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BackgroundImmune checkpoint inhibitors (ICI) have led to a prolongation of progression-free and overall survival in patients with metastatic Merkel cell carcinoma (MCC). However, immune-mediated adverse events due to ICI therapy are common and often lead to treatment discontinuation. The response duration after cessation of ICI treatment is unknown. Hence, this study aimed to investigate the time to relapse after discontinuation of ICI in MCC patients.MethodsWe analyzed 20 patients with metastatic MCC who have been retrospectively enrolled at eleven skin cancer centers in Germany. These patients have received ICI therapy and showed as best overall response (BOR) at least a stable disease (SD) upon ICI therapy. All patients have discontinued ICI therapy for other reasons than disease progression. Data on treatment duration, tumor response, treatment cessation, response durability, and tumor relapse were recorded.ResultsOverall, 12 of 20 patients (60%) with MCC relapsed after discontinuation of ICI. The median response durability was 10.0 months. Complete response (CR) as BOR to ICI-treatment was observed in six patients, partial response (PR) in eleven, and SD in three patients. Disease progression was less frequent in patients with CR (2/6 patients relapsed) as compared to patients with PR (7/11) and SD (3/3), albeit the effect of initial BOR on the response durability was below statistical significance. The median duration of ICI therapy was 10.0 months. Our results did not show a correlation between treatment duration and the risk of relapse after treatment withdrawal. Major reasons for discontinuation of ICI therapy were CR (20%), adverse events (35%), fatigue (20%), or patient decision (25%). Discontinuation of ICI due to adverse events resulted in progressive disease (PD) in 71% of patients regardless of the initial response. A re-induction of ICI was initiated in 8 patients upon tumor progression. We observed a renewed tumor response in 4 of these 8 patients. Notably, all 4 patients showed an initial BOR of at least PR.ConclusionOur results from this contemporary cohort of patients with metastatic MCC indicate that MCC patients are at higher risk of relapse after discontinuation of ICI as compared to melanoma patients. Notably, the risk of disease progression after discontinuation of ICI treatment is lower in patients with initial CR (33%) as compared to patients with initial PR (66%) or SD (100%). Upon tumor progression, re-induction of ICI is a feasible option. Our data suggest that the BOR to initial ICI therapy might be a potential predictive clinical marker for a successful re-induction.

Background: Established prognostic factors are of limited value to predict long-term survival and benefit from metastasectomy in advanced melanoma. This study aimed to identify prognostic factors in patients with distant metastasis. Methods: We analysed overall survival of 855 institutional melanoma patients with distant metastasis by bivariate Kaplan–Meier survival probabilities and multivariate Cox hazard regression analysis. Results: Serum lactate dehydrogenases (LDH), S100B, the interval between initial diagnosis and occurrence of distant metastasis, the site of distant metastases, and the number of involved distant sites were significant independent prognostic factors in both bivariate and multivariate analyses. Visceral metastases other than lung (hazard ratio (HR) 1.8), elevated S100B (HR 1.7) and elevated LDH (HR 1.6) had the highest negative impact on survival. Complete metastasectomy was likewise an independent prognostic factor in multivariate analysis. This treatment was associated with favourable survival for patients with normal LDH and S100B values (5-year survival, 37.2%). Conclusion: The serum markers LDH and S100B were both found to be prognostic factors in melanoma patients with distant metastasis. Furthermore, complete metastasectomy had an independent favourable prognostic impact in particular for the patient subgroup with normal LDH and S100B values.

Background: This retrospective study aimed to identify prognostic factors in patients with brain metastases from cutaneous melanoma. Methods: In all, 265 patients under regular screening according to valid national surveillance guidelines were included in the study. Kaplan–Meier analyses were performed to estimate and to compare overall survival. Cox modeling was used to identify independent determinants of the overall survival, which were used in explorative classification and regression tree analysis to define meaningful prognostic groups. Results: In total, 55.5% of our patients presented with two or less brain metastases, 82.6% had concurrent extracranial metastasis and 64% were asymptomatic and diagnosed during surveillance scans. In all, 36.7% were candidates for local treatment (neurosurgery or stereotactic radiosurgery (SRS)). The median overall survival of the entire collective was 5.0 months (95% confidence interval: 4.3–5.7). Favourable independent prognostic factors were: normal pre-treatment level of serum lactate dehydrogenase ( P <0.001), administered therapy (neurosurgery or SRS vs other, P =0.002), number of brain metastases (single vs multiple, P =0.032) and presence of bone metastasis (false vs true, P =0.044). Three prognostic groups with significantly different overall survival were identified. Candidates for local treatment (group I) had the longer median survival (9 months). Remaining patients could be further classified in two groups on the basis of serum lactate dehydrogenase. Conclusion: Applied treatment and serum lactate dehydrogenase levels were independent predictors of survival of patients with brain metastases from cutaneous melanoma. Patients receiving local therapy have overall survival comparable with general stage IV melanoma patients.

