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Objective: The frequency of metastasis to level VI lymph nodes in advanced pyriform sinus squamous cell carcinoma (PSSCC) is unknown. We intended to analyze the clinical features and pathological presence or absence of level VI lymph node metastasis in patients with PSSCC., Methods: The data of 270 patients with previously untreated hypopharyngeal squamous cell carcinoma from 2006 to 2016 were obtained. Patients who underwent pharyngolaryngectomy for the pyriform sinus subsite with a curative intent with level VI dissection were included. We retrospectively analyzed the clinical Tumor-Node (TN) status (TNM classification of malignant tumors, eighth edition) and the presence or absence of pathological level VI lymph node metastasis., Results: A total of 34 patients were included. Eight patients (24%) had pathological level VI lymph node metastasis. The rate of pathological level VI lymph node metastasis was directly proportional to the clinical N status ( P  = .0002, Chi-square test for trend). In all, 5 patients with cN2b- 3 were classified as cN3b. Ipsilateral pathological level VI lymph node metastasis was observed in 1 patient, and bilateral metastasis was observed in 3 patients. There was no association between clinical T status or pyriform sinus apex invasion and pathological level VI metastasis (both P  > .99, Fisher's exact test)., Conclusions: PSSCC with cN3b is prone to bilateral level VI metastasis. We recommend that patients with PSSCC with cN3b should undergo bilateral level VI lymph node dissection.

Purpose: The standard treatment for postoperative high-risk locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) is chemoradiotherapy with 3-weekly cisplatin (100 mg/m 2 ). However, whether chemoradiotherapy with weekly cisplatin (40 mg/m 2 ) yields comparable efficacy with 3-weekly cisplatin in postoperative high-risk LA-SCCHN is unknown., Patients and Methods: In this multi-institutional open-label phase II/III trial, patients with postoperative high-risk LA-SCCHN were randomly assigned to receive either chemoradiotherapy with 3-weekly cisplatin (100 mg/m 2 ) or with weekly cisplatin (40 mg/m 2 ) to confirm the noninferiority of weekly cisplatin. The primary end point of phase II was the proportion of treatment completion, and that of phase III was overall survival. A noninferiority margin of hazard ratio was set at 1.32., Results: Between October 2012 and December 2018, a total of 261 patients were enrolled (3-weekly cisplatin, 132 patients; weekly cisplatin, 129 patients). At the planned third interim analysis in the phase III part, after a median follow-up of 2.2 (interquartile range 1.19-3.56) years, chemoradiotherapy with weekly cisplatin was noninferior to 3-weekly cisplatin in terms of overall survival, with a hazard ratio of 0.69 (99.1% CI, 0.374 to 1.273 [< 1.32], one-sided P for noninferiority = .0027 < .0043). Grade 3 or more neutropenia and infection were less frequent in the weekly arm (3-weekly v weekly, 49% v 35% and 12% v 7%, respectively), as were renal impairment and hearing impairment. No treatment-related death was reported in the 3-weekly arm, and two (1.6%) in the weekly arm., Conclusion: Chemoradiotherapy with weekly cisplatin is noninferior to 3-weekly cisplatin for patients with postoperative high-risk LA-SCCHN. These findings suggest that chemoradiotherapy with weekly cisplatin can be a possible treatment option for these patients., Competing Interests: Naomi