Patterns of initial distant metastases in 151 patients undergoing surveillance for treated Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is associated with high rates of recurrence and distant metastatic progression. Current guidelines for surveillance imaging are not evidence based. Better characterization of the pattern of distant metastatic spread will better inform surveillance and facilitate earlier detection of metastases. OBJECTIVES: This retrospective study aimed to assess potential relationships between primary tumour site and site of initial distant metastasis, time to distant metastasis, overall survival (OS) and MCC-specific death (MSD). METHODS: Patients with local or regional (Stage I-III) disease who were treated with curative intent and progressed to Stage IV were included in this study (n = 151). Fisher's exact test was used to assess differences in patterns of initial distant metastases based on primary tumour site. Time to initial distant metastasis was calculated from date of MCC diagnosis. OS and MSD were calculated from date of initial distant metastasis to date of death from any or MCC-related causes, respectively. RESULTS: Of 151 patients included in analysis, 89 (58.9%) had a single initial distant metastatic site, and 62 (41.1%) had multiple sites. Patients with upper limb primary tumours were significantly less likely to develop distant lymph node or liver metastases (p = 0.02 and 0.04, respectively). Median time to distant metastasis was 11 months (IQR 6.7-17.9 months). Median OS was 15.3 months, and was shorter for patients with liver (7.0 months, p = 0.0004) or bone metastases (8.9 months, p < 0.0001). Using skin/soft tissue metastasis as a reference group, patients with multiple metastatic sites had significantly higher hazards of MSD (HR = 3.46 univariate, 3.77 multivariate analysis). Time to distant metastasis, OS and MSD did not differ by viral status. CONCLUSION: Sites of initial distant metastasis are related to primary tumour sites and survival outcomes. Because patients often have multiple initial metastases, full-body cross-sectional rather than region-specific imaging may facilitate earlier detection of metastatic disease.

Merkel Cell Carcinoma: A Bibliometric Analysis of the Top 100 Cited Publications.

BACKGROUND: Bibliometric studies provide a quantitative statistical analysis of the published literature within a field of interest and allow for easy identification of the major contributing authors, funding sources, and publication trends within the field. To date, no bibliometric studies have been performed pertaining to Merkel cell carcinoma (MCC). OBJECTIVE: To identify the 100 most frequently cited articles in MCC through a bibliometric analysis of the literature. METHODS: Web of science was queried to determine the 100 most frequently cited MCC publications published between the years 1970 and 2019. Articles were listed by title, authors and their affiliated institutions, journal title and type, year of publication, country of origin, funding sources, and citation frequency. RESULTS: Among the 100 most frequently cited MCC publications, articles were cited between 67 and 589 times with a mean of 136.3 times. Articles were cited between 2.0 and 98.2 times per year since publication with a mean of 11.3 times per year. 67% of the articles were published in oncology journals; 33% and 10% of the articles in dermatology and surgery journals, respectively. The most represented journal was Cancer (12%). Paul Nghiem was the most frequently identified author (18%). 36% of the top 100 articles were published out of the University of Washington. The most frequent funding agency was the National Institutes of Health (77%). CONCLUSION: Through this bibliometric analysis, researchers can easily identify key publications pertaining to MCC, which may in turn enhance their approach to understanding and practicing evidence-based medicine regarding MCC.

Merkel cell carcinoma in situ: A systematic review of prognosis and management.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine tumour. While dermally invasive MCC is known to have a five-year survival of only 30-40%, the prognosis and management of MCC in situ (MCCis) is not widely reported. OBJECTIVE: We present a systematic review to elucidate the prognosis and management of MCCis. METHODS: We performed a systematic review, searching three databases to 01 June 2021. Case reports, cohort studies, clinical trials and literature reviews were considered for inclusion. RESULTS: We identified 26 cases of MCCis published in the literature with a median age of 74 years and involving 19 males and 7 females. Most cases were on the face and neck (n = 17), followed by upper limb (n = 8) and lower limb (n = 1). Sentinel lymph node biopsy was performed in three patients, and all were negative. One subject underwent adjuvant radiotherapy. No MCCis-associated deaths were reported. CONCLUSION: This review suggests that MCCis has an excellent prognosis with minimal, if any, risk of mortality and a very low risk of dermal invasion and recurrence when treated with wide local excision alone. Sentinel lymph node biopsy is unlikely to be useful for MCCis.

