PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of brjcancerBJC HomepageBJC Advance online publicationBJC Current IssueSubmitting an article to BJCWeb feeds
 
Br J Cancer. 1998 April; 77(8): 1280–1286.
PMCID: PMC2150174

Randomized phase II trial of BCDT [carmustine (BCNU), cisplatin, dacarbazine (DTIC) and tamoxifen] with or without interferon alpha (IFN-alpha) and interleukin (IL-2) in patients with metastatic melanoma.

Abstract

The purpose of this study was to evaluate in a randomized phase II trial the efficacy and toxicity of combination biochemotherapy compared with chemotherapy alone in patients with metastatic melanoma. Sixty-five patients with metastatic melanoma (ECOG performance status 0 or 1) were randomized to receive intravenous BCNU 100 mg m(-2) (day 1, alternate courses), cisplatin 25 mg m(-2) (days 1-3), DTIC 220 mg m(-2) (days 1-3) and oral tamoxifen 40 mg (BCDT regimen) with (n = 35) or without (n = 30) subcutaneous interleukin 2 (IL-2) 18 x 10(6) iu t.d.s. (day - 2), 9 x 10(6) iu b.d. (day - 1 and 0) and interferon 2 alpha (IFN-alpha) 9 MU (days 1-3). Evidence for immune activation was determined by flow cytometric analysis of peripheral blood lymphocytes. Treatment was repeated every 4 weeks up to six courses depending on response. The overall response rate of BCDT with IL-2/IFN-alpha was 23% [95% confidence interval (CI) 10-40%] with one complete response (CR) and seven partial responses (PR), and for BCDT alone 27% (95% CI 12-46%) with eight PRs; the median durations of response were 2.8 months and 2.5 months respectively. Sites of response were similar in both groups. There was no difference between the two groups in progression-free survival or overall survival (median survival 5 months for BCDT with IL-2/IFNalpha and 5.5 months for BCDT alone). Although 3 days of subcutaneous IL-2 resulted in significant lymphopenia, evidence of immune activation was indicated by a significant rise in the percentage of CD56- (NK cells) and CD3/HLA-DR-positive (activated T cells) subsets, without any change in the percentage of CD4 or CD4 T-cell subsets. Toxicity assessment revealed a significantly higher incidence of severe thrombocytopenia in patients treated with combination chemotherapy than with chemotherapy alone (37% vs 13%, P = 0.03) and a higher incidence of grade 3/4 flu-like symptoms (20% vs 10%) and fatigue (26% vs 13%). The addition of subcutaneous IL-2 and IFNalpha to BCDT chemotherapy in a randomized phase II trial resulted in immune activation but did not improve response rates in patients with metastatic melanoma, and indeed may increase some treatment-related toxicity.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.2M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Atzpodien J, Körfer A, Franks CR, Poliwoda H, Kirchner H. Home therapy with recombinant interleukin-2 and interferon-alpha 2b in advanced human malignancies. Lancet. 1990 Jun 23;335(8704):1509–1512. [PubMed]
  • Atzpodien J, Kirchner H, Körfer A, Hadam M, Schomburg A, Menzel T, Deckert M, Franzke A, Volkenandt M, Dallmann I, et al. Expansion of peripheral blood natural killer cells correlates with clinical outcome in cancer patients receiving recombinant subcutaneous interleukin-2 and interferon-alpha-2. Tumour Biol. 1993;14(6):354–359. [PubMed]
  • Atzpodien J, Lopez Hänninen E, Kirchner H, Bodenstein H, Pfreundschuh M, Rebmann U, Metzner B, Illiger HJ, Jakse G, Niesel T, et al. Multiinstitutional home-therapy trial of recombinant human interleukin-2 and interferon alfa-2 in progressive metastatic renal cell carcinoma. J Clin Oncol. 1995 Feb;13(2):497–501. [PubMed]
  • Bajetta E, Di Leo A, Zampino MG, Sertoli MR, Comella G, Barduagni M, Giannotti B, Queirolo P, Tribbia G, Bernengo MG, et al. Multicenter randomized trial of dacarbazine alone or in combination with two different doses and schedules of interferon alfa-2a in the treatment of advanced melanoma. J Clin Oncol. 1994 Apr;12(4):806–811. [PubMed]
  • Buter J, Sleijfer DT, van der Graaf WT, de Vries EG, Willemse PH, Mulder NH. A progress report on the outpatient treatment of patients with advanced renal cell carcinoma using subcutaneous recombinant interleukin-2. Semin Oncol. 1993 Dec;20(6 Suppl 9):16–21. [PubMed]
  • Castello G, Comella P, Manzo T, Napolitano M, Parziale AP, Galati MG, Daponte A, Casaretti R, Celentano E, Comella G. Immunological and clinical effects of intramuscular rIFN alpha-2a and low dose subcutaneous rIL-2 in patients with advanced malignant melanoma. Melanoma Res. 1993 Feb;3(1):43–49. [PubMed]
