2018-19 Section 7-Neoplastic and Inflammatory Diseases of the Head and Neck eBook

A.M.M. Eggermont, R. Dummer / European Journal of Cancer 86 (2017) 101 e 105

4 e 5 nodes in an SN-biopsy procedure to determine whether a patient is considered stage IIIA or Stage IIIC. Recommendation for a stage IIIA patient depends on tumour load in the SN, and recommendation for a stage IIIC patient to choose adjuvant therapy is very strong.

[10] van der Ploeg AP, van Akkooi AC, Schmitz PI, Koljenovic S, Verhoef C, Eggermont AM. EORTC Melanoma Group sentinel node protocol identifies high rate of submicrometastases accord- ing to Rotterdam Criteria. Eur J Cancer 2010;46:2414 e 21 . [11] Van Akkooi ACJ, Nowecki ZI, Voit C, et al. Sentinel node tumor burden according to the Rotterdam criteria is the most important prognostic factor for survival in melanoma patients: a multicenter study in 388 patients with positive sentinel nodes. Ann Surg 2008; 248:949 e 55 . [12] Van der Ploeg APT, Van Akkooi ACJ, Rutkowski P, et al. Prognosis in patients with sentinel node-positive melanoma is accurately defined by the combined Rotterdam tumor load and Dewar topography criteria. J Clin Oncol 2011;29:2206 e 14 . [13] Van der Ploeg AP, van Akkooi AC, Haydu LE, et al. The prognostic significance of sentinel node tumour burden in mela- noma patients: an international, multicenter study of 1539 sentinel node-positive melanoma patients. Eur J Cancer 2014;50: 111 e 20 . [14] Schachter J, Ribas A, Long GV, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEY- NOTE-006). Lancet 2017 Aug 16. http://dx.doi.org/10.1016/S0140- 6736(17)31601-X . pii: S0140-6736(17)31601-X. [Epub ahead of print]. [15] Wolchok JD, Chiarion-Seleni V, Gonzalez R, et al. Overall survival with combined therapy with nivolumab and ipilimumab in mela- noma. N Engl J Med 2017 Sep 10. http://dx.doi.org/10.1056/NEJ- Moa1708539 [Epub ahead of print]. [16] Hofmann L, Forschner A, Loquai C, et al. Cutaneous, gastroin- testinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer 2016 Jun;60:190 e 209 . [17] Zimmer L, Goldinger SM, Hofmann L, et al. Neurological, res- piratory, musculoskeletal, cardiac and ocular side-effects of anti- PD-1 therapy. Eur J Cancer 2016 Jun;60:210 e 25 . [18] Coens C, Suciu S, Vanna Chiarion-Sileni V, et al. Phase III trial (EORTC 18071/CA184-029) of post-operative adjuvant ipilimu- mab compared to placebo in patients with resected stage III cutaneous melanoma: Health Related Quality of Life (HRQoL) results. Lancet Oncol 2017 Mar;18(3):393 e 403 . [19] Schadendorf D, Long GV, Stroiakovski D, et al. Three-year pooled analysis of factors associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 3 rando- mised trials. Eur J Cancer 2017;82:45 e 55 . [20] 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 e 17 . [21] Grob JJ, Dreno B, de la Salmonie`re P, et al. Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary mel- anoma thicker than 1.5 mm without clinically detectable node metastases. French Cooperative Group on Melanoma. Lancet 1998 Jun 27;351(9120):1905 e 10 . [22] Eggermont AMM, 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 e 26 . [23] Eggermont AM, Suciu S, Testori A, et al. 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 2012;30:3810 e 8 . [24] Eggermont AMM, Suciu S, MacKie R, et al. Post-surgery adju- vant 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 e 96 . [25] Eggermont AMM, 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. Eur J Cancer 2012;48:218 e 25 .

7. What is next?

Neoadjuvant use of highly active drugs such as nivolu- mab, or its combination with ipilimumab, and the use of a BRAF/MEK combination is a very attractive research concept for patients with palpable nodal stage III dis- ease. Both approaches have been reported to yield 40 e 50% pathologic complete responses and overall response rates of close to 100% [33,34] . Thereby, this approach may facilitate surgery and reduce the indica- tion for radiotherapy and potentially will result in increased locoregional control rates. It would be only logical to include a neoadjuvant component in further trials to improve overall outcome. Today, neoadjuvant therapies should be applied only in the context of clin- ical trials with a strong translational intent. Other de- velopments will emerge depending on efficacy and low- toxicity data of new combinations, such as low-dose ipilimumab in combination with anti-PD1 [35] . [1] Eggermont AMM, Spatz A, Robert C. Cutaneous melanoma. Lancet 2014;383:816 e 27 . [2] Ugurel S, Ro¨hmel J, Ascierto PA, et al. Survival of patients with advanced metastatic melanoma: the impact of novel therapies- update 2017. Eur J Cancer 2017;83:247 e 57 . [3] Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipi- limumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double- blind, phase 3 trial. Lancet Oncol 2015 May;16(5):522 e 30 . [4] Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged survival with Ipilimumab as adjuvant in stage III melanoma. New Engl J Med 2016;375:1845 e 55 . [5] Eggermont AM. Adjuvant ipilimumab in stage III melanoma: new landscape, new questions. Eur J Cancer 2016;69:39 e 42 . [6] Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 2017 Sep 10. http://dx.doi.org/10.1056/NEJMoa1709030 [Epub ahead of print]. [7] Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med 2017 Sep 10. http://dx.doi.org/10.1056/NEJMoa1708539 [Epub ahead of print]. [8] Balch CM, Gershenwald JE, Soong S-J, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009;27:6199 e 206 . [9] Balch CM, Gershenwald JE, Soong S-J, et al. Multivariate anal- ysis of prognostic factors among 2,313 patients with stage III melanoma: comparison of nodal micrometastases versus macro- metastases. J Clin Oncol 2010;28:2452 e 9 . Conflict of interest statement None declared. References

61