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© 2002 American Society for Clinical Oncology Cisplatin, Dacarbazine With or Without Subcutaneous Interleukin-2, and Interferon Alfa-2b in Advanced Melanoma Outpatients: Results From an Italian Multicenter Phase III Randomized Clinical TrialByFrom the Department of Medical Oncology, Pierantoni Hospital, Forlì; Department of Medical Oncology, Busonera Hospital, Padua; Department of Medical Oncology, Oncology Institute of Bari, Bari; Medical Oncology Unit, S. Chiara Hospital, Pisa; Department of Radiotherapy and Oncology, Riuniti Hospital, Bergamo; Aviano Cancer Institute, Aviano; Oncology Unit, S. Maria degli Angeli Hospital, Pordenone; Department of Medical Oncology, Maggiore Hospital, Verona; Oncology Center, S. Chiara Hospital, Trento; and Istituto Oncologico Romagnolo, Forlì, Italy. Address reprint requests to Ruggero Ridolfi, MD, Department of Medical Oncology, Pierantoni Hospital, Via Forlanini, 34, 47100 Forlì, Italy; email: i.o.r{at}fo.nettuno.it
PURPOSE: Phase II and III studies have shown that the addition of interleukin-2 (IL-2) and interferon alfa-2b (IFN  -2b) in multiagent chemotherapy (CT) for advanced melanoma increases overall response (OR), albeit without clear evidence of an improvement in overall survival (OS). Treatment with high-dose IL-2 can cause severe toxicity and is normally administered in an inpatient setting. We conducted a multicenter prospective randomized clinical trial in outpatients with metastatic melanoma to compare CT with biochemotherapy (bioCT) using immunomodulant doses of IL-2 and IFN-2b.
PATIENTS AND METHODS: One hundred seventy-six eligible patients with advanced melanoma were randomized to receive CT (cisplatin and dacarbazine with or without carmustine every 21 days) or bioCT comprising the same CT regimen followed by low-dose subcutaneous IL-2 for 8 days and IFN RESULTS: At a median follow-up of 18 (CT) and 16 (bioCT) months, median OS was 9.5 versus 11.0 months (P = .51), respectively. In the 89 CT-arm patients, 18 ORs (20.2%) (three complete responders [CRs] and 15 partial responders [PRs]) were observed according to World Health Organization criteria. In the 87 bioCT-arm patients, 22 ORs (25.3%) (three CRs and 19 PRs) (P = .70) were recorded. Treatment-related toxicity was fairly similar in both arms. CONCLUSION: The addition of low-dose immunotherapy did not produce a statistically significant advantage in OS, time to progression, or OR. However, the 11-month median OS in the bioCT arm does not differ greatly from the best results with high-dose IL-2–containing regimens reported in the literature. Furthermore, our treatment schedule was carried out on outpatients and had an acceptable level of toxicity.
MELANOMA ACCOUNTS FOR 1% to 3% of all malignant tumors and is increasing in incidence by 6% to 7% each year.1,2 It is curable with surgical resection in a high percentage of cases (> 50%), with a 5-year survival of 80% to 100%.3 However, when a patient presents with advanced disease, 5-year life expectancy is less than 10%, with a median survival of 6 to 8.5 months.4 Dacarbazine (DTIC) is the most widely used chemotherapeutic agent, obtaining an overall response (OR) of 10% to 20%. There is no general consensus as to whether polychemotherapy is more effective than single-agent treatment, even though OR rates of combined treatment with cisplatin (CDDP) and DTIC with or without vinca alkaloids (vindesine/vinblastine) range from 18% to 50%.5,6 Furthermore, recent phase III studies would seem to indicate that no significant therapeutic benefit is obtained from the addition of tamoxifen.7
The effectiveness of adding interferon alfa-2b (IFN
We conducted a multicenter randomized clinical trial to compare a standard chemotherapeutic regimen comprising DTIC and CDDP with the same schedule plus low-dose subcutaneous IL-2 and IFN
IL-2 and IFN An additional aim of the present study was to evaluate QoL by means of a specially prepared questionnaire. We also evaluated some prognostic factors in patient serum before and during therapy.
