Addition of S-1 to radiotherapy for treatment of T2N0 glottic cancer: Results of the multiple-center retrospective cohort study in Japan with a propensity score analysis.

OBJECTIVES: This multicenter retrospective cohort study aimed to evaluate the significance of adding S-1 to radiotherapy (RT) for the treatment of T2N0 glottic cancer using a propensity score matched analysis in Japan. MATERIALS AND METHODS: This study was conducted on 287 patients with T2N0 glottic cancer who were treated with definitive RT or chemoradiotherapy with S-1 (S-1 RT) between April 2007 and March 2017. Propensity score matched analysis was performed to ensure the well-balanced characteristics of the groups of patients who received RT alone and S-1 RT. Overall, progression-free and laryngectomy-free survivals and local control and laryngeal preservation rates were compared. RESULTS: Fifty-four pairs of patients were selected after performing propensity score matched analysis. Clinical characteristics were well-balanced between the two groups. The overall survival of patients in the S-1 RT group was significantly better than those in the RT alone group (P = 0.008). The progression-free and laryngectomy-free survivals of patients in the S-1 RT group were also better than those in the RT alone group; however, the differences were not significant. In contrast, patients in the S-1 RT group had slightly lower local control and laryngeal preservation rates compared with those in the RT alone group. The incidence of dermatitis in the S-1 RT group was significantly higher than that in the RT alone group in the matched population (P = 0.013). CONCLUSIONS: The addition of S-1 to RT for the treatment of T2N0 glottic cancer was not associated with better local control and laryngeal preservation rates in this study.

Phase II study of concurrent chemoradiotherapy with S-1 in patients with stage II (T2N0M0) squamous cell carcinoma of the Pharynx or Larynx.

OBJECTIVE: The goals of treatment for head and neck cancer are cure and organ-function preservation. For organ preservation, primary treatment via radiotherapy alone is thought to be insufficient for Stage II squamous cell carcinoma of the larynx, oropharynx or hypopharynx. The objective of the present study was to investigate the efficacy and safety of concurrent chemoradiotherapy with S-1 for patients with Stage II squamous cell carcinoma of the pharynx or larynx for primary organ preservation. METHODS: Previously untreated patients with Stage II squamous cell carcinoma of the larynx, oropharynx or hypopharynx received three courses of S-1 (40 or 50 mg twice a day; 2 weeks of administration followed by 1 week of rest every 3 weeks) during conventional radiotherapy (a single daily fraction of 1.8 Gy) to a total dose of 70.2 Gy. The primary endpoint was the local control rate at 3 years. RESULTS: From August 2009 to October 2012, 37 patients were evaluated for the study. The overall response rate was 100%. The 3-year local control rate was 89.0% (95% confidence interval, 78.9-99.2%), and the 3-year overall survival rate was 97.2% (95% confidence interval, 91.8-100%). Mucositis and dermatitis in the radiation field were the most common acute adverse events observed. The rates of Grade 3 mucositis and dermatitis were 27 and 35%, respectively. No patients experienced Grade 4 acute adverse events. The treatment completion rate was 89.2%. CONCLUSION: Concurrent chemoradiotherapy with S-1 was safe and effective in improving local control for Stage II squamous cell carcinoma of the pharynx or larynx.

Treatment results and prognostic factors for advanced squamous cell carcinoma of the head and neck treated with concurrent chemoradiotherapy.

