6004 Background: Platinum-based CRT is the standard treatment for LASCCHN. CET/RT is superior to RT alone and it is an alternative treatment to CRT. Induction TPF resulted to be superior to cisplatin/5fluorouracil but its efficacy when added to concomitant treatment is to be demonstrated. We designed this open-label multicenter 2x2 factorial study to assess 2 primary endpoints: 1) overall survival (OS) of induction vs. no induction; 2) Grade 3-4 in-field mucosal toxicity of CRT vs. CET/RT (already presented at ASCO 2013). Methods: 421 patients with LASCCHN of the oral cavity, oropharynx, hypopharynx, stage III-IV, ECOG PS 0-1 were randomized to one of four treatment options: Arm A1: CRT (cisplatin/5fluorouracil x 2 concomitant to standard RT fractionation); Arm A2: CET/RT; Arm B1: 3 cycles of TPF followed by the same CRT; Arm B2: 3 cycles of TPF followed by CET/RT. The superiority hypothesis of OS comparison of TPF induction vs. no induction (Arms B1+B2 vs. A1+A2), requires 204 deaths to detect a relative reduction of 33% with 2-sided 5% significance level for the log-rank test and a power of 80%. Results: 415 out of 421 patients (six major violations) were finally analyzed: 207 in induction and 208 in concomitant arm. By march 2014, at a median follow-up of 41.3 months (mos), 243 events for PFS and 201 deaths were observed. Radiological CR was 43.5% in induction and 28% in concomitant arm (p=0.002) Median PFS was 29.7 mos in induction vs 18.5 in concomitant arm with a 3-year PFS of 46.8% vs 36.7% (HR:0.73; 95%CI 0.57-0.94; p=0.015), respectively. Median OS was 53.7 mos in induction vs 30.3 in concomitant arm with a 3-year OS of 57.6% vs 45.7% (HR:0.72; 95%CI 0.55-0.96; p=0.025) respectively. Compliance to concomitant treatments was not affected by induction TPF. Conclusions: Induction TPF followed by CRT or CET/RT significantly improved PFS and OS (independently from the type of concomitant strategy) in LASCCHN patients without compromising compliance to the concomitant treatments. Clinical trial information: NCT01086826.

Baseline clinical prognostic factors for recurrent and/or metastatic (RM) head and neck squamous cell carcinoma (HNSCC) treated with immunotherapy are lacking. CT-based radiomics may provide additional prognostic information. A total of 85 patients with RM-HNSCC were enrolled for this study. For each tumor, radiomic features were extracted from the segmentation of the largest tumor mass. A pipeline including different feature selection steps was used to train a radiomic signature prognostic for 10-month overall survival (OS). Features were selected based on their stability to geometrical transformation of the segmentation (intraclass correlation coefficient, ICC > 0.75) and their predictive power (area under the curve, AUC > 0.7). The predictive model was developed using the least absolute shrinkage and selection operator (LASSO) in combination with the support vector machine. The model was developed based on the first 68 enrolled patients and tested on the last 17 patients. Classification performance of the radiomic risk was evaluated accuracy and the AUC. The same metrics were computed for some baseline predictors used in clinical practice (volume of largest lesion, total tumor volume, number of tumor lesions, number of affected organs, performance status). The AUC in the test set was 0.67, while accuracy was 0.82. The performance of the radiomic score was higher than the one obtainable with the clinical variables (largest lesion volume: accuracy 0.59, AUC = 0.55; number of tumoral lesions: accuracy 0.71, AUC 0.36; number of affected organs: accuracy 0.47; AUC 0.42; total tumor volume: accuracy 0.59, AUC 0.53; performance status: accuracy 0.41, AUC = 0.47). Radiomics may provide additional baseline prognostic value compared to the variables used in clinical practice.

