The efficacy and safety of dalpiciclib, a cyclin-dependent kinase 4/6 inhibitor, in patients with advanced head and neck mucosal melanoma harboring CDK4 amplification.

BACKGROUND: Mucosal melanoma (MM) is a rare but devastating subtype of melanoma. Our previous studies have demonstrated robust anti-tumor effects of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors in head and neck MM (HNMM) patient-derived xenograft models with CDK4 amplification. Herein, we aimed to investigate the efficacy and safety of dalpiciclib (SHR6390), a CDK4/6 inhibitor, in HNMM patients harboring CDK4 amplification. METHODS: The anti-tumor efficacy of dalpiciclib was assessed by HNMM patient-derived xenograft (PDX) models and patient-derived tumor cells (PDC) in vivo and in vitro. Immunohistochemical analyses and western blot were then performed to assess the markers of cell proliferation and CDK4/6 signaling pathway. For the clinical trial, advanced recurrent and/or metastatic HNMM patients with CDK4 amplification were treated with dalpiciclib 125 mg once daily for 21 consecutive days in 28-day cycles. The primary endpoint was disease control rate (DCR). Secondary endpoints included safety, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: Dalpiciclib profoundly suppressed growth of HNMM-PDX and PDC with CDK4 amplification, whereas it showed relatively weak suppression in those with CDK4 wild type compared with vehicle. And dalpiciclib resulted in a remarkable reduction in the expression levels of Ki-67 and phosphorylated Rb compared with control group. In the clinical trial, a total of 17 patients were enrolled, and 16 patients were evaluable. The ORR was 6.3%, and the DCR was 81.3%. The estimated median PFS was 9.9 months (95% CI, 4.8-NA), and the median OS was not reached. The rate of OS at 12 months and 24 months was 68.8% (95% CI, 0.494-0.957) and 51.6% (95% CI, 0.307-0.866), respectively. The most frequent adverse events were neutrophil count decrease, white blood cell count decrease, and fatigue. CONCLUSIONS: Dalpiciclib was well-tolerated and displayed a durable benefit for HNMM patients with CDK4 amplification in this study. Further studies on CDK4 inhibitors and its combination strategy for MM are worth further exploration. TRIAL REGISTRATION: ChiCTR2000031608.

Clinical outcomes of head and neck mucosal melanoma treated with surgery: a single-center study in Japan.

BACKGROUND: Head and neck mucosal melanomas are rare malignancies. Although the prognosis is poor owing to the high incidence of distant metastases, locoregional control remains important. It is difficult to obtain results in a large cohort because of its rarity. This study aimed to elucidate the survival outcomes of patients with head and neck mucosal melanoma treated with surgery in Japan. METHODS: Patients with head and neck mucosal melanoma who were surgically treated between 2007 and 2021 at the National Cancer Center Hospital were retrospectively analyzed. RESULTS: A total of 47 patients were included in this study. The 5-year overall survival, disease-specific survival, locoregional control and relapse-free survival rates were 42%, 50%, 79% and 13%, respectively. The disease-specific survival of the oral mucosal melanoma group was significantly better than that of the sinonasal mucosal melanoma group (5-year disease-specific survival rate: 70% versus 37%, respectively; P = 0.04). Multivariate analyses revealed that sinonasal mucosal melanoma were independently significant adverse prognostic factor, for overall survival and disease-specific survival. Patients with oral mucosal melanoma patients had a higher incidence of lymph node metastasis than those with sinonasal mucosal melanoma patients (P < 0.0001). CONCLUSION: This study demonstrated the survival outcomes of the largest cohort of patients with head and neck mucosal melanomas treated surgically at a single institution within the past 20 years in Japan. We found that survival outcomes and incidence of nodal metastases varied by site.

CDK4 and TERT amplification in head and neck mucosal melanoma.

