Head and Neck Merkel Cell Carcinoma: Therapeutic Benefit of Adjuvant Radiotherapy for Nodal Disease.

OBJECTIVES: To evaluate the therapeutic effect of post-operative radiotherapy (PORT) with respect to nodal status among patients with head and neck Merkel cell carcinoma (HNMCC). METHODS: In this retrospective study, we queried Surveillance, Epidemiology, and End Results (SEER) dataset from 2000 through 2019. We included all adult patients who received primary surgical resection for histologically confirmed treatment naive HNMCC. Entropy balancing was used to reweight observations such that there was covariate balance between patients who received PORT and patients who received surgical resection alone. Doubly robust estimation was achieved by incorporating weights into a multivariable cox proportional hazards model. Planned post hoc subgroup analysis was performed to evaluate the impact of PORT by pathological node status. RESULTS: Among 752 patients (mean age, 73.3 years [SD 10.8]; 64.2% male; 91.2% White; 41.9% node-positive), 60.4% received PORT. Among node-positive patients, we found that PORT was associated with improved overall survival (OS) (aHR, 0.55; 95% CI, 0.37-0.81; p = 0.003) and improved disease-specific survival (DSS) (aHR, 0.57; 95% CI, 0.35-0.92; p = 0.022). Among node-negative patients, we found that PORT was not associated with OS and was associated with worse DSS (aHR, 2.34; 95% CI, 1.30-4.23; p = 0.005). CONCLUSIONS: We found that PORT was associated with improved OS and DSS for node-positive patients and worse DSS for node-negative patients. For HNMCC treated with primary surgical resection, these data confirm the value of PORT for pathologically node-positive patients and support the use of single modality surgical therapy for pathologically node-negative patients without other adverse risk factors. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:3587-3594, 2024.

Adjuvant Radiotherapy for Surgically Resected Stage III Merkel Cell Carcinoma.

This case-control study evaluates whether adjuvant radiotherapy is associated with overall survival among patients with surgically resected stage III Merkel cell carcinoma.

Increased risk of recurrence and disease-specific death following delayed postoperative radiation for Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is often treated with surgery and postoperative radiation therapy (PORT). The optimal time to initiate PORT (Time-to-PORT [ttPORT]) is unknown. PURPOSE: We assessed if delays in ttPORT were associated with inferior outcomes. METHODS: Competing risk regression was used to evaluate associations between ttPORT and locoregional recurrence (LRR) for patients with stage I/II MCC in a prospective registry and adjust for covariates. Distant metastasis and death were competing risks. RESULTS: The cohort included 124 patients with median ttPORT of 41 days (range: 8-125 days). Median follow-up was 55 months. 17 (14%) patients experienced a LRR, 14 (82%) of which arose outside the radiation field. LRR at 5 years was increased for ttPORT >8 weeks vs ≤ 8 weeks, 28.0% vs 9.2%, P = .006. There was an increase in the cumulative incidence of MCC-specific death with increasing ttPORT (HR = 1.14 per 1-week increase, P = .016). LIMITATIONS: The relatively low number of LRRs limited the extent of our multivariable analyses. CONCLUSIONS: Delay of PORT was associated with increased LRR, usually beyond the radiation field. This is consistent with the tendency of MCC to spread quickly via lymphatics. Initiation of PORT within 8 weeks was associated with improved locoregional control and MCC-specific survival.

Delayed time to radiation and overall survival in Merkel cell carcinoma.

