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We conducted a phase II study to evaluate the efficacy and safety of chemoradiotherapy concurrent with S-1 plus cisplatin in patients with unresectable locally advanced squamous cell carcinoma of the head and neck. Chemotherapy consisted of S-1 twice daily on days 1-14 at 60 mg/m(2) /day and cisplatin at 20 mg/m(2) /day on days 8-11, repeated twice at a 5-week interval. Single daily radiation of 70 Gy in 35 fractions was given concurrently starting on day 1. For patients achieving an objective response after chemoradiotherapy, two additional cycles of chemotherapy were administered. Of the 45 enrolled patients, the percentage of clinical complete remission, the primary endpoint, was 64.4% (8 complete response, 21 good partial response) on central review. After a median follow-up of 3.52 years, 3-year local progression-free survival was 62.2%, with 3-year progression-free survival of 60.0%, 3-year overall survival of 64.4%, and 3-year time to treatment failure of 48.9%. Grade 3 or 4 toxicity included pharyngeal mucositis (46.7%), oral mucositis (44.4%), dysphagia (46.7%), anorexia (42.2%), radiation dermatitis (26.7%), neutropenia (26.7%), and febrile neutropenia (4.4%). No treatment-related deaths were observed. This combination showed promising efficacy with acceptable toxicities., (© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

Chemotherapy with cisplatin plus fluorouracil is the current standard treatment for metastatic or recurrent esophageal cancer. We have developed a 2-weekly docetaxel combined with CF regimen and conducted a Phase I/II trial for metastatic or recurrent esophageal cancer (JCOG0807). Promising efficacy and safety were shown in JCOG0807, and we have commenced a Phase III trial in September 2014 to confirm the superiority of 2-weekly DCF to CF for patients with metastatic or recurrent esophageal cancer. A total of 240 patients will be accrued from 41 Japanese institutions over a period of 4 years. The primary end point is overall survival. The secondary end points are progression-free survival, response rate and proportion of adverse events. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000015107 (http://www.umin.ac.jp/ctr/index.htm)., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

A randomized Phase II/III trial commenced in May 2014. Endoscopic balloon dilation with steroid injection is the current standard treatment for patients with refractory anastomotic stricture after esophagectomy. The purpose of this study is to confirm the superiority of radial incision and cutting with steroid injection in terms of both restricture-free survival and number of dilations within 24 weeks compared with endoscopic balloon dilation with steroid injection for these patients. A total of 130 patients will be accrued from 30 Japanese institutions over 3 years. The primary endpoint in the Phase II part is proportion of Grade 3/4 intraoperative hemorrhages, post-operative esophageal perforations, esophageal hemorrhages, pneumothorax, lung or mediastinum infections or other unexpected adverse events. Co-primary endpoints in the Phase III part are restricture-free survival and number of dilations within 24 weeks after treatment. Secondary endpoints are proportion of patients with anastomotic diameter >10 mm at 8 weeks after treatment, proportion of adverse events, proportion of patients experiencing improvement of dysphagia score at 2, 4, 8 and 24 weeks after treatment and proportion of patients with dysphagia score ≤1 at 24 weeks after treatment. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000014017 [http://www.umin.ac.jp/ctr/index.htm]., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: In order to determine indications for less radical surgery such as modified radical hysterectomy, the risk of pathological parametrial involvement and prognosis of FIGO stage IB1 cervical cancer patients undergoing standard radical hysterectomy with pre-operatively assessed tumor diameter≤2 cm were investigated., Methods: We conducted a retrospective multi-institutional chart review of patients with FIGO stage IB1 cervical cancer who underwent primary surgical treatment between 1998 and 2002. The eligibility criteria for the analyses were (i) histologically-proven squamous cell carcinoma, adenocarcinoma or, adenosquamous cell carcinoma, (ii) radical hysterectomy performed, (iii) clinical tumor diameter data available by MR imaging or specimens by cone biopsy, and (iv) age between 20 and 70. Based on the clinical tumor diameter, patients were stratified into those with the following tumors: i) 2 cm or less (cT≤2 cm) and ii) greater than 2 cm (cT>2 cm). We expected 5-year OS of ≥95% and parametrial involvement<2-3% for patients with cT≤2 cm who underwent radical hysterectomy., Results: Of the 1269 patients enrolled, 604 were eligible for the planned analyses. Among these, 571 underwent radical hysterectomy (323 with cT≤2 cm and 248 with cT>2 cm). Parametrial involvement was present in 1.9% (6/323) with cT≤2 cm and 12.9% (32/248) with cT>2 cm. Five-year overall survivals were 95.8% (95% CI 92.9-97.6%) in cT≤2 cm and 91.9% (95% CI 87.6-94.8%) in cT>2 cm patients., Conclusion: Patients with cT≤2 cm had lower risk of parametrial involvement and more favorable 5-year overall survival. They could therefore be good candidates for receiving less radical surgery., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: This phase III trial aimed to confirm the superiority of weekly docetaxel and cisplatin over docetaxel monotherapy in elderly patients with advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: Chemotherapy-naïve patients with stage III, stage IV, or recurrent NSCLC age ≥ 70 years with a performance status of 0 or 1 who were considered unsuitable for bolus cisplatin administration were randomly assigned to receive docetaxel 60 mg/m(2) on day 1, every 3 weeks, or docetaxel 20 mg/m(2) plus cisplatin 25 mg/m(2) on days 1, 8, and 15, every 4 weeks. The primary end point was overall survival (OS)., Results: In the first interim analysis, OS of the doublet arm was inferior to that of the monotherapy arm (hazard ratio [HR], 1.56; 95% CI, 0.98 to 2.49), and the predictive probability that the doublet arm would be statistically superior to the monotherapy arm on final analysis was 0.996%, which led to early study termination. In total, 276 patients with a median age of 76 years (range, 70 to 87 years) were enrolled. At the updated analysis, the median survival time was 14.8 months for the monotherapy arm and 13.3 months for the doublet arm (HR, 1.18; 95% CI, 0.83 to 1.69). The rates of grade ≥ 3 neutropenia and febrile neutropenia were higher in the monotherapy arm, and those of anorexia and hyponatremia were higher in the doublet arm., Conclusion: This study failed to demonstrate any survival advantage of weekly docetaxel plus cisplatin over docetaxel monotherapy as first-line chemotherapy for advanced NSCLC in elderly patients., (© 2015 by American Society of Clinical Oncology.)