Survival Benefit of Guideline-Concordant Postoperative Radiation for Local Merkel Cell Carcinoma.

BACKGROUND: Postoperative radiation therapy (RT) for early-stage Merkel Cell Carcinoma (MCC) decreases the risk of locoregional recurrence and improve overall survival. However, concordance with RT guidelines is unknown. MATERIALS AND METHODS: The National Cancer Database was queried for stage I/II MCC patients receiving surgical intervention from 2006-2017. The cohort was stratified by patients who had and did not have indication(s) for adjuvant RT of the primary tumor site based on National Comprehensive Cancer Network guidelines. We captured the use of RT, patient demographics, socioeconomic characteristics, and clinical characteristics. Logistic regression, Kaplan-Meier method, and propensity score weighted Cox proportional hazards model examined associations and survival benefits of RT. RESULTS: 2,330 stage I/II MCC patients underwent surgical intervention. 1,858 (79.7%) met National Comprehensive Cancer Network criteria for RT of the primary tumor site, of which 1,062 (57.2%) received RT. 472 (20.3%) did not meet criteria for RT, of which 203 (43.0%) received RT. Five-year overall survival advantage was identified for patients who received RT when it was indicated (P < 0.003). There was no evidence of overall survival advantage when patients received guideline-discordant RT (P = 0.478). CONCLUSIONS: Surgical resection with adjuvant RT of the primary tumor site has an overall survival benefit for local MCC when patients meet criteria for RT. This study found a group who received guideline-discordant RT with no survival advantage. Further investigation is warranted to identify the socio-demographic and oncologic reasons for guideline discordance in the treatment of MCC for both under- and over-treatment.

Improved survival in women versus men with merkel cell carcinoma.

BACKGROUND: Studies have observed that women have better outcomes than men in melanoma, but less is known about the influence of sex differences on outcomes for other aggressive cutaneous malignancies. OBJECTIVE: To investigate whether women and men have disparate outcomes in Merkel cell carcinoma (MCC). METHODS: Patients with nonmetastatic MCC undergoing surgery and lymph node evaluation were identified from the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier analysis and Cox proportional hazards regression models were used for overall survival, and competing-risks analysis and Fine-Gray models were used for cause-specific and other-cause mortality. RESULTS: The NCDB cohort (n = 4178) included 1516 (36%) women. Women had a consistent survival advantage compared with men in propensity score-matched analysis (66.0% vs 56.8% at 5 years, P < .001) and multivariable Cox regression (hazard ratio, 0.68; 95% confidence interval, 0.61-0.75; P < .001). Similarly, women had a survival advantage in the SEER validation cohort (n = 1202) with 457 (38.0%) women, which was entirely due to differences in MCC-specific mortality (5-year cumulative incidence: 16.4% vs 26.7%, P = .002), with no difference in other-cause mortality (16.8% vs 17.8%, P = .43) observed in propensity score-matched patients. LIMITATIONS: Potential selection bias from a retrospective data set. CONCLUSION: In MCC, women have improved survival compared with men, driven by MCC-related mortality.

Quantitative metastatic lymph node burden and survival in Merkel cell carcinoma.

BACKGROUND: Current lymph node (LN) staging for Merkel cell carcinoma (MCC) does not account for the number of metastatic LNs, which is a primary driver of survival in multiple cancers. OBJECTIVE: To determine the impact of the number of metastatic LNs on survival in MCC. METHODS: Patients with MCC undergoing surgery were identified from the National Cancer Database (NCDB). The association between metastatic LN number and survival was modeled with restricted cubic splines. A novel nodal classification system was derived by using recursive partitioning analysis. MCC patients undergoing surgery in the Surveillance, Epidemiology, and End Results (SEER) Program were used as validation cohort. RESULTS: Among 3670 patients in the NCDB, increasing metastatic LN number was associated with decreased survival (P < .001). Mortality risk increased continuously with each additional positive LN when using multivariable, nonlinear modeling. According to a novel staging system derived via recursive partitioning analysis, the hazard ratio for death in multivariable regression compared with patients without LN involvement was 1.24 (P = .049), 2.08 (P < .001), 3.24 (P < .001), and 6.13 (P < .001) for the proposed N1a (1-3 metastatic LNs with microscopic detection), N1b (1-3 metastatic LNs with macroscopic detection), N2 (4-8 metastatic LNs), and N3 (≥9 metastatic LNs), respectively. This system was validated in the SEER cohort and showed improved concordance compared with the American Joint Committee on Cancer, Eighth Edition. LIMITATIONS: Retrospective design. CONCLUSIONS: Number of metastatic LNs is the dominant nodal factor driving survival in patients with MCC.