BACKGROUND: Recent high-throughput sequencing studies have revealed frequent CDK4 and TERT amplification in mucosal melanoma, suggesting that they are potential therapeutic targets. In this study, we investigated the statuses of CDK4 and TERT in head and neck mucosal melanoma (HNMM) with the aim of providing preclinical data to support future clinical trials. METHODS: In total, 29 HNMM samples were collected, including 16 oral mucosal melanoma (OMM) samples and 13 nasal cavity/sinuses melanoma (SNMM) samples. Fluorescence in situ hybridization was used to analyze CDK4 and TERT amplification, and immunohistochemistry was used to analyze CDK4 and TERT protein expression patterns. CDK4 expression was knocked down in the ME cells (an OMM cell line), and changes in cell cycle were analyzed. Cell viability assays were performed to determine the sensitivity of ME to abemaciclib (a CDK4 inhibitor) combined with dacarbazine (an anti-melanoma chemotherapy drug). RESULTS: We detected five samples exhibited CDK4 amplifications and nine samples exhibited TERT amplifications in our HNMM series, and found that CDK4 amplification tended to occur in combination with TERT amplification. Amplifications of CDK4 and TERT were more common in OMM than in SNMM. Amplifications of CDK4 and TERT were associated with greater CDK4 and TERT protein expression levels. CDK4 knockdown led to delayed G1/S phase transition in ME cells. Furthermore, ME cells were sensitive to abemaciclib (IC50  = 5.23 nM). Abemaciclib and dacarbazine synergistically inhibited ME cells' viability. CONCLUSION: We confirmed high frequencies of CDK4 and TERT amplification in OMM. Combined therapy with a CDK4/6 inhibitor and anti-melanoma chemotherapeutic agents will be a reasonable strategy for future clinical trials concerning unresectable or metastatic OMM.

Head and neck mucosal melanoma: radiological considerations and UK imaging guidelines.

PURPOSE: Awareness of head and neck mucosal melanoma (HNMM) is important, as incorrect work-up can impact on the investigation and management of this rare and aggressive cancer. Following on from the 2020 HNMM UK guidelines, we set out the imaging recommendations and their rationale. To illustrate the key imaging characteristics, we also include a case series from our centre. METHODS: All HNMM cases managed at our institution from January 2016 to January 2021 were identified, and the available imaging for each patient was reviewed. For each patient, the age, gender and location of primary tumour was recorded together with key staging and diagnostic imaging parameters. RESULTS: A total of 14 patients were identified. The median age was 65 years with a female to male ratio of 1.33:1. Primary tumours were sinonasal in location in 93% of cases, with 7% of patients having metastatic neck nodes at presentation and 21% of cases having distant metastatic disease at presentation. CONCLUSION: This data set is in general concordance with other published series regarding the sinonasal origin of the vast majority of HNMM tumours along with the proportion of patients with metastatic neck nodes and distant metastases at presentation. We recommend dual-modality imaging with computed tomography (CT) and magnetic resonance imaging (MRI) of primary tumours whenever possible. In the systematic staging of HNMM, positron emission tomography (PET)-CT should be strongly considered, together with MRI of the brain. Pre-biopsy imaging of HNMM tumours is advisable whenever possible.

Genetic Analysis of Melanoma Types Using Japanese Genomic Database.

OBJECTIVES: The purpose of this study is to compare genetic mutations, tumor mutation burden (TMB), and the effects of molecular targeted drugs and immune checkpoint inhibitors (ICIs) in head and neck mucosal melanoma (HNMUM) with those in skin melanoma (SKM) and ocular melanoma (OM). METHODS: Data were analyzed for 72 consecutive patients with HNMUM, including 366 with SKM and 31 with OM, registered at the Japan National Cancer Center, Center for Cancer Genomics and Advanced Therapeutics (C-CAT) between June 2019 and October 2023. Genetic alterations and TMB were determined by FoundationOne CDx next-generation sequencing. RESULTS: The top 10 mutations in HNMUM were RAD21 (47.2%), NBN (45.8%), MYC (40.3%), LYN (31.9%), NRAS (29.1%), IRF4 (23.6%), DAXX (22.2%), KIT (22.2%), NOTCH3 (20.8%), and DDR1 (19.4%), with 16.6 ± 0.8 (mean ± SEM) mutations/individual. In SKM, BRAF (p = 0.04) mutation was associated with a significantly better prognosis. The TMB values were 5.7 ± 2.1 (mean ± SEM) in HNMUM, 4.1 ± 0.2 in SKM, and 3.4 ± 0.9 in OM, with no significant differences among the three groups. The median survival time for patients with distant metastases was 803 (95% confidence interval: 539-NA) days for HNMUM, 1413 (831-2172) days for SKM, and 1138 (438-NA) days for OM. CONCLUSIONS: The top 10 mutations in HNMUM are closer to those in OM than those in SKM. There was no significant difference in TMB values or survival rates with regard to the therapeutic effect of ICIs among the diseases, which suggests that current treatment of HNMUM with ICIs is appropriate. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Efficacy and Mechanism of Hypofractionation Radiotherapy Combined with PD-1 Inhibitors in a Model of Head and Neck Melanoma.

