Temozolomide and interferon-alpha in metastatic melanoma: a phase II study of the Italian Melanoma Intergroup

Abstract

Temozolomide (TMZ) is a new oral alkylating agent which has proven to be as active as dacarbazine (DTIC) in the treatment of melanoma, but with a lower toxicity. A multicentric phase II trial was conducted in an out-patient setting to determine the therapeutic activity and safety of TMZ in combination with interferon-alpha (IFN-alpha). From June 2000 to July 2001, 41 patients were recruited to receive TMZ 200 mg/m orally on days 1-5 every 28 days and with 5 MU IFN-alpha subcutaneously three times a week, continuously for eight cycles or until disease progression occurred. Of the 40 treated patients, two complete responses (5%) and three partial responses (7.5%) were observed, with a median duration of 4 months (range, 1.5-13.5 months). Thirteen patients (32.5%) had stable disease for a median of 2.5 months. Time to progression was 2.6 months and the median overall survival was 11.8 months. Nine patients (22.5%) developed brain metastases. The grade 4 toxicity observed in seven patients was of a transient haematological nature. This combination therapy is well tolerated but does not appear to increase the response rate or overall survival with respect to TMZ alone or to chemotherapeutic regimens. Further and more complex associations of these two drugs could be investigated in specific subsets of patients, in particular to evaluate its real efficacy in preventing brain metastases.

Temozolomide for the Treatment of Metastatic Melanoma: A Systematic Review

“…Eleven of the trials were published as full reports [8,10,12,13,15,16,19,20,24,26,28], while 10 were available only in abstract form [9, 11, 14, 17, 18, 21-23, 25, 27]. Patient characteristics and trial descriptions for those trials are shown in Table 2.…”

“…In addition, phase I or II trials investigating singleagent temozolomide (n ϭ 9) [8 -16], temozolomide plus IFN-␣ (n ϭ 6) [17][18][19][20][21][22], and temozolomide plus thalidomide (n ϭ 6) [23][24][25][26][27][28] were reviewed. Eleven of the trials were published as full reports [8,10,12,13,15,16,19,20,24,26,28], while 10 were available only in abstract form [9, 11, 14, 17, 18, 21-23, 25, 27].…”

“…Six single-arm phase I or II trials were located investigating temozolomide plus IFN-␣ [17][18][19][20][21][22]. Four were available Table 2).…”

Intrinsic Anticancer Drug Resistance of Malignant Melanoma Cells Is Abrogated by IFN-β and Valproic Acid

“…Still, the response rate of the patients suffering from melanoma treated with DTIC or TMZ remains poor, with median survival durations between 5.3 and 6.7 months (3,4). Treatment combining TMZ with IFN-a can increase median survival to 11.8 months (5). There is, however, no clear rationale for concomitant treatment with IFN and TMZ except the finding that IFNs may cause immunosensitization of the tumor (6).…”

Potentiation of antiglioma effect with combined temozolomide and interferon-β

“…It has been reported that the combination of IFN with chemotherapy drugs increases the antitumor effects (24)(25)(26). Recently, combined therapy using TMZ and IFN-· has been shown to be quite tolerable in patients with metastatic melanoma (27) and renal cell carcinoma (28). In the present study, we investigated the effects of combined TMZ and IFN-ß in U-87 orthotopic xenograft brain tumor models and the possible mechanisms involved.…”