Effective treatment for patients with advanced epithelial ovarian carcinoma remains a challenge for the oncologist. It has been approximately 20 years since the introduction of cisplatin into first-line combination chemotherapy regimens for advanced stage patients. During that interval, the 5-year survival rate has not risen above 15–20%. Despite objective response rates as high as 90%, most patients develop progressive tumor and die of their disease; the median survival rate ranges from 18 months to 36 months.1–8
On the basis of the results of a prospective randomized study of the Gynecologic Oncology Group (GOG) in which the new combination of paclitaxel and cisplatin was compared with the standard combination of cyclophosphamide and cisplatin in patients with suboptimal advanced epithelial ovarian carcinoma, most experts currently believe that a chemotherapy regimen including paclitaxel and a platinum drug represents optimal treatment for such women.9 In the GOG trial, the paclitaxel combination improved the response rate (73% vs. 60%), the median progression free survival (18 months vs. 14 months), and the median survival (38 months vs. 24 months). However, mature survival data from which to draw any conclusions regarding long term survival are not yet available from that study.
Nevertheless, the findings of the GOG trial are encouraging. While we await long term follow-up of the patients in this study, an attractive strategy is to build on the foundation of the combination of paclitaxel and a platinum drug with the hope of achieving even better survival. Among the many agents that might be incorporated into a paclitaxel-cisplatin combination is melphalan. Oral melphalan has been used extensively as a single agent in the treatment of patients with advanced epithelial ovarian carcinoma for over 3 decades.10–12 Several investigators also have reported the use of intravenous melphalan, either as a single agent or in combination with other drugs, for women with ovarian carcinoma.13–16 In the past several years, however, interest in melphalan has waned because of reports of its leukemogenicity.17–19 These studies indicate that the leukemogenic potential of melphalan is related directly to duration of use and cumulative dose.
In a retrospective study of 116 patients with optimal advanced stage epithelial ovarian carcinoma who underwent treatment at our institution between 1978 and 1988 on three consecutive prospective trials, patients received either the combination of oral melphalan and cisplatin (in the first trial) or the combination of cyclophosphamide and cisplatin (in the second and third trials).20 In a multivariate analysis, the use of melphalan versus cyclophosphamide was a significant predictor of progression free survival (P = 0.0002) and survival (P = 0.04). These findings suggested to us that melphalan may be a more active alkylating agent than cyclophosphamide against epithelial ovarian carcinoma when combined with cisplatin. Therefore, a Phase I trial combining melphalan with paclitaxel and cisplatin seemed to be worthwhile. The primary purpose of this study was to establish the maximum tolerated dose (MTD) of intravenous melphalan in combination with paclitaxel and cisplatin plus granulocyte-colony stimulating factor (G-CSF) in patients with suboptimal advanced epithelial ovarian carcinoma or primary peritoneal carcinoma.
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- MATERIALS AND METHODS
For almost 2 decades, platinum-based combination chemotherapy has been the standard postoperative treatment for patients with advanced epithelial ovarian carcinoma. Recently reported studies of cyclophosphamide in combination with a platinum drug (cisplatin, carboplatin, or both) in patients with suboptimal (>1 or 2 cm), Stage III and IV epithelial ovarian carcinoma indicate a median progression free survival rates of 12–18 months and a median survival rate of 17–27 months.26–29 There is no evidence that the 5-year survival rate for such patients has exceeded 15–20%.
In the mid-1990s, the GOG's randomized trial firmly established the combination of paclitaxel and a platinum drug as standard postoperative treatment for patients with advanced epithelial ovarian carcinoma in the United States.9 Ongoing clinical trials are attempting to identify the optimal paclitaxel dose, the optimal duration of infusion of paclitaxel, and the relative toxicity and efficacy of cisplatin compared with carboplatin. Building on the foundation of previous studies with paclitaxel and cisplatin, the current study was initiated in an effort to develop a new combination chemotherapy regimen that possibly may have acceptable toxicity and enhanced activity for patients with advanced epithelial ovarian carcinoma. We also included patients with peritoneal carcinoma, because several studies, including our own, have suggested that this malignancy is similar to advanced epithelial ovarian carcinoma in terms of chemoresponsiveness and survival.30–33 We chose to add melphalan to this combination principally because a previous retrospective study of our experience suggested that melphalan may be a more active alkylating agent than cyclophosphamide against epithelial ovarian carcinoma when combined with cisplatin.20 In addition, our group had extensive experience with melphalan, and a parenteral formulation of melphalan became more accessible at the time we developed the trial. We were concerned about the leukemogenicity of melphalan but theorized that the potential advantages might offset the risk of subsequent leukemia by limiting the exposure to melphalan to no more than 6 cycles of treatment. Previous studies have indicated that the risk of nonlymphocytic leukemia from melphalan is related directly to the duration of exposure to the drug and the total cumulative dose received.18, 19
Other groups have pursued a strategy similar to ours by adding other drugs to the nucleus of paclitaxel and cisplatin. Kohn and colleagues have reported their experience with the combination of dose-intensive paclitaxel, cisplatin, and cyclophosphamide plus G-CSF.34 In a Phase I–II study, they treated 36 patients with advanced epithelial ovarian carcinoma, most of whom had bulky residual disease. The MTDs were 250 mg/m2 for paclitaxel, 75 mg/m2 for cisplatin, and 750 mg/m2 for cyclophosphamide. The median survival was 26.5 months. The GOG currently is conducting two Phase I studies in patients with untreated ovarian carcinoma: In one study, topotecan is added to the combination of paclitaxel and cisplatin plus G-CSF; in the other study, oral etoposide is added to the combination of paclitaxel and carboplatin.