Complete lymph node dissection is recommended in patients with positive sentinel lymph node biopsy results. To date, the effect of complete lymph node dissection on prognosis is controversial. In the DeCOG-SLT trial, we assessed whether complete lymph node dissection resulted in increased survival compared with observation. In this multicentre, randomised, phase 3 trial, we enrolled patients with cutaneous melanoma of the torso, arms, or legs from 41 German skin cancer centres. Patients with positive sentinel lymph node biopsy results were eligible. Patients were randomly assigned (1:1) to undergo complete lymph node dissection or observation with permuted blocks of variable size and stratified by primary tumour thickness, ulceration of primary tumour, and intended adjuvant interferon therapy. Treatment assignment was not masked. The primary endpoint was distant metastasis-free survival and analysed by intention to treat. All patients in the intention-to-treat population of the complete lymph node dissection group were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02434107. Follow-up is ongoing, but the trial no longer recruiting patients. Between Jan 1, 2006, and Dec 1, 2014, 5547 patients were screened with sentinel lymph node biopsy and 1269 (23%) patients were positive for micrometastasis. Of these, 483 (39%) agreed to randomisation into the clinical trial; due to difficulties enrolling and a low event rate the trial closed early on Dec 1, 2014. 241 patients were randomly assigned to the observation group and 242 to the complete lymph node dissection group. Ten patients did not meet the inclusion criteria, so 233 patients were analysed in the observation group and 240 patients were analysed in the complete lymph node dissection group, as the intention-to-treat population. 311 (66%) patients (158 in the observation group and 153 in the dissection group) had sentinel lymph node metastases of 1 mm or less. Median follow-up was 35 months (IQR 20–54). Distant metastasis-free survival at 3 years was 77·0% (90% CI 71·9–82·1; 55 events) in the observation group and 74·9% (69·5–80·3; 54 events) in the complete lymph node dissection group. In the complete lymph node dissection group, grade 3 and 4 events occurred in 15 patients (6%) and 19 patients (8%) patients, respectively. Adverse events included lymph oedema (grade 3 in seven patients, grade 4 in 13 patients), lymph fistula (grade 3 in one patient, grade 4 in two patients), seroma (grade 3 in three patients, no grade 4), infection (grade 3 in three patients, no grade 4), and delayed wound healing (grade 3 in one patient, grade 4 in four patients); no serious adverse events were reported. Although we did not achieve the required number of events, leading to the trial being underpowered, our results showed no difference in survival in patients treated with complete lymph node dissection compared with observation only. Consequently, complete lymph node dissection should not be recommended in patients with melanoma with lymph node micrometastases of at least a diameter of 1 mm or smaller. German Cancer Aid.

Amplification and overexpression of the c-myc gene have been associated with neoplastic transformation in a plethora of malignant tumours. We applied interphase fluorescence in situ hybridization (FISH) with a locus-specific probe for the c-myc gene (8q24) in combination with a corresponding chromosome 8 α-satellite probe to evaluate genetic alterations in 8 primary melanomas and 33 advanced melanomas and compared it to 12 melanocytic nevi, 7 safety margins and 2 cases of normal skin. Additionally, in metaphase spreads of 7 melanoma cell lines a whole chromosome 8 paint probe was used. We investigated the functionality of the c-myc gene by detecting c-myc RNA expression with RT-PCR and c-myc protein by immunohistochemistry. 4/8 primary melanomas and 11/33 melanoma metastases showed additional c-myc signals relative to the centromere of chromosome 8 copy number. None of the nevi, safety margins or normal skin samples demonstrated this gain. In 2/7 melanoma cell lines (C32 and WM 266–4) isochromosome 8q formation with a relative gain of c-myc copies and a loss of 8p was observed. The highest c-myc gene expression compared to GAPDH was found in melanoma metastases (17.5%). Nevi (6.6%) and primary melanomas (5.0%) expressed the c-myc gene on a lower level. 72.7% of the patients with c-myc extra copies had visceral melanoma metastases (UICC IV), patients without c-myc gain in 35.0% only. The collective with additional c-myc copies also expressed the gene on a significantly higher level. These results indicate that a c-myc gain in relation to the centromere 8 copy number might be associated with advanced cutaneous melanoma. © 2001 Cancer Research Campaign