Narrow resection margins are not associated with mortality or recurrence in patients with Merkel cell carcinoma: A retrospective study.

BACKGROUND: Wide local excision constitutes the standard of care for Merkel cell carcinoma, but the optimal margin width remains controversial. OBJECTIVES: To assess whether narrow margins (0.5-1 cm) were associated with outcome. METHODS: Patients were recruited from a retrospective French multicentric cohort and included if they had had excision of primary tumor with minimum lateral margins of 0.5 cm. Factors associated with mortality and recurrence were assessed by multivariate regression. RESULTS: Among the 214 patients included, 58 (27.1%) had undergone excision with narrow margins (0.5-1 cm) versus 156 (72.9%) with wide margins (>1 cm). During a median follow-up of 50.7 months, cancer-specific survival did not differ between groups (5-year specific survival rate 76.8% [95% confidence interval 61.7%-91.9%] and 76.2% [95% confidence interval 68.8%-83.6%], respectively). Overall survival, any recurrence-free survival, and local recurrence-free survival did not significantly differ between groups. Cancer-specific mortality was associated with age, male sex, American Joint Committee on Cancer stage III, and presence of positive margins. LIMITATIONS: Retrospective design, heterogenous baseline characteristics between groups. CONCLUSION: Excision with narrow margins was not associated with outcome in this cohort, in which most patients had clear margins and postoperative radiation therapy. Residual tumor, mostly found on deep surgical margins, was independently associated with prognosis.

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.

BACKGROUND: Merkel cell carcinoma (MCC) management typically includes surgery with or without adjuvant radiation therapy (aRT). Major challenges include determining surgical margin size and whether aRT is indicated. OBJECTIVE: To assess the association of aRT, surgical margin size, and MCC local recurrence. METHODS: Analysis of 188 MCC cases presenting without clinical nodal involvement. RESULTS: aRT-treated patients tended to have higher-risk tumors (larger diameter, positive microscopic margins, immunosuppression) yet had fewer local recurrences (LRs) than patients treated with surgery only (1% vs 15%; P = .001). For patients who underwent surgery alone, 7 of 35 (20%) treated with narrow margins (defined as ≤1.0 cm) developed LR, whereas 0 of 13 patients treated with surgical margins greater than 1.0 cm developed LR (P = .049). For aRT-treated patients, local control was excellent regardless of surgical margin size; only 1% experienced recurrence in each group (1 of 70 with narrow margins ≤1 cm and 1 of 70 with margins >1 cm; P = .56). LIMITATIONS: This was a retrospective study. CONCLUSIONS: Among patients treated with aRT, local control was superb even if significant risk factors were present and margins were narrow. We propose an algorithm for managing primary MCC that integrates risk factors and optimizes local control while minimizing morbidity.

Systematic literature review of current treatments for stage I-III Merkel cell carcinoma.

Aim: There is a need to evaluate current treatments for stages I-III of Merkel cell carcinoma (MCC). Materials & methods: A systematic literature review was conducted to understand how patients with stage I-III MCC are treated and assess efficacy, safety, health-related quality of life and economic impact of current therapies. Embase was searched using the following inclusion criteria: publications from 2014 to 2019, in English, with adult patients (≥18 years) with early-stage MCC (i.e., stages I-III) and any interventions/comparators. Publications were excluded if they included only patients with stage IV MCC, had no distinction between early and advanced or metastatic MCC or had no extractable data. Results: A total of 18 retrospective studies were included. Few studies had evidence that surgery plus adjuvant radiotherapy significantly increased survival versus surgery alone in early MCC. Limited safety data were reported in three studies. None of the studies reported data on health-related quality of life or economic impact of treatment in patients with early-stage MCC. Conclusion: Although surgery plus adjuvant radiotherapy was a common treatment, no clear standard of care exists for stages I-III MCC and treatment outcomes need to be improved. All studies were retrospective with a high variability in sample sizes; hence, findings should be interpreted with caution.

