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© 1999 American Society for Clinical Oncology Phase III Multicenter Randomized Trial of the Dartmouth Regimen Versus Dacarbazine in Patients With Metastatic MelanomaFrom the Memorial Sloan-Kettering Cancer Center, New York, NY; Indiana University Medical Center, Indianapolis, IN; University of Pennsylvania Medical Center, Philadelphia, and University of Pittsburgh Medical Center, Pittsburgh, PA; Dartmouth Hitchcock Medical Center, Lebanon, NH; Hoosier Oncology Group, Indianapolis, IN; and Eastern Cooperative Oncology Group, Boston, MA. Address reprint requests to Paul B. Chapman, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021.
PURPOSE: Several single-institution phase II trials have reported that the Dartmouth regimen (dacarbazine, cisplatin, carmustine, and tamoxifen) can induce major tumor responses in 40% to 50% of stage IV melanoma patients. This study was designed to compare the overall survival time, rate of objective tumor response, and toxicity of the Dartmouth regimen with standard dacarbazine treatment in stage IV melanoma patients. PATIENTS AND METHODS: In this multicenter phase III trial, 240 patients with measurable stage IV melanoma were randomized to receive the Dartmouth regimen (dacarbazine 220 mg/m2 and cisplatin 25 mg/m2 days 1 to 3, carmustine 150 mg/m2 day 1 every other cycle, and tamoxifen 10 mg orally bid) or dacarbazine 1,000 mg/m2. Treatment was repeated every 3 weeks. Patients were observed for tumor response, survival time, and toxicity.
RESULTS: Median survival time from randomization was 7 months; 25% of the patients survived CONCLUSION: There was no difference in survival time and only a small, statistically nonsignificant increase in tumor response for stage IV melanoma patients treated with the Dartmouth regimen compared with dacarbazine. Dacarbazine remains the reference standard treatment for stage IV melanoma.
PATIENTS WITH STAGE IV melanoma, based on American Joint Committee on Cancer (AJCC) criteria, have a universally poor prognosis with a median survival time from 3 to 11 months, depending on the subgroup analyzed.1,2 The standard treatment has been dacarbazine, which induces objective tumor responses in only 5% to 20% of patients.1 Most responses are partial, and there is no evidence that dacarbazine prolongs survival of treated cohorts, although complete responses do occur and can be durable.3 Over the years, a variety of chemotherapeutic and immunologic drug combinations have been explored with the hopes of improving the response rates. Examples include vinblastine, bleomycin, cisplatin4; cisplatin, vinblastine, dacarbazine5; high-dose cisplatin with dacarbazine6; bleomycin, vincristine, lomustine, dacarbazine7; and interleukin-2/lymphokine-activated killer cells.8 Although initial response rates have often been encouraging in single-institution trials (typically 40% to 50%), subsequent phase II trials have not confirmed these response rates,9-14 and prospective phase III trials failed to demonstrate a superiority of many of these regimens over dacarbazine alone.15,16 In 1984, Del Prete et al17 reported a 55% response rate in 20 melanoma patients treated with dacarbazine, cisplatin, carmustine, and tamoxifen. This came to be known as the Dartmouth regimen, and subsequently, a variety of single-institution studies confirmed relatively high response rates of 40% to 50%.18-21 Given that previous chemotherapy combinations, using the same or similar drugs, had initially looked promising but failed to prove superior to dacarbazine in carefully controlled randomized trials, we carried out a multicenter, phase III randomized trial that compared the Dartmouth regimen directly to single-agent dacarbazine.
Patient Selection Eligible patients had biopsy-proven AJCC stage IV melanoma or stage III (N2) melanoma not potentially curable by surgery. Patients had to be 18 years or older, be able to give written informed consent, have a Karnofsky performance status  50%, have bi-dimensionally measurable disease, and be fully recovered from surgery. Bone metastases and malignant effusions were not considered measurable, and patients with melanoma confined only to the CNS were not eligible. Eligible patients were previously untreated for metastatic melanoma and had no other malignancy within the previous 5 years (except carcinoma of the skin or carcinoma-in-situ of the cervix). Patients were required to have clinically normal hearing, normal cardiac status (a gated cardiac scan showing an ejection fraction 50% was required for all patients with questionable cardiac status), WBC 4,000/µL, platelets 160,000/µL, bilirubin less than 1.5 mg/dL, and creatinine 1.4 mg/dL. Women with reproductive potential were required to use an effective form of contraception, but oral contraceptives were not permitted on this study. Patients were excluded if they had New York Heart Association class III or IV cardiac status, serious infections or systemic illness requiring treatment, or had received aminoglycosides within the previous 2 weeks. Patients could not have received any systemic treatment for melanoma or prior regional perfusion with any of the drugs used in the Dartmouth regimen. Radiation therapy was not allowed within the previous 4 weeks. Women who were pregnant or breastfeeding were ineligible.