Head and neck mucosal melanoma is one of the most common types of melanoma in China, but the prognosis is worse than other types, and there is no effective treatment plan to improve patient survival. This study analyzes the efficacy of hypofractionation radiotherapy combined with PD-1 inhibitor in the treatment of head and neck mucosal melanoma, as well as its impact on the tumor immune microenvironment. NPSG mice were used to construct a humanized bilateral lesion tumor model of the humanized immune system. The models were divided into an RT (8 Gy)+anti PD-1 group, an RT (2 GyX4)+anti PD-1 group, an Anti PD-1 group, an RT (8 Gy) group, and a blank group. Differences in efficacy and immune cells in blood, lymph nodes, and tumor tissues were compared between different treatment groups. The treatment effect of RT (8 Gy)+anti PD-1 was better than the other groups with a tumor growth inhibition value (TGI) over 60%. Significant recruitment and activation of CD8+T cells were found in the blood, lymph nodes, and tumor tissues and significantly inhibited the level of PD-1+CD8+T cells in the group of RT (8 Gy)+anti PD-1. This study confirmed the efficacy of hypofractionation radiotherapy combined with PD-1 inhibitors, which can inhibit tumor growth and produce distant effects. The appearance of a distant effect is related to the enhancement in the number and activity of CD8+T cells in the local tumor and peripheral blood and lymph nodes. This study confirms the therapeutic and immune regulatory effect of hypofractionation radiotherapy combined with PD-1 inhibitors.

Prognostic Nomograms for Predicting Overall Survival and Cancer-Specific Survival in Patients with Head and Neck Mucosal Melanoma.

Background: Accurate forecasting of the risk of death is crucial for people living with head and neck mucosal melanoma (HNMM). We aimed to establish and validate an effective prognostic nomogram for HNMM. Methods: Patients with HNMM who underwent surgery between 2010 and 2015 were selected from the Surveillance, Epidemiology, and End Results (SEER) database for model construction. After eliminating invalid and missing clinical information, 288 patients were ultimately identified and randomly divided into a training cohort (199 cases) and a validation cohort (54 cases). Univariate and multivariate Cox proportional hazards regression analyses were performed in the training cohort to identify prognostic variables. Independent influencing factors were used to build the model. Through internal verification (training cohort) and external verification (validation cohort), the concordance indexes (C-indexes) and calibration curves were used to evaluate the predictive value of the nomogram. Results: For the training cohort, five independent risk predictors, namely age, location, T stage, N stage, and surgery, were selected, and nomograms with estimated 1- and 3-year overall survival (OS) and cancer-specific survival (CSS) were established. The C-index showed that the predictive performance of the nomogram was better than that of the TNM staging system and was internally verified (through the training queue: OS: 0.764 vs 0.683, CSS: 0.783 vs 0.705) and externally verified (through the verification queue: OS: 0.808 vs 0.644, CSS: 0.823 vs 0.648). The calibration curves also showed good agreement between the prediction based on the nomogram and the observed survival rate. Conclusion: The nomogram prediction model can more accurately predict the prognosis of HNMM patients than the traditional TNM staging system and may be beneficial for guiding clinical treatment.

Management of Head and Neck Mucosal Melanoma.

Head and neck mucosal melanomas are uncommon and aggressive malignancies that arise mainly in the nasal cavity and paranasal sinuses, with the next commonest site being the oral cavity. The mainstay of treatment is radical surgical resection. Adjuvant radiotherapy improves locoregional control but does not improve overall survival. Systemic treatment with immunotherapy or targeted therapies can offer scope for modifying the course of the disease in both the adjuvant and the recurrent and metastatic setting. Further understanding of the genomic landscape and factors regulating immunogenicity will lead to further therapeutic opportunities in this challenging disease.

Gene mutations and clinical prognosis of mucosal melanoma in different locations of head and neck.