Prognostic Role of Tumoral PD-L1 and IDO1 Expression, and Intratumoral CD8+ and FoxP3+ Lymphocyte Infiltrates in 132 Primary Cutaneous Merkel Cell Carcinomas.

The association of immune markers and clinicopathologic features and patient outcome has not been extensively studied in Merkel cell carcinoma (MCC). We correlated tumoral PD-L1 and IDO1 expression, and intratumoral CD8+ and FoxP3+ lymphocytes count with clinicopathologic variables, Merkel cell polyomavirus (MCPyV) status, and patient outcomes in a series of 132 MCC. By univariate analyses, tumoral PD-L1 expression >1% and combined tumoral PD-L1 >1% and high intratumoral FoxP3+ lymphocyte count correlated with improved overall survival (OS) (p = 0.016, 0.0072), MCC-specific survival (MSS) (p = 0.019, 0.017), and progression-free survival (PFS) (p = 0.043, 0.004, respectively). High intratumoral CD8+ and FoxP3+ lymphocyte count correlated with longer MSS (p = 0.036) and improved PFS (p = 0.047), respectively. Ulceration correlated with worse OS and worse MSS. Age, male gender, and higher stage (3 and 4) significantly correlated with worse survival. MCPyV positivity correlated with immune response. By multivariate analyses, only ulceration and age remained as independent predictors of worse OS; gender and stage remained for shorter PFS. Tumoral PD-L1 expression and increased density of intratumoral CD8+ lymphocytes and FoxP+ lymphocytes may represent favorable prognosticators in a subset of MCCs. Tumoral PD-L1 expression correlated with intratumoral CD8+ and FoxP3+ lymphocytes, which is supportive of an adaptive immune response.

Merkel Cell Carcinoma Outcomes: Does AJCC8 Underestimate Survival?

INTRODUCTION: The eighth edition of the American Joint Committee on Cancer (AJCC8) Staging Manual provides important information for staging and prognostication; however, survival estimates for patients with Stage I-III Merkel cell carcinoma (MCC), a rare disease, may be as practical using data from large-volume centers as that collated for the AJCC analysis. As such, we compared our institutional outcomes to AJCC8. METHODS: Patients who presented from 2005 to 2017 with MCC to two high-volume centers were included. Demographics, clinicopathologic characteristics, survival and recurrence data were compiled, and outcomes compared to AJCC8. RESULTS: A total of 409 patients were included. Median age was 75 (range 29-98) years, and 68% were male. Median follow-up was 16 months (0-157). Five-year overall survival (OS) was 70%; 5-year disease-specific survival (DSS) was 84%. When stratified by extent of disease, 5-year OS was higher for patients with local disease compared to those with nodal disease (72.6% vs 62.7%, p=0.005). Similarly, patients with local disease had higher 5-year DSS than those with nodal disease (90.1% vs 76.8%, p=0.002). Five-year recurrence-free survival was 59.2% for all patients, 65.0% for local disease and 48.3% for nodal disease (p=0.033). CONCLUSIONS: Here, MCC patients with local or nodal disease have substantially higher OS rates than predicted in AJCC8 (5-year: 72.6% vs 50.6%; 62.7% vs 35.4%, respectively). Importantly, 5-year DSS was significantly better than the OS rates reported presently and in AJCC8. As clinicians and patients rely on AJCC to accurately prognosticate and guide treatment decisions, these estimates should be reassessed and updated to more accurately predict survival outcomes.

The association between facility volume and overall survival in patients with Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma is an uncommon malignancy often requiring multidisciplinary management. The purpose of this study was to determine whether high-volume facilities have improved outcomes in patients with Merkel cell carcinoma relative to lower-volume facilities. METHODS: A total of 5304 patients from the National Cancer Database with stage I-III Merkel cell carcinoma undergoing surgery were analyzed. High-volume facilities were the top 1% by case volume. Multivariable Cox regression and propensity score-matching were performed to account for imbalances between groups. RESULTS: Treatment at high-volume facilities (hazard ratio: 0.74; 95% confidence interval: 0.65-0.84, P < .001) was independently associated with improved overall survival (OS) in multivariable analyses. In propensity score-matched cohorts, 5-year OS was 62.3% at high-volume facilities vs 56.8% at lower-volume facilities (P < .001). Median OS was 111 months at high-volume facilities vs 79 months at lower-volume facilities. CONCLUSION: Treatment at high-volume facilities is associated with improved OS in Merkel cell carcinoma. Given the impracticality of referring all elderly patients with Merkel cell carcinoma to a small number of facilities, methods to mitigate this disparity should be explored.

