Adjuvant interferon alfa in malignant melanoma: An interdisciplinary and multinational expert review

Critical Reviews in Oncology/Hematology

Volumn 85, Issue 2, 2013, Pages 149-161

  Ascierto, Paolo A ^a   Gogas, Helen J ^b   Grob, Jean Jacques ^c   Algarra, Salvador Martín ^d   Mohr, Peter ^e   Hansson, Johan ^f   Hauschild, Axel ^g  

^a NATIONAL CANCER INSTITUTE   (Italy)

^b UNIVERSITY OF ATHENS   (Greece)

^c AIX MARSEILLE UNIVERSITY   (France)

^d UNIVERSITY OF NAVARRA   (Spain)

^e Elbeklinikum Buxtehude ^*  (Germany)

^f KAROLINSKA UNIVERSITY HOSPITAL   (Sweden)

^g UNIVERSITY HOSPITAL SCHLESWIG HOLSTEIN   (Germany)

Author keywords

Adjuvant; Disease free survival; Immunomodulation; Interferon alfa 2a; Interferon alfa 2b; Malignant melanoma; Peginterferon alfa 2b; Survival

Indexed keywords

ALPHA INTERFERON; ALPHA2A INTERFERON; AUTOANTIBODY; BETA 2 MICROGLOBULIN; BIOLOGICAL MARKER; C REACTIVE PROTEIN; CISPLATIN; DACARBAZINE; FERRITIN; GRANULOCYTE COLONY STIMULATING FACTOR; HLA ANTIGEN CLASS 1; INTERFERON; INTERFERON ALPHA2B; INTERLEUKIN 2; PEGINTERFERON ALPHA2B; PROTEIN S100B; STAT1 PROTEIN; STAT3 PROTEIN; UNCLASSIFIED DRUG; VINBLASTINE;

CANCER ADJUVANT THERAPY; CANCER RECURRENCE; CANCER STAGING; CONTINUOUS INFUSION; DISEASE FREE SURVIVAL; DOSAGE SCHEDULE COMPARISON; DRUG DOSE COMPARISON; DRUG EFFICACY; DRUG MEGADOSE; DRUG RESPONSE; EVIDENCE BASED MEDICINE; HIGH RISK PATIENT; HUMAN; LEUKOCYTE; LIFESTYLE; LOW DRUG DOSE; MELANOMA; META ANALYSIS (TOPIC); MICROMETASTASIS; MULTICENTER STUDY (TOPIC); MULTIPLE CYCLE TREATMENT; OVERALL SURVIVAL; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PREDICTION; RANDOMIZED CONTROLLED TRIAL (TOPIC); RECURRENCE RISK; REVIEW; TREATMENT RESPONSE; ULCER; UNSPECIFIED SIDE EFFECT;

ANTINEOPLASTIC AGENTS; BIOLOGICAL MARKERS; CHEMOTHERAPY, ADJUVANT; HUMANS; INTERFERON-ALPHA; MELANOMA; NEOPLASM STAGING; PROGNOSIS; TREATMENT OUTCOME;

EID: 84872614316     PISSN: 10408428     EISSN: 18790461     Source Type: Journal    
DOI: 10.1016/j.critrevonc.2012.07.004     Document Type: Review

References (60)