Apoptosis is an important cofactor in the pathogenesis of a plethora of malignancies. However, little is known about modulation of the expression of bcl gene family in melanocytic tumors. To determine the role of bcl-2, bcl-x and bax in melanocytic tumors we investigated the differential expression of these genes via RT-PCR in tissue samples from human benign nevi, primary melanomas and melanoma metastases in comparison with normal skin. Bcl-2 was strongly expressed in 14/16 metastases (87.5%), whereas only 7/13 primary melanomas (53%), 7/15 nevi (46%) and 7/16 normal tissue samples (43%) showed expression of bcl-2 (P < 0.05). There was a strong indication of a correlation between tumor thickness and bcl-2 expression in nodular malignant melanomas. Expression of bcl-x was found in 16/16 melanoma metastases (100%), 11/13 primary melanomas (84%), 12/15 nevi (80%) and 10/16 normal tissue samples (62%) (P < 0.05). Bcl-xL expression increased from primary melanoma to melanoma metastases, whereas bcl-xS showed a decreasing expression level during melanoma progression. No differences in bax expression were seen between melanoma metastases, primary melanoma, nevi and normal tissue. Immunohistochemical investigations of another 53 tissue samples showed similar results. Our results strongly indicate that bcl-2 and bcl-xL gene expression increases with progression of malignant melanoma. Bcl-2 and bcl-xL expression could reflect an increased malignant potential caused by an inhibition of apoptosis and growth advantage for metastatic melanoma cells.

Merkel cell carcinoma (MCC) is an immunogenic but aggressive skin cancer. Even after complete resection and radiation, relapse rates are high. PD-1 and PD-L1 checkpoint inhibitors showed clinical benefit in advanced MCC. We aimed to assess efficacy and safety of adjuvant immune checkpoint inhibition in completely resected MCC (ie, a setting without an established systemic standard-of-care treatment). In this multicentre phase 2 trial, patients (any stage, Eastern Cooperative Oncology Group performance status 0–1) at 20 academic medical centres in Germany and the Netherlands with completely resected MCC lesions were randomly assigned 2:1 to receive nivolumab 480 mg every 4 weeks for 1 year, or observation, stratified by stage (American Joint Committee on Cancer stages 1–2 vs stages 3–4), age (<65 vs ≥65 years), and sex. Landmark disease-free survival (DFS) at 12 and 24 months was the primary endpoint, assessed in the intention-to-treat populations. Overall survival and safety were secondary endpoints. This planned interim analysis was triggered when the last-patient-in was followed up for more than 1 year. This study is registered with ClinicalTrials.gov (NCT02196961) and with the EU Clinical Trials Register (2013-000043-78). Between Oct 1, 2014, and Aug 31, 2020, 179 patients were enrolled (116 [65%] stage 3–4, 122 [68%] ≥65 years, 111 [62%] male). Stratification factors (stage, age, sex) were balanced across the nivolumab (n=118) and internal control group (observation, n=61); adjuvant radiotherapy was more common in the control group. At a median follow-up of 24·3 months (IQR 19·2–33·4), median DFS was not reached (between-groups hazard ratio 0·58, 95% CI 0·30–1·12); DFS rates in the nivolumab group were 85% at 12 months and 84% at 24 months, and in the observation group were 77% at 12 months and 73% at 24 months. Overall survival results were not yet mature. Grade 3–4 adverse events occurred in 48 [42%] of 115 patients who received at least one dose of nivolumab and seven [11%] of 61 patients in the observation group. No treatment-related deaths were reported. Adjuvant therapy with nivolumab resulted in an absolute risk reduction of 9% (1-year DFS) and 10% (2-year DFS). The present interim analysis of ADMEC-O might suggest clinical use of nivolumab in this area of unmet medical need. However, overall survival events rates, with ten events in the active treatment group and six events in the half-the-size observation group, are not mature enough to draw conclusions. The explorative data of our trial support the continuation of ongoing, randomised trials in this area. ADMEC-O suggests that adjuvant immunotherapy is clinically feasible in this area of unmet medical need. Bristol Myers Squibb.

