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World Journal of Surgery

, Volume 16, Issue 2, pp 251–260 | Cite as

Active immunotherapy with viral lysates of micrometastases following surgical removal of high risk melanoma

  • Peter Hersey
World Progress In Surgery

Abstract

Patients who develop lymph node metastases from melanoma are known to be at risk of developing further recurrences from melanoma following surgical removal of lymph node metastases. The purpose of the present study was to examine whether immunization over a 2 year period with a vaccine made from vaccinia viral lysates of an allogeneic melanoma cell (VMCL), following surgical removal of lymph node metastases, would help prevent the development of distant metastases and improve survival from the disease. Eighty patients treated with VMCL alone and followed for a minimum of 5.5 years had improved survival compared to a historical control group of 151 patients and a concurrent non-randomized group of 55 patients. Similarly, the survival of 102 patients treated with VMCL + low dose cyclophosphamide for a minimum of 3.5 years was superior to that of the historical control group but not to that of the VMCL alone treated group. Improvement in survival was still evident when this was measured from the date of removal of the primary tumor. Analysis of subsets of patients showed that VMCL treatment appeared to benefit patients irrespective of the number of lymph nodes involved and whether surgery was carried out near to (synchronous metastases) or some time after removal of the primary delayed metastases). Analysis of the effect of treatment on duration to development of distant metastases suggested that there was a lower proportion of metastases during treatment with VMCL compared to the historical control groups. Treatment with VMCL also appeared to be associated with a lower incidence of cutaneous metastases but a higher proportion of visceral (including liver) metastases. Treatment was not associated with prolongation of survival after development of distant metastases. The results from this prolonged follow-up provide further support for an apparent survival benefit from immunotherapy with VMCL and suggest that the duration to and site of distant metastases is altered by this treatment. A randomized control (Phase III) study based on these results is in progress.

Keywords

Melanoma Vaccinia Historical Control Group Cutaneous Metastasis Risk Melanoma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Résumé

La survenue de métastases ganglionnaires d'un mélanome est un facteur de risque de récidive aprés l'ablation de métastases lymphatiques. Le but de cette étude était de savoir si l'immunisation par un vaccin pendant 2 ans, élaboré à partir des cellules de mélanome allogénéiques lysées (VMCL), pouvait prévenir le développement de métastases à distance et améliorer la survie de ces patients. La survie de 80 patients traités avec la VMCL seule et suivls pendant un minimum de 5 ans était meilleure que celle d'une série historique de 151 patients ainsi que celle d'un groupe de 55 patients non randomisés. De même, la survie de 102 patients, traités avec VMCL et cyclophosphamide à faible dose pour une période d'au moins 3.5 ans, était supérieure à celle d'un groupe contrôle historique mais pas à celle du groupe traité par VMCL seul. L'amélioration de la survie était toujours évidente même lorsque l'on mesurait la survie après l'éxérèse de la tumeur primitive. L'analyse d'un sous groupe de patients a démontré que le traitement par VMCL était bénéfique quel que soit le nombre de ganglions lymphatiques envahis, que le curage ganglionnaire ait été réalisé en même temps (métastases syndromes) ou après l'éxérèse (métastases retardées) de la tumeur primitive. L'analyse des effets du traitement sur le délai d'apparition de métastases suggère que la survenue de inétastases était moindre lorsque l'on traitait avec VMCL par rapport au groupe de contrôle historique. Le traitement par VMCL s'accompagnait d'une réduction de l'incidence des métastases cutanées mais d'un plus grand nombre de métastases (hépatiques) viscérales. La survie était inchangée par le traitement lorsque les métastases à distance existaient déjà. Les résultats à distance semblent en faveur d'un effet bénéfique de l'immunothérapie par VMCL et suggère que le délai avant l'apparition et le site de métastases sont modifiés par ce traitement. Une étude randomisée (phase III) basée sur ces résultats est en voie d'élaboration.