In general, the combination of paclitaxel, cisplatin, and melphalan plus G-CSF was well tolerated. In the initial phase of the study, as expected, the MTD of melphalan was established at a dose of 10 mg/m2, with thrombocytopenia being the dose-limiting toxicity. Dose levels of melphalan between 10 mg/m2 and 14 mg/m2 were not studied, and it is possible that we may have been able to achieve a slightly higher dose of melphalan, e.g., 12 mg/m2, if we had tested for it.
Nadir neutropenia typically occurred on Days 8–10 of each cycle and was of very brief duration. The use of G-CSF allowed us to deliver acceptable doses of this combination without a high incidence of severe neutropenia or neutropenic fever. When we designed this trial, G-CSF had just recently become commercially available, and we had minimal experience with its use. At the initial dose level, G-CSF was administered for a total of 19 days, as noted above. Thereafter, the protocol was revised to include G-CSF administration for a total of 12 days on each cycle. Although it was not a focus of our study, it is quite possible that the duration of G-CSF administration could have been limited to as few as 7 days, which is our current standard practice when treating with the combination of paclitaxel and cisplatin.
Based on preliminary information available at the time this trial was designed, the dose of paclitaxel was escalated in the second stage. Sarosy et al.35 had observed a 50% response rate to paclitaxel at doses up to 250 mg/m2 in patients with refractory ovarian carcinoma. In the second stage of the study, the MTD of paclitaxel, as defined using conventional criteria for defining the MTD, was reached at a dose level of 135 mg/m2 based on granulocyte toxicity at the next higher dose level. However, on the basis of exploratory discussions with our biostatisticians regarding the use of the continuous reassessment method to identify a safe dose to use in a Phase II trial, we revised the protocol and continued the study with escalation of the paclitaxel doses.24, 36 Using this approach, the probability of dose-limiting toxicity was <25% at dose levels of paclitaxel up to 200 mg/m2. Investigators conducting future Phase I studies of new drugs or combinations of drugs for the treatment of patients with ovarian carcinoma should consider employing the continuous reassessment method rather than the standard method to determine a safe dose to use in subsequent Phase II trials. However, this method was designed originally to be used for single-agent trials: Phase I studies of multidrug combinations introduce a new level of complexity.
Although antitumor activity was not the primary end point of this study, the combination of melphalan, paclitaxel, and cisplatin plus G-CSF showed good activity. Our study population was a very poor prognostic group; 18 of the 34 patients (53%) had either Stage IV ovarian carcinoma (n = 14 patients) or primary peritoneal carcinoma with a cytologically positive pleural effusion (n = 4 patients). Our median survival time of 32.8 months is very much in the range observed in the most recently reported GOG study.37 In that prospective randomized trial of patients with suboptimal Stage III and IV epithelial ovarian carcinoma, 615 evaluable patients were randomized to receive either single-agent cisplatin, single-agent paclitaxel, or the two-drug combination; median survival times in the three arms of the study were 30.2 months, 26.0 months, and 26.6 months, respectively. The findings of our study appear to warrant a Phase II study of this combination. In such a study, the recommended dose of melphalan would be 10 mg/m2. The optimal dose of paclitaxel remains unclear. Unless new information indicates a definite benefit associated with high dose paclitaxel (in the range of 200–250 mg/m2), we would recommend a dose of 135–175 mg/m2. Of course, any final recommendation of the addition of melphalan to the combination of paclitaxel and cisplatin plus G-CSF would require proof of a significant improvement in patient outcome, because this combination obviously would be associated with greater cost and potential toxicity.
There are now several drugs that have demonstrated activity in platinum-resistant disease: topotecan, gemcitabine, liposomal doxorubicin, oral etoposide, and vinorelbine. Most of these are already being tested in two-drug and three-drug combination regimens in patients with untreated advanced ovarian carcinoma. The combination of paclitaxel, cisplatin, and melphalan will be judged against these regimens in the design of future Phase III randomized trials.