1. de Vries E., Bray F.I., Coebergh J.W., Parkin D.M. Changing epidemiology of malignant cutaneous melanoma in Europe 1953-1997: rising trends in incidence and mortality but recent stabilizations in western Europe and decreases in Scandinavia. International Journal of Cancer 2003, 107:119-126.
2. de Vries E., Coebergh J.W. Melanoma incidence has risen in Europe. British Medical Journal 2005, 331:698.
3. European Cancer Observatory Cancer Fact Sheets (2012). Cancer: melanoma of skin. Available at: [accessed 23 January]. http://eu-cancer.iarc.fr/cancer-11-melanoma-of-skin.html,en.
4. Balch C.M., Gershenwald J.E., Soong S.J., et al. Final version of 2009 AJCC melanoma staging and classification. Journal of Clinical Oncology 2009, 27:6199-6206.
5. Kirkwood J.M., Strawderman M.H., Ernstoff M.S., Smith T.J., Borden E.C., Blum R.H. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. Journal of Clinical Oncology 1996, 14:7-17.
6. Kirkwood J.M., Ibrahim J.G., Sondak V.K., et al. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. Journal of Clinical Oncology 2000, 18:2444-2458.
7. Kirkwood J.M., Ibrahim J.G., Sosman J.A., et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. Journal of Clinical Oncology 2001, 19:2370-2380.
8. Eggermont A.M., Suciu S., Santinami M., et al. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet 2008, 372:117-126.
9. Eggermont A.M., Suciu S., Santinami M., et al. EORTC 18991 phase III trial: long-term adjuvant pegylated interferon-α2b (PEG-IFN) versus observation in resected stage III melanoma: long-term results at 7.6-years follow-up. Journal of Clinical Oncology 2011, 29. [Abstract 8506b].
10. Wheatley K., Ives N., Hancock B., Gore M., Eggermont A., Suciu S. Does adjuvant interferon-alpha for high-risk melanoma provide a worthwhile benefit? A meta-analysis of the randomised trials. Cancer Treatment Reviews 2003, 29:241-252.
11. Wheatley K., Ives N., Eggermont A., et al. Interferon-α as adjuvant therapy for melanoma: an individual patient data meta-analysis of randomised trials. Journal of Clinical Oncology 2007, 25. [Abstract 8526].
12. Mocellin S., Pasquali S., Rossi C.R., Nitti D. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. Journal of the National Cancer Institute 2010, 102:493-501.
13. Ascierto P.A., Daponte A., Parasole R., et al. Intermediate dose recombinant interferon-alpha as second-line treatment for patients with recurrent cutaneous melanoma who were pretreated with low dose interferon. Cancer 2000, 89:1490-1494.
14. Ascierto P.A., Kirkwood J.M. Adjuvant therapy of melanoma with interferon: lessons of the past decade. Journal of Translational Medicine 2008, 6:62.
15. Dummer R., Mangana J. Long-term pegylated interferon-alpha and its potential in the treatment of melanoma. Biologics 2009, 3:169-182.
16. Wang W., Edington H.D., Rao U.N., et al. Modulation of signal transducers and activators of transcription 1 and 3 signaling in melanoma by high-dose IFNalpha2b. Clinical Cancer Research 2007, 13:1523-1531.
17. Hervas-Stubbs S., Perez-Gracia J.L., Rouzaut A., Sanmamed M.F., Le Bon A., Melero I. Direct effects of type I interferons on cells of the immune system. Clinical Cancer Research 2011, 17:2619-2627.
18. Critchley-Thorne R.J., Yan N., Nacu S., Weber J., Holmes S.P., Lee P.P. Down-regulation of the interferon signaling pathway in T lymphocytes from patients with metastatic melanoma. PLoS Medicine 2007, 4:e176.
19. Moschos S.J., Edington H.D., Land S.R., et al. Neoadjuvant treatment of regional stage IIIB melanoma with high-dose interferon alfa-2b induces objective tumor regression in association with modulation of tumor infiltrating host cellular immune responses. Journal of Clinical Oncology 2006, 24:3164-3171.
20. Simons D.L., Lee G., Kirkwood J.M., Lee P.P. Interferon signaling patterns in peripheral blood lymphocytes may predict clinical outcome after high-dose interferon therapy in melanoma patients. Journal of Translational Medicine 2011, 9:52.
21. Mohty A.M., Grob J.J., Mohty M., Richard M.A., Olive D., Gaugler B. Induction of IP-10/CXCL10 secretion as an immunomodulatory effect of low-dose adjuvant interferon-alpha during treatment of melanoma. Immunobiology 2010, 215:113-123.
22. Ascierto P.A., Napolitano M., Celentano E., et al. Regulatory T cell frequency in patients with melanoma with different disease stage and course, and modulating effects of high-dose interferon-alpha 2b treatment. Journal of Translational Medicine 2010, 8:76.
