Biochemotherapy of metastatic malignant melanoma. Predictive value of tumour-infiltrating lymphocytes

Abstract

The therapeutic efficacy of biochemotherapy in metastatic malignant melanoma still carries a low remission rate, but with some durable responses. It would therefore be of considerable importance if patients with a high probability of responding could be identified using predictive tests. The response to interferon-alpha (IFN-α) correlates with the occurrence of CD4+ lymphocytes identified by fine-needle aspirates from melanoma metastases (Håkansson et al, 1996). The present investigation studies a possible correlation between tumour-infiltrating CD4+ lymphocytes in malignant melanoma metastases and the therapeutic effect of biochemotherapy. A total of 25 patients with systemic and 16 with regional metastatic melanoma were analysed before initiation of biochemotherapy (cis-platinum 30 mg/m2 d.1–3, DTIC 250 mg/m2 d.1–3 i.v. and IFN-α2b 10 million IU s.c. 3 days a week, q. 28d.). A monoclonal antibody, anti-CD4, was used to identify tumour-infiltrating lymphocytes in fine-needle aspirates before start of treatment. The presence of these lymphocytes was correlated to response, time to progression and overall survival. A statistically significant correlation (P = 0.01) was found between the occurrence of CD4+ lymphocytes and tumour regression during biochemotherapy in patients with systemic disease. Out of 14 patients with moderate to high numbers of infiltrating CD4+ lymphocytes, 12 achieved tumour regression. In contrast, among patients with low numbers of these cells in metastatic lesions, 8 out of 11 had progressive disease. We also found a significantly longer time to progression (P < 0.003) and overall survival (P < 0.01) among patients with moderate to high numbers of these cells compared to patients with low numbers of these cells before initiation of biochemotherapy. Furthermore, in patients with regional disease, we found a significantly longer time to progression (P = 0.01) and a trend toward a longer overall survival time (P = 0.09). Based on these results and as previously shown with IFN-α therapy alone, there seems to be a need for CD4+ lymphocytes infiltrating the tumours before the start of biochemotherapy to make the treatment successful. Determination of these cells in fine-needle aspirates seems to be a method to predict responders to biochemotherapy, thus increasing the cost–benefit of this treatment strategy considerably, both in terms of patient adverse reactions and health care costs. © 2001 Cancer Research Campaign http://www.bjcancer.com

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  • 16 November 2011

    This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication

References

  1. Arenberg DA, Kunkel SL, Burdick MD, Standiford TJ and Strieter RM (1995) Regulation of monocyte derived interleukin 1 receptor antagonist by cisplatinum. Cytokine 7: 89–96

  2. Balch CM, Murad TM, Soong S-J, Ingalls AL, Halpern NB and Maddox WA (1978) A multifactorial analysis of melanoma: Prognostic histopathological features comparing Clark’s and Breslow’s staging methods. Ann Surg 188: 732–742

  3. Clark WH, Elder DE, Guerry D, Braitman LE, Trock BJ, Schultz D, Synnestvedt M and Halpern AC (1989) Model predicting survival in stage I melanoma based on tumour progression. J Natl Cancer Inst 81: 1893–1904

  4. Clemente CG, Mihm MC, Bufalino R, Zurrida S, Collini P and Cascinelli N (1996) Prognostic value of tumour infiltrating-lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 77: 1303–1310

  5. Grob JJ, Dreno B, Salmoniere P, Delaunay M, Cupissol D, Guillot B, Souteyrand P, Sassolas B, Cesarini J-P, Lionnet S, Lok C, Chastang C and Bonerandi JJ (1998) Randomised trial of interferon α-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. Lancet 351: 1905–1910

  6. Halliday GM, Patel A, Hunt MJ, Tefany FJ and Barnetson RStC (1995) Spontaneous regression of human melanoma/nonmelanoma skin cancer: Association with infiltrating CD4+ T cells. World J Surg 19: 352–358

  7. Hansen MG and McCarten AB (1974) Tumour thickness and lymphocytic infiltration in malignant melanoma of the head and neck. Am J Surg 128: 557–561

  8. Hernberg M, Turunen JP, Muhonen T and Pyrhönen S (1997) Tumour-infiltrating lymphocytes in patients with metastatic melanoma receiving chemoimmunotherapy. J Immunother 20: 488–495

  9. Houghton AN, Legha S and Bajorin DF (1992) Chemotherapy for metastatic melanoma. Cutaneous Melanoma, J.B. Lippincott: Philadelphia 498–508

  10. Håkansson A, Gustafsson B, Krysander L and Håkansson L (1996) Tumour-infiltrating lymphocytes in metastatic malignant melanoma and response to interferon-alpha treatment. Br J Cancer 74: 670–676

  11. Håkansson A, Gustafsson B, Krysander L and Håkansson L (1998) Effect of interferon-α on tumour-infiltrating mononuclear cells and regressive changes in metastatic malignant melanoma. J Interferon Cytokine Res 18: 33–39

  12. Håkansson A, Gustafsson B, Krysander L, Hjelmqvist B, Rettrup B and Håkansson L (1999) On down-regulation of the immune response to metastatic malignant melanoma. Cancer Immunol Immunother 48: 253–262

  13. Kang S, Barnhill RL, Mihm MC and Sober AJ (1993) Histologic regression in malignant melanoma: an interobserver concordance study. J Cutan Pathol, 126–129