BACKGROUND: Clinically localized Merkel cell carcinoma (MCC) is commonly treated with surgical excision and radiotherapy. The relationship between time to adjuvant radiotherapy and overall survival (OS) remains understudied. METHODS: This retrospective study used data from the National Cancer Database (2006-2019). Patients with clinically localized MCC who received surgical excision and adjuvant radiotherapy were included. Multivariate regressions were used to account for various patient and tumor factors. The primary outcome was 5-year OS, and the secondary outcome was time from diagnosis to adjuvant radiation (TTR). RESULTS: Of the 1965 patients included, most were male (n = 1242, 63.2%) and white (n = 1915, 97.5%), and the median age was 74 years (interquartile range [IQR]: 66-81). The median TTR was 83 days (IQR: 65-106). A total of 83.6% of patients received radiotherapy to the primary site, 21.3% to the draining nodal basin, 17.1% to both, and 12.2% whose target location of radiotherapy was not recorded in the data. TTR of ≥79 days (the 45th percentile) was associated with worse OS on both univariate and multivariate analyses (log-rank p = 0.0014; hazard ratio [HR]: 1.258, 95% confidence interval [CI]: 1.055-1.500, p = 0.010). This persisted on sub-analyses of patients <80 years old (n = 1407; HR: 1.380, 95% CI: 1.080-1.764, p = 0.010) and of patients with Charlson comorbidity index (CCI) of 0 (n = 1411; HR: 1.284, 95% CI: 1.034-1.595, p = 0.024). Factors associated with delayed TTR included greater age (p = 0.039), male sex (p = 0.04), CCI > 1 (p = 0.036), academic facility (p < 0.001), rural county (p = 0.034), AJCC T2 stage (p = 0.010), negative margins (p = 0.017), 2+ pathologically positive regional nodes (p = 0.011), and margin size >2 cm (p = 0.015). CONCLUSIONS: Delayed radiotherapy (≥79 days) was associated with worse OS of MCC patients. Further study in controlled cohorts is needed to ascertain this relationship.

An Effective Primary Treatment Using Radiotherapy in Patients with Eyelid Merkel Cell Carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare type of neuroendocrine tumor. Palpebral localization represents 2.5% of MCCs. Surgery is not always possible due to the localization or comorbidities of elderly patients. We hypothesized that radiotherapy (RT) alone could be a curative treatment in patients contraindicated for oncological surgery. METHODS: We performed a retrospective monocentric study of patients with localized eyelid MCC treated with curative intent using curative radiotherapy. RESULTS: Overall, 11 patients with histologically confirmed eyelid MCC were treated with curative radiotherapy. The median age was 77 years old (range: 53-94). Curative RT was decided mainly due to difficult localization and significant co-morbidities. The median lesion dose was 57 Gy (range: 47-70). Most patients had adjuvant lymph nodes irradiation with a median dose of 50 Gy (n = 9; 82%). The median follow-up was 62 months (6-152 months). None of the seven deaths were MCC-related. None of our patients relapsed during follow-up. Side effects related to radiotherapy were mild (no grade ≥ 2) and rare (n = 3, 21%). CONCLUSION: Our data suggest that curative radiotherapy is an effective and safe treatment for Merkel cell carcinoma of the eyelid and periocular region. Radiotherapy alone allows limiting the aesthetic and functional sequelae in elderly and comorbid patients who are contraindicated for oncological surgery.

Radiation, Lymph Node Dissection, or Both: Management of Lymph Node Micrometastases from Merkel Cell Carcinoma.

BACKGROUND: Regional lymph node micrometastases from Merkel cell carcinoma (MCC) can be treated with completion lymph node dissection (CLND) and/or radiation therapy (RT). It is unclear how these options compare in terms of survival benefits for patients. PATIENTS AND METHODS: This retrospective cohort study used data from years 2012-2019 of the National Cancer Database. Patients with MCC and clinically negative, but pathologically positive, lymph node metastases who received RT to and/or CLND of the regional lymph node basin were included. Inverse probability weight balancing was performed using covariates followed by Cox proportional hazards modeling for survival analysis. RESULTS: A total of 962 patients were included [median (interquartile range) age, 74 (67-80) years, 662 (68.8%) male patients, 926 (96.3%) white patients]. The majority (63%, n = 606) had a CLND only, while 18% (n = 173) had RT only, and 19% (n = 183) had both CLND and RT. From 2016 to 2019, usage of RT only increased from 10% to 31.8%. Multivariate analysis demonstrated that treatment modality was not associated with survival [RT versus CLND, hazard ratio (HR) 0.842, 95% confidence interval (CI) 0.621-1.142, p = 0.269, RT+CLND versus CLND, HR 1.029, 95% CI 0.775-1.367, p = 0.844]. This persisted after balancing weights (RT versus CLND, HR 0.837, 95% CI 0.614-1.142, p = 0.262, RT+CLND versus CLND, HR 1.085, 95% CI 0.801-1.470, p = 0.599). CONCLUSIONS: The usage of RT for nodal micrometastasis in MCC is increasing as compared with CLND. This strategy appears to be safe, with no significant difference in survival outcomes.

