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© 2002 American Society for Clinical Oncology
Biochemotherapy for Advanced Melanoma: Maybe It Is RealSalpetrière Hospital, Paris, France WHEREAS EARLY-STAGE cutaneous melanoma is a readily curable neoplasm, the prognosis in metastatic disease remains poor despite years of research, hope, and expectations. Different therapeutic approaches have been evaluated, including chemotherapy and biologic therapies, both as single treatments and in combination. To date, however, none of these treatment options has shown a survival impact. Advanced melanoma is still associated with an extremely poor median survival, ranging from 2 to 8 months, and a 5-year survival rate of less than 10%. In the April 15, 2002, issue of the Journal of Clinical Oncology, Eton et al1 report the results of a large phase III randomized trial which demonstrates that a combination of cisplatin with interleukin-2 (IL-2) biochemotherapy is superior to a standard regimen of cisplatin, vinblastine, and dacarbazine (CVD), one of the most widely used regimens for metastatic melanoma. This new regimen has to be seen as a limited, but significant, step toward improvement of the management of advanced melanoma. In addition, it may be that the application of such treatment in the adjuvant setting in high-risk melanoma may increase the curability of the disease. This report comes after years of attempts to find any agent more active than single-agent dacarbazine, the only cytotoxic drug approved by the Food and Drug Administration for the treatment of metastatic melanoma.2 But this drug leads to a response rate of less than 20%, a complete response less than 5%, and a median duration of response of only 4 to 5 months. There are only anecdotal responses in CNS metastases, a frequent site of progression in this disease. Other cytotoxic compounds have not improved on these results, including temozolomide (a dacarbazine analog),3 cisplatin and carboplatin,2 vinca alcaloids,2,4 taxanes,2 and nitrosoureas.2 All of these are associated with response rates of less than 15%. The only other cytotoxic drug that might be of some interest for the treatment of advanced melanoma, although never directly compared with dacarbazine, is fotemustine. This drug has been widely tested in Europe and has shown overall response rates of 20% to 25% and response rates of 15% to 25% in brain metastases from melanoma.5-8 The role of polychemotherapy in this setting remains uncertain. The majority of studies have failed to demonstrate any significant benefit for combination chemotherapy when compared with single agents, except for a slight increase in response rates. There is usually no increase in time to progression (TTP) or survival, but increased toxicity compared with single-agent dacarbazine has been observed.9-12 The addition of tamoxifen to chemotherapy has influenced a whole generation of oncologists since McClay’s first report.13 However, there has been no demonstrated benefit for tamoxifen in randomized trials.14,15 Observation of the natural history of melanoma has alerted physicians to the possible role of immune defense mechanisms in advanced melanoma. Partial or complete spontaneous regression of melanoma has long been reported, occurring more frequently in patients with melanoma than with other tumors. Vitiligo is presumably secondary to a specific immune response directed toward melanocyte antigen(s) and has been associated with a good prognosis in patients with advanced melanoma who are receiving immunotherapy.
These particular features, apparently quite specific to the tumor biology of melanoma, have led to the development of noncytotoxic approaches. Since the 1970s and 1980s, immunostimulating agents such as bacillus Calmette-Guerin, Corynebacterium parvum, polyA-polyU, mercaptoethanol extracted residue, or isoprinosine have been evaluated as local or systemic treatments. After some early hopes, all have also failed to demonstrate a significant and consistent efficacy in the clinical management of advanced melanoma. More recently, recombinant interferon alfa (IFN IL-2 is another cytokine and is the main T-cell growth and stimulating factor. IL-2 has been the focus of extensive clinical research since the first reports in 1987 by Rosenberg18 of its activity in advanced melanoma. However, with different doses and schedules, alone or in combination with ex vivo activated and conditioned cells such as lymphocyte-activated killer cells or tumor-infiltrating lymphocytes, IL-2 achieves only an average response rate of 15% to 20%, with a small proportion of complete responses.19-21 Cytokines such as IL-2, although having response rates equivalent to chemotherapy, have been able to induce a significant number of long-term unmaintained remissions. However, although apparently disappointing at their first look, these results might have changed something, not in the improvement of the response rate, but in the shape of the survival curves.