KiyotaHonoraria: Ono Pharmaceutical, Bristol Myers Squibb Japan, Bayer, Chugai Pharma, Merck Serono, MSD, Eisai, AstraZenecaConsulting or Advisory Role: Shift Zero, Ono Pharmaceutical, Ascent Development ServicesSpeakers' Bureau: Ono Pharmaceutical, Bristol Myers Squibb Japan, Merck Serono, Eisai, Bayer, MSD, Chugai PharmaResearch Funding: Ono Pharmaceutical (Inst), Bristol Myers Squibb (Inst), Pfizer (Inst), Roche (Inst), Rakuten Medical (Inst), Adlai Nortye (Inst) Makoto TaharaHonoraria: Merck Serono, Bristol Myers Squibb, Eisai, Ono Pharmaceutical, MSDConsulting or Advisory Role: Ono Pharmaceutical, MSD, Pfizer, Bristol Myers Squibb, Rakuten Medical, Bayer, LillyResearch Funding: Merck Sharp & Dohme (Inst), AstraZeneca (Inst), Ono Pharmaceutical (Inst), Novartis (Inst), Pfizer (Inst), Bristol Myers Squibb (Inst), Rakuten Medical (Inst), Bayer (Inst), GlaxoSmithKline (Inst), Lilly (Inst) Junki MizusawaHonoraria: Chugai Pharma, Taiho Pharmaceutical Takeshi KodairaConsulting or Advisory Role: Ono Pharmaceutical, Chugai PharmaSpeakers' Bureau: Merck Serono, Hitachi, Bristol Myers Squibb Japan, Accuray, Elekta, Ono Pharmaceutical, Canon USA, AstraZeneca, Chugai Pharma Nobuhiro HanaiHonoraria: Ono Pharmaceutical, Bristol Myers Squibb, Merck, MSD K.K, Eisai, Ethicon/Johnson & Johnson, AmcoConsulting or Advisory Role: SanwaResearch Funding: Ono Pharmaceutical, Chugai Pharma, Rakuten Medical, Bristol Myers Squibb/Ono Pharmaceutical, GlaxoSmithKline K.K, MSD K.K Hiroki HaraHonoraria: Chugai Pharma, Taiho Pharmaceutical, Merck Serono, Yakult Honsha, Lilly, Ono Pharmaceutical, Takeda, Bristol Myers Squibb, Sanofi, MSD, Daiichi Sankyo, Kyowa Hakko Kirin, BayerConsulting or Advisory Role: Ono Pharmaceutical, MSD, Lilly, Boehringer Ingelheim, Dainippon SumitomoResearch Funding: AstraZeneca (Inst), Chugai Pharma (Inst), Merck Serono (Inst), MSD (Inst), Ono Pharmaceutical (Inst), Taiho Pharmaceutical (Inst), Boehringer Ingelheim (Inst), Dainippon Sumitomo Pharma (Inst), Daiichi Sankyo (Inst), Pfizer (Inst), Eisai (Inst), Incyte (Inst), BeiGene (Inst), Astellas Pharma (Inst), Bayer (Inst), Elevar Therapeutics (Inst) Kaoru TanakaHonoraria: AstraZeneca, Merck Serono, Ono Pharmaceutical, Bristol Myers Squibb, Eisai, MSD, Kyowa Kirin Co, Ltd Akihiro HommaConsulting or Advisory Role: Rakuten Medical Japan, Olympus Medical SystemsSpeakers’ Bureau: Bristol Myers Squibb Japan, Mitsubishi Tanabe Pharma, Eisai, Makichie, Merck Serono, MSD K.K, Ono Pharmaceutical, Sanofi, Nobelpharma, BayerResearch Funding: Taiho Pharmaceutical (Inst), Kyorin Pharmaceutical (Inst), Otsuka Pharmaceutical Factory (Inst), Eisai (Inst) Nobuhiko OridateSpeakers' Bureau: Ono Pharmaceutical, Bristol Myers Squibb Japan, Merck Biopharma/Japan, Taiho Pharmaceutical, MSDResearch Funding: Ono Pharmaceutical, Merck biopharma/Japan, Taiho Pharmaceutical, Daiichi Sankyo Japan Tsutomu UedaHonoraria: Mitsubishi Tanabe Pharma, Bayer, Taiho Pharmaceutical, MSD, Ono PharmaceuticalResearch Funding: Ono Pharmaceutical Kenichi NakamuraHonoraria: Bayer Yakuhin, Chugai Pharma, Taiho PharmaceuticalResearch Funding: Astellas Pharma (Inst), Eisai (Inst), Otsuka (Inst), Ono Pharmaceutical (Inst), Kyorin (Inst), Daiichi Sankyo (Inst), Taiho Pharmaceutical (Inst), Takeda (Inst), Chugai/Roche (Inst), Novartis (Inst), Pfizer (Inst), Bayer (Inst), Bristol Myers Squibb Japan (Inst), Boehringer Ingelheim Seiyaku (Inst) Ryuichi HayashiConsulting or Advisory Role: Rakuten Medical JapanNo other potential conflicts of interest were reported.