OBJECTIVE: To review our experience in the treatment of concurrent chemoradiotherapy (CCR) for patients with advanced squamous cell carcinoma of the head and neck (SCCHN) and to evaluate the different factors affecting survival and primary organ preservation. METHODS: We reviewed the records of 101 patients with SCCHN treated with CCR between February 1998 and April 2004. Of 101 patients, 76 were treated with a cisplatin, 5-fluorouracil, methotrexate, and leucovorin (PFML) regimen and 25 were treated with a carboplatin and uracil-tegafur (CBDCA-UFT) regimen. Overall survival (OS), disease-specific survival (DSS) and DSS with primary organ preservation were estimated using Kaplan-Meier methods. The log-rank test and Cox proportional hazards regression were employed to identify significant prognostic factors for OS, DSS, and DSS with primary organ preservation. RESULTS: The 5-year OS and DSS for all patients were 51.6 and 67.4%, respectively. On multivariate analysis, resectability of the tumor and degree of histological differentiation were significant predictors of survival for patients undergoing CCR; T stage and differentiation were significant prognostic factors for primary organ preservation. CONCLUSION: In the treatment of CCR for advanced SCCHN, the survival rate of the patients with resectable tumors was excellent and significantly greater compared with the patients with unresectable tumors. T1 to T3 disease in patients with advanced resectable SCCHN is a good predictor of organ preservation. CCR may improve not only primary organ preservation (local control) but also survival in patients with poorly differentiated tumors.

[Concurrent chemoradiotherapy with S-1 for T2N0 glottic carcinoma].

Early glottic carcinoma has a good prognosis compared to other head and neck carcinomas, but we must aim for larynx preservation in the treatment. Regarding T1N0, larynx preservation rates are favorable even with radiotherapy alone. However for T2N0, the treatment strategies differ in each institution, and larynx preservation rates range from 72% to 85%, and are not high enough. We conducted a study to determine the efficacy of the concurrent chemoradiotherapy with S-1 for T2N0 glottic carcinoma. In this study, 12 patients with T2N0 glottic type laryngeal squamous cell carcinoma enrolled from the year 2004 to 2006, received one reduction dose of S-1 (80 or 100 mg/day) with concomitant irradiation with a total dose of 60-70 Gy (2.0 Gy/fr). The 2-week administration of S-1 followed by one-week rest was repeated during irradiation. In terms of adverse events of Grade 3 and above, Grade 3 mucositis and dermatitis were found in 2 patients each, but there was no cancellation nor interruption of S-1 or irradiation. All patients achieved pathological CR at the time of evaluation after the primary treatment, and no recurrences have been seen yet in any of the primary sites. Concurrent chemoradiotherapy with S-1 showed efficacy in T2N0 glottis carcinoma. Further investigation of this treatment with long-term follow up results is warranted.

Early assessment of clinical response to concurrent chemoradiotherapy in head and neck carcinoma using fluoro-2-deoxy-d-glucose positron emission tomography.

OBJECTIVES: The aim of this study is to assess the utility of FDG-PET in the evaluation of therapeutic effects at 4 weeks after the completion of the concurrent chemoradiotherapy (CCR) in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: Thirty-one patients with previously untreated HNSCC were retrospectively investigated about FDG-PET, CT, MRI and biopsies of the carcinoma before and 4 weeks after the treatment. RESULTS: The results of pathological examinations after CCR showed 6 residual cases and 25 ones with a pathologically complete response (pCR). The specificity of FDG-PET was 80%, although the sensitivity was limited to 67%. CONCLUSIONS: FDG-PET has a high specificity but limited sensitivity to discriminate residual cancer from fibrosis or scar at 4 weeks after CCR. FDG-PET at 4 weeks after CCR was too early to perform because of limited sensitivity.

Maxillary sinus carcinoma: the only symptom was neck lymph node swelling.

OBJECTIVE: Since maxillary sinus is composed of bone structure, the main symptoms of maxillary sinus carcinoma are related to the anatomical feature and the destructive lesion of the bony wall, such as cheek pain and nasal obstruction. METHODS: We report a female case with undifferentiated carcinoma in the right maxillary sinus, only appearing cervical swelling which was revealed as lymph node metastasis. RESULTS: CT and MRI findings showed just maxillary sinusitis with minor bone destruction. However, fluorine 18-labelled deoxyglucose positron emission tomography (FDG-PET) was useful for the detection of the primary site. The patient received concomitant chemoradiotherapy, and showed a complete response both in the primary site and neck lymph nodes. She has no recurrence for 18 months after the primary therapy. CONCLUSION: The main symptoms of maxillary sinus carcinoma are related to the local progression, and known to have less cervical lymph node metastasis. However, like the present case, there is a rare case that has no symptom and organic features associated with the local mass. With the best use of advanced diagnostic technique, e.g., FDG-PET, we could diagnose and treat atypical maxillary sinus carcinoma patients.