Das Plattenepithelkarzinom der Haut ist eine der häufigsten Krebsarten der kaukasischen Population und umfasst 20 % aller Hauttumoren. Seit 2019 liegt eine S3-Leitlinie des deutschen Leitlinienprogramms Onkologie vor. Die Diagnose basiert auf der klinischen Untersuchung. Eine Exzision und histologische Sicherung ist bei allen klinisch verdächtigen Läsionen erforderlich, um eine prognostische Einschätzung und korrekte Behandlung zu ermöglichen. Die Therapie der ersten Wahl ist die vollständige Exzision mit histologischer Schnittrandkontrolle. Bei kutanen Plattenepithelkarzinomen mit Risikofaktoren wie einer Tumordicke >6 mm kann eine Sentinellymphknotenbiopsie diskutiert werden, derzeit gibt es aber noch keine klare Evidenz bezüglich der prognostischen und therapeutischen Bedeutung. Eine adjuvante Radiatio kann bei hohem Rezidivrisiko erwogen und sollte bei inoperablen Tumoren geprüft werden. Zur Therapie eines inoperablen lokalen bzw. lokoregionären Rezidivs sollte auch die Indikation zur Elektrochemotherapie geprüft werden. Bei inoperablen oder metastasierten Plattenepithelkarzinomen ist der Immuncheckpointinhibitor Cemiplimab zugelassen. Bei Kontraindikationen können Chemotherapeutika, EGFR(„epidermal growth factor receptor“)-Inhibitoren oder eine palliative Radiatio eingesetzt werden. Da die Evidenz hier gering ist, sollte eine Systemtherapie vorzugsweise in klinischen Studien erfolgen. Die Nachsorge sollte risikoadaptiert stattfinden und schließt eine dermatologische Kontrolle ergänzt um Ultraschalluntersuchungen bei Hochrisikopatienten ein.

Das Plattenepithelkarzinom (PEK) der Haut ist eine der häufigsten Krebsarten der kaukasischen Population und umfasst 20 % aller Hauttumoren. Seit 2019 liegt eine S3-Leitlinie des deutschen Leitlinienprogramms Onkologie vor. Die Diagnose basiert auf der klinischen Untersuchung. Eine Exzision und histologische Sicherung sind bei allen klinisch verdächtigen Läsionen erforderlich, um eine prognostische Einschätzung und korrekte Behandlung zu ermöglichen. Die Therapie der ersten Wahl ist die vollständige Exzision mit histologischer Schnittrandkontrolle. Bei kutanen PEK mit Risikofaktoren wie einer Tumordicke > 6 mm kann eine Sentinellymphknotenbiopsie („sentinel lymph node biopsy“, SLNB) diskutiert werden, derzeit gibt es aber noch keine klare Evidenz bezüglich der prognostischen und therapeutischen Bedeutung. Eine adjuvante Radiatio kann bei hohem Rezidivrisiko erwogen, eine Radiatio sollte bei inoperablen Tumoren geprüft werden. Bei inoperablen lokalen bzw. lokoregionären Rezidiven kann die Indikation zur Elektrochemotherapie geprüft werden. Bei inoperablen/metastasierten PEK ist der Immuncheckpointinhibitor Cemiplimab zugelassen und die Therapie der ersten Wahl. Bei Kontraindikationen können Chemotherapeutika, Inhibitoren des EGFR („epidermal growth factor receptor“) oder eine palliative Radiatio eingesetzt werden. Da die Evidenz hier gering ist, sollte eine Systemtherapie vorzugsweise in klinischen Studien erfolgen. Die Nachsorge sollte risikoadaptiert stattfinden und schließt eine dermatologische Kontrolle, ergänzt um Ultraschalluntersuchungen bei Hochrisikopatienten, ein.

Das Plattenepithelkarzinom (PEK) der Haut ist eine der häufigsten Krebsarten der kaukasischen Population und hat einen Anteil von 20 % aller malignen Hauttumoren. Die Diagnose basiert auf der klinischen Untersuchung. Eine Exzision und histologische Sicherung sind bei allen klinisch verdächtigen Läsionen erforderlich, um eine prognostische Einschätzung und korrekte Behandlung zu ermöglichen. Die Therapie der ersten Wahl ist die vollständige Exzision mit histologischer Schnittrandkontrolle. Eine Sentinellymphknotenbiopsie (SLNB) kann bei PEK >6 mm Tumordicke angewandt werden, derzeit liegt aber noch keine klare Evidenz bezüglich der prognostischen und therapeutischen Aussagekraft vor. Die Radiatio kann eine Alternative zur Chirurgie bei inoperablen PEKs darstellen oder adjuvant bei hohem Rezidivrisiko erwogen werden. Im fernmetastasierten Stadium können verschiedene Chemotherapeutika, EGFR („epidermal growth factor receptor“)-Inhibitoren oder Immun-Checkpoint-Blocker eingesetzt werden. Da die Evidenz hier jedoch gering ist, sollte eine medikamentöse Therapie vorzugsweise in klinischen Studien erfolgen. Die Nachsorge sollte risikoadaptiert stattfinden und schließt primär eine dermatologische Kontrolle – bei Hochrisikopatienten ergänzt um Ultraschalluntersuchungen – ein.