23. Cesana G.C., DeRaffele G., Cohen S., et al. Characterization of CD4+CD25+ regulatory T cells in patients treated with high-dose interleukin-2 for metastatic melanoma or renal cell carcinoma. Journal of Clinical Oncology 2006, 24:1169-1177.
24. Viguier M., Lemaître F., Verola O., et al. Foxp3 expressing CD4+CD25(high) regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. Journal of Immunology 2004, 173:1444-1453.
25. Yurkovetsky Z.R., Kirkwood J.M., Edington H.D., et al. Multiplex analysis of serum cytokines in melanoma patients treated with interferon-alpha2b. Clinical Cancer Research 2007, 13:2422-2428.
26. Kashani-Sabet M., Sagebiel R.W., Miller J.R., Shaikh L., Nosrati M., Ferreira C.M.M. Model of melanoma progression based on vascular interactions. Journal of Clinical Oncology 2003, 22. [Abstract 2859].
27. Kirkwood J.M., Richards T., Zarour H.M., et al. Immunomodulatory effects of high-dose and low-dose interferon alpha2b in patients with high-risk resected melanoma: the E2690 laboratory corollary of intergroup adjuvant trial E1690. Cancer 2002, 95:1101-1112.
28. Gogas H., Ioannovich J., Dafni U., et al. Prognostic significance of autoimmunity during treatment of melanoma with interferon. New England Journal of Medicine 2006, 354:709-718.
29. Chiarion-Sileni V., Guida M., Romanini A., et al. Intensified high-dose intravenous interferon alpha 2b (IFNa2b) for adjuvant treatment of stage III melanoma: a randomized phase III Italian Melanoma Intergroup (IMI) trial [ISRCTN75125874]. Journal of Clinical Oncology 2011, 29. [Abstract 8506].
30. Agarwala S.S., Lee S.J., Flaherty L.E., et al. Randomized phase III trial of high-dose interferon alfa-2b (HDI) for 4 weeks induction only in patients with intermediate- and high-risk melanoma (Intergroup trial E 1697). Journal of Clinical Oncology 2011, 29. [Abstract 8505].
31. McMasters K.M., Ross M.I., Reintgen D.S., et al. Final results of the Sunbelt Melanoma Trial. Journal of Clinical Oncology 2008, 26. [Abstract 9003].
32. Pectasides D., Dafni U., Bafaloukos D., et al. Randomized phase III study of 1 month versus 1 year of adjuvant high-dose interferon alfa-2b in patients with resected high-risk melanoma. Journal of Clinical Oncology 2009, 27:939-944.
33. Mao L., Si L., Chi Z., et al. A randomised phase II trial of 1month versus 1year of adjuvant high-dose interferon alpha-2b in high-risk acral melanoma patients. European Journal of Cancer 2011, 47:1498-1503.
34. Mohr P., Hauschild A., Trefzer U., et al. Intermittent high-dose intravenous interferon alpha 2b (IFNa2b) for adjuvant treatment of stage III malignant melanoma: final analysis of a randomized phase III DeCOG-trial (NCT00226408). Journal of Clinical Oncology 2012, 30. [Abstract 8504].
35. Mohr P., Hauschild A., Trefzer U., Weichenthal M. Quality of life in patients receiving high-dose interferon alfa-2b after resected high-risk melanoma. Journal of Clinical Oncology 2009, 27:e70.
36. Flaherty L.E., Moon J., Atkins M.B., et al. Phase III trial of high-dose interferon alpha-2b versus cisplatin, vinblastine, DTIC plus IL-2 and interferon in patients with high-risk melanoma (SWOG S0008): an intergroup study of CALGB, COG, ECOG, and SWOG. Journal of Clinical Oncology 2012, 30. [Abstract 8504].
37. Hansson J., Aamdal S., Bastholt L., et al. Two different durations of adjuvant therapy with intermediate-dose interferon alfa-2b in patients with high-risk melanoma (Nordic IFN trial): a randomised phase 3 trial. Lancet Oncology 2011, 12:144-152.
38. Hauschild A., Weichenthal M., Rass K., et al. Prospective randomized multicenter adjuvant dermatologic cooperative oncology group trial of low-dose interferon alfa-2b with or without a modified high-dose interferon alfa-2b induction phase in patients with lymph node-negative melanoma. Journal of Clinical Oncology 2009, 27:3496-3502.
39. Hauschild A., Weichenthal M., Rass K., et al. Efficacy of low-dose interferon {alpha}2a 18 versus 60 months of treatment in patients with primary melanoma of >=1.5mm tumor thickness: results of a randomized phase III DeCOG trial. Journal of Clinical Oncology 2010, 28:841-846.
40. Grob J.J., Jouary T., Dreno B., et al. Adjuvant therapy with pegylated interferon alfa-2b (36 months) versus low-dose interferon alfa-2b (18 months) in melanoma patients without macro-metastatic nodes: EADO trial. Journal of Clinical Oncology 2010, 28. [Abstract LBA8506].