A case of metastatic hepatocellular carcinoma in the nasal cavity.

Metastatic hepatocellular carcinoma in the nasal cavity and paranasal sinuses is rare. We report the case of a 71-year-old male afflicted with hepatocellular carcinoma with metastasis in the maxillary sinus and nasal cavity. He underwent radiation therapy with a total dose of 36 Gy, but he died of terminal liver failure. The possible metastatic route and prognosis of metastatic hepatocellular carcinoma in the sinonasal tract are discussed.

Myxofibrosarcoma of the hypopharynx.

Myxofibrosarcoma is common in the extremities, but rare in the head and neck region. Hypopharyngeal myxofibrosarcoma has not been reported previously. We report the first case of a patient with myxofibrosarcoma of the hypopharynx. We examined this patient once a month after the operation, and there has been no local recurrence and no distant metastasis. Sarcomas are rare in the hypopharynx, but we have to bear in mind their possibility. Though a low-grade myxofibrosarcoma is a low-grade malignancy, complete resection should be done. We have to pay more attention planning the treatment for neoplastic diseases.

[A randomized crossover study of ramosetron plus dexamethasone for the prevention of nausea and vomiting induced by chemotherapy including cisplatin-comparison of ramosetron combined with 8 mg and 12 mg of dexamethasone].

A randomized crossover study between 0.3 mg of ramosetron (RAM) combined with 8 mg of dexamethasone (DEX) and 0.3 mg of RAM combined with 12 mg of DEX was performed to investigate the prevention of nausea and vomiting due to chemotherapy including 60 mg/m2 or 70 mg/m2 of cisplatin (CDDP) in patients with advanced head and neck squamous cell carcinoma (HNSCC). Twenty-five patients the study consisted of who received chemotherapy with CDDP were enrolled in the present study between January 2001 and December 2002 at the Yokohama City University School of Medicine or Yokohama City University Medical Center. The antiemetic effectiveness in the group receiving 12 mg of DEX was not significantly superior to the group receiving 8 mg of DEX. It was suggested that the antiemetic therapy of RAM 0.3 mg plus DEX 8 mg was effective for the prevention of nausea and vomiting induced by CDDP in patients with advanced HNSCC.

A case of metastatic colon adenocarcinoma in the larynx.

Metastatic carcinomas in the larynx are uncommon, and laryngeal tumors originating from the colon are extremely rare. We report a case of metastatic laryngeal tumor originating from a colon adenocarcinoma in an 81-year-old female. Only a tracheostomy was performed because the patient presented with multiple metastases in other regions. The diagnosis, route of metastasis, treatment and prognosis of metastatic laryngeal tumors are discussed.

[Combined chemotherapy with docetaxel, cisplatin and 5-fluorouracil (TPF), and radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN)].

We evaluated the recommend dose and efficacy of chemotherapy (CTx) and concurrent chemoradiotherapy (ConcCRTx) with docetaxel (DOC), cisplatin (CDDP) and 5-FU (TPF) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Patients underwent 2 cycles of chemotherapy with TPF. In ConcCRTx, radiation was targeted to begin on Day 1. We compared the efficacy of ConcCRTx and induction chemotherapy followed by radiation (CTx followed by RTx) with TPF. In CTx followed by RTx, radiation was targeted to begin 21 days after the end of CTx. The recommend dose of CTx with TPF was DOC 60 (Day 1), CDDP 70 (Day 4) and 5 FU 750 (Day 1-5) mg/ m2/ day and overall response rate of CTx with TPF was 95%. The recommended dose of ConcCRTx was DOC 50 (Day 1), CDDP 60 (Day 4) and 5-FU 600 (Day 1-5) mg/ m2/ day. Overall response rate of ConcCRTx and CTx followed by RTx with TPF were both 100%, and CR rate of them were 87% and 84% (p > 0.05). One-year survival rate of them were 69% and 95% (p < 0.05). More patients had distant metastasis in CTx followed by RTx than in ConcCRTx. Toxicity, such as mucositis, leukocytopenia and neutropenia, was higher in ConcCRTx than in CTx followed by RTx.

