{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T11:14:26Z","timestamp":1777979666822,"version":"3.51.4"},"reference-count":25,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T00:00:00Z","timestamp":1777852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin malignancy associated with high rates of recurrence and disease-specific mortality. Although adjuvant platinum\u2013etoposide chemotherapy is used in high-risk disease, the optimal number of treatment cycles has not been established. Materials and Methods: This multicenter retrospective cohort study included 104 patients with resected high-risk MCC (pathological stage IIB\u2013III) treated at Israeli medical centers between September 1985 and February 2021. Patients were assigned to one of three treatment groups: radiotherapy alone, four cycles of platinum\u2013etoposide plus radiotherapy, or six cycles of platinum\u2013etoposide plus radiotherapy. The chemotherapy regimen consisted of cisplatin or carboplatin combined with etoposide in 21-day cycles, with the first two cycles administered concurrently with radiotherapy. Primary endpoints were disease-free survival (DFS) and overall survival (OS), analyzed using the Kaplan\u2013Meier method and multivariable Cox proportional hazards regression. Results: Four cycles of adjuvant platinum\u2013etoposide combined with radiotherapy were associated with the most favorable survival outcomes at all follow-up time points. Five-year DFS and OS in the four-cycle group were 65% (95% CI: 58\u201372%) and 75% (95% CI: 68\u201382%), respectively, compared with 55% and 60% in the six-cycle group, and 40% and 45% in the radiotherapy-only group (p &lt; 0.001). The survival advantage of four cycles over radiotherapy alone was sustained at 10- and 20-year follow-up (p &lt; 0.0001). In patients with stage III disease and nodal involvement, the four-cycle group achieved a median DFS of 93 months and a median OS of approximately 110 months, significantly exceeding outcomes in both the six-cycle and radiotherapy-alone groups. No statistically significant survival benefit from chemotherapy was identified in the small subgroup of patients with stage IIB\/T4N0 disease. Conclusions: In patients with high-risk resected MCC, the addition of adjuvant platinum\u2013etoposide chemotherapy to radiotherapy significantly improves DFS and OS, with the greatest benefit observed in patients with stage III disease and lymph node involvement. Four cycles represent an optimal treatment duration, delivering durable long-term survival benefit without the need for more prolonged chemotherapy exposure. These findings support a risk-adapted multimodality approach and provide real-world evidence to guide adjuvant therapy decisions in this rare and aggressive malignancy.<\/jats:p>","DOI":"10.3390\/medicina62050882","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T10:01:30Z","timestamp":1777975290000},"page":"882","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Optimal Duration of Adjuvant Platinum\u2013Etoposide in High-Risk Merkel Cell Carcinoma"],"prefix":"10.3390","volume":"62","author":[{"given":"Ronen","family":"Brenner","sequence":"first","affiliation":[{"name":"Oncology Institute, Edith Wolfson Medical Center, Holon 58220, Israel"},{"name":"Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanna T. Frumin","family":"Edri","sequence":"additional","affiliation":[{"name":"Oncology Institute, Edith Wolfson Medical Center, Holon 58220, Israel"},{"name":"Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8273-4723","authenticated-orcid":false,"given":"Keren","family":"Rouvinov","sequence":"additional","affiliation":[{"name":"The Legacy Heritage Cancer Center, Dr. Larry Norton Institute, Soroka Medical Center, Beer Sheva 84105, Israel"},{"name":"Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7708-042X","authenticated-orcid":false,"given":"Noa","family":"Shani Shrem","sequence":"additional","affiliation":[{"name":"The Legacy Heritage Cancer Center, Dr. Larry Norton Institute, Soroka Medical Center, Beer Sheva 84105, Israel"},{"name":"Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amichay","family":"Meirovitz","sequence":"additional","affiliation":[{"name":"The Legacy Heritage Cancer Center, Dr. Larry Norton Institute, Soroka Medical Center, Beer Sheva 84105, Israel"},{"name":"Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabri","family":"El-Saied","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilia","family":"Berezhnov","sequence":"additional","affiliation":[{"name":"Oncology