  • Dadian G, Riches PG, Henderson DC, MacLennan K, Lorentzos A, Moore J, Hobbs JR, Gore ME. Immune changes in peripheral blood resulting from locally directed interleukin-2 therapy in squamous cell carcinoma of the head and neck. Eur J Cancer B Oral Oncol. 1993 Jan;29B(1):29–34. [PubMed]
  • Del Prete SA, Maurer LH, O'Donnell J, Forcier RJ, LeMarbre P. Combination chemotherapy with cisplatin, carmustine, dacarbazine, and tamoxifen in metastatic melanoma. Cancer Treat Rep. 1984 Nov;68(11):1403–1405. [PubMed]
  • Demchak PA, Mier JW, Robert NJ, O'Brien K, Gould JA, Atkins MB. Interleukin-2 and high-dose cisplatin in patients with metastatic melanoma: a pilot study. J Clin Oncol. 1991 Oct;9(10):1821–1830. [PubMed]
  • Dillman RO, Oldham RK, Barth NM, Birch R, Arnold J, West WH. Recombinant interleukin-2 and adoptive immunotherapy alternated with dacarbazine therapy in melanoma: a National Biotherapy Study Group trial. J Natl Cancer Inst. 1990 Aug 15;82(16):1345–1349. [PubMed]
  • Falkson CI, Falkson G, Falkson HC. Improved results with the addition of interferon alfa-2b to dacarbazine in the treatment of patients with metastatic malignant melanoma. J Clin Oncol. 1991 Aug;9(8):1403–1408. [PubMed]
  • Flaherty LE, Redman BG, Chabot GG, Martino S, Gualdoni SM, Heilbrun LK, Valdivieso M, Bradley EC. A phase I-II study of dacarbazine in combination with outpatient interleukin-2 in metastatic malignant melanoma. Cancer. 1990 Jun 1;65(11):2471–2477. [PubMed]
  • Flaherty LE, Robinson W, Redman BG, Gonzalez R, Martino S, Kraut M, Valdivieso M, Rudolph AR. A phase II study of dacarbazine and cisplatin in combination with outpatient administered interleukin-2 in metastatic malignant melanoma. Cancer. 1993 Jun 1;71(11):3520–3525. [PubMed]
  • Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996 Jan;14(1):7–17. [PubMed]
  • Lakhani S, Selby P, Bliss JM, Perren TJ, Gore ME, McElwain TJ. Chemotherapy for malignant melanoma: combinations and high doses produce more responses without survival benefit. Br J Cancer. 1990 Feb;61(2):330–334. [PMC free article] [PubMed]
  • Legha SS, Buzaid AC. Role of recombinant interleukin-2 in combination with interferon-alfa and chemotherapy in the treatment of advanced melanoma. Semin Oncol. 1993 Dec;20(6 Suppl 9):27–32. [PubMed]
  • Legha SS, Ring S, Bedikian A, Plager C, Eton O, Buzaid AC, Papadopoulos N. Treatment of metastatic melanoma with combined chemotherapy containing cisplatin, vinblastine and dacarbazine (CVD) and biotherapy using interleukin-2 and interferon-alpha. Ann Oncol. 1996 Oct;7(8):827–835. [PubMed]
  • Richards JM, Mehta N, Ramming K, Skosey P. Sequential chemoimmunotherapy in the treatment of metastatic melanoma. J Clin Oncol. 1992 Aug;10(8):1338–1343. [PubMed]
  • Rosenberg SA, Lotze MT, Yang JC, Linehan WM, Seipp C, Calabro S, Karp SE, Sherry RM, Steinberg S, White DE. Combination therapy with interleukin-2 and alpha-interferon for the treatment of patients with advanced cancer. J Clin Oncol. 1989 Dec;7(12):1863–1874. [PubMed]
  • Rusthoven JJ, Quirt IC, Iscoe NA, McCulloch PB, James KW, Lohmann RC, Jensen J, Burdette-Radoux S, Bodurtha AJ, Silver HK, et al. Randomized, double-blind, placebo-controlled trial comparing the response rates of carmustine, dacarbazine, and cisplatin with and without tamoxifen in patients with metastatic melanoma. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1996 Jul;14(7):2083–2090. [PubMed]
  • Sparano JA, Fisher RI, Sunderland M, Margolin K, Ernest ML, Sznol M, Atkins MB, Dutcher JP, Micetich KC, Weiss GR, et al. Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma. J Clin Oncol. 1993 Oct;11(10):1969–1977. [PubMed]
  • Stoter G, Aamdal S, Rodenhuis S, Cleton FJ, Iacobelli S, Franks CR, Oskam R, Shiloni E. Sequential administration of recombinant human interleukin-2 and dacarbazine in metastatic melanoma: a multicenter phase II study. J Clin Oncol. 1991 Sep;9(9):1687–1691. [PubMed]
  • Thomson DB, Adena M, McLeod GR, Hersey P, Gill PG, Coates AS, Olver IN, Kefford RF, Lowenthal RM, Beadle GF, et al. Interferon-alpha 2a does not improve response or survival when combined with dacarbazine in metastatic malignant melanoma: results of a multi-institutional Australian randomized trial. Melanoma Res. 1993 Apr;3(2):133–138. [PubMed]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK