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Adjuvant Systemic Therapy for High-Risk Melanoma Patients

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Cutaneous Melanoma

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Abstract

Adjuvant therapy of cutaneous melanoma has advanced considerably since the approval of high-dose IFNalfa-2b with relapse free and overall survival in 1995 and the approval of Peg-IFN with improved relapse free survival in 2011. Immune checkpoint blockade in the adjuvant setting was first reported in 2015 with high-dose ipilimumab, showing improved relapse free and overall survival. This has been followed by the advent of anti-PD1 therapy with nivolumab and pembrolizumab and the first targeted BRAF and MEK inhibitor regimen for stage III disease in 2017, which have eclipsed prior therapies showing benefits of greater magnitude, and lesser toxicity. These have led to the development of studies that are currently directed at earlier stage IIB and IIC disease.

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References

  • Amaria RN, Prieto PA, Tetzlaff MT, Reuben A, Andrews MC, Ross MI, Glitza IC, Cormier J, Hwu WJ, Tawbi HA, Patel SP, Lee JE, Gershenwald JE, Spencer CN, Gopalakrishnan V, Bassett R, Simpson L, Mouton R, Hudgens CW, Zhao L, Zhu H, Cooper ZA, Wani K, Lazar A, Hwu P, Diab A, Wong MK, Mcquade JL, Royal R, Lucci A, Burton EM, Reddy S, Sharma P, Allison J, Futreal PA, Woodman SE, Davies MA, Wargo JA (2018) Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomised, phase 2 trial. Lancet Oncol 19:181–193

    Article  CAS  PubMed  Google Scholar 

  • Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Ding S, Byrd DR, Cascinelli N, Cochran AJ, Coit DG, Eggermont AM, Johnson T, Kirkwood JM, Leong SP, McMasters KM, Mihm MC Jr, Morton DL, Ross MI, Sondak VK (2010) Multivariate analysis of prognostic factors among 2,313 patients with stage III melanoma: comparison of nodal micrometastases versus macrometastases. J Clin Oncol 28:2452–2459

    Article  PubMed  PubMed Central  Google Scholar 

  • Balch CM, Smalley RV, Bartolucci AA, Burns D, Presant CA, Durant JR (1982) 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. Cancer 49:1079–1084

    Article  CAS  PubMed  Google Scholar 

  • Bystryn JC, Zeleniuch-Jacquotte A, Oratz R, Shapiro RL, Harris MN, Roses DF (2001) Double-blind trial of a polyvalent, shed-antigen, melanoma vaccine. Clin Cancer Res 7:1882–1887

    CAS  PubMed  Google Scholar 

  • Cameron DA, Cornbleet MC, Mackie RM, Hunter JA, Gore M, Hancock B, Smyth JF, Scottish Melanoma G (2001) Adjuvant interferon alpha 2b in high risk melanoma – the Scottish study. Br J Cancer 84:1146–1149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cascinelli N, Belli F, Mackie RM, Santinami M, Bufalino R, Morabito A (2001) Effect of long-term adjuvant therapy with interferon alpha-2a in patients with regional node metastases from cutaneous melanoma: a randomised trial. Lancet 358:866–869

    Article  CAS  PubMed  Google Scholar 

  • Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O’day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, Mcarthur GA, BRIM-3 Study Group (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507–2516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Coates A, Rallings M, Hersey P, Swanson C (1986) Phase-II study of recombinant alpha 2-interferon in advanced malignant melanoma. J Interf Res 6:1–4

    Article  CAS  Google Scholar 

  • Creagan ET, Ahmann DL, Green SJ, Long HJ, Frytak S, Itri LM (1985) Phase II study of recombinant leukocyte A interferon (IFN-rA) plus cimetidine in disseminated malignant melanoma. J Clin Oncol 3:977–981

    Article  CAS  PubMed  Google Scholar 

  • Creagan ET, Ahmann DL, Green SJ, Long HJ, Frytak S, O’fallon JR, Itri LM (1984a) Phase II study of low-dose recombinant leukocyte a interferon in disseminated malignant melanoma. J Clin Oncol 2:1002–1005

    Article  CAS  PubMed  Google Scholar 

  • Creagan ET, Ahmann DL, Green SJ, Long HJ, Rubin J, Schutt AJ, Dziewanowski ZE (1984b) Phase II study of recombinant leukocyte A interferon (rIFN-alpha A) in disseminated malignant melanoma. Cancer 54:2844–2849

    Article  CAS  PubMed  Google Scholar 

  • Creagan ET, Dalton RJ, Ahmann DL, Jung SH, Morton RF, Langdon RM Jr, Kugler J, Rodrigue LJ (1995) Randomized, surgical adjuvant clinical trial of recombinant interferon alfa-2a in selected patients with malignant melanoma. J Clin Oncol 13:2776–2783

    Article  CAS  PubMed  Google Scholar 

  • Czarnetzki BM, Macher E, Suciu S, Thomas D, Steerenberg PA, Rumke P (1993) Long-term adjuvant immunotherapy in stage I high risk malignant melanoma, comparing two BCG preparations versus non-treatment in a randomised multicentre study (EORTC protocol 18781). Eur J Cancer 29A:1237–1242

    Article  CAS  PubMed  Google Scholar 

  • De Veer MJ, Holko M, Frevel M, Walker E, Der S, Paranjape JM, Silverman RH, Williams BR (2001) Functional classification of interferon-stimulated genes identified using microarrays. J Leukoc Biol 69:912–920

    PubMed  Google Scholar 

  • Dorval T, Palangie T, Jouve M, Garcia-Giralt E, Israel L, Falcoff E, Schwab D, Pouillart P (1986) Clinical phase II trial of recombinant DNA interferon (interferon alpha 2b) in patients with metastatic malignant melanoma. Cancer 58:215–218

    CAS  PubMed  Google Scholar 

  • Dreno B, Thompson JF, Smithers BM, Santinami M, Jouary T, Gutzmer R, Levchenko E, Rutkowski P, Grob JJ, Korovin S, Drucis K, Grange F, Machet L, HERSEY P, Krajsova I, Testori A, Conry R, Guillot B, Kruit WHJ, Demidov L, Thompson JA, Bondarenko I, Jaroszek J, Puig S, Cinat G, Hauschild A, Goeman JJ, Van Houwelingen HC, Ulloa-Montoya F, Callegaro A, Dizier B, Spiessens B, Debois M, Brichard VG, Louahed J, Therasse P, Debruyne C, Kirkwood JM (2018) MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3-positive, stage III melanoma (DERMA): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 19:916–929

    Article  CAS  PubMed  Google Scholar 

  • Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, Chiarion-Sileni V, Dutriaux C, DE Groot JWB, Yamazaki N, Loquai C, Moutouh-De Parseval LA, Pickard MD, Sandor V, Robert C, Flaherty KT (2018) Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 19:603–615

    Article  CAS  PubMed  Google Scholar 

  • Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbe C, Ferraresi V, Smylie M, Weber JS, Maio M, Bastholt L, Mortier L, Thomas L, Tahir S, Hauschild A, Hassel JC, Hodi FS, Taitt C, DE Pril V, DE Schaetzen G, Suciu S, Testori A (2016a) Prolonged survival in stage III melanoma with Ipilimumab adjuvant therapy. N Engl J Med 375:1845–1855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbe C, Ferraresi V, Smylie M, Weber JS, Maio M, Konto C, Hoos A, DE Pril V, Gurunath RK, DE Schaetzen G, Suciu S, Testori A (2015) Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol 16:522–530

    Article  CAS  PubMed  Google Scholar 

  • Eggermont AM, Suciu S, Mackie R, Ruka W, Testori A, Kruit W, Punt CJ, Delauney M, Sales F, Groenewegen G, Ruiter DJ, Jagiello I, Stoitchkov K, Keilholz U, Lienard D, EORTC Melanoma Group (2005) 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 366:1189–1196

    Article  CAS  PubMed  Google Scholar 

  • Eggermont AM, Suciu S, Rutkowski P, Kruit WH, Punt CJ, Dummer R, Sales F, Keilholz U, De Schaetzen G, Testori A, EORTC Melanoma Group (2016b) Long term follow up of the EORTC 18952 trial of adjuvant therapy in resected stage IIB-III cutaneous melanoma patients comparing intermediate doses of interferon-alpha-2b (IFN) with observation: ulceration of primary is key determinant for IFN-sensitivity. Eur J Cancer 55:111–121