BACKGROUND: Mucosal melanoma is the second most common subtype of melanoma in China and head and neck region is one of the main sites of this disease. AIMS/OBJECTIVES: Analyzed the phenotypes of C-Kit, NRAS, PDGFRA and BRAF genes in patients with in different locations to explore the characteristics of gene mutations. MATERIAL AND METHODS: 96 patients were included in this study. C-Kit (exons 9, 11, 13, 17 and 18), NRAS (exons 1 and 2), PDGFRA (exons 12, 14 and 18) and BRAF (exons 11 and 15) were analyzed by PCR amplification and Sanger sequencing. RESULTS: 14 (14.58%) patients had C-Kit mutation, 6 (6.25%) had BRAF mutation, 23 (23.96%) had PDGFRA mutation, and 12 (12.50%) had NRAS mutation. The NRAS mutation (p = 0.037, 95%CI: 1.050-4.572) was an independent factor affecting distant metastasis and was most commonly found in the nasal cavity/paranasal sinuses (p = .043) while the BRAF mutation was more common in locations other than the nasal cavity/paranasal sinus (p = .008) and was associated with local recurrence. CONCLUSIONS AND SIGNIFICANCE: Gene phenotypes of mucosal melanoma in different locations has differences. Lesions in the nasal cavity and paranasal sinus should be assessed separately from other parts such as the nasopharynx.

Treatment outcomes of mucosal melanoma of head and neck: Efficacy of immune checkpoint inhibitors for advanced disease.

Background: Head and neck mucosal melanoma (HNMM) is a rare and aggressive subtype of melanoma. HNMM often develops as a recurrent or metastatic disease, and its prognosis is worse than that of cutaneous melanoma. Recent large-scale clinical studies have reported favorable outcomes with immune checkpoint inhibitors (ICIs) for melanoma. However, these clinical trials included only a small number of HNMM cases. This study aimed to estimate treatment outcomes and prognostic predictors of ICIs for advanced HNMM. Methods: Cases of advanced HNMM, defined as unresectable or metastatic HNMM at the initial diagnosis (five patients) or development of recurrent/metastatic HNMM after initial treatment (27 patients), were included in this study. Survival analysis and a search for prognostic factors were performed for these 32 patients. Furthermore, the detailed clinical course of patients who received ICI treatment was investigated. Results: The median overall survival (OS) of 32 patients with advanced HNMM was 25.3 months. The estimated 1-, 3-, and 5-year OS rates were 68.4%, 42.8%, and 34.3%, respectively. Fourteen patients (43.7%) received ICIs, whereas 18 (56.3%) did not. Univariate analysis showed that ICI treatment was the only factor associated with a better 1-year OS. Patients who received ICI treatment had significantly longer OS (median OS: not reached, 1-year OS: 85.7%) than those who did not (median OS: 11.3 months, 1-year OS: 54.5%). The overall response and disease control rates of patients who received ICI treatment were 50% and 64.3%, respectively. Patients who achieved complete response (CR) or partial response (PR) to ICI treatment survived significantly longer (1-year OS: 100%) than those who did not (1-year OS: 71.4%). Among the five patients who discontinued ICI treatment due to severe immune-related adverse events (irAEs), four did not receive salvage treatments but showed durable treatment effects and survived for 9.8-54.2 months at the end of the follow-up period. Conclusions: ICI treatment achieved a favorable OS for advanced HNMM. CR/PR to ICI treatment and discontinuation owing to severe irAEs were favorable predictors of OS.

Mucosal Melanoma.

Mucosal melanoma is a rare but aggressive cancer arising in mucosal surfaces most commonly in the head and neck. The clinical presentation is often nonspecific and differs in relation to the site of origin so often diagnosis is delayed resulting in poor prognosis. Mucosal melanoma has a 5-year survival of only 25%. Surgery with negative margins is the mainstay of treatment but dependent on several variables including anatomic location, involved structures, and size of tumor. Although not well defined given the rarity of mucosal melanoma, there is a role for radiation and systemic therapy in the treatment of this disease.

Prognostic Value of an Immunohistochemical Signature in Patients With Head and Neck Mucosal Melanoma.

