Chemotherapy for malignant melanoma: combinations and high doses produce more responses without survival benefit

Lakhani, SR; Selby, P.; Bliss, Judith; Perren, Timothy J.; Gore, M.; McElwain, T. J.

doi:10.1038/bjc.1990.65

Cited by 59 publications

(18 citation statements)

References 12 publications

(11 reference statements)

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“…The best-known single agent dacarbazine (DTIC) achieves a 15 -20% response rate with a median survival of 6 -7 months. The addition of other cytotoxic agents does not improve survival (Lakhani et al, 1990;Chapman et al, 1999). Therefore, interest has shifted to immunotherapy as malignant melanoma is considered to be an immunogenic tumour.…”

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confidence: 99%

Temozolomide followed by combined immunotherapy with GM-CSF, low-dose IL2 and IFNα in patients with metastatic melanoma

et al. 2003

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The purpose of this study is to determine the toxicity and efficacy of temozolomide (TMZ) p.o. followed by subcutaneous (s.c.) lowdose interleukin-2 (IL2), granulocyte -monocyte colony stimulating factor (GM-CSF) and interferon-a 2b (IFNa) in patients with metastatic melanoma. A total of 74 evaluable patients received, in four separate cohorts, escalating doses of TMZ (150 -250 mg m À2 ) for 5 days followed by s.c. IL2 (4 MIU m À2 ), GM-CSF (2.5 mg kg À1 ) and IFNa (5 MIU flat) for 12 days. A second identical treatment was scheduled on day 22 and cycles were repeated in stable or responding patients following evaluation. Data were analysed after a median follow-up of 20 months (12 -30 months). The overall objective response rate was 31% (23 out of 74; confidence limits 20.8 -42.9%) with 5% CR. Responses occurred in all disease sites including the central nervous system (CNS). Of the 36 patients with responding or stable disease, none developed CNS metastasis as the first or concurrent site of progressive disease. Median survival was 252 days (8.3 months), 1 year survival 41%. Thrombocytopenia was the primary toxicity of TMZ and was dose-and patientdependent. Lymphocytopenia (grade 3 -4 CTC) occurred in 48.5% (34 out of 70) fully monitored patients following TMZ and was present after immunotherapy in two patients. The main toxicity of combined immunotherapy was the flu-like syndrome (grade 3) and transient liver function disturbances (grade 2 in 20, grade 3 in 15 patients). TMZ p.o. followed by s.c. combined immunotherapy demonstrates efficacy in patients with stage IV melanoma and is associated with toxicity that is manageable on an outpatient basis.

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confidence: 99%

Temozolomide followed by combined immunotherapy with GM-CSF, low-dose IL2 and IFNα in patients with metastatic melanoma

et al. 2003

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“…Currently, the results of chemotherapy in the treatment of disseminated malignant melanoma continue to be mostly disappointing (Ahman et al, 1989). High dose chemotherapy with autologous bone marrow rescue has produced impressive response rates up to 81 % with a 25% complete response rate, but the median survival value remained as 6 months with no survival benefit (Thatcher et al, 1989;Lakhani et al, 1990).…”

Section: Resultsmentioning

confidence: 99%

“…Consequently, when the BOLD regimen has been tested among patients with a larger proportion of visceral or osseous metastases, the response rate has dropped from four to 20% (The Prudente Foundation Melanoma Study Group, 1989;York & Foltz, 1988). The median survival time with BOLD has varied from 4 to 7 months (Seigler et al, 1980;The Prudente Foundation Melanoma Study Group, 1989, Lakhani et al, 1990, which is not superior to the median surival time of 7 months obtained Months Months…”

Section: Resultsmentioning

confidence: 99%

Association between chemotherapy response and rate of disease progression in disseminated melanoma