Objective: Neoadjuvant chemotherapy with 5-fluorouracil plus cisplatin and subsequent esophagectomy with two- to three-field lymphadenectomy is a standard treatment for patients with clinical stage II/III squamous cell carcinoma (SCC) of the esophagus. This study investigates the prognostic factors for patients who received neoadjuvant chemotherapy., Methods: Of 164 patients assigned to receive neoadjuvant chemotherapy in the JCOG9907 trial, multivariate analyses were performed for 159 and 149 patients to evaluate the preoperative and the combined preoperative and postoperative prognostic factors, respectively., Results: The multivariate analyses using preoperative factors showed that clinical stage T3 [vs. cT1-2; hazard ratio (HR) 3.60, p = 0.0007] and serum albumin (Alb) <4.0 g/dl (vs. ≥ 4.0 g/dl; HR 2.29, p = 0.0005) were associated with a poor prognosis. Four independent prognostic factors were identified by multivariate analysis of both preoperative and postoperative factors: pathological curability B (pB; R0 with stage IV or pD < pN) or pC [microscopic or macroscopic residual tumor (R1/R2)] [vs. pA (R0); HR 1.93, p = 0.015], pathological stage N1 (vs. pN0; HR 3.86, p = 0.0012), cT3 (vs. cT1-2; HR 2.80, p = 0.0073), and serum Alb <4.0 g/dl (vs. ≥ 4.0 g/dl; HR 2.03, p = 0.0069)., Conclusions: Preoperative cT stage, Alb, and postoperative pathological findings are independent prognostic factors for patients undergoing neoadjuvant chemotherapy for advanced thoracic esophageal SCC. This analysis may aid in stratification according to individual patient risk., (© 2015 S. Karger AG, Basel.)