Resumen

Se sabe que los pacientes que desarrollan metástasis ganglionares de melanoma se encuentran en alto riesgo de desarrollar metástasis adicionales después de la resección quirúrgica de las metástasis ganglionares. El propósito del presente estudio fue el de examinar si la inmunización con una vacuna hecha de lisados virales de vaccinia de unal célula alogénica de melanoma (LVCM) a lo largo de un perído de 2 años después de la resección quirúrgica de metástasis ganglionares sería de ayuda en la prevención de metástasis distantes y majoraría la supervivencia. Ochenta pacientes tratados con LVCM solamente y seguidos por un mínimo de 5.5. años exhibieron mejor supervivencia en comparación con un grupo de control histórico de 151 pacíentes y un grupo concurrente no randomizado de 55 pacientes. En forma similar, la superviviencia de 102 pacientes tratados con LVCM + dosis baja de ciclosfosfamida por un período mínimo de 3.5 años fue superior a del grupo de control histórico pero no a la del grupo tratado con LVCM solamente. El incremento de la sobrevida apareció todavía evidente cuando se midió a partir de la fecha la remoción del tumor primario. El análisis de los subgrupos de pacientes mostró que el tratamiento con VCML pareció beneficiar los pacientes sin relación con el número de ganglios linfáticos afectados ni con la cirugía hecha cerca de la fecha de la resección del tumor primario (metástasis sincrónicas) o algún tiempo después (metástasis tardías). El análisis del efecto del tratamiento sobre la duración del intervalo hasta el desarrollo de metástasis distantes sugiere que hubo una más baja proporción de metástasis en el curso del tratamiento con LVCM en comparación con los grupos históricos de control. El tratamiento con LVCM también pareció estar asociado con una menor incidencia de metástasis cutáneas, pero con una mayor proporción de metástasis viscerales, incluyendo el hígado. El tratamiento no apareció asociado con una prolongación de la sobrevida después del desarrollo de metástasis distantes. Los resultados de este prolongado seguimiento provee apoyo adicional a la existencia de un beneficio aparente en cuanto a sobrevida de la inmonoterpia con LVCM y sugiere que la duración y ubicación de las metástasis distantes son no modificadas por el tratamiento. Está en progreso un estudio control randomizado (Fase III) fundamentado en estos resultados.

