Yasuhisa Hasegawa

Platinum-based Chemotherapy Plus Cetuximab for the First-line Treatment of Japanese Patients with Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck: Results of a Phase II Trial

Objective To assess the efficacy and safety of cetuximab in combination with cisplatin and 5-fluorouracil for first-line treatment of Japanese patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Methods In this open-label, single-arm, multicenter, Phase II study conducted in Japan, patients with confirmed recurrent and/or metastatic squamous cell carcinoma of the head and neck received weekly cetuximab (week 1, 400 mg/m2; subsequent weeks, 250 mg/m2) plus a maximum of six three-weekly cycles of cisplatin (100 mg/m2, day 1) and 5-fluorouracil (1000 mg/m2/day, 24-h infusion, days 1–4). The primary endpoint was the best overall response assessed by an independent review committee according to the modified World Health Organization criteria. Results In total, 33 patients received treatment. The most frequent primary tumor site was the hypopharynx (42%), and most patients had metastatic disease (85%). The best overall response rate as assessed by the independent review committee was 36% (95% confidence interval: 20, 55) and was significantly greater (P = 0.002) than the protocol-specified threshold of 15% at the one-sided 5% level. The disease control rate was 88%. The median progression-free survival and overall survival were 4.1 and 14.1 months, respectively. There were no unexpected safety concerns. Grade 3 or 4 adverse events were experienced by nearly all patients (32, 97%). No adverse events were fatal. Conclusions The demonstrated efficacy and safety of cetuximab in combination with cisplatin and 5-fluorouracil for the first-line treatment of Japanese patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck justify the further use of this combination treatment in this patient population (ClinicalTrials.gov number, NCT00971932).

Phase I/II Study of S-1 plus Cisplatin Combination Chemotherapy in Patients with Advanced/Recurrent Head and Neck Cancer

OBJECTIVEnThe objectives of this study were to determine the maximum tolerated dose (MTD) and recommended dose (RD) of S-1 plus cisplatin (CDDP) and to evaluate safety and efficacy using the defined RD in advanced/recurrent head and neck cancer (HNC).nnnMETHODSnS-1 was administered orally at 40 mg/m(2) twice daily for 14 consecutive days, and CDDP was infused on day 8 at a dose of 60 and 70 mg/m(2). Each course was repeated every 4 weeks.nnnRESULTSnA total of 38 patients were registered, 10 patients for the Phase I study and an additional 28 patients for the Phase II study. Although no dose-limiting toxicity (DLT) was observed in the CDDP 60 mg/m(2) (Level 1) group, two of six patients in the CDDP 70 mg/m(2) (Level 2) group exhibited DLT (fatigue/diarrhea). The MTD was not achieved in the Phase I study. Level 2 was therefore determined as the RD. In the Phase II study, 34 patients, including 6 patients from the Phase I study, were evaluated. At the termination of treatment, the confirmed response rate was 44.1% (15/34, 95% CI: 27.4-60.8). The best response rate without an adequate duration time was 67.6% (95% CI: 51.9-83.4). The median survival period was 16.7 months, and the 1-year survival rate was 60.1%. The main toxicities of Grade 3 or above were anorexia (26.5%), nausea (14.7%), neutropenia/thrombocytopenia (11.8%) and anemia/fatigue (8.8%).nnnCONCLUSIONSnThis is considered to be an effective regimen with acceptable toxicities for HNC.

Primary Tumor-Secreted Lymphangiogenic Factors Induce Pre-Metastatic Lymphvascular Niche Formation at Sentinel Lymph Nodes in Oral Squamous Cell Carcinoma

Objectives The objectives of this study were to evaluate the formation of lymphvascular niches in lymph nodes of patients with oral squamous cell carcinoma (OSCC), and investigate the roles of lymphangiogenic and angiogenic factors, such as vascular endothelial growth factor (VEGF)-A, VEGF-C, and VEGF-D, expressed in the primary tumors. Materials and Methods Forty-four patients with previously untreated clinically late T2 or T3 OSCC of cN0 were evaluated for primary tumors and 166 sentinel lymph nodes (SLNs). Primary tumors were immunohistochemically analyzed for expressions of VEGFs. Densities of lymphatic vessels (LVDpodoplanin) and high endothelial venules (HEVD) in the SLNs were also calculated using antibodies for each marker, podoplanin and MECA-79, respectively. Results In 25 patients, all lymph nodes were metastasis-negative, whereas, in 19 patients, metastasis was positive for at least one lymph node (either at SLN, non-SLN, or nodal recurrence). From the analyses of 140 SLNs without metastasis, LVDpodoplanin in 50 SLNs of metastasis-positive cases was significantly higher than that in 90 SLNs of metastasis-negative cases (p = 0.0025). HEVD was not associated with lymph node metastasis. The patients with VEGF-A-High or VEGF-D-High tumors had significantly higher LVDpodoplanin than patients with their Low counterparts (p = 0.0233 and p = 0.0209, respectively). In cases with lymph node metastasis, the VEGF-D-expression score was significantly higher than in those without lymph node metastasis (p = 0.0006). Conclusions These results suggest that lymph node lymphangiogenesis occurs before metastasis in OSCC. VEGF-A and VEGF-D play critical roles in this process. VEGF-D is a potential predictive marker of positive lymph node metastasis in cN0 patients.

Matched-pair analysis in patients with advanced oropharyngeal cancer: surgery versus concurrent chemoradiotherapy.