The expression of vascular endothelial growth factor-A and -C, and receptors 1 and 3: correlation with lymph node metastasis and prognosis in tongue squamous cell carcinoma.

We determined whether the expression of VEGF-A and -C and their receptors, Flt-1 and Flt-4, are associated with primary tumor size, regional lymph node metastasis, distant metastasis and prognosis in patients with tongue carcinoma. The expression of VEGF-A and -C, and their receptors, Flt-1 and Flt-4, in biopsy specimens taken from 73 patients with tongue carcinoma were examined by immunohistochemical staining. VEGF-A expression was associated with distant failure and VEGF-C expression correlated with locoregional recurrence and distant failure. Furthermore, VEGF-C expression was associated with lymph node recurrence in N0 cases. Multivariate analysis revealed that VEGF-C expression was an exclusively independent factor influencing lymph node metastasis. In terms of the overall 5-year survival rate, there was no significance correlation between the overall 5-year survival rate and expression of VEGF-A, Flt-1 and Flt-4 expression, whereas there was a significant difference between VEGF-C-positive and VEGF-C-negative cases (VEGF-C-positive, 51.7% vs VEGF-C-negative, 94.2%). Furthermore, there was a significant difference between positive and negative expression for both VEGF-A and VEGF-C. Multivariate analysis revealed that lymph node metastasis and VEGF-C expression were exclusive, independent factors influencing the overall survival rate. VEGF-C expression may be a predictive factor of regional lymph node recurrence and prognosis in patients with tongue carcinoma.

Pleomorphic adenoma of the lateral side of the tongue.

Pleomorphic adenoma is histopathologically the commonest tumor found in the major salivary glands. Pleomorphic adenoma originating from the tongue is very rare: only 26 cases have been reported in the world literature since 1960, only 2 of which originated from Ebner's gland. Herein we report the case of a 54-year-old female with pleomorphic adenoma of the tongue. The tumor was in contact with the molars. A partial glossectomy was performed with a surgical margin, as the preoperative pathological finding in the tissue specimen taken from the tumor was epithelial hyperplasia. The postoperative pathological diagnosis was pleomorphic adenoma with hyperplasia. It is unclear whether the teeth being in contact with the tumor caused tumorigenesis in this case. This case suggests that pleomorphic adenoma of the tongue originating from Ebner's gland should be considered in the differential diagnosis of lesions of the tongue.

Phase I trial of combined chemotherapy with docetaxel, cisplatin, and 5-fluorouracil for patients with locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: This phase I study was designed to determine the maximum tolerated dose (MTD) and toxicities of combination chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (5-FU) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). METHODS: Patients received two cycles of chemotherapy repeated every 4 weeks. Starting doses (dose level 0) were: docetaxel 60 mg/m(2), cisplatin 60 mg/m(2), and 5-day continuous infusion 5-FU 600 mg/m(2) per day. At least three patients were examined at each dose level before advancing to the next level. RESULTS: Nineteen male patients (median age, 59.5 years) were enrolled. Eighteen patients had previously untreated stage III or IV SCCHN and 1 had local relapse, rT4. In the 19 patients, the regimen was well tolerated, with neutropenia as the most common toxicity (grade 3; n = 11; grade 4; n = 1). Dose-limiting toxicity (DLT) was observed at the fifth dose level (docetaxel 70 mg/m(2), cisplatin 70 mg/m(2), 5-FU 750 mg/m(2) per day), when 1 patient developed grade 2 renal toxicity during the first course; another 2 patients had persistent neutropenia. These doses were thus deemed the MTD for the regimen. In the 18 assessable patients, the overall clinical response rate was 94% (17/18 patients) and primary-site complete response (CR) occurred in 4 (22%) patients. CONCLUSION: The MTD of this regimen was docetaxel 70 mg/m(2) on day 1, cisplatin 70 mg/m(2) on day 4, and 5-FU 750 mg/m(2) per day for 5 days. The regimen was safe and generally well-tolerated and demonstrated good efficacy in patients with locally advanced SCCHN. This phase I study was designed to determine the maximum tolerated dose (MTD) and toxicities of combination chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (5-FU) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).

