrandomized trials of this patient population. In a large phase 3 randomized trial, single-agent PLD and topotecan had similar efficacy overall in response rates, but PLD-treated patients had significantly improved overall survival compared with topotecan with a pronounced advantage in platinum-sensitive patients. Another randomized trial reported that PLD and paclitaxel were comparable with regards to response rate, progression-free survival, and overall survival, regardless of the degree of platinum sensitivity. Additional nonrandomized trials of PLD in combination with other active agents resulted in response rates ranging from 20% to 76%. PLD is generally well tolerated and its side-effect profile compares favorably with other commonly used chemotherapeutic agents in this clinical setting. Proper dosing and monitoring may further enhance tolerability while preserving the efficacy of this versatile agent for ovarian cancer.

Major advances in treatment for epithelial ovarian cancer have occurred over the last decade, giving hope to patients and families. Surgery remains a cornerstone of therapy. In early-stage epithelial ovarian cancer, a meticulous staging procedure should be performed to aid in determining patients who require appropriate adjuvant therapy and patients who can be monitored. The patient with advanced epithelial ovarian cancer significantly benefits from aggressive cytoreductive surgery and chemotherapy, affording the patient higher rates of complete response and partial response. In the new millenium, new therapeutic modalities should enhance the current response rates.

The effect of high-dose chemotherapy on the survival of women with ovarian cancer has been studied in numerous clinical trials. Approaches to dose intensity have included high-dose chemotherapy, combination platinum therapies, intraperitoneal therapy, and stem cell-supported high-dose chemotherapy. Taken together, the data demonstrate increased response rates with high-dose regimens, but any survival advantages observed have been limited. Patients with the most favorable outcome are those with low tumor burden and chemotherapy-sensitive tumors. An attempt to study this group of patients in a randomized trial in the United States (Gynecologic Oncology Group Protocol 164) was unsuccessful because of low accrual. Reasons for low accrual included physician bias, patient bias, and lack of third-party payer support. European randomized trials are under way to evaluate high-dose chemotherapy and stem cell transplantation as part of initial therapy or as consolidation after initial response to therapy and to compare high-dose chemotherapy with standard-dose chemotherapy. Until results from these trials become available, high-dose therapy remains limited to the clinical trial setting.

Combination chemotherapy with paclitaxel plus a platinum compound (carboplatin or cisplatin) is the current regimen of choice for the treatment of advanced epithelial ovarian cancer. The two most widely used combinations are paclitaxel (135 mg/m2, 24-hour infusion) plus cisplatin (75 mg/m2) or paclitaxel (175 mg/m2, 3-hour infusion) plus carboplating dosed to an area under curve of 7.5. Randomized trials are in progress comparing these two regimens. Numerous other clinical issues remain regarding how to maximize the effectiveness of this therapy, including dose and schedule, duration of treatment, route of administration, and incorporation of other agents with novel mechanisms of cytotoxicity. New agents currently undergoing evolution as part of novel induction regimens have been shown to have significant activity in recurrent ovarian cancer and include topotecan, gemcitabine, oral etoposide, and encapsulated doxorubicin.

This prospective study compared the combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and cisplatin with the standard therapy of cyclophosphamide/cisplatin in women with suboptimal stage III and stage IV ovarian cancer. Of the initial 410 women who presented with advanced disease and greater than 1 cm residual masses after initial surgery, 386 met all eligibility criteria and were randomly assigned to receive a regimen of cisplatin 75 mg/m2 and cyclophosphamide 750 mg/m2 or cisplatin 75 mg/m2 and paclitaxel 135 mg/m2 delivered over 24 hours. Dosage reductions were permitted in the event of significant toxicity. Among 216 patients with measurable disease, responses were reported in 73% of those receiving cisplatin/paclitaxel and in 60% of those receiving cisplatin/cyclophosphamide. Median progression-free survival was significantly longer (P < .001) in the group treated with cisplatin/paclitaxel, compared with those receiving cisplatin/cyclophosphamide (17.9 v 12.9 months, respectively).

Administration of an alkylating agent plus a platinum coordination complex is standard therapy for advanced epithelial ovarian cancer in the United States. The most commonly used combination is cyclophosphamide/ cisplatin; however, the benefit of this combination in overall survival has not been compelling. We report a prospective comparison of this regimen versus a combination of cisplatin with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), a new and well-tolerated agent with documented activity in cisplatin-refractory ovarian cancer. Three hundred eighty-six patients with advanced ovarian cancer and greater than 1 cm residual masses following initial surgery were randomly assigned to receive a regimen of cisplatin (75 mg/m2) and cyclophosphamide (750 mg/m2), or cisplatin (75 mg/m2) and paclitaxel (135 mg/m2), delivered over 24 hours. Dose reductions in cyclophosphamide or paclitaxel were permitted for significant toxicity. In 216 patients with measurable disease, responses were reported in 73% of those randomized to the cisplatin/paclitaxel arm and in 60% randomized to the cisplatin/cyclophosphamide arm. Progression-free survival was significantly longer (P < .001) with cisplatin/paclitaxel (median, 12.9 v 17.9 months). Overall survival was also significantly longer (P < .001) with cisplatin/paclitaxel (median, 37.5 v 24.4 months). Incorporating paclitaxel into first-line therapy for patients with suboptimally debulked stage III and stage IV ovarian cancer can increase the duration of the progression-free interval and extend overall survival while maintaining an acceptable toxicity profile.

