Yasumasa Nishimura

Phase III Study Comparing Second- and Third-Generation Regimens With Concurrent Thoracic Radiotherapy in Patients With Unresectable Stage III Non–Small-Cell Lung Cancer: West Japan Thoracic Oncology Group WJTOG0105

PURPOSE This phase III trial of concurrent thoracic radiotherapy (TRT) was conducted to compare third-generation chemotherapy with second-generation chemotherapy in patients with unresectable stage III non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Eligible patients received the following treatments: A (control), four cycles of mitomycin (8 mg/m(2) on day 1)/vindesine (3 mg/m(2) on days 1, 8)/cisplatin (80 mg/m(2) on day 1) plus TRT 60 Gy (treatment break for 1 week); B, weekly irinotecan (20 mg/m(2))/carboplatin (area under the plasma concentration-time curve [AUC] 2) for 6 weeks plus TRT 60 Gy, followed by two courses of irinotecan (50 mg/m(2) on days 1, 8)/carboplatin (AUC 5 on day 1); C, weekly paclitaxel (40 mg/m(2))/carboplatin (AUC 2) for 6 weeks plus TRT 60 Gy, followed by two courses of paclitaxel (200 mg/m(2) on day 1)/carboplatin (AUC 5 on day 1). RESULTS The median survival time and 5-year survival rates were 20.5, 19.8, and 22.0 months and 17.5%, 17.8%, and 19.8% in arms A, B, and C, respectively. Although no significant differences in overall survival were apparent among the treatment arms, noninferiority of the experimental arms was not achieved. The incidences of grade 3 to 4 neutropenia, febrile neutropenia, and gastrointestinal disorder were significantly higher in arm A than in arm B or C (P < .001). Chemotherapy interruptions were more common in arm B than in arm A or C. CONCLUSION Arm C was equally efficacious and exhibited a more favorable toxicity profile among three arms. Arm C should be considered a standard regimen in the management of locally advanced unresectable NSCLC.

An antiangiogenic agent (TNP-470) inhibited reoxygenation during fractionated radiotherapy of murine mammary carcinoma.

PURPOSE TNP-470, a synthetic analogue of fumagillin which is a natural product of Aspergillus fumigatus, has been noted as an angiogenesis inhibitor. Combined effects of TNP-470 with fractionated radiotherapy (RT) were investigated using a mouse tumor. METHODS AND MATERIALS Tumors were early generations of mammary carcinoma in C3H/He mice. Treatments were initiated when tumors reached an average diameter of 4-5 mm. Tumor response was evaluated by tumor growth (TG) time assay and 50% tumor control dose (TCD50) assay. Tumors were irradiated locally under hypoxic conditions or in air. Five fractionated radiation doses were given in the TG time assay, whereas a single dose or 10 fractionated doses were given in the TCD50 assay. TNP-470 (100 mg/kg) was administered subcutaneously twice a week during and/or after RT. RESULTS In the TG time assay, significant delay of tumor growth was observed by TNP-470 alone (100 mg/kg x 2) compared with control tumors (p < 0.001), indicating that TNP-470 alone has an antitumor effect in vivo. When TNP-470 was administered during fractionated RT, no additional delay of tumor growth was observed. However, additive effects of TNP-470 was noted when it was given after the end of fractionated RT. In the TCD50 assay, no significant difference in TCD50s was observed between RT alone and RT combined with TNP-470 in single dose experiments. Hypoxic fraction of tumors calculated from the TCD50s was not affected significantly by administrating TNP-470 24 h before RT. On the other hand, in 10-fraction experiments, the TCD50 (RT with TNP-470, in air) was significantly higher than the TCD50 (RT alone, in air) (p < 0.005), indicating that TNP-470 given during fractionated RT decreased radiocurability. This negative effect of TNP-470 was not observed when TNP-470 was combined with fractionated RT given under hypoxic conditions. CONCLUSION The tumor control probability decreased by administrating TNP-470 during fractionated RT in air. This unexpected result may be attributable to partial inhibition of reoxygenation by TNP-470, because no significant difference was noted between the TCD50 (RT with TNP-470) and the TCD50 (RT alone) under hypoxic conditions.

