Background: The role of adding chemotherapy to adjuvant radiation therapy in resectable Merkel cell carcinoma (MCC) remains controversial. Previous studies have shown conflicting results, and long-term outcome data are limited. Objectives: In this study, we aimed to evaluate the long-term survival outcomes of patients with resectable MCC treated with surgery followed by either radiation alone or combined chemoradiation. Methods: This retrospective multicenter cohort study analyzed 105 patients with resectable MCC treated between 1985 and 2023. Patients received either adjuvant radiation alone (n = 53) or chemoradiation (n = 52) following surgery. The primary endpoints were overall survival and disease-free survival. The secondary endpoints included an analysis of prognostic factors and treatment-related characteristics. The median follow-up was 12 years. Results: The 20-year overall survival rates were 53.4% for chemoradiation versus 30.7% for radiation alone (p = 0.324). Median survival in the chemoradiation groups was not reached during the follow-up period; in the radiation group, it was 8.8 years. Likewise, the twenty-year disease-free survival rates were not significantly different between the chemoradiation and radiation groups: 47% vs. 29.3%, respectively, p = 0.495. The chemoradiation group had significantly more advanced disease (88% vs. 28.3% stage III) but was younger (median 65.9 vs. 77.3 years, p = 0.002) and received higher radiation doses (median 50 Gy vs. 45 Gy, p = 0.002). After controlling for age, stage, and tumor location in a multivariable analysis, the survival differences were still not significantly different (hazard ratio (HR) = 1.36, 95% CI 0.61–3.00, p = 0.450). Conclusions: While the multivariate analysis did not indicate a survival advantage to adding chemotherapy to radiation, the comparable survival outcomes despite significantly more advanced disease in the chemoradiation group suggest a possible benefit in high-risk patients. Our results indicate the need for prospective studies with larger, stage-matched cohorts to definitively establish the role of adjuvant chemotherapy in high-risk resectable MCC.

Background: Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine malignancy. The prognostic impact of sun exposure at the primary tumor site in localized and locally advanced MCC remains incompletely defined. We aimed to compare clinicopathologic characteristics and survival outcomes between sun-exposed and non-sun-exposed MCC in a large, multi-center Israeli cohort. Methods: We retrospectively identified 249 patients diagnosed with localized or locally advanced MCC between January 1985 and December 2020. Of these, 225 patients met eligibility criteria and were included in the analysis: 142 with sun-exposed primary tumors (cohort A) and 83 with non-sun-exposed tumors (cohort B). Baseline characteristics included age, sex, tumor size, lymph node (LN) involvement at diagnosis, disease-free survival (DFS), and overall survival (OS). Results: Median age at diagnosis was similar between cohorts (~73 years), with a male predominance in both groups. LN involvement was significantly more frequent in non-sun-exposed tumors compared with sun-exposed tumors (57.0% vs. 30.0%, p < 0.001), while tumor size distribution did not differ significantly. Median DFS was numerically longer in sun-exposed patients (58.0 vs. 47.8 months, p ≈ 0.18), whereas median OS favored non-sun-exposed patients (89.7 vs. 79.7 months, p ≈ 0.21), though neither difference reached statistical significance overall. Females demonstrated longer DFS and OS than males across both cohorts. Among LN-negative patients, non-sun-exposed tumors were associated with significantly improved OS (105.9 vs. 91.4 months, p ≈ 0.03), particularly in males. Primary tumor size further stratified outcomes: non-sun-exposed patients had significantly superior OS for tumors <2 cm and both improved DFS and OS for tumors ≥2 cm. Conclusions: In this large real-world MCC cohort, sun exposure status was associated with distinct patterns of nodal involvement and survival in clinically relevant subgroups. Non-sun-exposed MCC demonstrated favorable survival outcomes, particularly in LN-negative disease and across tumor size categories, suggesting underlying biological differences that merit further investigation.