Analysis of cutaneous Merkel cell carcinoma outcomes after different surgical interventions.

BACKGROUND: Current guidelines recommend local excision margin (EM) with 1 to 2 cm on primary Merkel cell carcinoma (MCC) sites. OBJECTIVE: We compared survival outcomes of patients with MCC who were treated with different surgical interventions. METHODS: A retrospective analysis of MCC cases in the Surveillance, Epidemiology, and End Results database was performed using the Kaplan-Meier, competing risk, and Cox proportional hazards regression model analyses. Influence of age, T stage, American Joint Committee on Cancer stage, adjuvant radiotherapy, and other subgroups were also analyzed by pairwise log rank test. RESULTS: Our results indicated a significant association between local destruction method and inferior survival, while an EM >2 cm showed significantly higher overall survival. In addition, the competing risk analysis depicted a similar trend as the Kaplan-Meier analysis, and considerably reduced estimated cumulative incidence. Further subgroup pairwise analysis demonstrated that the EM >2 cm method had better survival in patients who were <60 years of age, having smaller tumor diameters (T1 and T2) or having undergone adjuvant radiotherapy (P < .05). In contrast, different EMs did not show any significant association with survival rate in patients ≥75 years of age or stage III tumors. LIMITATIONS: This study was not prospectively randomized without relapse data. CONCLUSIONS: It is challenging to make optimal EM recommendations, because surgical options may depend on individual case situations. Further prospective randomized studies are warranted.

Optimal adjuvant radiotherapy dose for stage I, II or III Merkel cell carcinoma: an analysis of the National Cancer Database.

BACKGROUND: We performed an analysis of the National Cancer Database to determine optimal doses of conventionally-fractionated adjuvant radiotherapy for patients with stage I/II or III Merkel cell carcinoma. METHODS: The cohort included 2735 patients with resected Merkel cell carcinoma of the head and neck, trunk or extremities receiving radiotherapy. Exclusion criteria included doses of radiotherapy <30 or >80 Gy, or dose per fraction >200 or <180 cGy. Recursive partitioning analysis and spline models were used to select dose thresholds. Multivariable Cox regression was performed to validate thresholds with respect to overall survival. RESULTS: Recursive partitioning analysis models defined a threshold of 57 Gy for stage I/II Merkel cell carcinoma, above which 3-year overall survival rate was decreased (P < 0.0001). The 3-year overall survival rate for patients receiving 50.0-57.0 Gy (81.2%) was greater compared to doses of 30.0-49.9 Gy (75.3%) or >57.0 Gy (70%, P < 0.0001). Doses > 57.0 Gy were associated with an increased hazard of death (1.31, confidence interval 1.07-1.60) with respect to doses of 50.0-57.0 Gy. Doses < 50.0 Gy for stage III Merkel cell carcinoma were associated with worsened 3-year overall survival (P < 0.0001) and increased hazard of death (2.01, confidence interval 1.43-2.82) with respect to doses between 50.0 and 57.0 Gy. CONCLUSIONS: Our results support doses of 50-57 Gy for most patients with stage I/II Merkel cell carcinoma receiving conventionally-fractionated adjuvant radiotherapy. In contrast to a prior National Cancer Database analysis, our results suggest doses ≥ 50 Gy should be strongly considered for patients with stage III Merkel cell carcinoma regardless of anatomic subsite.

Clinical Features and Prognosis of Merkel Cell Carcinoma in Elderly Patients.