    Article  CAS  PubMed  Google Scholar 

  • Eggermont AM, Suciu S, Rutkowski P, Marsden J, Santinami M, Corrie P, Aamdal S, Ascierto PA, Patel PM, Kruit WH, Bastholt L, Borgognoni L, Bernengo MG, Davidson N, Polders L, Praet M, Spatz A (2013) Adjuvant ganglioside GM2-KLH/QS-21 vaccination versus observation after resection of primary tumor >1.5 mm in patients with stage II melanoma: results of the EORTC 18961 randomized phase III trial. J Clin Oncol 31:3831–3837

    Article  CAS  PubMed  Google Scholar 

  • Eggermont AM, Suciu S, Santinami M, Testori A, Kruit WH, Marsden J, Punt CJ, Sales F, Gore M, Mackie R, Kusic Z, Dummer R, Hauschild A, Musat E, Spatz A, Keilholz U, EORTC Melanoma Group (2008) 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 372:117–126

    Article  CAS  PubMed  Google Scholar 

  • Eggermont AM, Suciu S, Testori A, Kruit WH, Marsden J, Punt CJ, Santinami M, Sales F, Schadendorf D, Patel P, Dummer R, Robert C, Keilholz U, Yver A, Spatz A (2012a) Ulceration and stage are predictive of interferon efficacy in melanoma: results of the phase III adjuvant trials EORTC 18952 and EORTC 18991. Eur J Cancer 48:218–225

    Article  CAS  PubMed  Google Scholar 

  • Eggermont AM, Suciu S, Testori A, Santinami M, Kruit WH, Marsden J, Punt CJ, Sales F, Dummer R, Robert C, Schadendorf D, Patel PM, DE Schaetzen G, Spatz A, Keilholz U (2012b) Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin Oncol 30:3810–3818

    Article  CAS  PubMed  Google Scholar 

  • Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Lichinitser M, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Maio M, Van Den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan P, Ibrahim N, Marreaud S, Van Akkooi ACJ, Suciu S, Robert C (2018a) Adjuvant Pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med 378:1789–1801

    Article  CAS  PubMed  Google Scholar 

  • Eggermont AMM, Robert C, Ribas A (2018b) The new era of adjuvant therapies for melanoma. Nat Rev Clin Oncol 15:535–536

    Article  CAS  PubMed  Google Scholar 

  • Ernstoff MS, Reiss M, Davis CA et al (1983) Intravenous (IV) recombinant alpha-2 interferon in metastatic melanoma. Proc Am Soc Clin Oncol 2:57

    Google Scholar 

  • Faries MB, Mozzillo N, Kashani-Sabet M, Thompson JF, Kelley MC, Deconti RC, Lee JE, Huth JF, Wagner J, Dalgleish A, Pertschuk D, Nardo C, Stern S, Elashoff R, Gammon G, Morton DL, MMAIT-IV Clinical Trial Group (2017) Long-term survival after complete surgical resection and adjuvant immunotherapy for distant melanoma metastases. Ann Surg Oncol 24:3991–4000

    Article  PubMed  Google Scholar 

  • Fisher RI, Terry WD, Hodes RJ, Rosenberg SA, Makuch R, Gordon HG, Fisher SG (1981) Adjuvant immunotherapy or chemotherapy for malignant melanoma. Preliminary report of the National Cancer Institute randomized clinical trial. Surg Clin North Am 61:1267–1277

    Article  CAS  PubMed  Google Scholar 

  • Flaherty LE, Othus M, Atkins MB, Tuthill RJ, Thompson JA, Vetto JT, Haluska FG, Pappo AS, Sosman JA, Redman BG, Moon J, Ribas A, Kirkwood JM, Sondak VK (2014) Southwest oncology group S0008: a phase III trial of high-dose interferon alfa-2b versus cisplatin, vinblastine, and dacarbazine, plus interleukin-2 and interferon in patients with high-risk melanoma – an intergroup study of cancer and leukemia group B, Children’s oncology group, eastern cooperative oncology group, and southwest oncology group. J Clin Oncol 32:3771–3778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gasser O, Sharples KJ, Barrow C, Williams GM, Bauer E, Wood CE, Mester B, Dzhelali M, Caygill G, Jones J, Hayman CM, Hinder VA, Macapagal J, Mccusker M, Weinkove R, Painter GF, Brimble MA, Findlay MP, Dunbar PR, Hermans IF (2017) A phase I vaccination study with dendritic cells loaded with NY-ESO-1 and alpha-galactosylceramide: induction of polyfunctional T cells in high-risk melanoma patients. Cancer Immunol Immunother 67:285–298

