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/m²). However, whether chemoradiotherapy with weekly cisplatin (40 mg/m²) 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/m²) or with weekly cisplatin (40 mg/m²) 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.

We sought to characterize the effectiveness of concomitant chemoradiotherapy (CCRT) for patients with squamous cell carcinoma of the temporal bone. We performed a retrospective chart review of 14 patients with cancer of the temporal bone who were provided initial treatment in our hospital from December 2001 to November 2008. Four patients with stage I tumors were treated by radiation therapy alone or with oral administration of S1. One patient with a stage II tumor was treated by radiation therapy concomitant with low dose docetaxel. Nine patients with stage IV tumors were treated by CCRT using the TPF regimen (docetaxel, cisplatin, and 5-fluorouracil). As an initial treatment, all patients but one were treated by radiation therapy with or without chemotherapy. Grade 4 adverse events of patients who received CCRT using the TPF regimen involved the leukopenia in one patient and the neutropenia in two patients. Local recurrences were observed in three patients including two patients with T4 tumors. Five-year disease-specific survival rates for all patients and for patients with T4 tumors were 78% and 67%, respectively. CCRT using the TPF regimen is safe and effective as the first treatment for patients with cancer of the temporal bone.

For the purpose of analyzing mechanisms related to the cis‐diamminedichloroplatinum resistance in head and neck squamous cell carcinoma, we analyzed RPMI2650 and its derived previously established cis‐diamminedichloroplatinum resistant cell line RPMI2650CR. To identify resistant phenotype‐related microRNAs, we compared microRNA expressions between RPMI2650CR and RPMI2650 by microarray. One of the microRNAs as downregulated, miR‐34a, was further investigated. Decreased expression of miR‐34a in RPMI2650CR was confirmed by quantitative reverse transcription‐polymerase chain reaction, but introduction of the miR‐34a precursor into RPMI2650CR or the inhibitor of miR‐34a into RPMI2650 did not change cis‐diamminedichloroplatinum sensitivities. However, 24 patients with sinonasal squamous cell carcinomas treated with intra‐arterial infusion of cis‐diamminedichloroplatinum showed a significant association between decreased expression of miR‐34a and poor disease specific survival (P = 0.0015), poor disease free survival (P = 0.0019), and poor local control rates (P = 0.017) (median follow‐up period: 53 months). Furthermore, multivariate analyses demonstrated significant associations between miR‐34a expression and the hazard ratios of disease free survival at 0.005 (95% confidence interval [CI] 0.00–0.29, P = 0.011) and local control rate at 0.008 (95% CI 0.00–0.44, P = 0.019), although other parameters such as age, gender, treatment method, T and N stages did not show any similar association. These results strongly suggest that miR‐34a expression can be an independent prognostic biomarker in patients with sinonasal squamous cell carcinoma who are undergoing treatment with cis‐diamminedichloroplatinum.

Regional lymph node metastasis in head and neck squamous cell carcinoma (HNSCC) is a crucial event for its progression, associated with a high rate of mortality. Sialidase, a key enzyme for the regulation of cellular sialic acids through catalyzing the initial step of degradation of glycoproteins and glycolipids, has been implicated in cancer progression. To facilitate the development of novel treatments for HNSCC, we have investigated whether sialidase is involved in the progression of this cancer. We found plasma membrane‐associated sialidase (NEU3) to be significantly upregulated in tumor compared to non‐tumor tissues; particularly, an increase in its mRNA levels was significantly associated with lymph node metastasis. To understand the mechanisms, we analyzed the NEU3‐mediated effects on the malignant phenotype using squamous carcinoma HSC‐2 and SAS cells. NEU3 promoted cell motility and invasion, accompanied by the increased expression of MMP‐9, whereas NEU3 silencing or the activity‐null mutant did not. NEU3 enhanced phosphorylation of epidermal growth factor receptor (EGFR), and an EGFR inhibitor, AG1478, abrogated the NEU3‐induced MMP9 augmentation. These findings identify NEU3 as a participant in HNSCC progression through the regulation of EGFR signaling and thus as a potential target for inhibiting EGFR‐mediated tumor progression.