Guidelines for Diagnosis and Treatment of Carcinoma of the Esophagus April 2012 edited by the Japan Esophageal Society

Purpose These guidelines are intended for doctors who are engaged in the diagnosis and treatment of esophageal carcinoma, for the following purposes: (1) to present the standard practice for the diagnosis and treatment of esophageal carcinoma with a high regard for the principles of evidence-based medicine (EBM); (2) to improve the safety and results of treatment, thereby reducing the difference in treatment results among different institutions; (3) to reduce unnecessary costs and efforts; (4) help enable people to undergo treatment without anxiety. These guidelines provide only guidance on the indications for treatment and do not restrict or prohibit the use of any treatment deviating from those described herein.

Radiofrequency Capacitive Hyperthermia for Deep-seated Tumors I. Studies on Thermometry

The thermometry results of radiofrequency (RF) capacitive hyperthermia for 60 deep‐seated tumors in 59 patients are reported. Hyperthermia was administered regionally using two RF capacitive heating equipments which the authors have developed in cooperation with Yamamoto Vinyter Company Ltd., (Osaka, Japan). Intratumor temperatures were measured by thermocouples inserted through angio‐catheters which were placed 5 cm to 12 cm deep into the tissues. Tumor center temperatures were measured for 307 treatments in all tumors; thermal distributions within tumors and surrounding normal tissues were obtained for 266 treatments of 53 tumors by microthermocouples.

Guidelines for diagnosis and treatment of carcinoma of the esophagus

Preoperative chemotherapy: there have been three reports of meta-analyses based on randomized controlled trials carried out in Europe or North America that compared surgical resection with preoperative chemotherapy and surgical resection alone. However, the conclusions are confl icting: one found that preoperative chemotherapy does not improve 1-year and 2-year survival rates, whereas the other showed preoperative chemotherapy to slightly improve the 2-year survival rate. At present, the effi cacy of preoperative chemotherapy for resectable cases (T1–3, N0,1, M0; 2002 edition of UICC classifi cation) is unclear. Preoperative chemoradiotherapy: the results of a meta-analysis of randomized controlled trials comparing surgery alone and surgery combined with preoperative chemoradiotherapy carried out in Europe and North America showed that preoperative concurrent chemoradiotherapy (20–45 Gy) for resectable cases (T1–3, N0,1, M0) caused a signifi cant increase in operation-related mortality while signifi cantly improving the 3-year survival rate. However, when the 1-year or 2-year survival rate was the endpoint, there was no clear survival benefi t of preoperative chemoradiotherapy. Thus, the results of this meta-analysis of randomized controlled trials performed in Europe and North America suggest that preoperative chemoradiotherapy combined with surgery has the potential to improve the long-term survival of patients undergoing surgical resection of esophageal carcinoma. In Japan, this therapy is performed for locally advanced cases in a number of institutions. However, no high-level evidence is available concerning Japanese patients, and there is no fi rm basis for recommending the use of preoperative chemoradiotherapy in Japan.

Role of Bcl-2 family proteins (Bax, Bcl-2 and Bcl-X) on cellular susceptibility to radiation in pancreatic cancer cells

The aim of this study was to examine Bax, Bcl-2 and Bcl-XL proteins in human pancreatic cancer cell lines and to clarify the mechanism of radiation resistance. PANC-1 and AsPC-1 pancreatic cell lines were used, both having mutated p53. Radioresistant PANC-1/Rad cells and AsPC-1/Rad cells were obtained by repeated 5 Gy irradiation of PANC-1 cells and AsPC-1 cells, respectively. Radiation was found to inhibit the growth of PANC-1 cells and AsPC-1 cells. After exposure to radiation, detached cells were subjected to FITC-TUNEL staining to calcualte the ratio of apoptosis. TUNEL positive ratios increased dose-dependently in both cell lines. Western blotting showed that the basal level of the Bax/Bcl-2 ratio reflected the radiosensitivity of these cell lines, and Bax expression was obviously upregulated after irradiation in the presence of mutated p53, but Bcl-2 expression remained almost constant. Both PANC-1/Rad and AsPC-1/Rad cells had greater Bcl-XL expression than the parental cells, and the basal level of the Bax/Bcl-2 ratio was no longer predictive of radiosensitivity. Upregulated expression of Bax protein after irradiation was not related to induction of apoptosis in these cells, suggesting that overexpression of Bcl-XL and functional reconstruction of Bcl-2 family proteins are important factors in acquired radioresistance.