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References

  1. 1.
    Balch, C.M., Soong, S.J., Shaw, H.M., Milton, G.W.: An analysis of prognostic factors in 4000 patients with cutaneous melanoma. In Cutaneous Melanoma, C.M. Balch, G.W. Milton, editors, Philadelphia, J.B. Lippincott Co., 1985, pp. 321–338Google Scholar
  2. 2.
    Balch, C.M., Soong, S.J., Shaw, H.M., Milton, G.W.: An analysis of prognostic factors in 4000 patients with cutaneous melanoma. In Cutaneous Melanoma, C.M. Balch, G.W. Milton, editors, Philadelphia, J.B. Lippincott Co., 1985, pp. 338–346.Google Scholar
  3. 3.
    Hersey, P., Balch, C.M.: Current status and future prospects for adjuvant therapy of melanoma. Aust. N. Z. J. Surg.54:303, 1984PubMedGoogle Scholar
  4. 4.
    Cascinelli, N., Rumke, P., MacKie R., Morabito, A., Bufalino, R.: The significance of conversion of skin reactivity to efficacy of bacillus Calmette-Guerin (BCG) vaccinations given immediately after radical surgery in stage II melanoma patients. Cancer Immunol. Immunother.28:282, 1989PubMedGoogle Scholar
  5. 5.
    Balch, C.M., Smalley, R.V., Bartolucci, A.A., Burns, D., Presant, C.A., Durant, J.R.: A randomized prospective clinical trial of adjuvant C. parvum immunotherapy in 260 patients with clinically localized melanoma (stage I): Prognostic factors analysis and preliminary results of immunotherapy. Cancer49:1079, 1982PubMedGoogle Scholar
  6. 6.
    McGovern, V.J.: Spontaneous regression of malignant melanoma. In Melanoma: Histological Diagnosis and Prognosis, A. Blaustein, editor, New York, Raven Press, 1982, pp. 138–147Google Scholar
  7. 7.
    Hersey, P., Murray, E., Grace, J., McCarthy, W.H.: Current research on immunopathology of melanoma: Analysis of lymphocyte populations in relation to antigen expression and histological features of melanoma. Pathology17:385, 1985PubMedGoogle Scholar
  8. 8.
    Brocker, E.B., Zwadlo, G., Holzmann, B., Macher, E., Sorg, C.: Inflammatory cell infiltrates in human melanoma at different stages of tumor progression. Int. J. Cancer42:562, 1988PubMedGoogle Scholar
  9. 9.
    Austin, F.C., Boone, C.W.: Virus augmentation of the antigenicity of tumor cell extracts. Adv. Cancer Res.30:301, 1979PubMedGoogle Scholar
  10. 10.
    Heicappell, R., Schirrmacher, V., Von Hoegen, P., Ahlert, T., Appelhans, B.: Prevention of metastatic spread by postoperative immunotherapy with virally modified autologous tumor cells: I. Parameters for optimal therapeutic effects, In. J. Cancer37:569, 1986Google Scholar
  11. 11.
    Cassel, W.A., Murray, D.R., Phillips, H.S.: A phase II study on the postsurgical management of stage II malignant melanoma with a Newcastle disease virus oncolysate. Cancer52:856, 1983PubMedGoogle Scholar
  12. 12.
    Cassel, W.A., Murray, D.R.: Viral oncolysate in the treatment of regional metastases of melanoma. In Cancer in the Neck: Evaluation and Treatment. Symposium on Head and Neck Cancers, M.D. Anderson Hospital and Tumor Institute, March 1985, New York, Macmillan, 1986, pp. 236–242Google Scholar
  13. 13.
    Wallack, M.K.: Specific immunotherapy with vaccinia oncolysates. Cancer Immunol. Immunother.12:1, 1981Google Scholar
  14. 14.
    Wallack, M.K., McNally, K.R., Leftheriotis, E., Seigler, H., Balch, C., Wanebo, H., Bartolucci, A.A., Bash, J.A.: A southeastern cancer study group phase I/II trial with vaccinia melanoma oncolysates. Cancer57:649, 1986PubMedGoogle Scholar
  15. 15.
    Freedman, R.S., Bowen, J.M., Herson, J., Wharton, J.T., Rutledge, F.N., Hamberger, A.D.: Virus modified homologous tumorcell extract in the treatment of vulvar carcinoma. Cancer Immunol. Immunother.8:33, 1980Google Scholar
  16. 16.
    Freeman, R.S., Rutledge, F.N., Wharton, J.T.: Adjunctive immunotherapy with virus modified tumor cell extract in patients with high risk squamous carcinoma of the uterine cervix. Am. J. Clin. Oncol.: Cancer Clin. Trials6:155, 1983Google Scholar
  17. 17.
    Hersey, P., Edwards, A., Coates, A., Shaw, H., McCarthy, W.H., Milton, G.W.: Evidence that treatment with vaccinia melanoma cell lysates (VMCL) may improve survival of patients with stage II melanoma. Cancer Immunol. Immunother.25:257, 1987PubMedGoogle Scholar
  18. 18.
    Peto, R., Pike, M.C., Armitage, P., Breslow, N.E., Cox, D.R., Howard, S.V., Mantel, N., McPherson, K., Peto, J., Smith, P.G.: Design and analysis of randomized clinical trials requiring prolonged observation of each patient. Br. J. Cancer35:1, 1977PubMedGoogle Scholar