Treatment
Arm A: Dartmouth Regimen
Arm B: Dacarbazine All treatments were given at full doses; dose reduction was not permitted on protocol. Treatment was administered every 3 weeks but could be delayed, if necessary, until patients recovered from toxicity. Granulocyte colony-stimulating factor was allowed for marrow support if a previous cycle of therapy was associated with grade 4 neutropenia and fever.
Pretreatment Evaluation
Outcome Measures Tumor responses were graded using standard criteria. A complete response (CR) required the disappearance of all signs, symptoms, and biochemical and radiographic evidence of tumor for at least 30 days. In the case of cutaneous or subcutaneous metastases, tissue biopsy of at least one tumor site was required. A partial response (PR) was defined as reduction of all measurable tumors by at least 50% of the sum of the products of the greatest and perpendicular diameters of each indicator lesion for at least 30 days. During this time, there could be no progression of tumors or development of new tumors. Any assessable patient who did not fit the definition of CR or PR was considered to be a nonresponder (NR).
Statistical Considerations Patients were observed until death. The date and cause of death were recorded. Survival time was measured from the date of randomization. Plots of estimated overall survival were calculated by the Kaplan-Meier method24 and compared using the log-rank test.25 Overall survival time, tumor response, and toxicity were analyzed by both intent to treat using all randomized patients and by considering only eligible and treated patients. Fisher's exact test was used to assess treatment differences for tumor response and toxicity.
Study Population From November 1991 through December 1997, 240 patients were enrolled onto the study (Table 1). Initial participating centers were Memorial Sloan-Kettering Cancer Center, Hoosier Oncology Group, Dartmouth Medical Center, and University of Pennsylvania. In 1996, the Eastern Cooperative Oncology Group became a participant in the study. Of the 240 patients, 119 were randomized to receive the Dartmouth regimen; 121 were randomized to the dacarbazine arm. The two treatment arms were well balanced for sex, age, Karnofsky performance status, stage, and sites of metastatic disease. Five patients were considered ineligible (two on Dartmouth, three on dacarbazine) because of failure to document stage III or IV melanoma. This left a total of 235 eligible patients. Although an additional six patients were formally ineligible, either because of receiving radiation therapy to nonindicator lesions within 4 weeks of starting treatment (three patients) or because an eligibility criterion which was subsequently amended had not been met at the actual time of registration (three patients), these six patients were analyzed with the eligible patients.
Survival Analysis
In a second survival analysis, we considered only the 235 eligible patients. In addition, we eliminated four patients who were randomized but never received treatment because of withdrawal of consent (two patients), death (one patient), or withdrawal from study after the patient's ejection fraction was discovered to have fallen below eligibility criteria (one patient). All four patients had been randomized to the Dartmouth arm. Of the remaining 231 eligible patients who had received treatment, the median survival time on the Dartmouth arm was 7.7 months (95% CI, 6.4 to 8.9) compared with 6.4 months (95% CI, 5.5 to 8.9) on the dacarbazine arm. The 1-year survival rate estimate on the Dartmouth regimen was 23% compared with 28% on the dacarbazine arm (P = .39). The Kaplan-Meier survival plots for these groups (Fig 2) demonstrate that there was no difference between the two groups (P = .51). Thus, excluding the nine patients who were either ineligible or who had never received treatment made no difference in the final analysis.
Of the 121 patients randomized to arm B (dacarbazine), 20 patients (16.5%) went on to receive the Dartmouth regimen off protocol after their disease had progressed.
Tumor Responses We also analyzed the tumor response rate among assessable patients (Table 2). As noted above, 231 patients were eligible and received treatment. Among these 231 patients, an additional five patients treated on the Dartmouth arm received only a single course of treatment but had no posttreatment tumor measurements recorded and could not be evaluated for tumor response. They had been taken off the study because of toxicity (two patients) or because they withdrew consent (three patients). A total of 226 patients were assessable for tumor response. Considering only these patients, the response rate to dacarbazine was 10.2%, whereas the response rate to the Dartmouth regimen was 18.5%. Although there was a trend toward a higher PR rate on the Dartmouth arm, this difference was not statistically significant (P = .09).
We considered the possibility that the Dartmouth regimen might offer an advantage to certain subsets of patients based on site of metastatic disease. There were 127 assessable patients with metastatic disease sites other than soft tissue. The response rate in the Dartmouth arm was 9% compared with 6% in the dacarbazine arm. This difference was not significant (P = .74). Among the 99 assessable patients with metastases confined to soft tissue sites (skin, lymph nodes, or lung), 22 responded to treatment. The response rate for dacarbazine was 14% compared with 32% for patients treated on the Dartmouth arm. This difference was statistically significant (P = .05), but this higher response rate did not translate into an improvement in overall survival for this subset of patients (P = .15). We also considered the possibility that response rates might differ between men and women, as noted in a previous study.26 In the Dartmouth arm, the response rates for men and women were similar (19% v 15%; P = .61). In the dacarbazine arm, men had a lower response rate than women, which was of borderline statistical significance (6% v 18%; P = .06). There was, however, no difference in median survival time among men and women in either treatment arm (data not shown).