Radiation therapy for T1,2 glottic carcinoma: impact of overall treatment time on local control

PURPOSE Local control probabilities of T1,2 glottic laryngeal cancer were evaluated in relation to dose and fractionation of radiation therapy (RT). MATERIALS AND METHODS Between 1975 and 1993, 96 T1N0M0 glottic cancers and 32 T2N0M0 glottic cancers were treated with definitive RT. Total RT dose was 60-66 Gy/2 Gy for most of the T1 and T2 tumors, although 10 T2 tumors were treated with hyperfractionation (72-74.4 Gy/1.2 Gy bid). Of the 128 patients, 90 T1 glottic tumors and 30 T2 glottic tumors were followed for > 2 years after treatment. Multivariate analyses using the Cox proportional hazards model and a logistic regression analysis were performed to evaluate the significance of prognostic variables on local control. RESULTS The 5-year local control probability for T1 tumors was 85%, whereas that for T2 tumors was 71%. Multivariate analyses demonstrated that only overall treatment time (OTT) was a significant variable for local control. Total RT dose, normalized total doses at a fraction size of 2 Gy, and fraction size were not significant. Local control probability of T1 tumors with an OTT of 42-49 days was significantly higher than that of tumors with an OTT of > 49 days (P < 0.02). Only a 1-week interruption of RT, due to holidays, significantly reduced the 5-year local control probability of T1 glottic tumors from 89 to 74% (P < 0.05). CONCLUSIONS These results indicate that OTT is a significant prognostic factor for local control of T1 glottic tumors.

External and intraoperative radiotherapy for resectable and unresectable pancreatic cancer: Analysis of survival rates and complications

PURPOSE Clinical results of intraoperative radiotherapy (IORT) and/or external beam radiotherapy (EBRT) for both resectable and unresectable pancreatic cancer were analyzed. METHODS AND MATERIALS Between 1980 and 1995, 332 patients with pancreatic cancer were treated with surgery and/or radiation therapy (RT). Of the 332 patients, 157 patients were treated with surgical resection of pancreatic tumor, and the remaining 175 patients had unresectable pancreatic tumors. Among the 157 patients with resected pancreatic cancer, 62 patients were not treated with RT, while 40 patients were treated with EBRT alone (mean RT dose; 46.3 Gy) and 55 patients with IORT (25.2 Gy) +/- EBRT (44.0 Gy). On the other hand, among the 175 patients with unresectable pancreatic cancer, 58 patients were not treated with RT, 46 patients were treated with EBRT alone (39.2 Gy), and the remaining 71 patients with IORT (29.3 Gy) +/- EBRT (41.2 Gy). RESULTS For 87 patients with curative resection, the median survival times (MSTs) of the no-RT, the EBRT, and the IORT +/- EBRT groups were 10.4, 13.0, and 15.5 months, respectively, without significant difference. For 70 patients with noncurative resection, the MSTs of the no-RT, the EBRT, and the IORT +/- EBRT groups were 5.3, 8.7, and 6.5 months, respectively. When the EBRT and the IORT +/- EBRT groups were combined, the survival rate was significantly higher than that of the no RT group for noncuratively resected pancreatic cancers (log rank test; p = 0.028). The 2-year survival probability of the IORT +/- EBRT group (16%) was higher than that of the EBRT group (0%). For unresectable pancreatic cancer, the MSTs of 52 patients without distant metastases were 6.7 months for palliative surgery alone, 7.6 months for EBRT alone, and 8.2 months for IORT +/- EBRT. The survival curve of the IORT +/- EBRT group was significantly better than that of the no-RT group (p < 0.05), and the difference between the IORT +/- EBRT and the EBRT alone groups was marginally significant (p = 0.056). In addition, the 2-year survival probability for the IORT +/- EBRT group was 14%, while no 2-year survival was observed in the no RT or the EBRT groups. Multivariate analysis using the Cox proportional hazards model revealed that tumor size, stage (Stages 1, 2 vs. Stages 3, 4), and curability of resection were significant variables for resectable pancreatic cancer, while distant metastases and performance of IORT were significant variables for unresectable pancreatic cancer. The dose of EBRT was a marginally significant factor for both resectable and unresectable tumors (both p = 0.06). In terms of complications, ulcers of gastrointestinal tract were noted in 14% of the 126 patients treated with IORT. CONCLUSION Although prolongation of the MST by IORT was not remarkable, long survivals (>2 years) were obtained by IORT +/- EBRT for noncuratively resected and unresectable pancreatic cancer. IORT combined with EBRT is indicated for noncurative resected or unresectable pancreatic cancer without distant metastases.