A dose-finding and efficacy confirmation trial was started in Japan in April 2014 to evaluate the efficacy and safety of superselective intra-arterial infusion of cisplatin and concomitant radiotherapy for locally advanced maxillary sinus cancer. A total of 18 patients will be enrolled in the dose-finding phase for the determination of the recommended number of cisplatin cycles, and 65 patients with T4aN0M0 and 62 patients with T4bN0M0, including those who received the recommended number of or fewer cycles in the dose-finding phase, will be enrolled from 16 institutions within a 5-year period in the efficacy confirmation phase. The primary endpoints of the dose-finding and the efficacy confirmation phases are dose-limiting toxicities and 3-year overall survival, respectively. This trial was registered at the UMIN Clinical Trials Registry (http://www.umin.ac.jp/ctr/) under Trial No. UMIN000013706., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

We carried out a phase I/II trial of adding 2-weekly docetaxel to cisplatin plus fluorouracil (CF) therapy (2-weekly DCF regimen) in esophageal cancer patients to investigate its safety and antimetastatic activity. Patients received 2-weekly docetaxel (30 mg/m(2) [dose level (DL)1] or 40 mg/m(2) [DL2] with a 3 + 3 design in phase I, on days 1 and 15) in combination with fixed-dose CF (80 mg/m(2) cisplatin, day 1; 800 mg/m(2) fluorouracil, days 1-5) repeated every 4 weeks. The primary endpoint was dose-limiting toxicity (DLT) in phase I and central peer review-based response rate in phase II. At least 22 responders among 50 patients were required to satisfy the primary endpoint with a threshold of 35%. Sixty-two patients were enrolled in phase I and II. In phase I, 10 patients were enrolled with DLT of 0/3 at DL1 and 2/7 in DL2. Considering DLT and treatment compliance, the recommended phase II dose was determined as DL1. In phase II, the response rate was 62% (P < 0.0001; 95% confidence interval, 48-75%); median overall survival and progression-free survival were 11.1 and 5.8 months, respectively. Common grade 3/4 adverse events were neutropenia (25%), anemia (36%), hyponatremia (29%), anorexia (24%), and nausea (11%). No febrile neutropenia was observed. Pneumonitis caused treatment-related death in one patient. The 2-weekly DCF regimen showed promising antimetastatic activity and tolerability. A phase III study comparing this regimen with CF therapy is planned by the Japan Clinical Oncology Group. This study was registered at the UMIN Clinical Trials Registry as UMIN 000001737., (© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

Background: NSABP C-06 demonstrated the non-inferiority of oral adjuvant uracil and tegafur plus leucovorin (UFT/LV) to weekly fluorouracil and folinate (5-FU/LV) with respect to disease-free survival (DFS) for stage II/III colon cancer. This is the first report of JCOG0205, which compared UFT/LV to standard 5-FU/levofolinate (l-LV) for stage III colorectal cancer patients who have undergone Japanese D2/D3 lymph node dissection., Methods: Patients were randomised to three courses of 5-FU/l-LV (5-FU 500 mg/m(2), l-LV 250 mg/m(2) on days 1, 8, 15, 22, 29, 36 every 8 weeks) or five courses of UFT/LV (UFT 300 mg m(-2)day(-1), LV 75 mg/day on days 1-28 every 5 weeks). The primary end-point was DFS. The sample size was 1100 determined with one-sided alpha of 0.05, power of 0.78 and non-inferiority margin of hazard ratio of 1.27. This trial is registered with UMIN-CTR (C000000193)., Findings: Between February 2003 and November 2006, 1,101 patients (1092 eligible patients) were randomised to 5-FU/l-LV (n=550) or UFT/LV (n=551). Median age: 61 years, colon/rectum: 67%/33%, number of positive nodes ⩽3/>3: 73%/27%, stage IIIa/IIIb: 75%/25%. The hazard ratio of DFS was 1.02 (91.3% confidence interval, 0.84-1.23), demonstrating the non-inferiority of UFT/LV (P=0.0236). Five-year overall survival (87.5%) was higher than that in NSABP C-06 (69.6%). Grade 3/4 toxicities were 8.4% neutropenia in 5-FU/l-LV and 8.7% alanine aminotransferase elevation in UFT/LV, respectively. The incidences of diarrhoea (9.6% versus 8.5%) and anorexia (4.0% versus 3.7%) were similar between the two arms. No treatment-related deaths were reported., Interpretation: Adjuvant UFT/LV is non-inferior to standard 5-FU/l-LV with respect to DFS. UFT/LV should be an oral treatment option for patients with stage III colon cancer who have undergone Japanese D2/D3 lymph node dissection., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A randomized Phase II/III trial was planned to commence in March 2014. Perioperative chemotherapy with adriamycin plus ifosfamide is the current standard treatment for T2bN0M0 high-grade non-round cell soft tissue sarcoma. The purpose of this study is to confirm the non-inferiority of perioperative chemotherapy with gemcitabine and docetaxel to adriamycin plus ifosfamide for patients with T2bN0M0 or any TN1M0 non-round cell soft tissue sarcoma in the extremities and body wall. A total of 140 patients will be accrued from 28 Japanese institutions over 6 years. The primary endpoint in the Phase II part is the proportion of completion of pre-operative chemotherapy without progressive disease and overall survival in the Phase III part. The secondary endpoints are progression-free survival, response rate of pre-operative chemotherapy, pathological response rate, proportion of preservation of diseased limbs, disease control rate and proportion of adverse events. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000013175 [http://www.umin.ac.jp/ctr/index.htm]., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