Protein levels of p21, p27, cyclin E and Bax predict sensitivity to cisplatin and paclitaxel in head and neck squamous cell carcinomas.

Regression of tumor mass by chemotherapy is caused by growth suppression and/or apoptosis of tumor cells. Therefore, expression levels of cell cycle molecules and apoptosis should be predictive markers for the efficacy of a drug. In the present study, the relationship between expression of molecules in the cell cycle and apoptosis and chemosensitivity was investigated in head and neck squamous cell carcinoma cell lines. Expression of p53, p21, p27, cyclin D1, cyclin E, and Bax in 17 such cell lines were analyzed by Western blot analysis. The concentrations of four chemotherapeutic agents (cisplatin, 5-FU, vincristine, and paclitaxel) resulting in 50% cell growth inhibition were calculated as IC50 values for each cell line. Cell cycle analysis was performed using a FACScan flow cytometer. Cells with strong expression of p21, p27, or Bax showed significantly higher sensitivity to cisplatin, and cells with strong expression of Bax or weak expression of cyclin E showed significantly higher sensitivity to paclitaxel. Cisplatin most effectively killed cells expressing both p21 and p27 or either at G1 phase. Though the assessments of p21, p27, Bax, and cyclin E expression in tumor tissues have been reported to be useful as prognostic factors in head and neck squamous cell carcinoma, these correlations might not only describe the malignant biological behavior of the tumor, but also the response to chemotherapy. Furthermore, p21/p27 expression might be a useful guide for the choice of chemotherapeutic agents.

[Two head and neck cancer patients who responded to chemotherapy consisting of only TS-1].

We report two head and neck cancer patients who responded to TS-1. Case 1, a 52-year-old man was admitted to our department a diagnosis of supraglottic laryngeal cancer (T3N2cM0) on January 25, 2000. Concurrent chemoradiotherapy consisting of 2 courses of chemotherapy and radiation therapy at 70.2 Gy was administered. After the treatment, a biopsy showed a remaining cancer in the primary lesion. Since the patient refused to undergo surgery, the patient was followed up at the outpatient clinic using UFT at 400 mg/day. Because pulmonary metastasis was detected by chest CT, administration of TS-1 was started. TS-1 was administered at the conventional dose of 120 mg/day for 4 weeks followed by a 2-week rest. According to a CT conducted after 2 courses, the mass in the lung field disappeared and the clinical outcome was judged to be a CR. The TS-1 administration is still continuing, and the patient's condition also remains a CR. Case 2 was a patient with highly-differentiated adenocarcinoma in the ethmoid sinus (T3N2bM0). The patient was inoperable and was given radiation therapy of 64.8 Gy. Because of no change of the tumor after radiotherapy, TS-1 was administered at 60 mg x 2/day for 4 weeks followed by a 2-week rest. After TS-1 was administered for 3 courses, a CT showed a remarkable regression of the tumor resulting in a PR for the primary and the neck lesion. Upper gastrointestinal endoscopy during the 4th course detected a gastric ulcer of the A1 stage, and the patient was immediately admitted to the hospital. The ulcer was an adverse reaction of grade 3, which was improved by conservative therapy. TS-1 was restarted with a dose of 100 mg/day on April 11. No particular adverse reaction has been observed since then. The patient has received 13 courses of TS-1 and is still receiving TS-1. No clear tumor has been observed, and the clinical outcome is considered to be a CR. TS-1 is considered to be an excellent oral anticancer drug in terms of its anti-tumor effect and the patient's QOL.