Toxicity
A total of 28 patients were taken off the study because of toxicity (25 on the Dartmouth arm and three on the dacarbazine arm, P < .01). The most common toxicities requiring discontinuation of treatment were cytopenias, renal toxicity, and neurotoxicity.
In this phase III randomized trial, we compared the overall survival of 240 stage IV melanoma patients treated with either dacarbazine or the Dartmouth regimen. In the standard dacarbazine arm, we observed a median survival time of 6.4 months and a 1-year survival rate of 28%. The main observation of the study was that there was no detectable difference in overall survival between the Dartmouth arm and the dacarbazine arm. This was true whether we considered all patients randomized or considered only patients who were eligible and treated. The survival curves are virtually superimposable. A second end point of the trial was to compare tumor response rates. The response rate to dacarbazine was 10.2%, which is consistent with previously published data.1 The response rate to the Dartmouth regimen was somewhat higher, 18.5%, but this difference did not reach statistical significance. Although this response rate for the Dartmouth regimen is lower than reported in the initial phase II trials, our results are consistent with the results of several recent multicenter trials that reported response rates for the Dartmouth regimen between 14% and 30%.27-30 Patients with metastases confined to soft tissue sites (skin, lymph nodes, or lung) are more likely to respond to chemotherapy and, in many databases, have a better prognosis than patients with metastases to other sites. Of the 226 patients assessable for tumor response, 99 (44%) had metastasis confined to soft tissue sites. In this group of patients, the response rate to the Dartmouth regimen was higher than the response rate to dacarbazine (32% v 14%), with the difference reaching statistical significance. Despite a higher rate of tumor responses in patients with soft tissue metastases treated on the Dartmouth arm, there was no improvement in overall survival. This is not surprising given that, in both treatment arms, the response rates were relatively low and there were no complete responses. The European Organization for Research and Treatment of Cancer Melanoma Cooperative Group has reported a similar observation in which interleukin-2–based treatments doubled the response rate but had no apparent impact on survival.31 Other subsets of patients were analyzed (women and patients with visceral metastases), but no increase in response rate or survival was observed for the Dartmouth arm. The Dartmouth treatment was associated with a higher incidence of grade 3/4 bone marrow suppression, nausea/vomiting, and fatigue than dacarbazine. Twenty-five patients (21%) on the Dartmouth regimen were taken off the study because of toxicity, compared with only three patients (2%) on the dacarbazine arm (P < .01). After the initial reports by Del Prete et al17 and McClay et al18 on treating stage IV melanoma patients with the Dartmouth regimen, several other small phase II studies from single institutions were also published that reported relatively high response rates. A consideration of these results, along with their laboratory observations suggesting that tamoxifen might increase melanoma sensitivity to cisplatin, led McClay and McClay32 to propose that, in the absence of a prospective randomized trial, the Dartmouth regimen should be considered as first-line therapy in melanoma. Indeed, the Dartmouth regimen has become a standard treatment for metastatic melanoma in many practices across the country. However, the results of our trial lead us to conclude that the Dartmouth regimen offers no discernible survival benefit over dacarbazine in the treatment of stage IV melanoma and that dacarbazine remains the reference treatment against which new treatments must be measured. This is consistent with more recently reported multicenter randomized trials. Past efforts to develop multidrug regimens with improved efficacy have built on dacarbazine by adding drugs with minimal single-agent activity in melanoma. Typically, these regimens have been reported to induce major tumor responses in 40% to 50% of patients in initial single-institution trials. Ultimately, however, these drug combinations have not proven to be superior to dacarbazine alone. We must continue to develop new strategies for the treatment of advanced melanoma. Our results remind us that promising new treatment regimens in melanoma must ultimately be brought quickly into randomized phase III trials against dacarbazine. The most promising regimen currently under investigation is the combination of cisplatin, vinblastine, dacarbazine, interferon alfa, and interleukin-2, initially developed by Legha et al,33 who reported a 60% response rate. A 45% response rate was seen by Atkins et al34 when a less toxic schedule of the same drug combination was used. As a result of this second encouraging phase II trial, a randomized intergroup clinical trial (ECOG3695) is currently underway to determine whether this biochemotherapy regimen offers a survival advantage compared with the identical chemotherapy alone.
Supported in part by National Cancer Institute grant no. CA05826.
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Legha SS, Ring S, Bedikian A, et al: Treatment of metastatic melanoma with combined chemotherapy containing cisplatin, vinblastine and dacarbazine (CVD) and biotherapy using interleukin-2 and interferon-alpha. Ann Oncol 7:827-835, 1996 34. McDermott DF, Mier JW, Lawrence DP, et al: A phase II pilot trial of concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine (CVD), interleukin-2 (IL-2), and interferon alpha-2B (IFN) in patients with metastatic melanoma. Proc Am Soc Clin Oncol 17:507a, 1998 (abstr 1956) Submitted February 24, 1999; accepted April 28, 1999. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