A randomized Phase II/III study was launched in Japan to evaluate the non-inferiority of concurrent chemoradiotherapy with weekly cisplatin (40 mg/m(2)) compared with concurrent chemoradiotherapy with 3-weekly cisplatin (100 mg/m(2)) for post-operative high-risk patients with locally advanced squamous cell carcinoma of head and neck. This study began in October 2012, and a total of 260 patients will be accrued from 18 institutions within 5 years. The primary endpoint of the Phase II part is proportion of treatment completion and that of the Phase III part is overall survival. The secondary endpoints are relapse-free survival, local relapse-free survival, nutrition-support-free survival, non-hospitalized treatment period during permissible treatment period and adverse events. This trial was registered at the UMIN Clinical Trials Registry as UMIN 000009125 [http://www.umin.ac.jp/ctr/]., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: A randomized controlled trial to confirm the non-inferiority of laparoscopic surgery to open surgery in terms of overall survival was conducted, and short-term surgical outcomes are demonstrated., Background: The efficacy and safety outcome of laparoscopic surgery for clinical stages II/III colon cancer undergoing Japanese D3 dissection are still unclear., Methods: Eligibility criteria included colon cancer; tumor located in the cecum, ascending, sigmoid, or rectosigmoid colon; T3 or T4 without involvement of other organs; N0-2; and M0. Patients were randomized preoperatively and underwent tumor resection with D3 dissection. Safety analyses were conducted by per-protocol set., Results: A total of 1057 patients were randomized between October 2004 and March 2009. By per-protocol set, 524 patients who underwent open surgery and 533 patients who underwent laparoscopic surgery were analyzed. D3 dissection was performed in 521 (99.4%) patients in the open surgery arm and 529 (99.2%) patients in the laparoscopic surgery arm. Conversion to open surgery was needed for 29 (5.4%) patients. Patients assigned to laparoscopic surgery had less blood loss (P < 0.001), although laparoscopic surgery lasted 52 minutes longer (P < 0.001). Laparoscopic surgery was associated with a shorter time to pass first flatus, decreased use of analgesics after 5 postoperative days, and a shorter hospital stay. Morbidity [14.3% (76/533) vs 22.3% (117/524), P < 0.001] was lower in the laparoscopic surgery arm., Conclusions: Short-term surgical safety and clinical benefits of laparoscopic D3 dissection were demonstrated. The primary endpoint will be reported after the primary analysis, planned for 2014.

Background: In advanced gastric cancer (AGC), no globally accepted prognostic scoring system has been developed. Therefore, we explored baseline prognostic factors in Japanese AGC patients using the data from a randomized controlled trial, Japan Clinical Oncology Group (JCOG) 9912, which investigated the efficacy of systemic chemotherapy as a first-line treatment., Patients and Methods: Prognostic factors and prognostic indices for overall survival were screened and evaluated in patients enrolled in JCOG9912 using the Cox proportional hazard model. The Royal Marsden Hospital prognostic model was also applied to the JCOG9912 trial., Results: A total of 650 (92.3%) of the 704 patients randomized in the JCOG9912 trial, for whom complete data were available for multivariate analyses, was included in the present study (5-fluorouracil arm, n = 215; irinotecan plus cisplatin arm, n = 216; S-1 arm, n = 219). The median survival time (MST) for all patients was 11.8 months. To construct a prognostic index, we selected four risk factors by multivariate analysis: performance status ≥ 1, number of metastatic sites ≥ 2, no prior gastrectomy, and elevated alkaline phosphatase. MSTs were 17.0 months for patients categorized into the low-risk group, who had zero or one risk factor (n = 225); 10.4 months for patients in the moderate-risk group, who had two or three risk factors (n = 368); and 5.0 months for patients in the high-risk group, who had all four risk factors (n = 57)., Conclusion: In the present study, we propose a new prognostic index for patients with AGC. This can be used for more appropriate patient stratification in future clinical trials.