Adjuvant Radiotherapy for Dissected Parotid Lymph Nodes Containing Merkel Cell Carcinoma from an Unknown Primary Skin Site: 2 Case Reports.

BACKGROUND Merkel cell carcinoma (MCC) is an aggressive neuroendocrine malignancy that has increased in incidence in recent decades. The management of MCC should involve multidisciplinary experts to achieve optimal patient outcomes. Radiotherapy is commonly used as adjuvant therapy. Our literature review of MCC indicates that aggressive adjuvant radiotherapy might have a positive impact on overall local control and survival. CASE REPORT The first case is a 75-year-old male patient who discovered a right preauricular mass 2 weeks prior. He underwent right parotidectomy with tumor removal on 2012/07/09, and pathology revealed MCC in 3 lymph nodes. The patient received postoperative adjuvant radiotherapy (61.2 Gy) to the remaining right parotid tumor bed and right neck lymph nodes. The patient refused adjuvant chemotherapy. During long-term follow-up, the patient remained disease free for 10 years. The other case is a 73-year-old female patient with metastatic MCC in a left parotid lymph node. She also underwent left parotidectomy with tumor removal, and pathological staging performed according to the 8th edition of the AJCC staging system showed pTxN1aMx, stage IIIA. After the operation, she received postoperative adjuvant radiotherapy (56 Gy) to the remaining left parotid and left neck lymph nodes. The patient remained disease free for 14 months. CONCLUSIONS Metastatic MCC of the parotid lymph nodes without a detectable primary skin tumor is very rare. Adjuvant radiotherapy to the tumor bed and regional nodal basin might be beneficial for preventing disease recurrence despite the absence of systemic medical therapy.

The role of radiotherapy in the updated German S2k guideline for management of Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a radiosensitive tumor and the role of radiotherapy in the management of this disease was newly defined in the recently published update of the S2k guideline on Merkel cell carcinoma of the Association of Scientific Medical Societies in Germany (AWMF). While adjuvant radiotherapy of the tumor bed is broadly recommended, irradiation of the regional nodal region can be performed in patients with negative sentinel lymph nodes and high-risk factors. In patients with positive sentinel lymph nodes, it is an alternative to completion lymphadenectomy. The standard dose for adjuvant radiotherapy remains 50 Gy.

Combined nivolumab and ipilimumab with or without stereotactic body radiation therapy for advanced Merkel cell carcinoma: a randomised, open label, phase 2 trial.

