Japan Clinical Oncology Group Study Research Articles

A Phase II Clinical Trial of Endoscopic Submucosal Dissection for Early Gastric Cancer of Undifferentiated Type: Japan Clinical Oncology Group Study JCOG1009/1010

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.

Concurrent Chemoradiotherapy for Localized Nasal Natural Killer/T-Cell Lymphoma: An Updated Analysis of the Japan Clinical Oncology Group Study JCOG0211

Concurrent Chemoradiotherapy for Localized Nasal Natural Killer/T-Cell Lymphoma: An Updated Analysis of the Japan Clinical Oncology Group Study JCOG0211

IS1-1 - Randomized Phase II Trial of Gemcitabine Plus S-1 Combination Therapy Versus S-1 in Advanced Biliary Tract Cancer: Results of the Japan Clinical Oncology Group Study (JCOG0805)

ABSTRACT Background Gemcitabine plus cisplatin combination (GC) therapy is the standard therapy for advanced biliary tract cancer (BTC). In previous trials, gemcitabine plus S-1 combination (GS) therapy and S-1 mono-therapy had shown considerable efficacy in patients with BTC. The aim of this trial is to evaluate the efficacy and safety of the two regimens and to determine which is more promising as a test arm regimen for a subsequent phase III trial. Methods Chemotherapy-naive patients with recurrent or unresectable BTC (gallbladder [GB], intrahepatic biliary duct [IHBD], extrahepatic biliary duct [EHBD], ampulla of Vater [AV]), an ECOG PS of 0-1, and adequate organ function were randomly assigned to receive GS (gemcitabine: 1000 mg/m2, i.v., days 1 and 8; S-1: 60 mg/m2, p.o., days 1–14, every 3 weeks) or S-1 (80 mg/m2, p.o., days 1–28, every 6 weeks). We assumed that the percentage of 1-year survival of one regimen is 30 and that of the other regimen is more than 40. To ensure at least 85% probability of correct selection, 98 eligible patients are required. The decision rule was that the regimen with higher percentage of 1-year survival will be considered as more promising regimen. Results From February 2009 to April 2010, 101 patients (GB, n = 38; IHBD, n = 35; EHBD, n = 20; AV, n = 8) were randomized (GS, n = 51; S-1, n = 50). For the GS arm and S-1 arm, the percenatge of 1-year survival was 52.9% and 40.0%, the median survival time were 12.5 and 9.0 months (hazard ratio 0.86 [95% CI 0.54–1.36]; P = 0.52), and the median progression-free survival time were 7.1 and 4.2 months (0.44 [0.29–0.67]; P Conclusions The GS arm was superior in the percentage of 1-year survival to S-1. Here we consider GS to be more promising as the test arm for a subsequent phase III trial comparing with GC.

IS8-5 - Phase II Trial of Chemoradiotherapy Concurrent with S-1 Plus Cisplatin in Patients with Unresectable Locally Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN): Results of the Japan Clinical Oncology Group Study, JCOG 0706

ABSTRACT Background To evaluate the efficacy and safety of chemoradiotherapy (CRT) concurrent with S-1 plus cisplatin in patients with unresectable locally advanced SCCHN. Methods Eligibility criteria included histologically proven SCCHN with unresectable locally advanced lesions, PS 0-1, age 20–75, and no prior treatment. Chemotherapy consisted of administration of S-1 twice daily on days 1–14 at 60 mg/m2/day, and cisplatin at 20 mg/m2/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 CRT, two additional cycles of chemotherapy were administered. The primary end point was clinical complete response rate (% CR), which was the proportion of complete response (CR) and good partial response (good PR). Good PR was defined as remaining tissue with tumor shrinkage, which was not regarded as residual tumor but rather as scar material. The planned sample size was 45 patients, which was calculated by SWOG's two-stage attained design based on an expected %CR of 60% and a threshold of 45%, with a one-sided alpha of 0.1 and a power of 0.9. Results From July 2008 to July 2010, 45 eligible subjects were accrued, including 43 males, with median age 63 years, ECOG PS 0/1 (36/9), oropharynx/hypopharynx/larynx (26/15/4), T1/T2/T3/T4a/T4b (1/11/7/17/9) and N0/N2a/N2b/N2c/N3 (2/3/10/24/6). %CR was 64.4% (8 CR, 21 good PR) on central review. After a median follow-up of 1.56 years, 1-year local progression-free survival was 77.8%, with 1-year progression-free survival of 70.9%, 1-year overall survival of 93.3% and 1-year time to treatment failure of 57.6%. Grade 3 or 4 toxicity included mucositis (46.7%), dysphagia (46.7%), anorexia (42.2%), radiation dermatitis (26.7%), neutropenia (26.7%) and febrile neutropenia (4.4%). No treatment-related deaths were observed. Conclusion This combination showed promising efficacy with acceptable toxic effects. Further investigation in a phase III trial is planned.