Background: To evaluate the feasibility and accuracy of diagnosis using sentinel node (SN) biopsy in T1 gastric cancer, a multicenter trial was conducted by the Japan Clinical Oncology Group (JCOG)., Methods: Sentinel node biopsy with indocyanine green (ICG) was performed in patients with T1 gastric cancer. Green-stained nodes (GNs), representing SNs, were removed first, and gastrectomy with lymphadenectomy was then performed. GNs in one plane (with the largest dimension) were histologically examined intraoperatively by frozen section with hematoxylin and eosin (H&E) stain. All harvested lymph nodes (GNs and non-GNs) were histologically examined by paraffin section after surgery. The primary endpoint was to determine the proportion of false negatives, which was defined as the number of patients with negative GNs by frozen section divided by those with positive GNs and/or positive non-GNs by paraffin section. The sample size was set at 1,550, based on the expected and threshold value as 5 and 10 % in the proportion of false negatives., Results: Accrual was suspended when 440 patients were enrolled because the proportion of false negatives was high. In the primary analysis, the proportion of false negatives was 46 % (13/28) after a learning period with 5 patients for each institution. Seven of 13 patients had nodal metastases outside the lymphatic basin. False negatives remained at 14 % (4/28) even by examining additional sections of GNs by paraffin section., Conclusions: The proportion of false negatives was much higher than expected. Intraoperative histological examination using only one plane is not an appropriate method for clinical application of SN biopsy in gastric cancer surgery.

Background: Four cycles of etoposide plus cisplatin and accelerated hyperfractionated thoracic radiotherapy (AHTRT) is the standard of care for limited-stage small-cell lung cancer (SCLC). Irinotecan plus cisplatin significantly improved overall survival compared with etoposide plus cisplatin for extensive-stage SCLC. We compared these regimens for overall survival of patients with limited-stage SCLC., Methods: We did this phase 3 study in 36 institutions in Japan. Eligibility criteria included age 20-70 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate organ functions. Eligible patients with previously untreated limited-stage SCLC received one cycle of etoposide plus cisplatin (intravenous etoposide 100 mg/m(2) on days 1-3; intravenous cisplatin 80 mg/m(2) on day 1) plus AHTRT (1.5 Gy twice daily, 5 days a week, total 45 Gy over 3 weeks). Patients without progressive disease following induction therapy were randomised (1:1 ratio, using a minimisation method with biased-coin assignment balancing on ECOG performance status [0 vs 1], response to induction chemoradiotherapy [complete response plus near complete response vs partial response and stable disease], and institution) to receive either three further cycles of consolidation etoposide plus cisplatin or irinotecan plus cisplatin (intravenous irinotecan 60 mg/m(2) on days 1, 8, 15; intravenous cisplatin 60 mg/m(2) on day 1). Patients, physicians, and investigators were aware of allocation. The primary endpoint was overall survival after randomisation; primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00144989, and the UMIN Clinical Trials Registry, number C000000095., Findings: 281 patients were enrolled between Sept 1, 2002, and Oct 2, 2006. After induction etoposide plus cisplatin and AHTRT, 258 patients were randomised to consolidation etoposide plus cisplatin (n=129) or irinotecan plus cisplatin (n=129). In the etoposide plus cisplatin group, median overall survival was 3.2 years (95% CI 2.4-4.1). In the irinotecan and cisplatin group, median overall survival was 2.8 years (95% CI 2.4-3.6); overall survival did not differ between the two groups (hazard ratio 1.09 [95% CI 0.80-1.46], one-sided stratified log-rank p=0.70). The most common adverse events of grade 3 or 4 were neutropenia (120 [95%] in the etoposide plus cisplatin group vs 101 [78%] in the irinotecan plus cisplatin group), anaemia (44 [35%] vs 50 [39%]), thrombocytopenia (26 [21%] vs six [5%]), febrile neutropenia (21 [17%] vs 18 [14%]), and diarrhoea (two [2%] vs 13 [10%]). There was one treatment-related adverse event leading to death in each group (radiation pneumonitis in the etoposide plus cisplatin group; brain infarction in the irinotecan plus cisplatin group)., Interpretation: Four cycles of etoposide plus cisplatin and AHTRT should continue to be the standard of care for limited-stage SCLC., Funding: National Cancer Center and the Ministry of Health, Labour, and Welfare of Japan., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Although many in vitro and animal studies have suggested a protective effect of green tea against breast cancer, only a few epidemiological studies have examined this association, and findings have been inconsistent. We examined the association between green tea consumption and breast cancer risk in consideration of the hormone receptor status of tumors and investigated whether the association was modified by dietary and genetic factors based on a hospital-based case-control study in Nagano, Japan. A total of 369 pairs completed a validated food frequency questionnaire and provided blood samples. Four single nucleotide polymorphisms (SNPs) were genotyped: CYP19A1 (rs10046), COMT (rs4680), MTHFR C677T (rs1801133), and MTHFR A1298C (rs1801131). We found no inverse association between green tea consumption and breast cancer risk. Compared with women who drank less than 120 ml of green tea per day, the adjusted odds ratio for women who drank more than 600 ml was 1.27 (95% confidence interval = 0.75-2.14; P for trend = 0.20). We also found no inverse association for either tumor subtype. No substantial effect modification was observed for menopausal status, 4 SNPs, or dietary intake of folate or isoflavone. This study provides additional evidence that green tea consumption is not associated with a decreased risk.