BACKGROUND: Merkel cell carcinoma is among the most aggressive and lethal of primary skin cancers, with a high rate of distant metastasis. Anti-programmed death receptor 1 (anti-PD-1) and programmed death ligand 1 (PD-L1) monotherapy is currently standard of care for unresectable, recurrent, or metastatic Merkel cell carcinoma. We assessed treatment with combined nivolumab plus ipilimumab, with or without stereotactic body radiotherapy (SBRT) in patients with advanced Merkel cell carcinoma as a first-line therapy or following previous treatment with anti-PD-1 and PD-L1 monotherapy. METHODS: In this randomised, open label, phase 2 trial, we randomly assigned adults from two cancer sites in the USA (one in Florida and one in Ohio) to group A (combined nivolumab and ipilimumab) or group B (combined nivolumab and ipilimumab plus SBRT) in a 1:1 ratio. Eligible patients were aged at least 18 years with histologically proven advanced stage (unresectable, recurrent, or stage IV) Merkel cell carcinoma, a minimum of two tumour lesions measureable by CT, MRI or clinical exam, and tumour tissue available for exploratory biomarker analysis. Patients were stratified by previous immune-checkpoint inhibitor (ICI) status to receive nivolumab 240 mg intravenously every 2 weeks plus ipilimumab 1 mg/kg intravenously every 6 weeks (group A) or the same schedule of combined nivolumab and ipilimumab with the addition of SBRT to at least one tumour site (24 Gy in three fractions at week 2; group B). Patients had to have at least two measurable sites of disease so one non-irradiated site could be followed for response. The primary endpoint was objective response rate (ORR) in all randomly assigned patients who received at least one dose of combined nivolumab and ipilimumab. ORR was defined as the proportion of patients with a complete response or partial response per immune-related Response Evaluation Criteria in Solid Tumours. Response was assessed every 12 weeks. Safety was assessed in all patients. This trial is registered with ClinicalTrials.gov, NCT03071406. FINDINGS: 50 patients (25 in both group A and group B) were enrolled between March 14, 2017, and Dec 21, 2021, including 24 ICI-naive patients (13 [52%] of 25 group A patients and 11 [44%] of 25 group B patients]) and 26 patients with previous ICI (12 [48%] of 25 group A patients and 14 [56%] of 25 group B patients]). One patient in group B did not receive SBRT due to concerns about excess toxicity. Median follow-up was 14·6 months (IQR 9·1-26·5). Two patients in group B were excluded from the analysis of the primary endpoint because the target lesions were irradiated and so the patients were deemed non-evaluable. Of the ICI-naive patients, 22 (100%) of 22 (95% CI 82-100) had an objective response, including nine (41% [95% CI 21-63]) with complete response. Of the patients who had previously had ICI exposure, eight (31%) of 26 patients (95% CI 15-52) had an objective response and four (15% [5-36]) had a complete response. No significant differences in ORR were observed between groups A (18 [72%] of 25 patients) and B (12 [52%] of 23 patients; p=0·26). Grade 3 or 4 treatment-related adverse events were observed in 10 (40%) of 25 patients in group A and 8 (32%) of 25 patients in group B. INTERPRETATION: First-line combined nivolumab and ipilimumab in patients with advanced Merkel cell carcinoma showed a high ORR with durable responses and an expected safety profile. Combined nivolumab and ipilimumab also showed clinical benefit in patients with previous anti-PD-1 and PD-L1 treatment. Addition of SBRT did not improve efficacy of combined nivolumab and ipilimumab. The combination of nivolumab and ipilimumab represents a new first-line and salvage therapeutic option for advanced Merkel cell carcinoma. FUNDING: Bristol Myers Squibb Rare Population Malignancy Program.

Characterization of clinical outcomes after shorter course hypofractionated and standard-course radiotherapy for stage I-III curatively-treated Merkel cell carcinoma.