BACKGROUND Merkel cell carcinoma (MCC) occurs primarily among elderly patients over 70 years old, but the ability to predict the prognosis of these elderly patients is poor. This population-based study aimed to identify prognostic risk factors for elderly patients with MCC. MATERIAL AND METHODS The survival and disease information of MCC patients age 65 years or older was downloaded from the SEER database, and all data were split into 2 groups based on age 80 years, with overall survival and MCC-specific survival as the main outcome indicators. RESULTS Application of the inclusion criteria yielded 1973 patients with MCC, of whom 55.6% were age 65-80 years. Among them, 1258 were males, accounting for 63.8%. In survival analysis, factors that were significantly correlated with overall survival and MCC-specific survival were N stage, M stage, liver metastasis, and lymph node surgery. CONCLUSIONS We provide epidemiological insights into Merkel cell carcinoma in elderly patients and confirmed that patients receiving lymph node surgery have better outcomes. To the best of our knowledge, this is the first study to show that the occurrence of liver metastasis is associated with poor prognosis. Our results will help strengthen monitoring of the liver condition of elderly patients and to perform necessary lymph node surgery within the patient's tolerance.

Multidisciplinary Treatment, Including Locoregional Chemotherapy, for Merkel-Polyomavirus-Positive Merkel Cell Carcinomas: Perspectives for Patients Exhibiting Oncogenic Alternative Δ exon 6-7 TrkAIII Splicing of Neurotrophin Receptor Tropomyosin-Related Kinase A.

Merkel cell carcinomas (MCCs) are rare, aggressive, cutaneous neuroendocrine tumours, approximately 80% of which are caused by the genomic integration of Merkel cell polyomavirus (MCPyV). MCPyV-positive MCCs carry poor prognosis in approximately 70% of cases, highlighting the need for greater understanding of the oncogenic mechanisms involved in pathogenesis, progression and post-therapeutic relapse, and translation into novel therapeutic strategies. In a previous pilot study, we reported a potential relationship between MCPyV gene expression and oncogenic alternative Δ exon 6-7 TrkAIII splicing in formalin-fixed paraffin-embedded (FFPE) MCC tissues from a 12-patient cohort of >90% MCPyV-positive MCCs, diagnosed at San Salvatore Hospital, L'Aquila, Italy, characterising a new MCC subgroup and unveiling a novel potential MCPyV oncogenic mechanism and therapeutic target. This, however, could not be fully verified due to poor RNA quality and difficulty in protein extraction from FFPE tissues. Here, therefore, we extend our previous observations to confirm the relationship between MCPyV and oncogenic alternative Δ exon 6-7 TrkAIII splicing in fresh, nonfixed, MCPyV-positive MCC metastasis by detecting sequence-verified RT-PCR products, including full-length Δ exon 6-7 TrkAIII, and by Western blot detection of a 100 kDa TrkA protein isoform of identical size to 100 kDa Δ exon 6-7 TrkAIII expressed by stable transfected SH-SY5Y cells. We also report that in three MCC patients submitted for multidisciplinary treatment, including locoregional chemotherapy, MCPyV large T-antigen mRNA expression, Δ exon 6-7 TrkAIII mRNA expression and intracellular indirect immunofluorescence (IF) TrkA and phosphorylation protein isoform(s) immunoreactivity in FFPE tissues were not reduced in postchemotherapeutic-relapsed MCCs compared to pretherapeutic MCCs, extending the possible roles of this novel potential MCPyV oncogenic mechanism from MCC pathogenesis to post-therapeutic relapse and progression. Detection of alternative Δ exon 6-7 TrkAIII splicing in MCC, therefore, not only characterises a new MCPyV-positive MCC subgroup and unveils a novel potential MCPyV oncogenic mechanism but also identifies patients who may benefit from inhibitors of MCPyV T-antigen and/or TrkAIII expression or clinically approved Trk kinase inhibitors such as larotrectinib or entrectinib, which are known to inhibit activated TrkA oncogenes and to elicit durable responses in TrkA-fusion oncogene-driven cancers, supporting the call for a large-scale multicentre clinical study.

Early objective response to avelumab treatment is associated with improved overall survival in patients with metastatic Merkel cell carcinoma.