Background: This study aimed to reveal the influence of the invasion site of external auditory canal (EAC) cancer by analyzing the outcome of patients with advanced tumor., Methods: A total of 111 patients with T4 EAC cancer were enrolled in this study. Of these patients, 79 underwent chemoradiotherapy and 32 underwent surgery under curative intent. Univariate and multivariate analyses and the Kaplan-Meier method were used to focus on the tumor invasion sites and overall survival of the patients., Results: The 3-year overall survival rate of all patients was 55.0%. In multivariate analysis, the only significant invasion site for overall survival was the facial nerve, with the dura mater being the next most influential site. When Kaplan-Meier survival curve was calculated, facial nerve and dura mater were the significant factors resulting in poor patient outcomes., Conclusion: The facial nerve and dura mater are crucial sites of EAC cancer for patient outcomes., (© 2021 Wiley Periodicals LLC.)

Objectives: This study aimed to evaluate the efficacy of chemoradiotherapy (CRT) for patients with advanced cancer of the external auditory canal (EAC) by analyzing the outcome of the patients., Methods: This is a multi-institutional retrospective survey, and we reviewed the medical records of the subjects. A total of 181 patients with tumor (T)3 or T4 tumor in 17 institutions were enrolled. Further analysis was performed for 74 patients who underwent CRT under curative intent., Results: Overall 5-year survival rates of the patients who underwent CRT (n = 74) were 54.6%. Those of the patients who underwent CRT with modified TPF (docetaxel, cisplatin [CDDP], and 5-fluorouracil) regimen (n = 50) and CRT with CDDP regimens (n = 24) were 64.4% and 36.7%, respectively. Significant differences were observed between these two groups., Conclusion: Given the tendency that head and neck surgeons prefer CRT for advanced larger cancer of the EAC, CRT for advanced EAC cancer using the modified TPF regimen showed good clinical outcomes., Level of Evidence: 4 Laryngoscope, 131:E870-E874, 2021., (© 2020 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Although the American Joint Committee on Cancer TNM classification has been amended to include human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) as an independent entity, to the authors' knowledge the optimized de-escalating treatment modality has not been established to date., Methods: The authors conducted a retrospective, nationwide, observational study in patients with HPV-related OPSCC who were treated from 2011 to 2014 in Japan to determine the best treatment modality., Results: A total of 688 patients who were newly diagnosed with HPV-related OPSCC who were treated with curative intent at 35 institutions and had coherent clinical information and follow-up data available were included in the current study. In patients with T1-T2N0 disease (79 patients), both the 3-year recurrence-free survival and overall survival (OS) rates were 100% in the group treated with radiotherapy (RT) as well as the group receiving concurrent chemoradiotherapy (CCRT). The 3-year OS rates were 94.4% (for patients with T1N0 disease) and 92.9% (for patients with T2N0 disease) among the patients treated with upfront surgery. In patients with stage I to stage II HPV-related OPSCC, the 5-year recurrence-free survival and OS rates were 91.4% and 92%, respectively, in the patients treated with CCRT with relatively high-dose cisplatin (≥160 mg/m 2 ; 114 patients) and 74.3% and 69.5%, respectively, in the patients treated with low-dose cisplatin (<160 mg/m 2 ; 17 patients)., Conclusions: Despite it being a retrospective observational trial with a lack of information regarding toxicity and morbidity, the results of the current study demonstrated that patients with T1-T2N0 HPV-related OPSCC could be treated with RT alone because of the equivalent outcomes of RT and CCRT, and patients with stage I to stage II HPV-related OPSCC other than those with T1-T2N0 disease could be treated with CCRT with cisplatin at a dose of ≥160 mg/m 2 ., (© 2020 American Cancer Society.)