BACKGROUND: Limited data exists regarding the efficacy of curative hypofractionated radiotherapy (hypo-RT) regimens compared to conventionally-fractionated radiotherapy (conv-RT) for Merkel cell carcinoma (MCC). METHODS: A retrospective analysis of 241 patients diagnosed with non-metastatic MCC from 2005-2021 and who received RT at Dana-Farber/Brigham & Women's Cancer Center. The primary outcome was cumulative incidence of in-field locoregional relapse using Gray's test with competing risks of death and isolated out-of-field recurrence. Secondary outcomes included overall survival (OS) and MCC-specific survival using log-rank tests, and risk factors of recurrence using Cox-proportional hazards regression. RESULTS: There were 50 (20.6 %) and 193 (79.4 %) courses of hypo-RT and conv-RT, respectively. The hypo-RT cohort was older (≥73 years at diagnosis: 78.0 % vs 41.5 %, p < 0.01), and received a lower equivalent total RT dose in 2 Gy per fraction (<50 Gy: 58.0 % vs 5.2 %, p < 0.01). Median follow-up was 65.1 months (range: 1.2-194.5) for conv-RT and 25.0 months (range: 1.6-131.3) for hypo-RT cohorts. Two-year cumulative incidence of in-field locoregional relapse was low in both groups (1.1 % conv-RT vs 4.1 % hypo-RT, p = 0.114). While two-year OS was lower for the hypo-RT group (62.6 % vs 84.4 %, p = 0.0008), two-year MCC-specific survival was similar (84.7 % vs 86.6 %, p = 0.743). On multivariable analysis, immunosuppression, clinical stage III disease, and lymphovascular invasion were associated with any-recurrence when controlling for sex, age, and hypo-RT. CONCLUSIONS AND RELEVANCE: There was no difference in cumulative incidence of in-field locoregional relapse or MCC-specific survival between hypo-RT and conv-RT. Prospective studies are needed to confirm hypo-RT as an efficacious treatment option for MCC.

Lymph node ratio predicts efficacy of postoperative radiation therapy in nonmetastatic Merkel cell carcinoma: A population-based analysis.

BACKGROUND: After radical resection of a nonmetastatic Merkel cell carcinoma (M0 MCC), postoperative radiation therapy (RT) is recommended as it improves survival. However, the role of RT in specific subgroups of M0 MCC is unclear. We sought to identify whether there is a differential survival benefit from RT in specific M0 MCC patient subgroups. METHODS: M0 MCC patients from the Surveillance, Epidemiology, and End Results (SEER) database registry were collected. The best prognostic age, tumor size, and lymph node ratio (LNR, ratio between positive lymph nodes and resected lymph nodes) cutoffs were calculated. The primary endpoint was overall survival (OS). RESULTS: A total of 5644 M0 MCC patients (median age 77 years, 62% male) were included: 4022 (71%) node-negative (N0) and 1551 (28%) node-positive (N+). Overall, 2682 patients (48%) received RT. Age > 76.5 years, tumor size >13.5 mm, and LNR >0.215 were associated with worse OS. RT was associated with longer OS in the M0 MCC, N0, and N+ group and independently associated with a 25%, 27%, and 26% reduction in the risk for death, respectively. RT benefit on survival was increased in tumor size >13.5 mm in the N0 group and LNR >0.215 in the N+ group. No OS benefit from RT was observed in T4 tumors (N0 and N+ groups). CONCLUSIONS: RT was associated with improved survival in M0 MCC, irrespective of the nodal status. LNR >0.215 is a useful prognostic factor for clinical decision-making and for stratification and interpretation of clinical trials.

Postoperative radiotherapy in stage I-III Merkel cell carcinoma.

BACKGROUND: Postoperative radiotherapy (PORT) is currently recommended for the treatment of Merkel cell carcinoma. Nevertheless, deviations occur frequently due to the generally elderly and frail patient population. We aimed to evaluate the influence of PORT on survival in stage I-III MCC patients treated in the Netherlands. METHODS: Patients were included retrospectively between 2013 and 2018. Fine-Gray method was used for cumulative incidence of recurrence and MCC-related death, cox regression was performed for overall mortality. Analyses were performed in patients with clinical (sentinel node biopsy [SN] not performed) stage I/II (c-I/II-MCC), pathologic (SN negative) stage I/II (p-I/II-MCC) and stage III MCC (III-MCC), separately. Propensity score matching (PSM) was performed to assess confounding by indication. RESULTS: In total 182 patients were included, 35 had p-I/II-MCC, 69 had c-I/II-MCC and 78 had III-MCC. Median follow up time was 53.5 (IQR 33.4-67.4), 30.5 (13.0-43.6) and 29.3 (19.3-51.0) months, respectively. Multivariable analysis showed PORT to be associated with less recurrences and reduced overall mortality, but not with MCC-related mortality. In stage III-MCC, extracapsular extension (sub-distribution hazard [SDH] 4.09, p = 0.012) and PORT (SDH 0.45, p = 0.044) were associated with recurrence, and ≥ 4 positive lymph nodes (SDH 3.24, p = 0.024) were associated with MCC-related mortality. CONCLUSIONS: PORT was associated with less recurrences and reduced overall mortality in patients with stage I-III MCC, but not with MCC-related mortality. Trends in overall survival benefit are likely to be caused by selection bias suggesting further refinement of criteria for PORT is warranted, for instance by taking life expectancy into account.