Objective: The current study aimed to compare the therapeutic outcomes of surgery with those of chemoradiation for patients with advanced oropharyngeal cancer (OPC). Methods: The data for 523 patients with previously untreated OPC were obtained from 12 institutions belonging to the Head and Neck Cancer Study Group in the Japan Clinical Oncology Group from April 2005 to March 2007. In this study, we matched a group of patients who underwent surgery with a second group treated with chemoradiation according to age, gender, subsite, and T and N classification, and analyzed the overall survival, progression-free survival, local control and swallowing function. Results: The final matched-pair analysis included 186 patients. The 5-year overall survival, progression-free survival and local control rates were 69.8 and 71.4% (p = 0.762), 51.0 and 54.4% (p = 0.531), and 75.2 and 80.3% (p = 0.399), respectively, in patients treated with surgery and those treated with chemoradiation. Swallowing function in patients treated with chemoradiation was significantly better than that in patients treated with surgery (p = 0.015). Conclusion: Although this study was not randomized, this matched-pair analysis of patients treated with surgery or chemoradiation showed that chemoradiation is as effective as surgery in the treatment of OPC.

Lymph node ratio predicts survival in hypopharyngeal cancer with positive lymph node metastasis

The lymph node density (LND) has been reported to be a significant prognostic factor in various types of carcinoma. This study investigated whether the LND is associated with survival in patients with hypopharyngeal squamous cell carcinoma (HPSCC) who have positive lymph nodes without distant metastasis. Forty-six patients who were pathologically diagnosed with HPSCC with positive lymph nodes and without distant metastasis were enrolled in this study. The LND was defined as the ratio of positive lymph nodes to the total number of lymph nodes. An LND of ≥0.09 was found to be significantly correlated with a shorter overall (pxa0=xa00.044) and disease-specific (pxa0=xa00.019) survival according to a log-rank test. In a multivariate survival analysis using a Cox proportional hazards model adjusted for the pathological T category (pT3–4/pT1–2), pathological N category (pN2/pN1) and positive surgical margin and/or extracapsular spread (presence/absence), both an LND of ≥0.09 and pT3–4 category were associated with significantly shorter overall survival (pxa0<xa00.01) and disease-specific survival (pxa0<xa00.01). These results suggest that the LND functions as a prognostic factor for HPSCC patients with positive lymph nodes who do not have distant metastasis.

The Charlson comorbidity index is a prognostic factor in sinonasal tract squamous cell carcinoma

OBJECTIVEnHigh Charlson comorbidity indexxa0values have been reported to be associated with shorter overall survival in various types of cancer. We investigated whether Charlson comorbidity index values were correlated with overall survival in patients with resectable sinonasal tract squamous cell carcinoma.nnnMETHODSnSeventy-nine patients with resectable sinonasal tract squamous cell carcinoma were treated with curative intent. The Charlson comorbidity index values were calculated by the summation of the weight scores of 19 medical conditions (other than sinonasal tract squamous cell carcinoma) before treatment. The survival rate was analyzed according to the Kaplan-Meier method. Univariate and multivariate survival analyses were performed using the Wilcoxon test and the Cox proportional hazards model, respectively.nnnRESULTSnAccording to a univariate analysis, a Charlson comorbidity index valuexa0≥6 was found to be significantly correlated with shorter overall survival (P <xa00.02). In the multivariate survival analysis with adjustment for the clinical T and N classification, age, sex, anatomical location, treatment group (radiotherapy/surgery) and chemotherapy (presence/absence), a Charlson comorbidity index value ≥6 was found to be associated with the significantly shorter overall survival.nnnCONCLUSIONSnThese results suggest that the Charlson comorbidity index functions as a prognostic factor in cases of resectable sinonasal tract squamous cell carcinoma.

Complication and surgical site infection for salvage surgery in head and neck cancer after chemoradiotherapy and bioradiotherapy

OBJECTIVEnWe aimed to investigate the complications, surgical site infection (SSI), and survival in salvage surgery without free-flap reconstruction for patients with head and neck squamous cell carcinoma who were treated by platinum-based chemoradiotherapy (Plat-CRT) or cetuximab-based bioradiotherapy (Cet-BRT).nnnMETHODSnThirty-three patients treated by Plat-CRT and six treated by Cet-BRT had salvage surgery. We categorized postoperative complications according to the Clavien-Dindo classification and SSI according to the wound grading scale. Overall survival calculated by Kaplan-Meier method.nnnRESULTSnPatients with Cet-BRT were significantly associated with the presence of SSI (P<0.01) and grades IIIb-V of the Clavien-Dindo classification (P<0.01) compared with those with Plat-CRT. Patients with Cet-BRT had a significantly lower overall survival than those with Plat-CRT (P<0.05).nnnCONCLUSIONnWe demonstrated that patients with Cet-BRT were significantly more associated with the presence of SSI and grades IIIb-V in the Clavien-Dindo classification than those with CRT.

Sinonasal squamous cell carcinoma and EGFR mutations: a molecular footprint of a benign lesion

Molecular targeted therapy against EGFR kinase domain mutations has been successfully established for lung cancer. These mutations have now also been reported in head and neck tumours, particularly in inverted sinonasal papillomas (ISPs). The aim of this study was to clarify the spectrum of EGFR mutations in head and neck squamous cell carcinomas and papillomas.