    Article  PubMed  CAS  Google Scholar 

  • Gershenwald JE, Scolyer RA, Hess KR, Sondak VK, Long GV, Ross MI, Lazar AJ, Faries MB, Kirkwood JM, McArthur GA, Haydu LE, Eggermont AMM, Flaherty KT, BALCH CM, Thompson JF, For members of the AmericanJoint Committee on Cancer Melanoma Expert Panel, The International Melanoma Database, Discovery Platform (2017) Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin 67:472–492

    Article  PubMed  PubMed Central  Google Scholar 

  • Grander D, Sangfelt O, Erickson S (1997) How does interferon exert its cell growth inhibitory effect? Eur J Haematol 59:129–135

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Hancock BW, Wheatley K, Harris S, Ives N, Harrison G, Horsman JM, Middleton MR, Thatcher N, Lorigan PC, Marsden JR, Burrows L, Gore M (2004) Adjuvant interferon in high-risk melanoma: the AIM HIGH study – United Kingdom coordinating Committee on Cancer research randomized study of adjuvant low-dose extended-duration interferon alfa-2a in high-risk resected malignant melanoma. J Clin Oncol 22:53–61

    Article  CAS  PubMed  Google Scholar 

  • Hansson J, Aamdal S, Bastholt L, Brandberg Y, Hernberg M, Nilsson B, Stierner U, Von Der Maase H, Nordic Melanoma Cooperative, Group (2011) 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 Oncol 12:144–152

    Article  CAS  PubMed  Google Scholar 

  • Hauschild A, Dummer R, Schadendorf D, Santinami M, Atkinson V, Mandalá M, Chiarion-Sileni V, Larkin J, Nyakas M, Dutriaux C, Haydon A, Robert C, Mortier L, Schachter J, Lesimple T, Plummer R, Dasgupta K, Haas T, Shilkrut M, Gasal E, Kefford R, Kirkwood JM, Long GV (2018). Longer follow-up confirms relapse-free survival benefit with adjuvant Dabrafenib plus Trametinib in patients with resected BRAFV600–mutant stage III melanoma. J Clin Oncol 36(35):3441–3449

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E, Martin-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V, Chapman PB (2012) Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380:358–365

    CAS  PubMed  Google Scholar 

  • Hauschild A, Weichenthal M, Rass K, Linse R, Berking C, Bottjer J, Vogt T, Spieth K, Eigentler T, Brockmeyer NH, Stein A, Naher H, Schadendorf D, Mohr P, Kaatz M, Tronnier M, Hein R, Schuler G, Egberts F, Garbe C (2010) Efficacy of low-dose interferon {alpha}2a 18 versus 60 months of treatment in patients with primary melanoma of >= 1.5 mm tumor thickness: results of a randomized phase III DeCOG trial. J Clin Oncol 28:841–846

    Article  CAS  PubMed  Google Scholar 

  • Hersey P, Coates AS, McCarthy WH, Thompson JF, Sillar RW, McLeod R, Gill PG, Coventry BJ, McMullen A, Dillon H, Simes RJ (2002) Adjuvant immunotherapy of patients with high-risk melanoma using vaccinia viral lysates of melanoma: results of a randomized trial. J Clin Oncol 20:4181–4190

    Article  CAS  PubMed  Google Scholar 

  • Hodi FS, O’day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, Van Den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ives NJ, Suciu S, Eggermont AMM, Kirkwood J, Lorigan P, Markovic SN, Garbe C, Wheatley K, International Melanoma Meta-Analysis Collaborative Group (IMMCG) (2017) Adjuvant interferon-alpha for the treatment of high-risk melanoma: an individual patient data meta-analysis. Eur J Cancer 82:171–183

    Article  CAS  PubMed  Google Scholar 

  • Kilbridge KL, Cole BF, Kirkwood JM, Haluska FG, Atkins MA, Ruckdeschel JC, Sock DE, Nease RF Jr, Weeks JC (2002) Quality-of-life-adjusted survival analysis of high-dose adjuvant interferon alpha-2b for high-risk melanoma patients using intergroup clinical trial data. J Clin Oncol 20:1311–1318

    CAS  PubMed  Google Scholar 

  • Kirkwood JM, Ibrahim J, Lawson DH, Atkins MB, Agarwala SS, Collins K, Mascari R, Morrissey DM, Chapman PB (2001a) High-dose interferon alfa-2b does not diminish antibody response to GM2 vaccination in patients with resected melanoma: results of the multicenter eastern cooperative oncology group phase II trial E2696. J Clin Oncol 19:1430–1436

