Combination of Chemotherapy With Interleukin-2 and Interferon Alfa for the Treatment of Metastatic Melanoma

Richards, Jon M.; Gale, Danielle; Mehta, Natasha; Lestingi, Timothy M.

doi:10.1200/jco.1999.17.2.651

Cited by 89 publications

(35 citation statements)

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“…Recently, a combination of chemo-and immunotherapy has been investigated in several phase II studies (Khayat et al, 1993;Legha et al, 1998;O'Day et al, 1999;Richards et al, 1999) with responses of 40 -60%. However, in a recent phase III trial, survival did not improve with the addition of high-dose IL2 and IFNa to chemotherapy compared to chemotherapy alone (Rosenberg et al, 1999).…”

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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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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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“…DTIC) (Dummer et al, 1995) or to IFNα . In the last years, several phase II-trials have focused on biochemotherapy consisting of a combination of several cytotoxic substances with IFNα and IL-2 Proebstle et al, 1998;Richards et al, 1999;Sertoli et al, 1999). Legha and coworkers reported on encouraging tumour responses (21% CR, 43% PR) achieved with biochemotherapy in advanced metastatic melanoma patients .…”

Section: Discussionmentioning

confidence: 99%

“…Complex combinations of cytotoxic drugs with biological response modifiers, such as interferon α (IFNα) and interleukin 2 (IL-2), demonstrated encouraging results in achieving long-lasting tumour responses Richards et al, 1999). A relatively large number (about 10%) of patients with lasting complete remissions will survive for many years.…”

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confidence: 99%

“…A relatively large number (about 10%) of patients with lasting complete remissions will survive for many years. However, most results were drawn from single-institutional phase II-trials with patients who were probably selected Richards et al, 1999). Recently, a prospective-randomized trial compared treatment with cisplatin, DTIC and tamoxifen only to a combination of these substances with IL-2 and IFNα .…”

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Dacarbazine and interferon α with or without interleukin 2 in metastatic melanoma: a randomized phase III multicentre trial of the Dermatologic Cooperative Oncology Group (DeCOG)

Hauschild¹,

Garbe

Stolz³

et al. 2001

Br J Cancer

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In several phase II-trials encouraging tumour responses rates in advanced metastatic melanoma (stage IV; AJCC-classification) have been reported for the application of biochemotherapy containing interleukin 2. This study was designed to compare the efficacy of therapy with dacarbazine (DTIC) and interferon α (IFN-α) only to that of therapy with DTIC and IFN-α with the addition of interleukin 2 (IL-2) in terms of the overall survival time and rate of objective remissions and to provide an elaborated toxicity profile for both types of therapy. 290 patients were randomized to receive either DTIC (850 mg/m 2 every 28 days) plus IFN-α2a/b (3 MIU/m 2 , twice on day 1, once daily from days 2 to 5; 5 MIU/m 2 3 times a week from week 2 to 4) with or without IL-2 (4.5 MIU/m 2 for 3 hours i.v. on day 3; 9.0 MIU/m 2 i.v. day 3/4; 4.5 MIU/m 2 s.c. days 4 to 7). The treatment plan required at least 2 treatment cycles (8 weeks of therapy) for every patient. Of 290 randomized patients 281 were eligible for an intention-to-treat analysis. There was no difference in terms of survival time from treatment onset between the two arms (median 11.0 months each). In 273 patients treated according to protocol tumour response was assessable. The response rates did not differ between both arms ( P = 0.87) with 18.0% objective responses (9.7% PR; 8.3% CR) for DTIC plus IFN-α as compared to 16.1% (8.8% PR; 7.3% CR) for DTIC, IFN-α and IL-2. Treatment cessation due to adverse reactions was significantly more common in patients receiving IL-2 (13.9%) than in patients receiving DTIC/IFN-α only (5.6%). In conclusion, there was neither a difference in survival time nor in tumour response rates when IL-2, applied according to the combined intravenous and subcutaneous schedule used for this study, was added to DTIC and IFN-α. However, toxicity was increased in melanoma patients treated with IL-2. Further phase III trials with continuous infusion and higher dosages must be performed before any final conclusions can be drawn on the potential usefulness of IL-2 in biochemotherapy of advanced melanoma. © 2001 Cancer Research Campaign http://www.bjcancer.com

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“…For theoretical reasons of synergy and in an attempt to improve the efficacy of existing regimens, these agents have been combined with cytotoxic agents. It is unclear whether such combinations offer a therapeutic advance over simpler and less toxic treatments [18][19][20][21][22][23][24][25][26][27][28][29] . A multivariate análisis in patients with disseminated melanoma comparing dacarbacine monochemotherapy versus dacarbacine plus immunotherapy showed that the combination of DTIC and interferon-alpha appears more active than standard singleagent DTIC in metastatic melanoma 30 .…”

Section: Discusionmentioning

confidence: 99%

Prognostic value of quantitative immune alterations in melanoma patients

Andrés¹,

Mayordomo²,

Isla³

et al. 2006

Oncología (Barc.)

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Summary• Purpose: The immune response is altered in patients with neoplasms. Immunosuppression has important consequences in patients with melanoma. The aim of this study was to assess quantitative immune alterations in melanoma patients..• Material and methods: We obtained a peripheral blood sample in EDTA from 86 melanoma patients (63 of them disease-free and 23 with distant disease). Total leukocytes and lymphocytes, B lymphocytes (CD19), types CD3, CD4, CD8 lymphocytes, and NK lymphocytes (CD56) were counted by determining the surface markers by flow cytometry, using a Coulter Epics Elite (Coulter Corp.). IgA, IgG, IgE and IgM were assayed by nephelometric methods employing a Hyland PDQ laser nephelometer.

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Combination of Chemotherapy With Interleukin-2 and Interferon Alfa for the Treatment of Metastatic Melanoma

Cited by 89 publications

References 16 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

Dacarbazine and interferon α with or without interleukin 2 in metastatic melanoma: a randomized phase III multicentre trial of the Dermatologic Cooperative Oncology Group (DeCOG)

Prognostic value of quantitative immune alterations in melanoma patients

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