Advantages of Concurrent Biochemotherapy Modified by Decrescendo Interleukin-2, Granulocyte Colony-Stimulating Factor, and Tamoxifen for Patients With Metastatic Melanoma

O’Day, Steven; Gammon, Guy; Boasberg, Peter D.; Martin, Mike; Kristedja, Tim S.; Guo, Matthew; Stern, Stacey L.; Edwards, Susan; Fournier, Patricia; Weisberg, Monica; Cannon, Maureen; Fawzy, Nancy W.; Johnson, Timothy D.; Essner, Richard; Foshag, Leland J.; Morton, Donald L.

doi:10.1200/jco.1999.17.9.2752

Cited by 86 publications

(70 citation statements)

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“…In this study, brain metastasis did not develop as the first or concurrent site of progressive disease in patients with either responsive disease (n ¼ 23) or with stable disease (n ¼ 13). Two prior published reports have indicated brain metastasis as a first site of progressive disease in four out of nine patients with a complete remission (Legha et al, 1998;O'Day et al, 1999). Moreover, in a retrospective case-controlled study of responders to DTIC or TMZ, it was found that responders to TMZ developed significantly less CNS relapses than responders to DTIC (Paul et al, 2002).…”

Section: Discussionmentioning

confidence: 83%

“…In previous studies of chemo-immunotherapy in metastatic melanoma, no response was observed in brain metastases despite objective tumour regression at extracranial sites (Legha et al, 1998;O'Day et al, 1999).…”

Section: Discussionmentioning

confidence: 90%

“…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%

“…Its incidence is up to 75% in patients who die from metastatic melanoma (Amer et al, 1978). Brain metastases occur as the first site of progression in a significant proportion of patients with a CR, and in a large majority of patients with a PR following systemic treatment with DTIC or cisplatin as neither of these agents cross the blood -brain barrier (Legha et al, 1998;O'Day et al, 1999).…”

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confidence: 99%

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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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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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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 90%

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confidence: 99%

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confidence: 99%

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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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“…There are a variety of treatments available for patients with poor prognosis such as chemotherapy, active-specific immunotherapy (vaccine), cytokine therapy, and biochemotherapy that have shown some promising clinical responses. [3][4][5][6] In addition, many new treatments are being developed that need to be validated in randomized clinical trials. To date, although these therapeutic interventions may prolong survival, there is basically no cure rate for advanced disease.…”

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confidence: 99%

Induction of melanoma-associated antigen systemic immunity upon intratumoral delivery of interferon-γ retroviral vector in melanoma patients

et al. 2000

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High-dose tamoxifen added to concurrent biochemotherapy with decrescendo interleukin-2 in patients with metastatic melanoma

O’Day

Boasberg

Kristedja

et al. 2001

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BACKGROUND In vitro cell culture data and preclinical models suggest that tamoxifen modulates tumor cell sensitivity to a wide range of therapeutic agents. In the current study, the authors examined whether high‐dose tamoxifen (HDT) improved the overall and complete response in patients with metastatic melanoma who were treated with concurrent biochemotherapy. METHODS Forty‐nine patients were treated with a biochemotherapy regimen of dacarbazine, vinblastine, cisplatin, decrescendo interleukin‐2, interferon‐α‐2b, and tamoxifen. The study had a 2‐step design, beginning with a tamoxifen dose escalation from 40 mg to 320 mg (17 subjects) to evaluate safety and tolerability, followed by Phase II accrual of 32 patients to HDT (320 mg) to assess clinical efficacy. Efficacy was compared with a similar modified biochemotherapy regimen with low‐dose tamoxifen (LDT). Pharmacokinetic studies were performed to determine in vivo tamoxifen levels. RESULTS Tamoxifen dose escalation was completed without any reported dose‐limiting toxicity. The overall response rate in the HDT group was 50% (95% confidence interval, 33.2%–66.8%), with a complete response rate of 6% and a median survival of 9.5 months. The overall response rate was not improved and the complete response and survival appeared inferior compared with that of patients recently treated with concurrent biochemotherapy and LDT. Serum tamoxifen levels were found to correlate with the dose administered, with a mean of 0.9 μM at the 40‐mg dose to 4.6 μM at the 320‐mg dose. Ultrafiltered protein‐free sera demonstrated low (< 0.01 μM) concentrations of tamoxifen. CONCLUSIONS The addition of HDT to a regimen of concurrent biochemotherapy did not appear to improve response rates or overall survival, despite reaching the targeted plasma concentration. Unknown drug interactions or high protein binding of tamoxifen may account for the lack of clinical effectiveness. Cancer 2001;92:609–19. © 2001 American Cancer Society.

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Advantages of Concurrent Biochemotherapy Modified by Decrescendo Interleukin-2, Granulocyte Colony-Stimulating Factor, and Tamoxifen for Patients With Metastatic Melanoma

Abstract: The data from this study indicate that the modified concurrent biochemotherapy regimen reduces the toxicity of concurrent biochemotherapy with no apparent decrease in response rate in patients with poor prognosis metastatic melanoma.

Cited by 86 publications

References 22 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

Induction of melanoma-associated antigen systemic immunity upon intratumoral delivery of interferon-γ retroviral vector in melanoma patients

High-dose tamoxifen added to concurrent biochemotherapy with decrescendo interleukin-2 in patients with metastatic melanoma

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