Joensuu

1991

Br J Cancer

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Summary Fifty-five evaluable patients with disseminated malignant melanoma were treated with the combination of dacarbazine (DTIC) 400 mg i.v. on days 1 to 3 and lomustine (CCNU) 50 to 80 mg m-2 orally on day 1 with intervals of 6 weeks as the first line chemotherapy. Three (5%) patients had complete and 6 (11%) partial response, and 7 (13%) patients had stable disease at least for 3 months. The patients with an objective response (n = 9) survived longer than the rest of the patients if the length of survival was calculated from the start of chemotherapy (P = 0.0006). However, the responding patients also had longer time interval from the diagnosis to the detection of distant metastases (P = 0.05), and survival time from disease progression following DTIC and CCNU therapy (P = 0.005). These findings suggest that patients with an objective response to DTIC-CCNU therapy have melanoma with a slow progression rate, and prolonged survival in such patients may in part result from the less aggressive biological nature of their tumours.Combination chemotherapy has in nonrandomised series been reported to increase survival of the responding patients with metastatic melanoma (Seigler et al., 1980), and based on such results combination chemotherapy has been recommended instead of single-agent therapy despite its greater toxicity in this uniformly fatal disease (Young et al., 1985). Subcutaneous, lymph node, and pulmonary melanoma metastases respond to chemotherapy more often than visceral or osseous ones (Joensuu et al., 1986;Mulder et al., 1989;Thatcher et al., 1989). However, disseminated melanoma with subcutaneous, lymph node, or pulmonary metastases may be associated with less aggressive biological behaviour, and, therefore, the longer survival of the responding patients might not merely result from a favourable response to chemotherapy. However, there are currently little data available in the literature indicating that responding melanoma metastases have a slower progression rate than those that do not respond to chemotherapy.In the present retrospective series of 55 patients treated with the combination of dacarbazine (DTIC) and lomustine (CCNU) the progression rate of melanoma was assessed by calculating the time from the diagnosis to the detection of distant metastases, and the length of survival after disease progression following DTIC-CCNU therapy to death, and these estimates of rate of disease progression were correlated with response to chemotherapy. Materials and methodsSixty patients with histologically diagnosed malignant melanoma with distant metastases were treated with DTIC 400 mg i.v. on days 1 to 3 and with CCNU 50-80 mg m-2 p.o. on day 1 with 6 weeks' intervals in the Department of Radiotherapy and Oncology, Turku University Central Hospital, in 1979 to 1987. Dosage was reduced at some stage of treatment because of side-effects only in nine cases (in three responders and in six nonresponders). Fifty-five patients were evaluable and five nonevaluable for response (two patients refused to continue the...

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“…Hence, new strategies are being tried to improve the therapeutic index of antitumor drugs for management of melanoma. Several clinical trials using combination chemotherapy [24][25][26][27][28] particularly the BOLD and related regimens (bleomycin, vincristine, CCNU, and dacarbazine) have been reported [29][30][31][32]. In recent years there has been a renewal of interest in the use of hyperthermia as a treatment modality for melanoma therapy, and research has focused on treatment with the combination of hyperthermia and drugs [33,34].…”

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confidence: 99%

Enhanced Antitumor Effect of Radiation in Combination with Heat-Sensitive Liposome-Encapsulated Drug and Hyperthermia on Murine Tumors.

Tamiz

Ralhan

1995

J. Clin. Biochem. Nutr.

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SummaryAdjuvant hyperthermia enhances the response of melanoma to irradiation or antineoplastic drugs. Radiation in combination with a targeted drug delivery system combining a thermosensitive Liposome-encapsulated antitumor drug with hyperthermia may thus result in enhancement of therapeutic efficacy for more effective management of melanoma. The present study was based on this rationale. The therapeutic effect of radiation alone, or in combination with thermosensitive liposome-encapsulated melphalan and hyperthermia, was determined on B16F10 murine melanoma transplanted into C57B1/6 mice. This multimodality regimen resulted in marked enhancement of the antitumor efficacy in treated animals, as determined by significant tumor growth regression (p < 0.001) and prolongation of survival, compared with the level of enhancement seen in animals receiving single-modality treatment. The results suggest that radiothermochemotherapy using radiation in combination with heat-mediated selective delivery of liposomal melphalan to tumor tissue would result in more effective management of melanoma.

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Chemotherapy for malignant melanoma: combinations and high doses produce more responses without survival benefit

Cited by 59 publications

References 12 publications

Temozolomide followed by combined immunotherapy with GM-CSF, low-dose IL2 and IFNα in patients with metastatic melanoma

Temozolomide followed by combined immunotherapy with GM-CSF, low-dose IL2 and IFNα in patients with metastatic melanoma

Association between chemotherapy response and rate of disease progression in disseminated melanoma

Enhanced Antitumor Effect of Radiation in Combination with Heat-Sensitive Liposome-Encapsulated Drug and Hyperthermia on Murine Tumors.

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