Patients From March 1, 1997, to December 31, 1999, patients with advanced melanoma were enrolled onto the study. All patients had previously undergone surgery to remove a primary cutaneous melanoma, with or without subsequent adjuvant IFN -2b, and none had received chemotherapy (CT) or chemoimmunotherapy. Patients were required to satisfy the following criteria: age 18 years or older, histologically confirmed diagnosis of melanoma and measurable disease, WBC count greater than 3,000/mm3, platelet count greater than 100,000/mm3, serum creatinine less than 1.7 mg/dL, and bilirubin less than 1.6 mg/dL. Exclusion criteria were performance status higher than two and cerebral metastasis or cardiovascular, renal, or metabolic diseases, including conditions requiring continuous cortisone treatment. Randomization was carried out telephonically by Istituto Oncologico Romagnolo, the Forlì data center, which collected all patient documentation and was responsible for data management. A system of random permuted blocks within the strata (oncologic center variable) was used with a block size of four. Initially, treatment and follow-up data were collected on case record forms in no-carbon-required booklets. Data were then recorded on a computerized database designed specifically for the management of the clinical trial data. All patients underwent clinical examination, complete blood count and biochemical analysis, chest computed tomography scan or x-ray, liver computed tomography scan or ultrasonography, brain computed tomography or magnetic resonance imaging scan, and cardiologic evaluation in the 60 days before randomization. Before each treatment cycle, patients underwent clinical examination, determination of complete blood count, and biochemical analysis. After two cycles and thereafter every 3 months until progression, they were required to have a chest computed tomography scan or x-ray and a liver computed tomography scan or ultrasonography. Response evaluations were assessed according to World Health Organization criteria.13 When progression occurred, no indications for second-line therapy were given to the investigators. Recruited patients underwent QoL assessment using the Rotterdam Symptom Check List questionnaire. The baseline assessment was performed before therapy and subsequently before each cycle. Serum was also collected for biologic tests at baseline and before each treatment cycle. All patients gave their informed written consent to receive treatment, and the study was examined and approved by the ethics committee of the local health and social services of each center taking part in the study, in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.
Treatment
Patients were assessed before starting each cycle using World Health Organization toxicity criteria. Doses were reduced in the following cases. If the WBC count was less than 3,000, then neutrophils were evaluated, and if they were less than 1,500 or if the platelets were less than 90,000, treatment was delayed for 1 week. If these two counts persisted, the dose of the CT drugs was reduced by 25% but IL-2 and IFN -2b doses remained unvaried. This dose reduction was maintained for all of the remaining cycles. If in the second week of delayed treatment the neutrophil count remained less than 1,000 or platelet count was less than 70,000, growth factors were allowed. In the event of grade 4 hematologic toxicity, the CT drug dosage was additionally reduced by 25% and maintained at this level; a continuous neutrophil count of less than 1,000 after the second week of delay or platelet count of less than 70,000 resulted in the discontinuation of treatment. In the presence of grade 1 or 2 renal toxicity, treatment was delayed for 1 week. Persistent grade 1 toxicity led to a 50% and 30% reduction in CT and IL-2, respectively; treatment was discontinued for persistent grade 2 toxicity. In the event of grade 2 hepatic toxicity, treatment was delayed for 1 week. If the situation persisted, CT was reduced by 50%, IL-2 was reduced to 3,000,000 IU/die, and IFN-2b was suspended. All dose reductions for renal and hepatic toxicity were maintained for the remaining cycles. In other cases of grade 3 toxicity (excluding fever and alopecia), treatment was delayed for 1 or 2 weeks. For other grade 4 toxicities, treatment was discontinued.
Statistical Analysis Starting from an assumed 40% 1-year OS from randomization for patients treated with CT alone and hypothesizing an absolute increase of 20% in patients treated with bioCT (5% error fixed for a two-sided test and a power of 80%), a recruitment of at least 150 patients over 3 years was required. No interim analysis was planned. Survival was defined as the time interval between randomization and either death of the patient attributable to any cause or the last recorded follow-up. TTP was defined as the time interval between the date of randomization and the date of disease progression or last follow-up. OS and TTP curves for the two arms were estimated by the Kaplan-Meier method and compared using the log-rank test. The effect of prognostic factors on OS and TTP was estimated using Cox regression models. Analysis for some clinical and biologic subgroups was planned in advance as a secondary aim with exploratory intent; adjustments for multiplicity were not made. As regards the response analysis, 95% confidence interval (CI) of response rates was calculated, and comparison between groups was assessed using Fisher’s exact test. All P values were based on two-sided testing, and statistical analyses were carried out with SAS statistical software (SAS/STAT user’s guide, version 6; SAS Institute, Cary, NC).
Patient and Treatment Characteristics Between March 1997 and December 1999, a total of 178 patients were randomized. Two patients, one from each treatment arm, did not satisfy eligibility criteria and were excluded from the study; both underwent surgical resection of a suspected liver metastasis, which histologically resulted in angioma. Of the 176 eligible patients, 89 (57 men and 32 women) were allocated to receive CT and 87 (48 men and 39 women) were allocated to receive bioCT. Only three centers chose to add carmustine, for a total of 18 patients (nine in each arm). The two treatment arms were similar in terms of patient characteristics (Table 1).