Background/objective: The Amatsu tracheoesophageal shunt (ATES) represents a nonprosthesis surgical option for voice restoration in laryngectomized patients. However, data regarding the long-term efficacy of ATES are lacking., Study Design: Retrospective, single-institution study., Methods: Between 2001 and 2010, 16 patients with laryngeal cancer underwent total laryngectomy with ATES at the Hyogo Cancer Center (Akashi, Hyogo, Japan). Of these, 11 achieved long-term tracheoesophageal speech that was maintained for a follow-up exceeding 5 years (range 75-161 months; median 95 months). All patients were male and ranged from 46 to 74 years of age at the time of ATES surgery., Results: Of 11 eligible patients, eight were able to speak intelligibly with ATES at last follow-up. Regarding aspiration, three patients experienced no leakage, and six experienced mild leakage of saliva without medical intervention at last follow-up. Almost all patients maintained an unchanged degree of voice quality (9 of 11) and leakage (8 of 11)., Conclusion: The favorable voice restoration and low aspiration rates achieved in this study appear to support the long-term efficacy of ATES., Level of Evidence: 4. Laryngoscope, 128:1395-1397, 2018., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: To assess efficacy and safety of nivolumab versus investigator's choice of therapy (IC) in Asian patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN)., Materials and Methods: Thirty-four patients from Japan, Taiwan, Hong Kong, and Korea received nivolumab 3mg/kg (n=23) every 2weeks or IC (n=11), as part of a global trial (n=361), until intolerable toxicity or disease progression. The primary endpoint was overall survival (OS)., Results: Median OS was 9.5months (95% confidence interval [CI] 9.1-NR) with nivolumab and 6.2months (95% CI 2.6-NR) with IC. Seven (30.4%) patients receiving nivolumab and six (54.5%) receiving IC died. The hazard ratio (HR) for risk of death (nivolumab vs. IC) was 0.50 (95% CI 0.17-1.48). Median progression-free survival was 1.9months (95% CI 1.6-7.5) with nivolumab and 1.8months (95% CI 0.4-6.1) with IC (HR 0.57 [95% CI 0.25-1.33]). Objective response rates (complete+partial responses) were 26.1% (6/23 patients; 95% CI 10.2-48.4) for nivolumab and 0% (0/11 patients; 95% CI 0.0-28.5) for IC. Sixteen (69.6%) nivolumab-treated patients and 10 (90.9%) patients receiving IC had a treatment-related adverse event, most commonly decreased appetite (21.7%), pruritus, rash, and fatigue (17.4% each) with nivolumab, and nausea, stomatitis, and decreased appetite (27.3% each) with IC., Conclusion: Nivolumab demonstrated a survival advantage compared with conventional treatments in Asian patients with platinum-refractory recurrent or metastatic SCCHN, and was well tolerated. Clinical trial registration NCT02105636., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Renal function influences decisions regarding treatment for patients with oropharyngeal squamous cell carcinoma (SCC). However, the importance of renal function in oropharyngeal SCC has not yet been reported., Methods: Four hundred sixty patients with oropharyngeal SCC treated with curative intent between April 2005 and March 2007 in 12 institutions in Japan were analyzed retrospectively., Results: Four hundred three patients (87.6%) showed a creatinine clearance (CrCl) ≥50 mL/min and 57 (12.4%) with a CrCl <50 mL/min. Age was associated with worse overall survival (OS), whereas stage IVB, radiotherapy (RT), and CrCl <50 were associated with worse OS on univariate analyses. Surgery and hypertension were associated with better OS on univariate analyses. On multivariate analysis, age, stage, hypertension, and CrCl were also found to be significantly associated with OS., Conclusion: Based on this retrospective study, impaired renal function is an independent predictor of increased risk of death in patients with oropharyngeal SCC. © 2016 Wiley Periodicals, Inc. Head Neck 38: First-1500, 2016., (© 2016 Wiley Periodicals, Inc.)