  14. Keilholz U, Conradt C, Legha SS, Khayat D, Scheibenbogen C, Thatcher N, Goey SH, Gore M, Dorval T, Hancock B, Punt CJA, Dummer R, Avril MF, Bröcker EB, Benhammouda A, Eggermont AMM and Pritsch M (1998) Results of interleukin-2-based treatment in advanced melanoma: A case record-based analysis of 631 patients. J Clin Oncol 16: 2921–2929

  15. Khayat D, Borel C, Tourani JM, Benhammouda A, Antonie E, Rixe O, Vuillemin E, Bazex PA, Thill L, Franks R, Auclerc G, Soubrane C, Banzet P and Weil M (1993) Sequential chemoimmunotherapy with cisplatin, interleukin-2, and interferon alfa-2a for metastatic malignant melanoma. J Clin Oncol 11: 2173–2180

  16. Kirkwood JM, Hunt Strawderman M, Ernstoff MS, Smith TJ, Borden EC and Blum RH (1996) Interferon alpha-2b adjuvant therapy of high-risk resected cutaneous melanoma: The Eastern Cooperative Oncology Group trial EST 1648. J Clin Oncol 14: 7–17

  17. Kirkwood JM, Ibrahim JG, Sondak VK, Richards J, Flaherty LE, Ernstoff MS, Smith TJ, Rao U, Steele M and Blum RH (2000) High-and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup Trial E1690/S9111/C9190. J Clin Oncol 18, (12): 2444–2458

  18. Larsen TE and Grude TH (1978) A retrospective histological study of 669 cases of primary cutaneous malignant melanoma in clinical stage I. Acta Pathol Microbiol Scand 86: 523–530

  19. Legha SS, Ring S, Papadopoulos N, Plager C, Chawala S and Benjamin R (1989) A prospective evaluation of a triple drug regimen containing cisplatin, vinblastine, and dacarbazine (CVD) for metastatic melanoma. Cancer 64: 2024–2029

  20. Legha SS (1997) Durable complete responses in metastatic melanoma treated with interleukin-2 in combination with interferon alfa and chemotherapy. Semin Oncol 24 (Suppl 4):S39–S43

  21. McClay EF, Mastrangelo MJ, Berd D and Bellet RE (1992) Effective combination chemo/hormonal therapy for malignant melanoma: Experience with three consecutive trials. Int J Cancer 50: 553–556

  22. McGovern VJ (1975) Spontaneous regression of melanoma. Pathology 7: 91–99

  23. Mihm MC, Clemente CG and Cascinelli N (1996) Tumour-infiltrating lymphocytes in lymph node melanoma metastases: A histopathologic prognostic indicator and an expression of local immune response. Lab Invest 74: 43–47

  24. Mizutani Y, Yoshida O and Bonavida B (1998) Sensitization of human bladder cancer cells to Fas-mediated cytotoxicity by cis-diamminedichloroplatinum. J Urol 160: 561–570

  25. Pehamberger H, Soyer P, Steiner A, Kofler R, Binder M, Mischer P, Pachinger W, Auböck J, Fritsch P, Kerl H and Wolff K (1998) Adjuvant interferon α-2a treatment in resected primary stage II cutaneous melanoma. J Clin Oncol 16: 1425–1429

  26. Proebstle TM, Fuchs T, Scheibenbogen C, Sterry W and Keilholz U (1998) Long-term outcome of treatment with dacarbazine, cisplatin, interferon-α and intravenous high dose interleukin-2 in poor risk melanoma patients. Melanoma Res 8: 557–563

  27. Richards JM, Gale D, Metha N and Lestingi T (1999) Combination chemotherapy with interleukin-2 and interferon alfa for the treatment of metastatic melanoma. J Clin Oncol 17: 651–657

  28. Ronan SG, Eng AM, Briele HA, Shioura NN and Das Gupta TK (1987) Thin malignant melanomas with regression and metastases. Arch Dermatol 123: 1326–1330

  29. Rosenberg SA, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM, Topalian SL, Seipp CA, Einhorn JH, White DE and Steinberg SM (1999) Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon-alpha 2b. J Clin Oncol 17: 968–975

  30. Si Z, Hersey P and Coates A (1996) Clinical responses and lymphoid infiltrates in metastatic melanoma following treatment with intralesional GM-CSF. Melanoma Res 6: 247–255

  31. Sondergaard K and Hou-Jensen K (1985) Partial regression in thin primary cutaneous malignant melanomas clinical stage I. Virchows Arch A Pathol Anat Histopathol 408: 241–247

  32. Tefany FJ, Barnetson RStC, Halliday GM, McCarthy SW and McCarthy WH (1991) Immunocytochemical analysis of the cellular infiltrate in primary regressing and non-regressing malignant melanoma. J Invest Dermatol 97: 197–202

  33. Thomas WD and Hersey P (1998) CD4 T cells kill melanoma cells by mechanisms that are independent of Fas (CD95). Int J Cancer 75: 384–389

  34. Zehntner S, Townsend W, Parkes J, Schmidt C, Down M, Bell J, Mulligan R, O’Rourke M, Ellem K and Thomas R (1999) Tumour metastasis biopsy as a surrogate marker of response to melanoma immunotherapy. Pathology 31: 116–122

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Håkansson, A., Gustafsson, B., Krysander, L. et al. Biochemotherapy of metastatic malignant melanoma. Predictive value of tumour-infiltrating lymphocytes. Br J Cancer 85, 1871–1877 (2001). https://doi.org/10.1054/bjoc.2001.2169

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Keywords

  • malignant melanoma
  • biochemotherapy
  • prediction of response
  • tumour-infiltrating lymphocytes (TILs)

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