The median age in the CT arm was 59 years (range, 26 to 76 years) and in the bioCT arm, 56 years (range, 25 to 77 years). More than two thirds (67%) of patients had an Eastern Cooperative Oncology Group performance status (PS) of zero, and only 10 patients (six in the CT arm and four in the bioCT arm) had a PS of 2. Approximately one third of patients had liver metastases with or without involvement of other sites, one third had viscera or lung metastases, and almost one third had soft tissue and lymph node involvement. All the patients had previously undergone radical resection of primary cutaneous melanoma, and 50 patients (28%) had received adjuvant IFN -2b, of whom 24 were in the CT arm and 26 were in the bioCT arm (six in the CT arm and five in the bioCT arm received high-dose IFN-2b according to Kirkwood’s scheme; the remaining 39 received low-dose IFN-2b).14 Time from first diagnosis varied from 0 to 292 months, with a median value of 27 months for the CT arm and 22 for the bioCT arm.
Survival
Although the study was not designed to have the power for comparison within subgroups, a breakdown analysis was performed with exploratory intent. However, a cautious interpretation of P values is recommended (Table 2). Subgroup analysis according to sex, PS, and age showed no statistically significant differences between the two treatments. However, patients with liver metastases had a better OS when treated by bioCT with respect to CT (median OS, 8.7 v 4.8 months; P = .002).
Response to Treatment Analysis of the 176 eligible patients showed an OR of 20.2% (95% CI, 11.8% to 28.6%) in the CT arm and 25.3% (95% CI, 16.1% to 34.5%) in the bioCT arm. This difference was not statistically significant (P = .715). Two patients could not be assessed because one (in the CT arm) was lost to follow-up immediately after randomization and the other (in the bioCT arm) suspended treatment after the first cycle because of grade 4 neurologic toxicity. Of 89 patients randomized to receive CT alone, there were three complete responders (CRs) and 15 partial responders (PRs); of the 87 patients randomized to receive bioCT, there were three CRs and 19 PRs (Table 3).
The duration of the three CRs in the CT arm was 4, 6, and 33+ months and in the bioCT arm was 6, 12, and 16+ months. Median duration of OR was 6.9 and 8.3 months, respectively. The subgroup of 18 patients who received carmustine was too small to analyze efficacy in terms of OS, TTP, or OR.
Treatment and Toxicity Profile Treatment interruptions were mainly attributable to disease progression or, to a lesser extent, toxicity (96% and 1.8% in the CT arm and 87% and 5.5% in the bioCT arm, respectively).
Few dose reductions and delays in treatment were required. Thirty-two patients received a reduced CT dosage in at least one cycle (14 in the CT arm and 18 in the bioCT arm), and IFN Table 4 summarizes grade 3 and 4 toxicities. Hematologic toxicity was the most common side-effect; the percentage of patients reporting grade 3 and 4 leukocytes/granulocytes was quite similar in the two groups, 18.4% and 18.4% in the CT arm and 23.3% and 11.6% in the bioCT arm, respectively. Nausea or vomiting was severe in 13 CT-arm and 21 bioCT-arm patients. In the latter arm, fever and asthenia were observed in 80% of cases, but only in few cases did they reach grade 3 toxicity. With regard to the 18 patients who received carmustine, a greater frequency of grade 3 or 4 leucopenia and thrombocytopenia, both of which resolved spontaneously, was observed with respect to patients who were not treated with BCNU. There were no treatment-related deaths.