Coelomic epithelial carcinoma of the ovary, the most common cause of death from cancer of the female genital tract in the United States, presents most commonly as advanced (stage III or IV) disease. Management consists of aggressive surgical cytoreduction followed by combination chemotherapy, until recently, a platinum compound plus an alkylating agent. The recent identification of the activity of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) offers the potential to improve further the management of patients with advanced disease. That this agent might enhance current front-line therapy is supported by its unique mechanism of action and by the significant numbers of responses reported in patients clinically resistant to the platinum compounds: more than 20% of these patients responded to paclitaxel as salvage therapy in four different phase II trials. These observations led to a phase I Gynecologic Oncology Group trial that showed that paclitaxel 135 mg/m2 over 24 hours followed by cisplatin 75 mg/m2 could be given every 3 weeks. This group then compared six cycles of the identified regimen with six cycles of standard cisplatin/cyclophosphamide chemotherapy given every 3 weeks in a phase III trial in 388 previously untreated patients with large-volume (residual nodules > 1 cm after surgery) disease. The results show the superiority of the paclitaxel/cisplatin regimen: overall response rate 77% versus 62%, clinical complete response 54% versus 33%, frequency of achieving a grossly disease-free state at second-look laparotomy 40% versus 22%, progression-free survival 18 versus 13 months, and overall survival 38 versus 24 months. Thus, paclitaxel/cisplatin is the new standard of care for patients with advanced ovarian carcinoma. Current phase III studies explore further the role of paclitaxel in front-line therapy: the relative merits of single-agent versus combination chemotherapy, the role of interval surgical cytoreduction combined with paclitaxel/cisplatin, the value of carboplatin-based versus cisplatin-based combinations with paclitaxel, the significance of the paclitaxel infusion length (3 v 24 v 96 hours), and the value of more dose-intense combinations.

Ovarian cancer is an important disease due to its occurrence in women in the prime of life (40-70) and its responsiveness to therapy but generally poor outcome due to the emergence of drug-resistant cells. In early-stage disease, adjuvant therapies may improve outcome, but previous studies have concentrated more on the reduction of toxicity of therapy than on improved survival, although modern approaches are evaluating more aggressive intervention in these patients with good survival rates (40%-90% cure with surgery). In advanced disease, the most common presentation, it appears that more aggressive staging and surgical debulking as well as new classes of drugs for treatment have altered, albeit modestly, the outcome in this disease. Future approaches will evaluate taxol, a new active agent, as well as more dose-intense therapy and a continued search will be made for new active drugs and methods to overcome intrinsic and acquired drug resistance.

Table 1 summarizes studies in which clinical or pathologic response rates can be determined. The majority of patients in these studies had macroscopic drug-resistant tumors, and most had received cisplatin-based chemotherapy. It is noteworthy that the response rate in this group of patients is considerably higher than the 30% to 36% seen with the most active salvage therapies, such as taxol (paclitaxel). Like most trials of salvage chemotherapy for refractory ovarian carcinoma, many responses were short-lived. Toxicity in these studies is comparable to that seen in trials of ASCT in other solid tumors. The promising results observed in these small studies of ASCT in ovarian carcinoma warrant further investigation focused on defining which groups of patients are likely to benefit from this approach. Based on evidence from the lymphohematopoietic malignancies, it would seem reasonable to use ASCT in patients early in the course of their disease before extensive pretreatment and preferably at a time of minimal tumor burden. Some groups have been exploring ASCT as consolidation therapy after surgery and limited debulking chemotherapy. Based on kinetic models of tumor growth, other investigators have suggested that multiple courses of high-dose chemotherapy with ASCT after debulking surgery may result in more cures than a single ASCT after conventional chemotherapy. The feasibility of performing sequential ASCT has been well documented. So far the best drug regimens, the number of cycles that should be used, and the patients who should be candidates for high-dose chemotherapy and ASCT remain undefined. Presently, there is no role for this therapeutic modality outside of well-designed clinical trials.

Ovarian carcinoma is the most common cause of death among the gynecologic malignancies. Primary therapy in advanced disease involves debulking surgery followed by platinum-containing chemotherapy. Despite such treatment, most patients die of residual or recurrent disease. Paclitaxel (TAXOL), a new antineoplastic agent, has response rates of 20% to 35% in phase II studies in patients with refractory ovarian cancer. Most women treated in these studies had platinum-resistant disease. Toxicity was primarily hematologic and neurologic. The findings from a large European-Canadian study suggest that hematologic toxicity is schedule dependent whereas neurologic toxicity is dose dependent. Dose escalation of paclitaxel with granulocyte colony-stimulating factor support and combinations of paclitaxel with cisplatin have been tested and shown to be feasible. Intraperitoneal administration of paclitaxel also is possible and advantageous from a pharmacokinetic perspective. In a multi-institutional randomized trial, primary treatment of patients with suboptimal disease with the combination of paclitaxel and cisplatin was compared with cyclophosphamide and cisplatin. Toxicity data from this completed trial show paclitaxel to be safe in this setting. Efficacy awaits maturity of survival data. Future clinical development of paclitaxel will include its use in less bulky disease and further evaluation of its dose escalation in advanced platinum-resistant disease. Paclitaxel currently is considered first-line treatment for platinum-resistant ovarian carcinoma. Further clinical investigation will determine its role in the primary management of ovarian cancer.