    Article  CAS  PubMed  Google Scholar 

  • Kirkwood JM, Ibrahim JG, Sondak VK, Richards J, Flaherty LE, Ernstoff MS, Smith TJ, Rao U, Steele M, 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 18:2444–2458

    Article  CAS  PubMed  Google Scholar 

  • Kirkwood JM, Ibrahim JG, Sosman JA, Sondak VK, Agarwala SS, Ernstoff MS, Rao U (2001b) 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. J Clin Oncol 19:2370–2380

    Article  CAS  PubMed  Google Scholar 

  • Kirkwood JM, Manola J, Ibrahim J, Sondak V, Ernstoff MS, Rao U, Eastern Cooperative Oncology Group (2004) A pooled analysis of eastern cooperative oncology group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res 10:1670–1677

    Article  CAS  PubMed  Google Scholar 

  • Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH (1996) Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the eastern cooperative oncology group trial EST 1684. J Clin Oncol 14:7–17

    Article  CAS  PubMed  Google Scholar 

  • Kleeberg UR, Suciu S, Brocker EB, Ruiter DJ, Chartier C, Lienard D, Marsden J, Schadendorf D, Eggermont AM, EORTCMelanoma Group in cooperation with the German Cancer Society (DKG) (2004) Final results of the EORTC 18871/DKG 80-1 randomised phase III trial. rIFN-alpha2b versus rIFN-gamma versus ISCADOR M versus observation after surgery in melanoma patients with either high-risk primary (thickness >3 mm) or regional lymph node metastasis. Eur J Cancer 40:390–402

    Article  CAS  PubMed  Google Scholar 

  • Koops HS, Vaglini M, Suciu S, Kroon BB, Thompson JF, Gohl J, Eggermont AM, Di Filippo F, Krementz ET, Ruiter D, Lejeune FJ (1998) Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. J Clin Oncol 16:2906–2912

    Article  CAS  PubMed  Google Scholar 

  • Larkin J (2018) Dabrafenib plus trametinib (D + T) as adjuvant treatment of resected BRAF-mutant stage III melanoma: findings from the COMBI-AD trial analyzed based on AJCC 8 classification. J Clin Oncol 36:9591

    Article  Google Scholar 

  • Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD (2015) Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373:23–34

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Legha SS, Papadopoulos NE, Plager C, Ring S, Chawla SP, Evans LM, Benjamin RS (1987) Clinical evaluation of recombinant interferon alfa-2a (Roferon-A) in metastatic melanoma using two different schedules. J Clin Oncol 5:1240–1246

    Article  CAS  PubMed  Google Scholar 

  • Lipton A, Harvey HA, Balch CM, Antle CE, Heckard R, Bartolucci AA (1991) Corynebacterium parvum versus bacille Calmette-Guerin adjuvant immunotherapy of stage II malignant melanoma. J Clin Oncol 9:1151–1156

    Article  CAS  PubMed  Google Scholar 

  • Livingston PO, Wong GY, Adluri S, Tao Y, Padavan M, Parente R, Hanlon C, Calves MJ, Helling F, Ritter G et al (1994) Improved survival in stage III melanoma patients with GM2 antibodies: a randomized trial of adjuvant vaccination with GM2 ganglioside. J Clin Oncol 12:1036–1044

    Article  CAS  PubMed  Google Scholar 

  • Long GV, Flaherty KT, Stroyakovskiy D, Gogas H, Levchenko E, De Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Chiarion-Sileni V, Lebbe C, Mandala M, Millward M, Arance A, Bondarenko I, Haanen J, Hansson J, Utikal J, Ferraresi V, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, Davies MA, Lane SR, Legos JJ, Mookerjee B, Grob JJ (2017a) Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann Oncol 28:1631–1639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Long GV, Hauschild A, Santinami M, Atkinson V, Mandala M, Chiarion-Sileni V, Larkin J, Nyakas M, Dutriaux C, Haydon A, Robert C, Mortier L, Schachter J, Schadendorf D, Lesimple T, Plummer R, Ji R, Zhang P, Mookerjee B, Legos J, Kefford R, Dummer R, Kirkwood JM (2017b) Adjuvant Dabrafenib plus Trametinib in stage III BRAF-mutated melanoma. N Engl J Med 377:1813–1823

