Nutritional support dependence after curative chemoradiotherapy in head and neck cancer: supplementary analysis of a phase II trial (JCOG0706S1).

OBJECTIVES: To explore the risk factors of laryngo-esophageal dysfunction-free survival and nutritional support dependence over 12 months in patients with unresectable locally advanced head and neck carcinomas who received chemoradiotherapy in a phase II trial of JCOG0706 (UMIN000001272). METHODS: Forty-five patients received radiation therapy for a total of 70 Gy/35fr concurrently with S-1 and cisplatin. Risk factors of laryngo-esophageal dysfunction-free survival and nutritional support dependence over 12 months were analyzed using Cox regression models and logistic regression models, respectively, with consideration to patient laboratory data just before chemoradiotherapy. Radiation fields were reviewed to analyze the relationship between the extent of the irradiated field and functional outcome. RESULTS: With a median follow-up period of 3.5 years, 3-year laryngo-esophageal dysfunction-free survival was 48.9%. For laryngo-esophageal dysfunction-free survival, hazards ratio of 2.35 in patients with nutritional support at registration (vs. without nutritional support; 95% confidence interval 0.96-5.76). For nutritional support dependence over 12 months, odds ratio was 6.77 in patients with hemoglobin less than the median of 13.4 g/dl (vs. higher than or equal to the median; 95% confidence interval 1.24-36.85) and was 6.00 in patients with albumin less than the median of 3.9 g/dl (vs. higher than or equal to the median; 95% confidence interval 1.11-32.54). Primary sites in disease-free patients with nutritional support dependence over 12 months were the oropharynx (N = 2) or hypopharynx (N = 1), and all pharyngeal constrictor muscles were included in irradiated fields with a curative dose. CONCLUSIONS: This supplementary analysis showed that pretreatment severe dysphagia requiring nutritional support, anemia and hypoalbuminemia might have a negative prognostic impact on long-term functional outcomes after curative chemoradiotherapy in head and neck cancer.

Induction TPF chemotherapy followed by CRT with fractionated administration of cisplatin in patients with unresectable locally advanced head and neck cancer.

BACKGROUND: In treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN), the use of docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by high-dose cisplatin chemoradiotherapy (CRT) carries concerns over toxicity. We evaluated the feasibility of TPF as induction chemotherapy (IC) to Japanese patients and the tolerability of CRT with fractionated administration of cisplatin after IC. METHODS: Patients with unresectable stage III, IV SCCHN received IC followed by CRT. IC consisted of three 3-week cycles of docetaxel 70-75 mg/m2 on day 1, cisplatin 70-75 mg/m2 on day 1, and 5-fluorouracil 750 mg/m2 on days 1-5. Patients subsequently received IMRT concomitant with fractionated administration of cisplatin (20 mg/m2) on days 1-4, repeated every 3 weeks. The primary endpoint was completion of the three cycles of IC. RESULTS: Forty-eight patients were enrolled. The IC treatment completion rate was 85%. Grade 3-4 toxicities of TPF were neutropenia (79%) and febrile neutropenia (15%). Thirty-eight patients (79%) achieved a response after IC. Forty patients subsequently underwent CRT. Thirty-three patients (83%) completed the planned cycles of fractionated administration of cisplatin, but seven (18%) did not. Grade 3-4 toxicities during CRT were neutropenia (23%), mucositis (53%), and dysphagia (33%). With a median follow-up of 36.1 months, 3-year overall survival was 65%. CONCLUSION: TPF IC is feasible and CRT with fractionated administration of cisplatin after IC is tolerable. IC followed by CRT appears to be a useful and safe sequential treatment. (Trial registration no. UMIN000024686).

Long-term Clinical Results of Concurrent Chemoradiotherapy for Patients with Cervical Esophageal Squamous Cell Carcinoma.

BACKGROUND/AIM: We assessed the efficacy and toxicity of concurrent chemoradiotherapy (CCRT) in patients with squamous cell carcinoma of the cervical esophagus. PATIENTS AND METHODS: We retrospectively analyzed 37 patients treated with definitive CCRT. The patients received radiotherapy at a fraction dose of 2 Gy (total; 60 or 70 Gy) and concurrent chemotherapy. Adjuvant chemotherapy consisted of 1 to 2 cycles of 5-fluorouracil plus cisplatin or nedaplatin. RESULTS: The median follow-up was 119.0 months, the 10-year overall survival, progression-free survival and laryngectomy-free survival rates were 35.6, 19.9 and 30.2% respectively. In the univariate analysis, T stage (T4 vs. T1-3) was the only prognostic factor for PFS. The most common acute toxicity was leukocytopenia (Grade 3; 27%). As for late toxicities, 4 patients (11%) developed Grade 2 or 3 esophageal strictures. CONCLUSION: The results of this study demonstrated that CCRT yielded satisfactory clinical outcomes with acceptable toxicities.

Pharmacokinetics of initial full and subsequent reduced doses of S-1 in patients with locally advanced head and neck cancer-effect of renal insufficiency.