Prospective trial of concurrent chemoradiotherapy with protracted infusion of 5-fluorouracil and cisplatin for T4 esophageal cancer with or without fistula.

PURPOSE A prospective trial of concurrent chemoradiotherapy (CT-RT) with a protracted infusion of 5-fluorouracil and cisplatin was performed to evaluate the safety and efficacy of this protocol for T4 esophageal cancer (UICC 1997). METHODS AND MATERIALS Between 1998 and 2000, 28 patients with T4 esophageal squamous cell carcinomas were treated with concurrent CT-RT. Of the 28 patients, 15 had Stage III, 5 Stage IVA, and 8 Stage IV disease. Five of the T4 tumors had evidence of fistula before treatment. Patients received a protracted infusion of 5-fluorouracil 300 mg/m(2)/24 h on Days 1-14, a 1-h infusion of cisplatin 10 mg/body on Days 1-5 and 8-12, and concurrent radiation at a dose of 30 Gy in 15 fractions during 3 weeks. This schedule was repeated twice, with a 1-week split, for a total RT dose of 60 Gy during 7 weeks for 25 patients. For the remaining 3 patients, 30 Gy of preoperative CT-RT was administered. RESULTS Of the 25 patients who were treated with the full dose of CT-RT, 14 (56%) completed the two courses of the CT-RT protocol, and 8 patients (32%) received the full dose of RT but a reduced dose of chemotherapy. Eight (32%) of the 25 tumors showed complete regression. Although Grade 3 hematologic toxicities were frequently noted, Grade 4 or more hematologic toxicities were few. Of the 5 T4 fistulous tumors, 2 demonstrated the disappearance of the fistula after CT-RT. However, the worsening or development of an esophageal fistula was noted in 5 patients. The 2-year survival rate for patients with Stage III was 27%, and the median survival time for those with Stage III and Stage IVA+IV was 12 and 5 months, respectively. CONCLUSION Despite its significant toxicity for esophageal fistula, this concurrent CT-RT protocol of protracted 5-fluorouracil infusion and cisplatin appears feasible and effective for T4 esophageal cancer with or without fistulas.

Guidelines for Diagnosis and Treatment of Carcinoma of the Esophagus April 2007 edition: part I Edited by the Japan Esophageal Society

Guidelines for Treatment of Carcinoma of the Esophagus were developed by an outstanding group of experts designated the Committee to Develop Guidelines for Treatment of Carcinoma of the Esophagus set up in the Japanese Society for Esophageal Diseases (presently the Japan Esophageal Society) and published in December 2002. As mentioned in the fi rst edition, these guidelines were developed to provide recommendations concerning standard treatments for carcinoma of the esophagus that are currently most appropriate and generally applicable in most institutions, facilitating the daily clinical practice of eso phageal carcinoma treatment. However, as esophageal carcinoma treatments have been changing, and treatment recommendations may include a variety of issues, it is often diffi cult to prescribe uniform treatments. Specifi c issues to be addressed are as follows.