Patterns and predictors of relapse in Merkel cell carcinoma: Results from a population-based study.

BACKGROUND AND PURPOSE: Prospective data evaluating the role of adjuvant radiotherapy (RT) for Merkel Cell Carcinoma(MCC) is lacking. To better understand the efficacy of adjuvant RT, a population-based patterns of failure study was conducted. METHODS: We identified MCC patients treated from 1988 to 2018.Primary outcome measures were recurrence-free survival (RFS), overall survival (OS) and MCC-specific survival (MCC-SS). Charlson Co-morbidity Index (CCI) was also calculated. RESULTS: 217 patients with mean age 79 (range: 33-96) were analyzed. The median follow-up was 40 months. Treatments were: surgery(S) alone (n = 101, 45%) or S + RT(n = 116, 55%).Local recurrence (LR) was low in stage I (n = 6, 6.5%) with clear margin of ≥1 cm, negative sentinel lymph node biopsy (SLNB) without high-risk factors, irrespective of adjuvant RT. Tumor size ≥ 2 cm (HR:2.95; p = 0.024) and immunosuppression(HR:3.98; p = 0.001) were associated with high risk of nodal failure. Adjuvant RT was associated with significant reduction in regional failure (HR:0.36; p = 0.002). Distant metastases (DM) were infrequent in stage I (4/90) and stage II (4/34), compared to stage III (32/93). Adjuvant RT improvedRFS but did not influence MCC-SS and OS. CCI was a significant predictor of OS. CONCLUSIONS: Adjuvant RT improvedRFS, withoutimpact on MCC-SS and OS. Co-morbidity rather than RT influenced OS. Adjuvant RT may be avoided instage I patients with negative SLNB and no associated high-risk factors. Prophylactic RNI could be considered in stage II with high risk features, inspite of negative SLNB. Stage III patients benefited from adjuvant RNI, but no impact on prevention of DM.

Radiation therapy of cutaneous cancers.

We present the update of the recommendations of the French society of oncological radiotherapy on radiotherapy of cutaneous cancers. The indications of radiotherapy for skin cancers are not clearly defined because of the lack of randomized trials or prospective studies. For basal cell carcinomas, radiotherapy frequently offers a good local control, but a randomized trial showed that surgery is more efficient and less toxic. Indications of radiotherapy are contra-indications of surgery for patients older than 60, non-sclerodermiform histology and located in non-sensitive areas. Adjuvant radiotherapy could be proposed to squamous cell carcinomas, in case of poor prognostic factors. Dose of 60 to 70Gy are usually required, and must be modulated to the size of the lesions. Adjuvant radiotherapy seems beneficial for desmoplastic melanomas but not for the other histological types. Prophylactic nodal irradiation (45 to 50Gy), for locally advanced tumors (massive nodal involvement), decreases the locoregional failure rate but do not increase survival. Adjuvant radio- therapy (50 to 56Gy) for Merkel cell carcinomas increases also the local control rate, as demonstrated by meta-analysis and a large epidemiological study. Nodal areas must be included, if there is no surgical exploration (sentinel lymph node dissection). Kaposi sarcomas are radiosensitive and could be treated with relatively low doses (24 to 30Gy). Also, cutaneous lymphomas are good indications for radiotherapy: B lymphomas are electively treated with limited fields. The role of total skin electron therapy for T-lymphomas is still discussed; but palliative radiotherapy is very efficient in case of cutaneous nodules.