BACKGROUND: S-1 is a combination of tegafur [metabolized to 5-fluorouracil (5-FU)] with the modulators gimeracil (5-chloro-2,4-dihydroxypyridine) and oteracil potassium. 5-Chloro-2,4-dihydroxypyridine maintains plasma 5-FU concentrations by inhibiting dihydropyrimidine dehydrogenase, a pyrimidine catabolism enzyme that degrades 5-FU. As 50% of 5-chloro-2,4-dihydroxypyridine is excreted in urine, renal insufficiency may increase its blood level, increasing 5-FU concentrations. We investigated whether special dose modification is needed in the presence of renal insufficiency. OBJECTIVE: We compared steady state pharmacokinetics of 5-FU for the initial S-1 dose and reduced doses in patients with head and neck cancer requiring dose reduction due to renal and non-renal toxicities. METHODS: Chemoradiotherapy with S-1 and cisplatin was administered every 5 weeks for two courses with a radiation dose totaling 70 Gy over 33-35 fractions. Two additional courses of adjuvant chemotherapy were administered in the case of an objective response. The S-1 and/or cisplatin dose was reduced in response to renal, hematologic or other toxicities. The primary endpoint was the change in area under the plasma concentration-versus-time curve from time 0-10 hours (5-FU AUCss 0-10) between the initial and reduced S-1 doses. RESULTS: Although the mean 5-FU levels in patients with non-renal toxicities significantly decreased between the full and reduced dose, the full-dose and reduced-dose mean maximum 5-FU plasma concentrations at steady state (Css max) and AUCss 0-10 in patients with renal insufficiency were similar. CONCLUSIONS: Standard S-1 dose reduction for renal toxicity did not result in a significant decrease in 5-FU levels at steady state. A greater reduction to lower plasma 5-chloro-2,4-dihydroxypyridine may be necessary in patients with renal insufficiency.

Multicenter Phase 2 Study of Cisplatin and 5-Fluorouracil With Concurrent Radiation Therapy as an Organ Preservation Approach in Patients With Squamous Cell Carcinoma of the Cervical Esophagus.

PURPOSE: To clarify, in a multicenter, single-arm, phase 2 study (UMIN Clinical Trials Registry no. UMIN000001439), the clinical profile of chemoradiotherapy (CRT) for cervical esophageal cancer. PATIENTS AND METHODS: Patients with operable cervical esophageal cancer, excluding candidates for endoscopic resection, were enrolled. Protocol treatment consisted of CRT and adjuvant chemotherapy (CT). First, patients received concurrent CRT with 5-fluorouracil (5-FU) plus cisplatin (CDDP). Chemotherapy consisted of 5-FU at 700 mg/m2 intravenous on days 1 to 4 and CDDP at 70 mg/m2 intravenous on day 1, repeated every 4 weeks for 2 cycles. Radiation therapy consisted of 60 Gy in 30 fractions. After completion of CRT, 2 additional cycles of CT with 5-FU (800 mg/m2, days 1-5) and CDDP (80 mg/m2, day 1) were repeated at a 4-week interval. The primary endpoint was 3-year overall survival. RESULTS: Thirty patients were enrolled across 8 institutions in Japan, consisting of 26 men and 4 women with a median age of 64.5 years (range, 50-75 years). No grade 4 hematologic toxicity was seen in the CRT phase, and 1 grade 4 thrombocytopenia was seen in the CT phase. Grade 3 nonhematologic acute toxicities in the CRT phase were nausea (10%), mucositis (13.3%), and dysphagia (13.3%). No treatment-related death in either phase occurred. Overall complete response rate was 73%, and 3-year overall and laryngectomy-free survival were 66.5% and 52.5%, respectively. Regarding T4 disease, 3-year overall and laryngectomy-free survival were 58.3% and 38.5%, respectively. CONCLUSIONS: This study, the first prospective study for cervical esophageal cancer, showed that CRT has sufficient efficacy and safety for use as an alternative to surgery for these patients.

Combined effect of hyperthermia at 42 degrees C and irradiation dose of 2 Gy on two rat yolk sac tumor cell lines with different radio-thermosensitivity in vitro.

BACKGROUND: Two rat yolk sac tumor cell lines, NMT-1 and NMT-1R, are of the same origin and of different sensitivity to irradiation and to heat. The aim of this study was to investigate the sensitivities of these two cell lines to combined treatments of low-dose irradiation at 2 Gy and hyperthermia at 42 degrees C. MATERIALS AND METHODS: The cell survival was assayed by soft agar clonogenic assay. After the survival curves of radiation alone and of heat alone at various temperatures were estimated, not only the effect of irradiation on heat, but the effect of heat on irradiation were evaluated with sequential treatments in both cell lines. These effects on survival curves were evaluated by the enhancement ratios at isosurvival levels of 37%, 10% and 1%, respectively. RESULTS: NMT-1 was more sensitive to radiation but more resistant to heat than NMT-1R. For 1% survival level, radiosensitivity in NMT-1 was 1.32 times that in NMT-1R, while thermal sensitivity at 42 degrees C in NMT-1R was 2.73 times that in NMT-1. For sequential treatment, thermosensitization by a radiation dose of 2 Gy in radiosensitive NMT-1 was greater than that in radioresistant NMT-1R. Following heat at 42 degrees C for 1 hour, increased radiosensitivity in NMT-1R was significant, whereas the same heat treatment produced an increase in the radiation sensitivity of NMT-1 with a reduction of the survival curve shoulder but with less slope modification. There was no difference in the surviving fraction in the time-course of a combination of heat and irradiation at various intervals within 6 hours for NMT-1 except for heating immediately after irradiation. However a significant increase in survival was observed when heat was applied more than 3 hours after 2 Gy irradiation for NMT1-R. CONCLUSION: These results from our cell lines with the same origin were useful for investigation into the interaction of irradiation with heat.