Institute, Edith Wolfson Medical Center, Holon 58220, Israel"},{"name":"Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Ievko","sequence":"additional","affiliation":[{"name":"Oncology Institute, Edith Wolfson Medical Center, Holon 58220, Israel"},{"name":"Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sofiia","family":"Turaieva","sequence":"additional","affiliation":[{"name":"Oncology Institute, Edith Wolfson Medical Center, Holon 58220, Israel"},{"name":"Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shlomit","family":"Fenig","sequence":"additional","affiliation":[{"name":"Institute of Oncology, Kaplan Medical Center, Faculty of Medicine, Hebrew University, Jerusalem 91905, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nashat","family":"Abu Yasin","sequence":"additional","affiliation":[{"name":"The Legacy Heritage Cancer Center, Dr. Larry Norton Institute, Soroka Medical Center, Beer Sheva 84105, Israel"},{"name":"Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eyal","family":"Fenig","sequence":"additional","affiliation":[{"name":"Institute of Oncology, Davidoff Center, Rabin Medical Center, Beilinson Hospital, Petah Tikva 49414, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samer","family":"Hussany","sequence":"additional","affiliation":[{"name":"The Legacy Heritage Cancer Center, Dr. Larry Norton Institute, Soroka Medical Center, Beer Sheva 84105, Israel"},{"name":"Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Yakobson","sequence":"additional","affiliation":[{"name":"The Legacy Heritage Cancer Center, Dr. Larry Norton Institute, Soroka Medical Center, Beer Sheva 84105, Israel"},{"name":"Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7570-4550","authenticated-orcid":false,"given":"Walid","family":"Shalata","sequence":"additional","affiliation":[{"name":"The Legacy Heritage Cancer Center, Dr. Larry Norton Institute, Soroka Medical Center, Beer Sheva 84105, Israel"},{"name":"Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.jaad.2007.11.020","article-title":"Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: The AEIOU features","volume":"58","author":"Heath","year":"2008","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.jaad.2017.10.028","article-title":"Merkel cell carcinoma: Current US incidence and projected increases based on changing demographics","volume":"78","author":"Paulson","year":"2018","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1126\/science.1152586","article-title":"Clonal integration of a polyomavirus in human Merkel cell carcinoma","volume":"319","author":"Feng","year":"2008","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"17077","DOI":"10.1038\/nrdp.2017.77","article-title":"Merkel cell carcinoma","volume":"3","author":"Becker","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"742","DOI":"10.6004\/jnccn.2018.0055","article-title":"Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology","volume":"16","author":"Bichakjian","year":"2018","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.jaad.2020.07.079","article-title":"Narrow excision margins are appropriate for Merkel cell carcinoma when combined with adjuvant radiation: Analysis of 188 cases of localized disease and proposed management algorithm","volume":"84","author":"Tarabadkar","year":"2021","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Bi, A., Yang, S., Ding, Y., Yu, Y., Zhan, W., and Song, T. (2022). Prognostic Value of Radiotherapy and Chemotherapy in Stage I\u2013III Merkel Cell Carcinoma. Front. Med., 9.","DOI":"10.3389\/fmed.2022.845905"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1002\/hed.24776","article-title":"Impact of total radiotherapy dose on survival for head and neck Merkel cell carcinoma after resection","volume":"39","author":"Patel","year":"2017","journal-title":"Head Neck"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2493","DOI":"10.1200\/JCO.2000.18.12.2493","article-title":"Chemotherapy in neuroendocrine\/Merkel cell carcinoma of the skin: Case series and review of 204 cases","volume":"18","author":"Tai","year":"2000","journal-title":"J. Clin. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Shalata, W., Edri, H.T.F., Sarel, I., Ievko, A., Turaieva, S., Tairov, T., Berezhnov, I., Fenig, S., Fenig, E., and Ziv-Baran, T. (2025). Is the Addition of Chemotherapy to Adjuvant Radiation in Merkel Cell Cancer Beneficial? Real-World Data with Long-Term Follow-Up. Cancers, 17.","DOI":"10.3390\/cancers17060945"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.jss.2021.03.062","article-title":"Survival Benefit of Guideline-Concordant Postoperative Radiation for Local Merkel Cell Carcinoma","volume":"266","author":"Wong","year":"2021","journal-title":"J. Surg. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1016\/S1470-2045(16)30364-3","article-title":"Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: A multicentre, single-group, open-label, phase 2 trial","volume":"17","author":"Kaufman","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2542","DOI":"10.1056\/NEJMoa1603702","article-title":"PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma","volume":"374","author":"Nghiem","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2300","DOI":"10.1200\/JCO.2005.02.329","article-title":"Merkel cell carcinoma: Prognosis and treatment of patients from a single institution","volume":"23","author":"Allen","year":"2005","journal-title":"J. Clin. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1862","DOI":"10.1002\/lary.27031","article-title":"Adjuvant radiation therapy improves patient survival in early-stage merkel cell carcinoma: A 15-year single-institution study","volume":"128","author":"Han","year":"2018","journal-title":"Laryngoscope"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"djw042","DOI":"10.1093\/jnci\/djw042","article-title":"Adjuvant Radiation Therapy and Chemotherapy in Merkel Cell Carcinoma: Survival Analyses of 6908 Cases From the National Cancer Data Base","volume":"108","author":"Bhatia","year":"2016","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Brenner, R., Frumin Edri, H.T., Sarel, I., Levko, A., Turaieva, S., Tairov, T., Berezhnov, I., Fenig, S., Fenig, E., and Ziv-Baran, T. (2025). Worse prognosis of local and locally advanced head and neck Merkel cell carcinoma: Is it time to change the treatment paradigm?. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1691000"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2589","DOI":"10.1002\/(SICI)1097-0142(19990615)85:12<2589::AID-CNCR15>3.0.CO;2-F","article-title":"Chemotherapy for patients with locally advanced or metastatic Merkel cell carcinoma","volume":"85","author":"Voog","year":"1999","journal-title":"Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.ijrobp.2005.04.042","article-title":"Does chemotherapy improve survival in high-risk stage I and II Merkel cell carcinoma of the skin?","volume":"64","author":"Poulsen","year":"2006","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_20","first-page":"e240002","article-title":"NCCN Guidelines\u00ae Insights: Merkel Cell Carcinoma, Version 1.2024","volume":"22","author":"Schmults","year":"2024","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1056\/NEJMoa1713709","article-title":"Duration of Adjuvant Chemotherapy for Stage III Colon Cancer","volume":"378","author":"Grothey","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.21037\/jtd.2019.05.34","article-title":"Changes in store for early-stage non-small cell lung cancer","volume":"11","author":"Sandler","year":"2019","journal-title":"J. Thorac. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Rubatto, M., Sciamarrelli, N., Borriello, S., Pala, V., Mastorino, L., Tonella, L., Ribero, S., and Quaglino, P. (2023). Classic and new strategies for the treatment of advanced melanoma and non-melanoma skin cancer. Front. Med., 9.","DOI":"10.3389\/fmed.2022.959289"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1080\/14796694.2025.2610172","article-title":"Avelumab real-world use in advanced Merkel cell carcinoma: A systematic review and non-comparative meta-analysis","volume":"22","author":"Freitag","year":"2026","journal-title":"Future Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e1077","DOI":"10.1634\/theoncologist.2020-0184","article-title":"FDA Accelerated Approval of Pembrolizumab for Recurrent Locally Advanced or Metastatic Merkel Cell Carcinoma","volume":"25","author":"Bradford","year":"2020","journal-title":"Oncologist"}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/62\/5\/882\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T10:46:30Z","timestamp":1777977990000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/62\/5\/882"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,4]]},"references-count":25,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["medicina62050882"],"URL":"https:\/\/doi.org\/10.3390\/medicina62050882","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,4]]}}}