    Article  CAS  PubMed  Google Scholar 

  • Long GV, Menzies AM, Nagrial AM, Haydu LE, Hamilton AL, Mann GJ, Hughes TM, Thompson JF, Scolyer RA, Kefford RF (2011) Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol 29:1239–1246

    Article  PubMed  Google Scholar 

  • Maio M, Lewis K, Demidov L, Mandala M, Bondarenko I, Ascierto PA, Herbert C, Mackiewicz A, Rutkowski P, Guminski A, Goodman GR, Simmons B, Ye C, Yan Y, Schadendorf D, brim8 Investigators (2018) Adjuvant vemurafenib in resected, BRAF(V600) mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol 19:510–520

    Article  CAS  PubMed  Google Scholar 

  • Markovic S, Suman VJ, Dalton RJ, Woods JE, Fitzgibbons RJ Jr, Wold LE, Buckner JC, Kugler JW, Mailliard JA, Rowland KM, Krook JE, Brown DW, Tirona MT, Creagan ET (2002) Randomized, placebo-controlled, phase III surgical adjuvant clinical trial of megestrol acetate (Megace) in selected patients with malignant melanoma. Am J Clin Oncol 25:552–556

    Article  PubMed  Google Scholar 

  • McCarty MF, Bielenberg D, Donawho C, Bucana CD, Fidler IJ (2002) Evidence for the causal role of endogenous interferon-alpha/beta in the regulation of angiogenesis, tumorigenicity, and metastasis of cutaneous neoplasms. Clin Exp Metastasis 19:609–615

    Article  CAS  PubMed  Google Scholar 

  • McMasters KM, Edwards MJ, Ross MI, Reintgen DS, Martin RC 2nd, Urist MM, Noyes RD, Sussman JJ, Stromberg AJ, Scoggins CR (2010) Ulceration as a predictive marker for response to adjuvant interferon therapy in melanoma. Ann Surg 252:460–465. Discussion 465–6

    PubMed  Google Scholar 

  • Mcmasters KM, Egger ME, Edwards MJ, Ross MI, Reintgen DS, Noyes RD, Martin RC 2nd, Goydos JS, Beitsch PD, Urist MM, Ariyan S, Sussman JJ, Davidson BS, Gershenwald JE, Hagendoorn LJ, Stromberg AJ, Scoggins CR (2016) Final results of the Sunbelt Melanoma trial: a multi-institutional prospective randomized Phase III study evaluating the role of adjuvant high-dose interferon Alfa-2b and completion Lymph node dissection for patients staged by sentinel Lymph node biopsy. J Clin Oncol 34:1079–1086

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meisenberg BR, Ross M, Vredenburgh JJ, Jones R, Shpall EJ, Seigler HF, Coniglio DM, Wu K, Peters WP (1993) Randomized trial of high-dose chemotherapy with autologous bone marrow support as adjuvant therapy for high-risk, multi-node-positive malignant melanoma. J Natl Cancer Inst 85:1080–1085

    Article  CAS  PubMed  Google Scholar 

  • Menzies AM, Johnson DB, Ramanujam S, Atkinson VG, Wong ANM, Park JJ, Mcquade JL, Shoushtari AN, Tsai KK, Eroglu Z, Klein O, Hassel JC, Sosman JA, Guminski A, Sullivan RJ, Ribas A, Carlino MS, Davies MA, Sandhu SK, Long GV (2017) Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol 28:368–376

    Article  CAS  PubMed  Google Scholar 

  • Meyskens FL Jr, Liu PY, Tuthill RJ, Sondak VK, Fletcher WS, Jewell WR, Samlowski W, Balcerzak SP, Rector DJ, Noyes RD et al (1994) Randomized trial of vitamin A versus observation as adjuvant therapy in high-risk primary malignant melanoma: a southwest oncology group study. J Clin Oncol 12:2060–2065

    Article  PubMed  Google Scholar 

  • Miller LL, Spitler LE, Allen RE, Minor DR (1988) A randomized, double-blind, placebo-controlled trial of transfer factor as adjuvant therapy for malignant melanoma. Cancer 61:1543–1549

    Article  CAS  PubMed  Google Scholar 

  • Neefe JR, Legha SS, Markowitz A, Salmon S, Meyskens F, Groopman J, Campion M, Evans L (1990) Phase II study of recombinant alpha-interferon in malignant melanoma. Am J Clin Oncol 13:472–476