Background: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer, with prognosis influenced by tumor location and primary status. This study evaluated clinicopathological features and survival outcomes in patients with MCC from multiple centers in Israel. Methods: Data on demographics, tumor characteristics, lymph node (LN) involvement, treatment, and survival were collected. Patients were stratified by primary tumor status (known vs. unknown) and tumor location (sun-exposed vs. non-sun-exposed). Disease-free survival (DFS) and overall survival (OS) were estimated using Kaplan–Meier analysis, and multivariate analyses were performed. Results: The cohort included 80 patients diagnosed with stage 3 (with LN involvement) MCC, of whom 52 (65%) had primary MCC with lymph node involvement, and 28 patients (35%) with unknown primary MCC. The majority were male (81.3%), with a median age of 71.2 years (range, 37–92). The median DFS and OS for the entire cohort were 24 and 32 months, respectively. Patients with unknown primary tumors had longer DFS (34 vs. 18 months; p = 0.0503) and OS (43 vs. 28 months; p = 0.0362) compared with those with known primary MCC. Non-sun-exposed tumors were associated with longer median DFS (32 vs. 18.5 months; p = 0.0663) and OS (41 vs. 23 months; p = 0.0353). Five-year survival analysis showed improved outcomes in patients with unknown primary tumors (DFS 54% vs. 35%, p = 0.04; OS 57% vs. 42%, p = 0.03) and in non-sun-exposed tumors (DFS 51% vs. 33%, p = 0.05; OS 57% vs. 40%, p = 0.04). Conclusions: Unknown primary status and non-sun-exposed tumor location are potentially associated with improved long-term survival in patients with MCC. These findings highlight the prognostic importance of tumor origin and anatomical site in MCC management.

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–etoposide 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–III) 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–etoposide plus radiotherapy, or six cycles of platinum–etoposide 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–Meier method and multivariable Cox proportional hazards regression. Results: Four cycles of adjuvant platinum–etoposide 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: 58–72%) and 75% (95% CI: 68–82%), respectively, compared with 55% and 60% in the six-cycle group, and 40% and 45% in the radiotherapy-only group (p < 0.001). The survival advantage of four cycles over radiotherapy alone was sustained at 10- and 20-year follow-up (p < 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–etoposide 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.

Background: Ripretinib, a switch-control kinase inhibitor approved for advanced gastrointestinal stromal tumor (GIST), inhibits primary and secondary KIT and PDGFRA mutations. Real-world data from Western and Middle Eastern populations remain limited. We report outcomes from a molecularly characterized Israeli multicenter cohort. Methods: We conducted a multicenter retrospective cohort study across seven university-affiliated medical centers in Israel. Patients with advanced GIST receiving Ripretinib at any treatment line were eligible. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method, and response was assessed according to modified RECIST v1.1. Results: Sixteen patients were identified (median age, 67.5 years; 75.0% received Ripretinib in the fourth-line setting). KIT exon 11 mutations were present in 62.5% of patients, including five with secondary resistance mutations involving exon 13 or exons 17/18. Median PFS was 7.0 months (95% CI, 2.0–13.0) and median OS was 14.7 months (95% CI, 4.4–NR). Individual outcomes varied substantially, with PFS ranging from 2.0 to 60.2 months and OS from 2.2 to 60.2 months. Three patients achieved complete responses, with PFS of 20.0, 33.6, and 60.2 months. ORR was 56.3% (CR, n = 3; PR, n = 6) and DCR was 81.3%. No dose reductions or treatment discontinuations due to adverse events were documented; however, adverse events were recorded in only 4 of 16 patients. Conclusions: Ripretinib demonstrated clinical activity in this small, heavily pre-treated cohort. The relatively high ORR and wide variability in outcomes should be interpreted cautiously given the small sample size, retrospective design, and absence of central radiological review. Durable responses were observed in some patients with KIT exon 11 and secondary exon 17/18 mutations, but this exploratory observation does not establish a predictive molecular subgroup. Larger prospective studies with systematic molecular, radiological, and safety assessment are warranted.