We conducted a phase II study to evaluate the efficacy and safety of chemoradiotherapy concurrent with S-1 plus cisplatin in patients with unresectable locally advanced squamous cell carcinoma of the head and neck. Chemotherapy consisted of S-1 twice daily on days 1-14 at 60 mg/m(2) /day and cisplatin at 20 mg/m(2) /day on days 8-11, repeated twice at a 5-week interval. Single daily radiation of 70 Gy in 35 fractions was given concurrently starting on day 1. For patients achieving an objective response after chemoradiotherapy, two additional cycles of chemotherapy were administered. Of the 45 enrolled patients, the percentage of clinical complete remission, the primary endpoint, was 64.4% (8 complete response, 21 good partial response) on central review. After a median follow-up of 3.52 years, 3-year local progression-free survival was 62.2%, with 3-year progression-free survival of 60.0%, 3-year overall survival of 64.4%, and 3-year time to treatment failure of 48.9%. Grade 3 or 4 toxicity included pharyngeal mucositis (46.7%), oral mucositis (44.4%), dysphagia (46.7%), anorexia (42.2%), radiation dermatitis (26.7%), neutropenia (26.7%), and febrile neutropenia (4.4%). No treatment-related deaths were observed. This combination showed promising efficacy with acceptable toxicities., (© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

Background: The purpose of this retrospective analysis was to evaluate ocular function and survival rates among treatment modalities in patients with maxillary sinus cancer with orbital invasion., Methods: Eighty-seven patients were classified according to the main treatment modality. Ocular function preservation rates and survival rates were evaluated for each therapeutic modality., Results: The 5-year overall survival rate for the en bloc resection, conservative surgery, superselective intra-arterial chemotherapy, and radiotherapy (RADPLAT), intravenous chemoradiotherapy (IV-CRT) was 70%, 35%, 49%, and 31%, respectively. The ocular function preservation rate for each group was 15%, 27%, 30%, and 17%, respectively. In the en bloc resection group, there was no significant difference in the 5-year overall survival rate between patients with orbital exenteration and those without orbital exenteration (72% vs 71%; p = .9321)., Conclusion: The en bloc resection group showed a favorable survival rate but a low preservation rate. Preservation of orbital contents did not reduce the survival rate., (© 2014 Wiley Periodicals, Inc.)

Background: We conducted a phase III study to evaluate S-1 as compared with UFT as control in patients after curative therapy for stage III, IVA, or IVB squamous-cell carcinoma of the head and neck (SCCHN)., Patients and Methods: Patients were randomly assigned to the UFT group (300 or 400 mg day-1 for 1 year) or the S-1 group (80, 100, or 120 mg day-1 for 1 year). The primary end point was disease-free survival (DFS). Secondary end points were relapse-free survival, overall survival (OS), and safety., Results: A total of 526 patients were enrolled, and 505 were eligible for analysis. The 3-year DFS rate was 60.0% in the UFT group and 64.1% in the S-1 group (HR, 0.87; 95%CI, 0.66-1.16; p = 0.34). The 3-year OS rate was 75.8% and 82.9%, respectively (HR, 0.64; 95% CI, 0.44-0.94; p = 0.022). Among grade 3 or higher adverse events, the incidences of leukopenia (5.2%), neutropenia (3.6%), thrombocytopenia (2.0%), and mucositis/stomatitis (2.4%) were significantly higher in the S-1 group., Conclusions: Although DFS did not differ significantly between the groups, OS was significantly better in the S-1 group than in the UFT group. S-1 is considered a treatment option after curative therapy for stage III, IVA, IVB SCCHN., Trial Registration: ClinicalTrials.gov NCT00336947 http://clinicaltrials.gov/show/NCT00336947.