Background: Two randomized phase III trials of first-line chemotherapy for advanced gastric cancer (JCOG9205 and JCOG9912) conducted by the Japan Clinical Oncology Group used 5-fluorouracil continuous infusion (5-FUci) as the control arm. New active agents (e.g., S-1, irinotecan, and taxanes) were introduced as second-line chemotherapy in the late 1990s after JCOG9205. This combined analysis evaluated whether patients in the 5-FUci arm of JCOG9912 exhibited better survival after adjusting for baseline factors and also investigated the cause of survival prolongation., Patients and Methods: The subjects were patients assigned to the 5-FUci arms who met the eligibility criteria of both JCOG9205 and JCOG9912. Overall survival (OS), time to treatment failure (TTF), and survival after treatment failure in the first-line chemotherapy (OS-TTF) were compared after adjusting baseline characteristics using the Cox proportional hazard model. Second-line chemotherapy details were also reviewed., Results: The combined analysis included 89 and 230 patients in JCOG9205 and JCOG9912, respectively. After adjusting baseline characteristics, TTF was similar between groups (HR 0.95; 95 % CI, 0.73-1.26). However, both OS (HR, 0.74; 95 % CI, 0.56-0.99) and OS-TTF (HR, 0.76; 95 % CI, 0.57-1.01) were longer in JCOG9912. More patients in JCOG9912 received second-line chemotherapy (83 vs. 52 %) with new drugs (77 vs. 10 %) than in JCOG9205. OS-TTF was substantially prolonged in patients who received second-line chemotherapy (HR, 0.66; 95 % CI, 0.46-0.95)., Conclusion: OS and OS-TTF were longer in JCOG9912 than JCOG9205. Second-line chemotherapy with new drugs is a potential reason for the observed prolongation of survival.

The oral fluoropyrimidine, S-1, combined with or without gemcitabine is considered to be a promising agent for treating advanced biliary tract cancer; gemcitabine plus cisplatin is the current standard regimen. This randomized phase II trial was designed to evaluate the safety and efficacy of two regimens: gemcitabine plus S-1 (GS) (gemcitabine: 1000 mg/m(2) , day 1 and day 8; S-1: 60 mg/m(2) , twice daily on days 1-14, repeated every 3 weeks); and S-1 (80 mg/m(2) , days 1-28, given orally twice daily for 4 weeks, followed by a 2-week rest, repeated every 6 weeks). The regimen with a higher 1-year survival would be selected for a subsequent phase III trial. Between February 2009 and April 2010, 101 patients were randomized. For the GS (n = 51) and S-1 (n = 50) arms, the 1-year survival was 52.9% (95% confidence interval, 38.5-65.5) and 40.0% (95% confidence interval, 26.5-53.1), and the median survival times were 12.5 and 9.0 months, respectively. Grade 3/4 hematological toxicities were more frequent in the GS arm (leucocytes 29.4%, neutrophils 60.8%, hemoglobin 11.8%, platelets 11.8%) than in the S-1 arm (leucocytes 2.0%, neutrophils 4.0%, hemoglobin 4.0%, platelets 4.0%). Although two treatment-related deaths occurred in the GS arm, all other grade 3/4 non-hematological toxicities were reversible. In conclusion, GS was considered to be more promising and was selected as the test regimen for a subsequent phase III trial comparing GS with gemcitabine plus cisplatin combination therapy. This study was registered at the UMIN Clinical Trials Registry as UMIN 000001685 (http://www.umin.ac.jp/ctr/index.htm)., (© 2013 Japanese Cancer Association.)

