UvA-DARE (Digital Academic Repository) Who needs adjuvant therapy in stage III melanoma? Madu, M.F. Link to publication

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1 UvA-DARE (Digital Academic Repository) Who needs adjuvant therapy in stage III melanoma? Madu, M.F. Link to publication Citation for published version (APA): Madu, M. F. (2018). Who needs adjuvant therapy in stage III melanoma? General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 13 Jan 2019

2 CHAPTER 3 Immediate completion lymph node dissection in stage IIIA melanoma does not provide signifi cant additional staging information beyond EORTC SN tumor burden criteria

3 58 CLND in stage IIIA melanoma

4 Effective adjuvant therapy has arrived in melanoma with the approval of high-dose ipilimumab for stage III patients with a lymph node tumor burden of >1 mm. The EORTC study showed a clear survival benefit for 10 mg/kg ipilimumab compared with placebo 1,2. However, toxicity was a major problem in the treatment group, with 5 (1%) therapy-related deaths and more than half developing severe (grade 3-5) adverse events. More trials are underway, evaluating likely less toxic immunotherapy regimens, but based on experiences in stage IV, significant toxicity is still to be expected 3-7. This signifies the need for accurate risk prediction, allowing high-risk patients to reap the rewards from adjuvant therapy, whereas low-risk patients can be spared its toxicity. The best risk prediction tool currently available for patients with localized melanoma is sentinel node biopsy (SNB), which provides an accurate assessment of the regional lymph node status 8,9. The tumor burden present in the SN correlates with prognosis There has been a long-standing controversy regarding the role of completion lymph node dissection (CLND) in SN-positive patients. This issue has now finally been resolved, thanks to the recent publication of the MSLT-II and DeCOG-SLT trials that did not find a melanoma- specific survival benefit for CLND compared with observation in SN-positive patients 14,15. The authors of the MSLT-II trial argued however, that CLND did offer the most complete staging, since it detected additional lymph node metastases in 11.5% of the patients. We performed an analysis of our prospective institutional database to evaluate the actual frequency of stage change by CLND. Patients with AJCC 7 th edition stage IIIA cutaneous melanoma who were treated consecutively in the Netherlands Cancer Institute between 2000 and 2015 were included in a database for this study. Stage IIIA melanoma was defined as a non-ulcerated primary tumor with 1 or 2 metastatic SNs (pt1-4an1-2am0) 16. Exclusion criteria were (neo-)adjuvant treatment in clinical trials and multiple primary melanomas with distant metastases. Primary outcome measures were distant metastasis-free survival (DMFS) and disease-free survival (DFS). SNB was performed according to the triple technique, which is described elsewhere in detail 17,18. All SNs were formalin-fixated, bisected, paraffin-embedded, and cut at a minimum of three levels at 50- to 150-mm intervals. Pathologic evaluation included hematoxylin and eosin staining as well as immunohistochemical staining using S-100 in combination with HMB45 or Melan-A. An expert melanoma pathologist (BW) reviewed all SN slides for this study. The maximum diameter of the largest metastasis, micro-anatomic location and tumor penetrative depth (TPD) were scored according to the EORTC recommendations and Starz criteria 19,20. SNpositive patients were eligible for axillary, inguinal, or neck completion lymph node dissection (CLND). CLND could be foregone in case of minimal SN tumor burden, co-morbidities, trial participation (MSLT-II) or patient preferences. CLND in stage IIIA melanoma 59

5 Treatment characteristics were compared across treatment groups using the χ 2 -test, the Fisher s exact test or the Mann-Whitney-U test. The correlation of baseline characteristics and tumor burden with non-sn metastasis was assessed using logistic regression. Survival curves were generated with the Kaplan-Meier method and compared with the log-rank test. Hazard ratios (HR) were calculated using Cox s proportional hazards model. All baseline and treatment characteristics with a p-value of <0.1 in univariable models were subsequently added to a multivariable model. Distant metastasis-free survival (DMFS) was calculated from the date of SNB to the date of distant metastasis, death or last follow-up. Disease-free survival (DFS) was calculated from the date of SNB to the date of first disease recurrence, death or last followup. The proportionality assumptions for all Cox models were checked and fulfilled. A p-value of <0.05 was considered statistically significant. All statistical analyses were performed using SPSS version 22.0 or STATA version 13. Tabel 1 Variables Overall (n = 140) CLND (n = 86) Observation (n = 54) P N % N % N % Sex Female Male N/S Age at SNB Median / IQR N/S Location of primary tumor Extremity Trunk Head/neck N/S Breslow (mm) Median / IQR N/S Breslow (T) T T T T N/S Ulceration Absent CLND in stage IIIA melanoma