Because they are typically excluded from clinical trials for head and neck cancers. Surgery represents the mainstay of treatment, but due to the frequent involvement of critical structures such as the orbit, nasal pyramid, internal carotid artery and brain, it often leads to functional and aesthetic sequelae that can severely impact quality of life.The aim of this Research Topic was to collect articles on these rare and complex cancers, with the goal of refining the understanding of their biological and clinical profile.Three original research articles and three case reports were published in this collection.Smaadahl et al contributed by reporting a retrospective study of treatment modalities and associated morbidity in 156 patients with sinonasal malignancies of various histologies. Surgery was the primary treatment in approximately two-thirds of the patients, and adjuvant radiotherapy (with or without concurrent chemotherapy) was found to follow surgery in several cases. The authors found a negative association of some factors, mainly histology and skull base involvement, with local control and survival outcomes.In line with other reports 3 , patients with mucosal melanoma had the worst prognosis, as well as non-surgically treated patients, reflecting the poor outcome of unresectable and inoperable patients.Hoshi et al presented a retrospective series of 11 patients treated with systemic therapy for incurable recurrent and/or metastatic (R/M) olfactory neuroblastoma (ONB). ONB accounts for approximately 2-3% of all sinonasal tumors. It is usually a low-grade cancer with an indolent course, but high-grade tumors can rarely show aggressive behaviour, especially those with dural extension. ONB is typically treated with surgery followed by radiotherapy while systemic treatment is usually palliative and limited to patients with metastatic disease. There is no standard systemic treatment for R/M ONB. However, similar to other small-cell malignancies, the most commonly used chemotherapy regimen is cisplatin plus etoposide. Limited data have been reported on targeted therapies, while there are no data on immunotherapy which is an off-label therapy for this rare cancer. Hoshi et al found promising efficacy results for anti-PD1 therapy with nivolumab or pembrolizumab, opening up a possible alternative to chemotherapy in ONB, for which systemic treatment remains limited and not standardized. The lack of apparent association with PD-L1 expression highlights the need to identify predictive biomarkers even in this rare cancer.Chen M et al. contributed to this collection by reporting the molecular characterisation of nuclear protein in testis (NUT) carcinoma in two patients and reviewing the literature on the pathologic and molecular features. NUT carcinoma is one of the rarest and most aggressive sinonasal cancers with a very poor prognosis and a median overall survival of less than 12 months. The authors found that NUT carcinoma typically presents with undifferentiated or poorly differentiated small cells, sometimes with evidence of focal abrupt keratinization, and with variable expression of p40 and CK protein. All cases with available data stained positive for NUTM1 protein and showed heterogeneous genotypes including different NUTM1 fusion partners, with a, low tumor mutational burden and stable microsatellites. There is currently no standard treatment for NUT carcinoma. The mainstay is a multimodal approach including surgery, radiotherapy and possibly systemic therapy. Targeted therapy with histone deacetylase inhibitors (HDACi) and BET inhibitors are under investigation. The molecular characterization of NUT carcinoma may provide new opportunities to test new drugs in this poor-prognosis patient population.Three interesting case reports describe the management of different sinonasal cancer subtypes. In the first case reported by Chen F et al, the authors describe the case of a patient with sinonasal squamous cell carcinoma who was treated with 2 cycles of neoadjuvant docetaxel and cisplatin chemotherapy plus the anti-PD-1 agent tislelizumab. To date, there is no established role for neoadjuvant treatment in resectable sinonasal squamous cell carcinoma, and immunotherapy-based treatment is not approved for sinonasal cancers.However, preoperative systemic therapy may be of potential benefit in reducing tumor size and achieving adequate surgical margins, which has been shown to impact survival in large retrospective series. The complete pathologic response observed in the clinical case provides a signal to further investigate the potential benefit of early systemic therapy in selected cases. This strategy may be particularly useful in patients where invasion of critical structures could compromise both the adequacy of surgical margins and organ function.Another case report by Cubides-Cordoba et al, focuses on human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC), a new entity recently recognized in the latest WHO classification and provisionally included in the previous edition as "HPV-related carcinoma with adenoid cystic-like features". It is characterized by myoepithelial differentiation, squamous atypia, and the presence of high-risk HPV (usually type 33, followed by type 35) with strong and diffuse positivity for p16. The authors present a clinical case of a patient with HPV 35-associated HMSC, in whom whole exome sequencing (WES) revealed some potential targets for personalized treatment.The final case report by Quan R et al, describes an unusual and rare case of coexistence of small cell lung cancer (SCLC) and primary sinonasal small cell carcinoma. Sinonasal small cell neuroendocrine carcinoma is an aggressive and extremely rare cancer for which there is no standard treatment. The authors highlight the need for an accurate immunohistochemical and genomic characterization of this rare cancer, as well as the potential benefit of multimodal treatment combining...