    Article  CAS  PubMed  Google Scholar 

  • Paterson AH, Willans DJ, Jerry LM, Hanson J, McPherson TA (1984) Adjuvant BCG immunotherapy for malignant melanoma. Can Med Assoc J 131:744–748

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pectasides D, Dafni U, Bafaloukos D, Skarlos D, Polyzos A, Tsoutsos D, Kalofonos H, Fountzilas G, Panagiotou P, Kokkalis G, Papadopoulos O, Castana O, Papadopoulos S, Stavrinidis E, Vourli G, Ioannovich J, Gogas H (2009) Randomized phase III study of 1 month versus 1 year of adjuvant high-dose interferon alfa-2b in patients with resected high-risk melanoma. J Clin Oncol 27:939–944

    Article  CAS  PubMed  Google Scholar 

  • Pehamberger H, Soyer HP, Steiner A, Kofler R, Binder M, Mischer P, Pachinger W, Aubock J, Fritsch P, Kerl H, Wolff K (1998) Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. Austrian Malignant Melanoma Cooperative Group. J Clin Oncol 16:1425–1429

    Article  CAS  PubMed  Google Scholar 

  • Quirt IC, Shelley WE, Pater JL, Bodurtha AJ, McCulloch PB, McPherson TA, Paterson AH, Prentice R, Silver HK, Willan AR et al (1991) Improved survival in patients with poor-prognosis malignant melanoma treated with adjuvant levamisole: a phase III study by the National Cancer Institute of Canada clinical trials group. J Clin Oncol 9:729–735

    Article  CAS  PubMed  Google Scholar 

  • Rizos H, Menzies AM, Pupo GM, Carlino MS, Fung C, Hyman J, Haydu LE, Mijatov B, Becker TM, Boyd SC, Howle J, Saw R, Thompson JF, Kefford RF, Scolyer RA, Long GV (2014) BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clin Cancer Res 20:1965–1977

    Article  CAS  PubMed  Google Scholar 

  • Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbe C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA (2015a) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372:320–330

    Article  CAS  PubMed  Google Scholar 

  • Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A, KEYNOTE-006 investigators (2015b) Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med 372:2521–2532

    Article  CAS  PubMed  Google Scholar 

  • Robert C, Thomas L, Bondarenko I, O'day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517–2526

    Article  CAS  PubMed  Google Scholar 

  • Rozeman EA, Fanchi L, Van Akkooi ACJ et al (2017) (Neo-)adjuvant ipilimumab 1 nivolumab (IPI1NIVO) in palpable stage 3 melanoma – updated relapse free survival (RFS) data from the OpACIN trial and first biomarker analyses. Ann Oncol 28(Suppl 5):1221

    Google Scholar 

  • Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68:7–30

    Article  PubMed  Google Scholar 

  • Sondak VK, Liu PY, Tuthill RJ, Kempf RA, Unger JM, Sosman JA, Thompson JA, Weiss GR, Redman BG, Jakowatz JG, Noyes RD, Flaherty LE (2002) Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with an allogeneic tumor vaccine: overall results of a randomized trial of the southwest oncology group. J Clin Oncol 20:2058–2066

    Article  CAS  PubMed  Google Scholar 

  • Spitler LE (1991) A randomized trial of levamisole versus placebo as adjuvant therapy in malignant melanoma. J Clin Oncol 9:736–740

    Article  CAS  PubMed  Google Scholar 

  • Tarhini A (2017) A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma (U.S. Intergroup E1609): preliminary safety and efficacy of the ipilimumab arms. ASCO 35:9500

    Google Scholar 

  • Thyrell L, Erickson S, Zhivotovsky B, Pokrovskaja K, Sangfelt O, Castro J, Einhorn S, Grander D (2002) Mechanisms of interferon-alpha induced apoptosis in malignant cells. Oncogene 21:1251–1262

    Article  CAS  PubMed  Google Scholar 

  • Veronesi U, Adamus J, Aubert C, Bajetta E, Beretta G, Bonadonna G, Bufalino R, Cascinelli N, Cocconi G, Durand J, De Marsillac J, Ikonopisov RL, Kiss B, Lejeune F, Mackie R, Madej G, Mulder H, Mechl Z, Milton GW, Morabito A, Peter H, Priario J, Paul E, Rumke P, Sertoli R, Tomin R (1982) A randomized trial of adjuvant chemotherapy and immunotherapy in cutaneous melanoma. N Engl J Med 307:913–916