A three-arm Phase III trial was started in November 2012. Preoperative chemotherapy with cisplatin plus 5-fluorouracil is the current standard treatment for locally advanced esophageal cancer in Japan, while preoperative chemoradiotherapy with cisplatin plus 5-fluorouracil is the standard in Western countries. Preoperative chemotherapy with docetaxel, cisplatin plus 5-fluorouracil is another promising regimen. The purpose of this study is to confirm the superiority of docetaxel, cisplatin plus 5-fluorouracil over cisplatin plus 5-fluorouracil and the superiority of cisplatin plus 5-fluorouracil with chemoradiotherapy over cisplatin plus 5-fluorouracil as preoperative therapy for squamous cell carcinoma of esophagus. A total of 501 patients will be accrued from 41 Japanese institutions within 6.25 years. The primary endpoint is overall survival and the secondary endpoints include progression-free survival, %R0 resection, response rate, pathologic complete response rate and adverse events.

A Phase III study was started in Japan to evaluate the non-inferiority of overall survival of laparoscopy-assisted distal gastrectomy with open distal gastrectomy in patients with clinical IA (T1N0) or IB [T1N1 or T2(MP)N0] gastric cancer. This study followed the previous Phase II study to confirm the safety of laparoscopy-assisted distal gastrectomy (JCOG0703) and began in March 2010. A total of 920 patients will be accrued from 33 institutions within 5 years. The primary endpoint is overall survival. The secondary endpoints are relapse-free survival, proportion of laparoscopy-assisted distal gastrectomy completion, proportion of conversion to open surgery, adverse events, short-term clinical outcomes, postoperative quality of life. Only a credentialed surgeon can be responsible for both open distal gastrectomy and laparoscopy-assisted distal gastrectomy.

Purpose: Glioblastoma (GBM) is one of the worst cancers in terms of prognosis. Standard therapy consists of resection with concomitant chemoradiotherapy. Resistance to nimustine hydrochloride (ACNU), an alkylating agent, has been linked to methylguanine DNA methyltransferase (MGMT). Daily administration of procarbazine (PCZ) has been reported to decrease MGMT activity. This study investigated the efficacy of ACNU + PCZ compared to ACNU alone for GBM and anaplastic astrocytoma (AA)., Methods: Patients (20-69 years) who had newly diagnosed AA and GBM were randomly assigned to receive radiotherapy with ACNU alone or with ACNU + PCZ. The primary endpoint was overall survival (OS). This was designed as a phase II/III trial with a total sample size of 310 patients and was registered as UMIN-CTR C000000108., Results: After 111 patients from 19 centers in Japan were enrolled, this study was terminated early because temozolomide was newly approved in Japan. The median OS and median progression-free survival (PFS) with ACNU alone (n = 55) or ACNU + PCZ (n = 56) in the intention-to-treat population were 27.4 and 22.4 months (p = 0.75), and 8.6 and 6.9 months, respectively. The median OS and median PFS of the GBM subgroup treated with ACNU alone (n = 40) or ACNU + PCZ (n = 41) were 19.0 and 19.5 months, and 6.2 and 6.3 months, respectively. Grade 3/4 hematologic adverse events occurred in more than 40 % of patients in both arms, and 27 % of patients discontinued treatment because of adverse events., Conclusions: The addition of PCZ to ACNU was not beneficial, in comparison with ACNU alone, for patients with newly diagnosed AA and GBM.

A Phase II clinical trial has been initiated to evaluate the efficacy and safety of endoscopic submucosal dissection for intramucosal (cT1a) gastric cancer of undifferentiated type. Patients with cT1a gastric cancer with undifferentiated-type adenocarcinoma are eligible for the study. The tumor size should be 2 cm or less without ulceration. The study will enroll a total of 325 patients from 51 institutions over a 4-year period. The primary endpoint is proportion of 5-year overall survival (% 5-year overall survival) in patients with undifferentiated dominant type. The secondary endpoints are overall survival, relapse-free survival, distant metastasis-free survival, % 5-year overall survival without either recurrence or gastrectomy, % en-bloc resection with endoscopic submucosal dissection, % pathological curative resection with endoscopic submucosal dissection, % 5-year overall survival in patients with differentiated dominant type, % 5-year overall survival in patients with pathologically curative resection with endoscopic submucosal dissection and adverse events.