Background: We analyzed the effects of local extension sites on survival in patients with locally advanced maxillary sinus cancer., Methods: The criteria for inclusion in this study were as follows: (1) previously untreated maxillary sinus cancer; (2) squamous cell carcinoma; (3) T4 disease; and (4) curative-intent treatment. The data for 118 patients were obtained from 28 institutions across Japan and analyzed for overall survival and local control rates by local extension site., Results: Sites with a poor prognosis included the cribriform plate, dura, nasopharynx, middle cranial fossa, and cranial nerves other than V2. There was a significant correlation among these sites, except for the cranial nerves. Additionally, the hard palate was the only site that correlated with nodal involvement and showed a poor treatment outcome., Conclusion: Even in cases presenting with similar T4 maxillary sinus cancer, treatment should be performed in consideration of the local extension site., (© 2013 Wiley Periodicals, Inc.)

Background: The current study sought to assess the role of initial neck dissection (ND) for patients with node-positive oropharyngeal squamous cell carcinomas (OPSCC)., Methods: The data for 202 patients with previously untreated node-positive OPSCC were gathered from 12 institutions belonging to the Head and Neck Cancer Study Group in the Japan Clinical Oncology Group. These patients were categorized into two groups, consisting of the initial ND group and the wait-and-see group, according to treatment policy., Results: Regional recurrence was observed in 17 of 93 patients undergoing initial ND, whereas, recurrent or persistent diseases were observed in 40 of 109 patients who did not undergo initial ND. The 4-year overall survival rates (OS) for the wait-and-see group and initial ND groups were 74.0% and 78.7%, respectively, and the 4-year regional control rates (RC) for each group were 77.6% and 84.9%. There were no significant differences in either OS or RC (p=0.3440 and p=0.2382, respectively). However, for patients with N3 disease, the 4-year OS of the initial ND group (100%) was favorable. For patients with N2a disease, the 4-year RC of the initial ND group was higher than that of the wait-and-see group statistically (100% vs 62.5%, p=0.0156)., Conclusions: The role of initial ND was limited in patients with node-positive OPSCC. The treatment strategy not involving initial ND is considered feasible and acceptable when nodal evaluation after definitive radiotherapy or chemoradiotherapy is applied adequately. However, it is possible that initial ND improves outcomes in patients with resectable large-volume nodal disease., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: The purpose of this study was to evaluate the incidence of lymph node metastasis among patients with T4 maxillary sinus squamous cell carcinoma (MS-SCC) as well as the delayed metastasis rate and the treatment outcome for untreated N0 neck in patients with T4 MS-SCC., Methods: Consecutive series of all patients (n = 128) with previously untreated T4 maxillary sinus SCC between 2006 and 2007 were obtained from 28 institutions belonging to or cooperating in the Head and Neck Cancer Study Group of the Japan Clinical Oncology Group., Results: Of the 128 patients, 28 (21.9 %) had lymph node metastasis, and six patients (4.7 %) had distant metastasis at diagnosis. Among the 111 patients who were treated with curative intent, 98 had clinically N0 neck disease and did not receive prophylactic neck irradiation. A total of 11 patients (11.2 %) subsequently developed evidence of lymph node metastasis, of whom eight were among the 83 patients with an N0 neck and had not received elective neck treatment. There were 15 patients who received an elective neck dissection as part of the initial treatment, of whom three had pathologically positive for lymph node metastases. Of 11 patients, six patients with nonlateral retropharyngeal lymph node metastasis without primary or distant disease were successfully salvaged., Conclusions: This study identified the incidence of lymph node metastasis among patients with T4 MS-SCC as well as the delayed metastasis rate and the treatment outcome for untreated N0 neck in patients with T4 MS-SCC. These results will be of assistance in selecting treatment strategy for T4 MS-SCC in the future.