  19. 19.
    Cox, D.R.: Regression model and life tables. J. Royal Stat. Soc.B34:187, 1972Google Scholar
  20. 20.
    Hersey, P., Edwards, A., D'Alessandro, G., MacDonald, M.: Phase II study of vaccinia melanoma cell lysates (VMCL) as adjuvant to surgical treatment of stage II melanoma: II. Effects on cell mediated cytotoxicity and leukocyte dependent antibody activity. Cancer Immunol. Immunother.22:221, 1986PubMedGoogle Scholar
  21. 21.
    Hersey, P.: Vaccinia viral lysates in treatment of melanoma. In Biomodulation of Cancer, M.S. Mitchell, editor, Pergamon Press, 1990 (in press)Google Scholar
  22. 22.
    Berd, D., Maquire, H.C., Mastrangelo, M.J.: Induction of cellmediated immunity to autologous melanoma cells and regression of metastases after treatment with a melanoma cell vaccine preceded by cyclophosphamide. Cancer Res.46:2572, 1986PubMedGoogle Scholar
  23. 23.
    Berd, D., Mastrangelo, M.J.: Effect of low dose cyclophosphamide on immune system of cancer patients: Reduction of T suppressor function without depletion of the CD8+ subset. Cancer Res.47:3317, 1987PubMedGoogle Scholar
  24. 24.
    Berd, D., Mastrangelo, M.J.: Active immunotherapy of human melanoma exploiting the immunopotentiating effects of cyclophosphamide. Cancer Invest.6:335, 1988Google Scholar
  25. 25.
    Oratz, R., Cockerell, C., Speyer, J., Roses, D.F., Harris, M.N., Bystryn, J.C.: Induction of lymphocytic infiltrate in human melanoma nodules by active immunization to melanoma antigen vaccine. Proc. Annu. Meet. Am. Assoc. Cancer Res.28:374, 1987Google Scholar
  26. 26.
    Cassel, W.A., Weidenheim, K.M., Campbell, W.G., Murray, D.R.: Malignant melanoma: Inflammatory mononuclear cell infiltrates in cerebral metastases during concurrent therapy with viral oncolysate. Cancer57:1302, 1986PubMedGoogle Scholar
  27. 27.
    Sacks, H., Chalmers, T.C., Smith, H.: Randomized versus historical controls for clinical trials. Am. J. Med.72:233, 1982PubMedGoogle Scholar
  28. 28.
    Hill, G.J., Moss, S.E., Golumb, F.M., Grage, T.B., Fletcher, W.S., Minton, J.P., Krementz, E.T.: DTIC and combination therapy for melanoma. III. DTIC (NSC45388) surgical adjuvant study COG protocol 7040. Cancer47:2556, 1981PubMedGoogle Scholar
  29. 29.
    Hilal, E.Y., Pinsky, C.M., Hirshaut, Y., Wanebo, H.J., Hansen, J.A., Braun, D.W., Fortner, J.G., Oettgen, H.F.: Surgical adjuvant therapy of malignant melanoma with Corynebacterium parvum. Cancer48:245, 1981PubMedGoogle Scholar
  30. 30.
    Cascinelli, N., Vaglini, M., Nava, M., Santinami, M., Marolda, R., Rovini, D., Clemente, C., Bufalino, R., Morabito, A.: Prognosis of skin melanoma with regional node metastases. J. Surg. Oncol.25:240, 1984PubMedGoogle Scholar
  31. 31.
    Gehan, E.A., Freireich, E.J.: Non randomized controls in cancer clinical trials. N. Engl. J. Med.290:198, 1974PubMedGoogle Scholar
  32. 32.
    Hersey, P., MacDonald, M., Werkman, H.: Western blot analysis of antigens on melanoma cells recognized by cytotoxic T cells. J. Natl. Cancer Inst.80:826, 1988PubMedGoogle Scholar
  33. 33.
    Notter, M., Schirrmacher, V.: Tumor-specific T-cell clones recognize different protein determinants of autologous human malignant melanoma cells. Int. J. Cancer45:834, 1990PubMedGoogle Scholar
  34. 34.
    Mukherji, B., Wilhelm, S.A., Guha, A., Ergin, M.T.: Regulation of cellular immune response against autologous human melanoma: I. Evidence for cell-mediated suppression of in vitro cytotoxic immune response. J. Immunol.136:1888, 1986PubMedGoogle Scholar
  35. 35.
    Mukherji, B., Mashed, A.L., Guha, A., Ergin, M.T.: Regulation of cellular immune response against autologous human melanoma: II. Mechanism of induction and specificity of suppression. J. Immunol.136:1893, 1986PubMedGoogle Scholar
  36. 36.
    Mukherji, B., Guha, A., Chakraborty, N.G., Sivanandham, M., Nashed, A.L., Sporn, J.R., Ergin, M.T.: Clonal analysis of cytotoxic and regulatory T cell responses against human melanoma. J. Exp. Med.169:1961, 1989PubMedGoogle Scholar

Copyright information

© the Société Internationale de Chirurgie 1992

Authors and Affiliations

  • Peter Hersey
    • 1
  1. 1.Department of Oncology and ImmunologyRoyal Newcastle HospitalNewcastleAustralia

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