A Phase II trial was initiated in Japan to evaluate the efficacy and safety of preoperative chemotherapy with docetaxel, cisplatin and S-1 for gastric cancer with extensive lymph node metastasis. Patients are eligible to participate in the study if they have para-aortic lymph node metastases (stations no. 16a2/16b1) and/or a bulky lymph node (≥3 cm × 1 or ≥1.5 cm × 2) along the celiac, splenic, common or proper hepatic arteries or the superior mesenteric vein, while patients with other distant metastases are ineligible. A total of 50 patients will be enrolled over 2.5 years. The primary endpoint is the response rate of the preoperative chemotherapy, which will be assessed based on the Response Evaluation Criteria in Solid Tumors ver. 1.0. The secondary endpoints are %3-year survival, %5-year survival, proportion of patients with R0 resection, proportion of patients who complete the preoperative chemotherapy and surgery, proportion of patients who complete the protocol treatment, pathological response rate and adverse events. This trial was registered at the UMIN Clinical Trials Registry (www.umin.ac.jp/ctr/) as UMIN000006069.

Background: Mesorectal excision is the international standard surgical procedure for lower rectal cancer. However, lateral pelvic lymph node metastasis occasionally occurs in patients with clinical stage II or stage III rectal cancer, and therefore mesorectal excision with lateral lymph node dissection is the standard procedure in Japan. We did a randomised controlled trial to confirm that the results of mesorectal excision alone are not inferior to those of mesorectal excision with lateral lymph node dissection., Methods: This study was undertaken at 33 major hospitals in Japan. Eligibility criteria included histologically proven rectal cancer of clinical stage II or stage III, with the main lesion located in the rectum with the lower margin below the peritoneal reflection, and no lateral pelvic lymph node enlargement. After surgeons had confirmed macroscopic R0 resection by mesorectal excision, patients were intraoperatively randomised to mesorectal excision alone or with lateral lymph node dissection. The groups were balanced by a minimisation method according to clinical N staging (N0 or N1, 2), sex, and institution. Allocated procedure was not masked to investigators or patients. This study is now in the follow-up stage. The primary endpoint is relapse-free survival and will be reported after the primary analysis planned for 2015. Here, we compare operation time, blood loss, postoperative morbidity (grade 3 or 4), and hospital mortality between the two groups. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00190541., Findings: 351 patients were randomly assigned to mesoretcal excision with lateral lymph node dissection and 350 to mesorectal excision alone, between June 11, 2003, and Aug 6, 2010. One patient in the mesorectal excision alone group underwent lateral lymph node dissection, but was analysed in their assigned group. Operation time was significantly longer in the mesorectal excision with lateral lymph node dissection group (median 360 min, IQR 296-429) than in the mesorectal excision alone group (254 min, 210-307, p<0·0001). Blood loss was significantly higher in the mesorectal excision with lateral lymph node dissection group (576 mL, IQR 352-900) than in the mesorectal excision alone group (337 mL, 170-566; p<0·0001). 26 (7%) patients in the mesorectal excision with lateral lymph node dissection group had lateral pelvic lymph node metastasis. Grade 3-4 postoperative complications occurred in 76 (22%) patients in the mesorectal excision with lateral lymph node dissection group and 56 (16%) patients in the mesorectal excision alone group. The most common grade 3 or 4 postoperative complication was anastomotic leakage (18 [6%] patients in the mesorectal excision with lateral lymph node dissection group vs 13 [5%] in the mesorectal excision alone group; p=0·46). One patient in the mesorectal excision with lateral lymph node dissection group died of anastomotic leakage followed by sepsis., Interpretation: Mesorectal excision with lateral lymph node dissection required a significantly longer operation time and resulted in significantly greater blood loss than mesorectal excision alone. The primary analysis will help to show whether or not mesorectal excision alone is non-inferior to mesorectal excision with lateral lymph node dissection., Funding: National Cancer Center, Ministry of Health, Labour and Welfare of Japan., (Copyright © 2012 Elsevier Ltd. All rights reserved.)