Purpose: We aimed to develop a prognostic immunohistochemistry (IHC) signature for patients with head and neck mucosal melanoma (MMHN). Methods: In total, 190 patients with nonmetastatic MMHN with complete clinical and pathological data before treatment were included in our retrospective study. Results: We extracted five IHC markers associated with overall survival (OS) and then constructed a signature in the training set (n=116) with the least absolute shrinkage and selection operator (LASSO) regression model. The validation set (n=74) was further built to confirm the prognostic significance of this classifier. We then divided patients into high- and low-risk groups according to the IHC score. In the training set, the 5-year OS rate was 22.0% (95% confidence interval [CI]: 11.2%- 43.2%) for the high-risk group and 54.1% (95% CI: 41.8%-69.9%) for the low-risk group (P<0.001), and in the validation set, the 5-year OS rate was 38.1% (95% CI: 17.9%-81.1%) for the high-risk group and 43.1% (95% CI: 30.0%-61.9%) for the low-risk group (P=0.26). Multivariable analysis revealed that IHC score, T stage, and primary tumor site were independent variables for predicting OS (all P<0.05). We developed a nomogram incorporating clinicopathological risk factors (primary site and T stage) and the IHC score to predict 3-, 5-, and 10-year OS. Conclusions: A nomogram was generated and confirmed to be of clinical value. Our IHC classifier integrating five IHC markers could help clinicians make decisions and determine optimal treatments for patients with MMHN.

Clinical outcomes and patterns of failure of head and neck mucosal melanoma treated with multiple treatment modalities.

OBJECTIVES: The study aims to analyze the clinical characteristics of head and neck mucosal melanoma (MMHN) and the effects of multiple treatment modalities on distant metastasis, recurrence and survival rates to provide a reference for the individualized treatment of MMHN. METHODS: We retrospectively reviewed 262 patients with stage III-IVb MMHN treated from March 1986 to November 2018 at our cancer center. RESULTS: The median follow-up time was 34.0 months (range 1-262 months). The 5-year overall survival (OS), distant metastasis-free survival (DMFS) and disease-free survival (DFS) probabilities were 37.7%, 30.2%, and 20.3%, respectively. The 5-year OS rates for patients with stage III, stage IVA, and stage IVB MMHN were 67.0%, 24.1% and 8.3%, respectively (P < 0.001). A total of 246 (93.9%) patients received surgery, 149 (56.9%) patients received chemotherapy, and 69 (26.3%) patients received immunologic/targeted therapy. A total of 106 (40.5%) patients were treated with radiotherapy: 9 were treated with preoperative radiotherapy, 93 were treated with postoperative radiotherapy, and 4 were treated with radiotherapy alone. In the multivariate Cox regression analysis, primary tumor site, T stage, and immunologic/targeted therapy were independent factors for OS (all P < 0.05). Irradiation technique, T stage, and N stage were independent prognostic factors for DMFS (all P < 0.05). T stage, N stage, and surgery were independent prognostic factors for DFS (all P < 0.05). Distant metastasis was observed in 107 of 262 patients (40.8%), followed by local [74 (28.2%)] and regional [52 (19.8%)] recurrence. CONCLUSIONS: The main reason for treatment failure in MMHN is distant metastasis. Immunologic/targeted therapy and surgery are recommended to improve the survival of MMHN. The American Joint Committee on Cancer (AJCC) 8th edition staging system for MMHN does stage this disease effectively.

Matched analysis of the prognosis of amelanotic and pigmented melanoma in head and neck.

Background: The prognosis of mucosal melanoma is poor, and the difference in clinical prognosis between patients with and without pigment needs further study.Aim: To analyze data with head and neck mucosal melanoma, and compare the prognosis of patients with and without pigment.Material and methods: The patients of amelanotic melanoma were matched with pigmented type according to age, sex, stage, location of disease, treatment history, tobacco and alcohol history. The Kaplan-Meier and Cox proportional risk regression model was used for analyzation.Results: 46 patients of amelanotic melanoma and 46 of pigmented type were included in this study. The overall survival rate and progression-free survival rate of patients with pigmented melanoma were higher than in patients with amelanotic melanoma (HR = 0.533, p = .035, 95% CI = 0.296-0.957; HR = 0.530, p = .034, 95% CI = 0.294-0.953, respectively), and the risk of distant metastases in patients with amelanotic melanoma was significantly higher than that in patients with pigmented melanoma (HR = 0.474, p = .046, 95% CI = 0.228-0.987).Conclusions and significance: The prognosis and disease-free survival of amelanotic melanoma is worse than for the pigmented type group. More identifying the differences in clinical characteristics will help to further individualized treatment decisions.