The median survival of patients with advanced melanoma varies between 6 and 9 months, and only 1% to 2% have long-term complete responses after treatment.15 In one study reporting 11 trials of the Southwest Oncologic Group on 813 patients, 5-year survival rate was only 2%.16
Single chemotherapeutic agents give OR percentages ranging from 10% to 20%, and DTIC is still the most commonly used drug. In a recent phase III trial, the Dartmouth regimen, one of the most widely used polychemotherapeutic schemes, did not obtain a statistically significant increase in OR compared with DTIC alone (18.5% v 10.2%).17 Moreover, the addition of single therapeutic agents such as tamoxifen or IFN
However, significantly higher response percentages have been observed when the combination of IFN
A meta-analysis carried out by Keilholz et al26 on 631 patients treated with various drug combinations showed that when CT was combined with IL-2 and IFN
In 1999, Rosenberg et al11 reported the results of a preliminary trial that compared CT (CDDP + DTIC + TAM) with the same scheme plus IFN
The data from the study by Rosenberg et al11 warrant additional analysis in an attempt to explain such a contradictory outcome. However, high-dose IL-2 undoubtedly causes severe toxicity, as indicated in preliminary results reported by Eton et al12 on 183 patients subdivided into two treatment arms. In the study by Eton et al, which compared CT alone (CDDP + DTIC + vinblastine) with bioCT (the same CT regimen + IFN In line with present European practice, we used low-dose immunotherapy for immune modulation, and treatment was administered in an outpatient setting, mainly to favor QoL.28 OR rates (20.2% for CT v 25.3% for bioCT) did not differ significantly, and TTP was similar in both groups (3.0 v 3.6 months). However, in our opinion, OS rates, albeit not significantly different, merit additional consideration, because although the 9.5-month survival obtained in the CT arm reflected literature data, that of 11-month survival obtained with bioCT could be considered fairly similar to the results reported in the phase III trial by Eton et al.12 In our study, an analysis of potential predictive factors confirmed the importance of well-known clinical and biochemical characteristics and highlighted the need for additional investigation in others. Preliminary data showed that liver metastasis, high lactate dehydrogenase levels, and high fibrinogen levels, when evaluated as pretreatment factors, were associated with a poorer prognosis.29 The identification of subgroups of patients with different prognoses should be an important future end point to optimize the choice of therapeutic regimens.30,31 Greater effort is needed to improve drug combinations and investigate new cytokines (ie, granulocyte-macrophage colony-stimulating factor), paying particular attention to dosage and method of administration of IL-2 to maintain the improved OS, acceptable toxicity, and QoL.32 In conclusion, our study reinforces the already widespread opinion that advanced melanoma is best treated with combined chemoimmunotherapeutic drugs. Our aim for the future should be to improve or optimize the immunotherapeutic regimen without, however, neglecting QoL, given that most of these patients have a life expectancy of 1 year at most. Furthermore, patient subgroups and targeted therapies could be better identified on the basis of proven predictive factors.
Italian Melanoma Intergroup participants and authors:Alessandra Ravaioli, Istituto Oncologico Romagnolo, Forlì; Laura Ridolfi, Department of Medical Oncology, Pierantoni Hospital, Forlì; Roberta Redelotti, Grazia Artioli, Department of Medical Oncology, Busonera Hospital, Padua; Vito Lorusso, Department of Medical Oncology, Oncology Institute of Bari; Lucia Tanganelli, Medical Oncology Unit, S. Chiara Hospital, Pisa; Paola Poletti, Medical Oncology Unit, Riuniti Hospital, Bergamo; Stella Porrozzi, Enrichetta Corgna, Medical Oncology Unit, Monteluce Polyclinic, Perugia; Giuseppe Lo Presti, Carmelo Iacono, Department of Medical Oncology, Ragusa Hospital, Ragusa; Anna Chiara, Giovanna Luchena, Medical Oncology Center, Sant’Anna Hospital, Como; Elvira Scelzi, Paolo Manente, Medical Oncology Unit, S. Giacomo Apostolo Hospital, Castelfranco Veneto; Laura Scaltriti, Fabrizio Artioli, Oncology Outpatient Clinic, B. Ramazzini Hospital, Carpi (Modena); Sergio Palmeri, Salvatore Miceli, Department of Medical Oncology and Oncohematology, University of Palermo; Antonio Muggiano, Department of Medical Oncology, A. Businco Hospital, Cagliari; Sergio Montanara, Sergio Cozzi, Department of Oncology, Castelli Hospital, Verbania; Franca Pari, Enrico Aitini, Department of Medical Oncology and Hematology, Mantova; Vittorio Mascia, Daniele Farci, Department of Medical Oncology III, A. Businco Hospital, Cagliari; Angelo Gambi, Maria Cristina Cappelli, Oncology Unit, per gli Infermi Hospital, Faenza; Domenico De Toma, Anna Giacobone, Oncology I, Polyclinic Institute San Donato Milanese, Milan; Maurizio Bertuccelli, Oncology Center, Riuniti Hospital, Livorno; Guido Biasco, Simona Casadei, Institute of Hematology and Medical Oncology, University of Bologna; Salvatore Toma, Department of Oncology, Biology and Genetics, University of Genoa, National Institute for Cancer Research, Genoa, Italy.
Supported by Istituto Oncologico Romagnolo, Forlì, Italy. We thank Lindsay Haynes and Gráinne Tierney for editing the manuscript.
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Vaughan MM, Moore J, Riches PG, et al: GM-CSF with biochemotherapy (cisplatin, DTIC, tamoxifen, IL-2 and interferon alpha): A phase I trial in melanoma. Ann Oncol 11: 1183-1189, 2000 Submitted July 30, 2001; accepted November 19, 2001.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