6 Variables Overall (n = 140) CLND (n = 86) Observation (n = 54) P Number of positive SNs 1 (N1) (N1) (N2) N/S Maximum diameter of metastasis Median/ IQR Rotterdam classification <0.1 mm mm >1.0 mm N/S Dewar classification Subcapsular Parenchymal Combined Multifocal Extensive N/S TPD Median / IQR <0.001 Starz classification SI SII SIII Non-SN metastasis Absent Present NA NA NA SN, sentinel node; CLND, completion lymph node dissection; N/S, non-significant; IQR, interquartile range; NA, not applicable; N/S, non-significant. MSLT-II: Multicenter Selective Lymphadenectomy Trial - 2. P-value for statistical significance of difference in distribution of variables between operation sites (Chi-square test, Fisher s exact test or Mann-Whitney-U test as applicable). One hundred forty patients were included in this study. Baseline and treatment characteristics are reported in Table 1. Median follow-up was 56 months. Five-year DMFS was 75%. Five-year DFS was 68%. Eighty-six patients underwent CLND. Ten of these patients (11.6%) had additional non- SN lymph node metastases in the dissection specimen. In 5 cases (5.8%), non-sn metastases would have increased the N-status (to N3, and therefore AJCC stage IIIC). Non-SN metastasis in CLND in stage IIIA melanoma 61

7 CLND patients failed to reach significance as a prognostic factor for DMFS or DFS. EORTC SN tumor burden >1 mm was a clear independent prognostic factor, however. The final report of the MSLT-II trial showed that immediate CLND in SN-positive patients has no therapeutic value 14. However, Faries et al. argue that foregoing immediate CLND can impede the most appropriate risk stratification and selection for adjuvant therapy trials, because non- SN metastasis, which is present in 11.5% of patients, carries an almost twofold higher risk of melanoma-related death. In our cohort of stage IIIA melanoma patients, the non-sn metastasis rate in the CLND group was 11.6%, similar to the MSLT-II results. This means that at least 88.4% of patients underwent unnecessary immediate CLND. These patients did not benefit from an improved prognosis or additional staging value but did suffer a significant risk of lifelong morbidity. Even among the patients with non-sn metastases, the additional staging information led to a stage change in only half of the cases (5.8% of the CLND group). This increases the percentage of unnecessary CLNDs to 94.2%. The MSLT-II report unfortunately did not detail the specifics of patients with non-sn metastases and in how many cases CLND led to a stage change. In this study, EORTC SN tumor burden criteria correlated strongly with survival in stage IIIA melanoma patients. When stratified according to accepted cutoffs, maximum diameter was the strongest parameter, showing significantly worse DFS for patients with tumor burden >1 mm. This is in line with the literature that shows maximum diameter has the least interobserver variability of all tumor burden parameters and offers the most reliable prognostic information 11,21,22. The currently reported adjuvant studies and/or the ongoing studies that will report in the near future have all mandated CLND as an inclusion criterion, since this was the accepted standard of care before the publication of the MSLT-II and DeCOG-SLT results. Now, the inclusion criteria need to be rethought. We propose that patients with high-risk stage III disease (>1 mm SN tumor diameter according to EORTC SN tumor burden criteria) should be eligible for future adjuvant therapy (trials). In conclusion, CLND does not improve survival and leads to a change in disease stage in less than 6% of patients. In our opinion, CLND is not defensible anymore and should be abolished. In the absence of better prognosticators, eligibility for adjuvant therapy (trials) can be determined based on the EORTC SN tumor burden and AJCC staging criteria. 62 CLND in stage IIIA melanoma