Management of Noncutaneous Melanomas.

Noncutaneous melanomas are rare subtypes of melanoma with high rates of metastatic disease and poor overall survival. One-third to one-half of cases are amelanotic, which may contribute to a delay in diagnosis. Immunohistochemistry staining with typical melanoma markers helps confirm the diagnosis. There is no standard staging system across mucosal melanomas. Elective nodal dissection is not recommended and there is a paucity of data to support use of sentinel lymph node biopsy. Mutational analysis should be routinely performed. Systemic therapy options include targeted inhibitors, immunotherapy, and cytotoxic chemotherapy, although further studies are needed to confirm their efficacy.

Efficacy and safety of primary surgery with postoperative radiotherapy in head and neck mucosal melanoma: a single-arm Phase II study.

BACKGROUND: There still remains no well-established treatment strategy for head and neck mucosal melanoma (HNMM). We aim to evaluate the effectiveness and safety of primary surgery with postoperative radiotherapy for this disease. PATIENTS AND METHODS: A single-arm, Phase II clinical trial was conducted at Sun Yat-Sen University Cancer Center. Patients with nonmetastatic, histologically proven HNMM were prospectively enrolled. Patients received primary surgery followed by intensity-modulated radiotherapy with an equivalent dose at 2 Gy per fraction of 65-70 Gy to CTV1 (high-risk regions including tumor bed) and 50-55 Gy to CTV2 (low-risk regions). Additional use of adjuvant chemotherapy (AC) depended on consultation from a multidisciplinary team. This trial is registered with ClinicalTrials.gov, number NCT03138642. RESULTS: A total of 33 patients were enrolled and analyzed between July 2010 and November 2016. There were 18 (54.5%) patients with T3 disease and 15 (45.5%) patients with T4a disease. The median age at diagnosis was 58 years (range 27-83 years), and 61% of the cohort were males. The overall median follow-up duration was 25.3 months (range 5.3-67.1 months). The 3-year overall survival (OS), local relapse-free survival (LRFS), regional relapse-free survival (RRFS), and distant metastasis-free survival (DMFS) rates were 44.4, 91.7, 78.1, and 41.7%, respectively. Patients with T4a disease showed significantly inferior OS (P=0.049) and DMFS (P=0.040) than those with T3 disease. Prophylactic neck radiation (PNR) was nearly associated with superior RRFS (P=0.078). However, there was no significant difference in OS, LRFS, RRFS, and DMFS for patients treated with or without AC (P>0.05 for all). Toxicities were generally mild to moderate. CONCLUSION: Primary surgery with postoperative radiotherapy yielded excellent local control and acceptable toxicity profile for HNMM. Nevertheless, high rates of distant metastases resulted in limited survival.

Postoperative adjuvant radiotherapy improves loco-regional recurrence of head and neck mucosal melanoma.

Primary head and neck mucosal melanoma (HNMM) is a rare tumor with a poor prognosis. Controversy remains as to whether postoperative adjuvant radiotherapy (PORT) achieves a significant benefit in HNMM treatment. Because of the lack of available conclusive prospective data, we performed a systematic review and meta-analysis of all relevant available studies to clarify the benefits of PORT. A comprehensive literature search of PubMed and Google Scholar electronic databases was conducted to collect relevant studies until April 30, 2014. Studies published in the English language comparing surgery alone and surgery plus PORT for HNMM were included, with more than 15 study populations. All statistical analyses were performed using STATA version 12.0. A total of 423 patients were available from eight studies and the median sample size was 53 cases. The median follow-up time was 38.2 months (range 18.3-65.2 months). There was a positive association between PORT and loco-regional recurrence of HNMM (odds ratio [OR] = 0.36, 95% confidence interval [CI] = 0.22-0.60, P = 0.000). No associations were found between the PORT and 3-year and 5-year overall survival (OS) (OR = 1.41, 95% CI = 0.94-2.09, P = 0.093 and OR = 1.06, 95% CI = 0.70-1.61, P = 0.161, respectively). PORT had no impact on 3-year and 5-year OS (hazard ratio [HR] = 1.14, 95% CI = 0.80-1.61, P = 0.472 and HR = 1.34, 95% CI = 0.97-1.85, P = 0.227, respectively). PORT improved loco-regional recurrence of HNMM independent of OS.