BACKGROUND: Response rates are primary endpoints in many oncology trials; however, correlation with overall survival (OS) is not uniform across cancer types, treatments, or lines of therapy. This study explored the association between objective response (OR) and OS in patients with chemotherapy-refractory metastatic Merkel cell carcinoma who received avelumab (anti-PD-L1). METHODS: Eighty-eight patients enrolled in JAVELIN Merkel 200 (part A; NCT02155647) received i.v. avelumab 10 mg/kg every 2 weeks until confirmed progression, unacceptable toxicity, or withdrawal. Using conditional landmark analyses, we compared OS in patients with and without confirmed OR (RECIST v1.1). We applied a Cox model that included OR as a time-varying covariate and adjusted for age, visceral disease, and number of previous therapies. RESULTS: Twenty-nine patients had confirmed OR; 20 by study week 7 and 7 more between study weeks 7 and 13. Survival probabilities 18 months after treatment initiation were 90% [95% confidence interval (CI) 65.6-97.4] in patients with OR at week 7 and 26.2% (95% CI 15.7-37.8) in patients without OR but who were alive at week 7. Median OS was not reached in patients with OR and was 8.8 months (95% CI 6.4-12.9) in patients without. Similar results were observed for the week 13 landmark. The adjusted Cox model showed OR was associated with a 95% risk reduction of death [hazard ratio 0.052 (95% CI 0.018-0.152)] compared with a nonresponse. CONCLUSIONS: Patients with OR by 7 or 13 weeks had significantly longer OS than patients without, confirming that early OR is an endpoint of major importance.

Treatment and survival of Merkel cell carcinoma since 1993: A population-based cohort study in The Netherlands.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare and potentially lethal skin cancer. MCC is known for its potential rapid growth and its propensity to metastasize. OBJECTIVE: To describe the incidence, treatment, and survival of MCC in a population-based setting. METHODS: All MCCs diagnosed in The Netherlands between 1993 and 2016 were selected from the Netherlands Cancer Registry. Patient and tumor characteristics, therapy, and vital status were obtained. Cox proportional hazards were computed, and relative survival analyses were performed. RESULTS: Our cohort included 1977 patients with MCC. Incidence increased from 0.17 per 100,000 person-years in 1993 to 0.59 per 100,000 in 2016. The mean age at diagnosis was 75.5. Most MCCs (59.8%) were treated with surgery alone. Relative 5-year survival was low (63.0%) and did not improve. Mortality was higher among males (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.11-1.39), higher age (HR, 1.07; 95% CI, 1.06-1.07), and nodal (HR, 1.26; 95% CI, 1.08-1.48) and distant spread of disease (HR, 2.44; 95% CI, 1.99-2.99). LIMITATIONS: We lacked data on cause of death, comorbidity, and pathologic margins, which may have led to misinterpretation of the data. CONCLUSION: This study shows continuously increasing incidence rates of MCC in The Netherlands. Survival after a diagnosis of MCC remained low. Our results emphasize the need for implementation of new therapies.

Sentinel lymph node biopsy in Merkel cell carcinoma: Predictors of sentinel lymph node positivity and association with overall survival.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive malignancy with high rates of recurrence and metastasis. OBJECTIVE: To evaluate predictors of sentinel lymph node (SLN) positivity in MCC using the National Cancer Database. METHODS: The National Cancer Database, from 2012 to 2014, was used to identify 3048 patients with MCC, of whom 1174 received an SLN biopsy. Predictors of SLN positivity were evaluated using logistic regression. Overall survival was evaluated using a Cox proportional hazards model. RESULTS: Of patients who underwent SLN biopsy, those with primary lesions on the trunk (odds ratio, 1.98; 95% confidence interval [CI], 1.23-3.17; P = .004), tumor-infiltrating lymphocytes (odds ratio, 1.58; 95% CI, 1.01-2.46; P = .04), or lymphovascular invasion (odds ratio, 3.45; 95% CI, 2.51-4.76; P < .001) were more likely to have positive SLNs on multivariate analysis. Overall survival was negatively affected by age ≥75 years (hazard ratio [HR], 2.55; 95% CI, 1.36-4.77; P = .003), male sex (HR, 1.78; 95% CI, 1.09-2.91, P = .022), immunosuppression (HR, 3.51; 95% CI, 1.72-7.13; P = .001), and SLN positivity (HR, 3.15; 95% CI, 1.98-5.04; P < .001). LIMITATIONS: Lack of disease-specific survival and potential selection bias from a retrospective data set. CONCLUSIONS: Truncal MCC, tumor-infiltrating lymphocytes, and presence of lymphovascular invasion were independent predictors of positive SLNs. Overall survival was negatively affected by advancing age, male sex, immunosuppression, and SLN positivity.