41. Cascinelli N., Belli F., MacKie R.M., Santinami M., Bufalino R., Morabito A. Effect of long-term adjuvant therapy with interferon alpha-2a in patients with regional node metastases from cutaneous melanoma: a randomised trial. Lancet 2001, 358:866-869.
42. Grob J.J., Dreno B., de la Salmonière P., et al. Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma thicker than 1.5mm without clinically detectable node metastases. French Cooperative Group on Melanoma. Lancet 1998, 351:1905-1910.
43. Pehamberger H., Soyer H.P., Steiner A., et al. Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. Austrian Malignant Melanoma Cooperative Group. Journal of Clinical Oncology 1998, 16:1425-1429.
44. Anaya D.A., Xing Y., Feng L., et al. Adjuvant high-dose interferon for cutaneous melanoma is most beneficial for patients with early stage III disease. Cancer 2008, 112:2030-2037.
45. Eggermont A.M., Suciu S., MacKie R., et al. Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial. Lancet 2005, 366:1189-1196.
46. McMasters K.M., Edwards M.J., Ross M.I., et al. Ulceration as a predictive marker for response to adjuvant interferon therapy in melanoma. Annals of Surgery 2010, 252:460-465. [discussion 5-6].
47. Eggermont A.M., Suciu S., Testori A., et al. Ulceration and stage are predictive of interferon efficacy in melanoma: results of the phase III adjuvant trials EORTC 18952 and EORTC 18991. European Journal of Cancer 2012, 48:218-225.
48. Bouwhuis M.G., Suciu S., Collette S., et al. Autoimmune antibodies and recurrence-free interval in melanoma patients treated with adjuvant interferon. Journal of the National Cancer Institute 2009, 101:869-877.
49. Bouwhuis M.G., Suciu S., Testori A., et al. Phase III trial comparing adjuvant treatment with pegylated interferon Alfa-2b versus observation: prognostic significance of autoantibodies-EORTC 18991. Journal of Clinical Oncology 2010, 28:2460-2466.
50. Meyer S., Wild P.J., Vogt T., et al. Methylthioadenosine phosphorylase represents a predictive marker for response to adjuvant interferon therapy in patients with malignant melanoma. Experimental Dermatology 2010, 19:e251-e257.
51. Tarhini A.A., Stuckert J., Lee S., Sander C., Kirkwood J.M. Prognostic significance of serum S100B protein in high-risk surgically resected melanoma patients participating in Intergroup Trial ECOG 1694. Journal of Clinical Oncology 2009, 27:38-44.
52. Bouwhuis M.G., Suciu S., Kruit W., et al. Prognostic value of serial blood S100B determinations in stage IIB-III melanoma patients: a corollary study to EORTC trial 18952. European Journal of Cancer 2011, 47:361-368.
53. Gogas H., Kirkwood J.M., Falk C.S., et al. Correlation of molecular human leukocyte antigen typing and outcome in high-risk melanoma patients receiving adjuvant interferon. Cancer 2010, 116:4326-4333.
54. Hofmann M.A., Kiecker F., Küchler I., Kors C., Trefzer U. Serum TNF-α B2M and sIL-2R levels are biological correlates of outcome in adjuvant IFN-α2b treatment of patients with melanoma. Journal of Cancer Research and Clinical Oncology 2011, 137:455-462.
55. Bouwhuis M.G., Collette S., Suciu S., et al. Changes of ferritin and CRP levels in melanoma patients treated with adjuvant interferon-α (EORTC 18 952) and prognostic value on treatment outcome. Melanoma Research 2011, 21:344-351.
56. Rao U.N., Lee S.J., Luo W., Mihm M.C., Kirkwood J.M. Presence of tumor-infiltrating lymphocytes and a dominant nodule within primary melanoma are prognostic factors for relapse-free survival of patients with thick (t4) primary melanoma: pathologic analysis of the e1690 and e1694 intergroup trials. American Journal of Clinical Pathology 2010, 133:646-653.
57. de La Salmonière P., Grob J.J., Dreno B., Delaunay M., Chastang C. White blood cell count: a prognostic factor and possible subset indicator of optimal treatment with low-dose adjuvant interferon in primary melanoma. Clinical Cancer Research 2000, 6:4713-4718.
58. Kirkwood J.M., Dreno B., Hauschild A., et al. DERMA phase III trial of MAGE-A3 antigen-specific cancer immunotherapeutic (ASCI) as adjuvant therapy in patients with MAGE-A3-positive resected stage III melanoma. Journal of Clinical Oncology 2011, 29. [Abstract TPS232].
59. Chapman P.B., Hauschild A., Robert C., et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. New England Journal of Medicine 2011, 364:2507-2516.
60. Hodi F.S., O'Day S.J., McDermott D.F., et al. Improved survival with ipilimumab in patients with metastatic melanoma. New England Journal of Medicine 2010, 363:711-723.