Because chemotherapy and cytokines have different, and perhaps synergistic, mechanisms of action, the combination of these two treatments has been evaluated since the early 1990s as a potentially worthwhile investigational approach. This approach, biochemotherapy, was also supported by a meta-analysis of more than 3,000 patients from 20 randomized trials showing that the combination of dacarbazine and IFN However, it is the combination of IL-2 with cisplatin-based chemotherapy that has raised the greatest enthusiasm. The literature on this topic has been recently summarized, including our own large experience at the Salpetrière Hospital in Paris.26 Based on the results of several phase II studies using different drugs, doses, and schedules, several trends or conclusions could be drawn that required confirmation by prospective randomized studies. Compared with chemotherapy or immunotherapy alone, IL-2–based biochemotherapy seemed to provide higher response rates, longer time to disease progression, and a higher long-term, unmaintained remission rate. Among this population were some patients who might be considered as definitively cured.27 The impression was that the critical cytotoxic drug in these biochemotherapy regimens was cisplatin and that the dose and the route of administration of recombinant IL-2 affected only the response rate, but not the complete response rate, the duration of response, or the long- term unmaintained remission rate.
Meta-analyses have supported these suggestions. Allen et al28 have shown that IL-2, alone or with IFN
Some apparently conflicting results were reported recently by Rosenberg et al.30 In a small trial, which was terminated prematurely, patients with advanced melanoma were randomized to high-dose intravenous bolus IL-2 combined with subcutaneous IFN
This is why the study reported by Eton et al1 is so important. They compared biochemotherapy to chemotherapy alone in terms of response rate, time to tumor progression, overall survival, and toxicity in 190 patients with advanced melanoma who were treated at the M.D. Anderson Cancer Center. Patients received either CVD alone or CVD combined with continuous intravenous IL-2 and subcutaneous IFN
Biochemotherapy was statistically superior to chemotherapy, both in response rate and TTP, roughly doubling these end points (response rate, 48% v 25%, P = .001; TTP, 4.9 v 2.4 months, P = .008). The difference in overall survival was improved (11.9 v 9.2 months), although this difference was not statistically significant (P = .06). Notably, 51% of the patients treated with chemotherapy alone were subsequently crossed over to receive IL-2 and INF
These superior results were associated with a high level of toxicity, with significantly more grade 3 or 4 toxicities in the biochemotherapy arm than in the chemotherapy arm. However, three treatment-related deaths occurred in the chemotherapy group and only one in the biochemotherapy group. Moreover, nearly all the toxic effects associated with biochemotherapy were reversible at cessation of treatment and readily managed on an inpatient ward. The superiority of biochemotherapy over biotherapy alone was demonstrated by a European Organization for Research and Treatment of Cancer randomized study, in which patients with advanced melanoma were randomized between IL-2–IFN Evidence is accumulating to suggest that cisplatin-IL-2–based biochemotherapy is an interesting and active approach to the management of metastatic melanoma. It increases response rate, TTP, and long-term unmaintained remission rate. But it is associated with an increased, although nearly always reversible, toxicity. The extent of benefit, however, is still limited and needs to be improved. This may be achieved by the search for better combinations, including the demonstration that the addition of another cytotoxic drug, cisplatin, adds anything more than toxicity. In addition, it will be important to evaluate the best IL-2 dose and route of administration. One option, for example, would be to use subcutaneous IL-2, which is usually associated with a lower incidence of toxicity. However, the greatest progress will be made when effective strategies are used earlier in the course of malignancies. The question, therefore, is whether cisplatin-IL-2–based biochemotherapy should now be tested in the adjuvant setting in high-risk melanoma. REFERENCES
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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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) has shown some clinical activity, with a response rate of approximately 15% and a complete response rate of less than 5%. Most of these responses were achieved in skin, lymph nodes, and soft tissue metastases.