8 References 1. Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med 2016 Nov 10;375(19):1845e55 Epub 2016 Oct Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol 2015;16(5):522e Hodi FS, O Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363(8):711e Larkin J, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl J Med 2015;373(13):1270e1. 5. Egger ME, Bower MR, Czyszczon IA, Farghaly H, Noyes RD, Reintgen DS, et al. Comparison of sentinel lymph node micrometastatic tumor burden measurements in melanoma. J Am Coll Surg 2014;218(4):519e Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015;372(4):320e Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015;372(26):2521e Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Elashoff R, Essner R, et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 2006;355(13):1307e Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Nieweg OE, Roses DF, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med 2014;370(7):599e van der Ploeg AP, van Akkooi AC, Rutkowski P, Nowecki ZI, Michej W, Mitra A, 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(16):2206e van der Ploeg AP, van Akkooi AC, Haydu LE, Scolyer RA, Murali R, Verhoef C, et al. The prognostic significance of sentinel node tumour burden in melanoma patients: an international, multicenter study of 1539 sentinel node-positive melanoma patients. Eur J Cancer 2014;50(1):111e van Akkooi AC, Nowecki ZI, Voit C, Schafer-Hesterberg G, Michej W, de Wilt JH, 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(6):949e Gershenwald JE, Andtbacka RH, Prieto VG, Johnson MM, Diwan AH, Lee JE, et al. Microscopic tumor burden in sentinel lymph nodes predicts synchronous nonsentences lymph node involvement in patients with melanoma. J Clin Oncol 2008;26(26):4296e Faries MB, Thompson JF, Cochran AJ, Andtbacka RH, Mozzillo N, Zager JS, et al. Completion dissection or observation for sentinel-node metastasis in melanoma. N Engl J Med 2017;376(23):2211e Leiter U, Stadler R, Mauch C, Hohenberger W, Brockmeyer N, Berking C, et al. Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial. Lancet Oncol 2016;17(6):757e Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009;27(36):6199e CLND in stage IIIA melanoma 63

9 17. Morton DL, Wen DR, Wong JH, Economou JS, Cagle LA, Storm FK, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Archives Surg 1992;127(4):392e Uren RF, Thompson JF, Howman-Giles R. Sentinel lymph node biopsy in patients with melanoma and breast cancer. Intern Med J 2001;31(9):547e van Akkooi AC, Spatz A, Eggermont AM, Mihm M, Cook MG. Expert opinion in melanoma: the sentinel node; EORTC Melanoma Group recommendations on practical methodology of the measurement of the micro-anatomic location of metastases and metastatic tumour burden. Eur J Cancer 2009;45(16):2736e Starz H, Siedlecki K, Balda BR. Sentinel lymphadenectomy and s-classification: a successful strategy for better prediction and improvement of outcome of melanoma. Ann Surg Oncol 2004;11(3 Suppl):162Se8S. 21. Murali R, Hughes MT, Fitzgerald P, Thompson JF, Scolyer RA. Interobserver variation in the histopathologic reporting of key prognostic parameters, particularly clark level, affects pathologic staging of primary cutaneous melanoma. Ann Surg 2009;249(4):641e Madu MF, Wouters MW, van Akkooi AC. Sentinel node biopsy in melanoma: current controversies addressed. Eur J Surg Oncol 2017;43(3):517e CLND in stage IIIA melanoma

10 Author contributions Max F. Madu Viola Franke Maarten M. Bruin Danique M.S. Berger Carolien Bierman Katarzyna Jóźwiak Willem M.C. Klop Michel W.J.M. Wouters Alexander C.J. van Akkooi Bart A. Van de Wiel Acquisition of data, analysis and interpretation of data, drafting of manuscript Acquisition of data Acquisition of data Acquisition of data Acquisition of data Analysis and interpretation of data, critical revision Critical revision Study conception and design, critical revision Study conception and design, critical revision Acquisition of data 3 CLND in stage IIIA melanoma 65