    Article  CAS  PubMed  Google Scholar 

  • Wallack MK, Sivanandham M, Balch CM, Urist MM, Bland KI, Murray D, Robinson WA, Flaherty L, Richards JM, Bartolucci AA, Rosen L (1998) Surgical adjuvant active specific immunotherapy for patients with stage III melanoma: the final analysis of data from a phase III, randomized, double-blind, multicenter vaccinia melanoma oncolysate trial. J Am Coll Surg 187:69–77. Discussion 77–9

    Article  CAS  PubMed  Google Scholar 

  • Wallack MK, Sivanandham M, Balch CM, Urist MM, Bland KI, Murray D, Robinson WA, Flaherty LE, Richards JM, Bartolucci AA et al (1995) A phase III randomized, double-blind multiinstitutional trial of vaccinia melanoma oncolysate-active specific immunotherapy for patients with stage II melanoma. Cancer 75:34–42

    Article  CAS  PubMed  Google Scholar 

  • Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, Schenker M, Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, Middleton MR, Maio M, Atkinson V, Queirolo P, Gonzalez R, Kudchadkar RR, Smylie M, Meyer N, Mortier L, Atkins MB, Long GV, Bhatia S, Lebbe C, Rutkowski P, Yokota K, Yamazaki N, Kim TM, De Pril V, Sabater J, Qureshi A, Larkin J, Ascierto PA, Checkmate C (2017) Adjuvant Nivolumab versus Ipilimumab in resected stage III or IV melanoma. N Engl J Med 377:1824–1835

    Article  CAS  PubMed  Google Scholar 

  • Weber JS (2018) Adjuvant therapy with nivolumab versus ipilimumab after complete resection of stage III/IV melanoma: updated results from a phase III trial (CheckMate 238). J Clin Oncol 36:9502. Abstract presented at ASCO 2018

    Article  Google Scholar 

  • Wheatley K, Ives N, Hancock B, Gore M, Eggermont A, Suciu S (2003) Does adjuvant interferon-alpha for high-risk melanoma provide a worthwhile benefit? A meta-analysis of the randomised trials. Cancer Treat Rev 29:241–252

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Hematology-Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, USA

    Yana G. Najjar

  2. Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    Ryan Massa

  3. Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA

    Vernon K. Sondak

  4. Gustave Roussy Cancer Campus Grand Paris, Villejuif, France

    Alexander M. M. Eggermont

  5. First Department of Medicine, Laiko Hospital, University of Athens, Athens, Greece

    Helen Gogas

  6. Departments of Medicine, Dermatology, and Translational Science, University of Pittsburgh and UPMC Hillman Cancer Center, Pittsburgh, PA, USA

    John M. Kirkwood

Authors
  1. Yana G. Najjar
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  2. Ryan Massa
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  3. Vernon K. Sondak
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  4. Alexander M. M. Eggermont
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  5. Helen Gogas
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  6. John M. Kirkwood
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Correspondence to John M. Kirkwood .

Editor information

Editors and Affiliations

  1. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Charles M. Balch

  2. Department of Oncology, Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Washington, DC, USA

    Michael B. Atkins

  3. Centre for Dermatooncology, Department of Dermatology, Eberhard Karls University, Tuebingen, Germany

    Claus Garbe

  4. Departments of Surgical Oncology and Cancer Biology, Melanoma and Skin Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Jeffrey E. Gershenwald

  5. Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Allan C. Halpern

  6. Departments of Medicine, Dermatology, and Translational Science, University of Pittsburgh and UPMC Hillman Cancer Center, Pittsburgh, PA, USA

    John M. Kirkwood

  7. Divisions of Cancer Medicine and Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    Grant A. McArthur

  8. Melanoma Institute Australia, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia

    John F. Thompson

  9. Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Arthur J. Sober

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Najjar, Y.G., Massa, R., Sondak, V.K., Eggermont, A.M.M., Gogas, H., Kirkwood, J.M. (2020). Adjuvant Systemic Therapy for High-Risk Melanoma Patients. In: Balch, C., et al. Cutaneous Melanoma. Springer, Cham. https://doi.org/10.1007/978-3-030-05070-2_33

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  • DOI: https://doi.org/10.1007/978-3-030-05070-2_33

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