Pegylated-Interferon Plus Dacarbazine for Metastatic Melanoma
Pegylated-Interferon Plus Dacarbazine for Metastatic Melanoma
Abstract & Commentary
By William B. Ershler, MD
Synopsis: Hauschild et al present the results of a phase II trial of pegylated interferon and dacarbazine for metastatic melanoma. The combination appeared well tolerated, and 7 of 25 patients either had stable disease, partial or complete remission. This combination is worthy of additional study in larger, randomized clinical trials for the treatment of melanoma.
Source: Hauschild A, et al. Combined treatment with pegylated interferon-a-2-a and dacarbazine in patients with advanced metastatic melanoma. Cancer. 2008;113:1404-1411.
The incidence of skin cancer is increasing in Caucasian populations worldwide. Of these, melanoma is of greatest concern, because surgical excision alone is often insufficient to control the disease, and local recurrence, metastatic disease, and death are all too often the outcome. In fact, melanoma survival mainly depends on primary tumor thickness, emphasizing the importance of primary and secondary prevention by early detection and prompt excision. Because of a lack of effective systemic therapy, removal of localized metastases remains the most effective approach to control metastatic melanoma when at all feasible. Systemic therapy with drugs or biological agents has been used for several decades, but response rates remain on the order of 10% or less.1 Of the agents that remain in clinical use, dacarbazine (DTIC) and interferon have both demonstrated some efficacy when used alone, or in combination.2 Pegylated interferon-a-2a (PEG-IFN-a-2-a) is a bio-engineered form of interferon-a-2-a, modified by the covalent attachment of a branched 40kDamethory-polyethyleneglycol moiety, which serves to extend the half-life of the molecule and allow less frequent dosing.
The current study, conducted by Hauschild et al at three sites in Germany and Switzerland, was designed to assess the safety and efficacy of DTIC and PEG-IFN-a-2-a in patients with metastatic melanoma. For this, 28 patients with stage IV melanoma without brain metastases were treated with DTIC (at a dose of 850 mg/m2 every three weeks) combined with weekly pegylated IFN-a-2-a at a dose of 180ug. The primary study endpoint was objective response.
Of the 28, 25 patients were evaluable for response. Two patients (8%) achieved a complete response that continued for > 480 days and 746 days, respectively. Four patients (16%) demonstrated a partial response, and another patient experienced stable disease. Six of seven nonprogressive patients had either not received earlier treatment or had not developed disease progression during adjuvant IFN treatment for stage II/III disease. The median duration of response was 236 days, the median progression-free survival was 56 days, and the overall survival time was 403 days. Few grade 3 toxicities and only one grade 4 toxicity were observed.
Commentary
The take home message from this trial is that combined DTIC and pegylated IFN-a-2-a was well tolerated in patients with metastatic melanoma. Although not directly compared with standard interferon, the description of reported adverse events would indicate that the pegylated form is more tolerable, a finding not unlike what has been observed in other clinical situations in which pegylated form of interferon has been employed. Furthermore, the response rate of 24%, including two long-lasting complete responses, is encouraging. This, however, must be accepted with great caution, as the number of patients in this trial was small. Indeed, if similar response rates are observed in larger, randomized trials, it would appear that pegylated IFN- -2a would represent a step forward in the systemic treatment of advanced melanoma. Furthermore, this agent should also be tested with temozolomide or other agents to assess its potential for enhancing response rates even further.
References
1. Eigentler TK, et al. Palliative therapy of disseminated malignant melanoma: a systematic review of 41 randomised clinical trials. Lancet Oncol. 2003;4:748-759.
2. Huncharek M, et al. Single-agent DTIC versus combination chemotherapy with or without immunotherapy in metastatic melanoma: a meta-analysis of 3273 patients from 20 randomized trials. Melanoma Res. 2001;11:75-81.
Hauschild et al present the results of a phase II trial of pegylated interferon and dacarbazine for metastatic melanoma. The combination appeared well tolerated, and 7 of 25 patients either had stable disease, partial or complete remission. This combination is worthy of additional study in larger, randomized clinical trials for the treatment of melanoma.Subscribe Now for Access
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