SY1-1 - Current Status and Challenges in Jcog Data Center (DC) And Operations Office (OPS)

ABSTRACT Japan Clinical Oncology Group (JCOG) is the largest cooperative group in Japan. The yearly accrual of 2011 was 2744 in total. Currently, there are 30 trials on accrual and 20 trials on follow-up. Those trials are supported by about 40 staffs including 5 physicians in JCOG DC/OPS. JCOG has now 15 study groups and has an established peer-review system for protocol and adverse events. There are 180 participating institutions and all roster information is managed in JCOG DC/OPS. JCOG DC/OPS issues monitoring reports for all studies twice a year. Until now, 25 JCOG studies were adopted as a reference of various cancer treatment guidelines.Current challenges in JCOG DC/OPS are as follow: (i) streamlining study process. The project for protocol development acceleration has been activated since 2009. The speed has been improved afterward and the shortest duration from concept approval to protocol approval is 173 days. Acceleration of manuscript writing is also underway. (ii) Correlative studies and biospecimen repository. Recently the demand for correlative studies is growing. We have implemented several correlative studies along with regular JCOG studies and accumulated the know-how in such type of studies. In addition, JCOG biospecimen repository has been established and specimens are to be collected under the common procedure before long. (iii) Promotion of ‘Kodo-iryo’ trials. JCOG is now planning two ‘Kodo-iryo’ trials (clinical trials using the evaluation system of investigational medical care). We are now developing a standardized procedure for conducting future ‘Kodo-iryo’ trials more smoothly. (iv) International collaborative trials. JCOG is now conducting two international collaborative studies. The harmonization of database definitions is sometimes hard and the number of staffs is not enough to handle many international trials. (v) Introduction of remote data entry system. In JCOG, all forms are still paper-based. It is mainly due to few supports by clinical research coordinator in the participating institutions. On the other hand, the yearly accrual becomes more and now we are considering introducing remote data entry system. Through all of those challenges, we aim to conduct well-designed, high-quality clinical trials rapidly and establish a large number of new standard treatments for cancer patients.

Watchful Waiting Versus Intravesical BCG Therapy for High-grade pT1 Bladder Cancer with pT0 Histology After Second Transurethral Resection: Japan Clinical Oncology Group Study JCOG1019

A Phase III clinical trial has been started in Japan to determine the optimal treatment strategy for patients with high-grade pT1 bladder cancer who have pT0 histology after second transurethral resection. The aim of this trial is to demonstrate the non-inferiority of relapse-free survival (excluding Tis or Ta intravesical recurrence) for watchful waiting compared with intravesical bacillus Calmette-Guérin therapy for pT0 after second transurethral resection. Patients with high-grade pT1 bladder cancer at the first registration and pT0 after second transurethral resection at the second registration are randomized to either a watchful waiting arm or an intravesical bacillus Calmette-Guérin therapy arm. A total of 575 patients at the first registration and 260 patients at the second registration will be accrued for this study from 38 institutions over 5 years. The primary endpoint is relapse-free survival (excluding Tis or Ta intravesical recurrence), and the secondary endpoints are overall survival, metastasis-free survival with bladder preserved, annual proportion of intravesical relapse-free survival, annual proportion of T2 or deeper relapse-free survival, adverse events and serious adverse events.

Phase II study of ABV (doxorubicin with increased dose, bleomycin and vinblastine) therapy in newly diagnosed advanced-stage Hodgkin lymphoma: Japan Clinical Oncology Group study (JCOG9705)

The role of dacarbazine in ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) therapy in Hodgkin lymphoma (HL) remains unclear. This phase II study assessed the efficacy and safety of ABV therapy with an increased doxorubicin dose (30 mg/m2) in advanced-stage HL. The primary endpoint was complete response rate (%CR). Patients received six or eight cycles of ABV every 4 weeks followed by involved-field radiation therapy (IFRT) in residual disease and initial bulky mass. Seventy-two patients were enrolled. An interim analysis in 46 assessable patients showed that %CR had exceeded the stopping criteria.However, the 2-year progression-free survival (%PFS) rate of 49.4% (95% confidence interval [CI] 32.2–66.6) was markedly lower than the 79.2% PFS (95% CI 70.6–87.7) seen in our previously reported study (JCOG9305) of ABVd with two-thirds the dose of dacarbazine of the original ABVD. Therefore, the study was closed early. The %CR in the 70 eligible patients after ABV was 31.4% (95% CI 20.9–43.6) and was increased to 70.0% (95% CI 57.9–80.4) after the addition of IFRT. ABV was inferior to ABVd for PFS in patients with advanced HL, suggesting that dacarbazine is indispensable in ABVD/ABVd.

Evaluation of Three Definitions of Progression-free Survival in Preoperative Cancer Therapy (JCOG0801-A)

Progression-free survival is an often-used endpoint in clinical trials comparing preoperative therapy and surgery-first therapy. Because the surgery date is always later in the preoperative arm than in the surgery-first arm, it is difficult to define progression-free survival optimally. We evaluated three progression-free survival definitions that used different methods to handle incomplete resection. The three definitions specify the event date of incomplete resection (IR) as follows: 'IR = event' method, date of surgery; 'IR not event' method, date of radiological or clinical progression after incomplete resection; landmark method, landmark time. According to these definitions, the theoretical strengths and weaknesses of the three definitions are investigated. Three patterns of progression-free survival and overall survival were estimated using the data of the Japan Clinical Oncology Group studies. Theoretically, 'IR = event' inflates alpha error while 'IR not event' method and landmark method reduce the statistical power under the alternative hypothesis. In JCOG9907, hazard ratios for the three definitions were: 'IR = event', 0.80 (95% confidence interval, 0.59-1.07; P = 0.13); 'IR not event', 0.81 (95% confidence interval, 0.60-1.09; P = 0.16); landmark, 0.80 (95% confidence interval, 0.59-1.07; P = 0.15). No P value of any methods corresponded with the positive result for overall survival (P = 0.03). In the preoperative arms of the four studies, maximum differences in median and percentage of 1 year progression-free survival among the three definitions were 0-6.4 months and 1.2-5.2%. Progression-free survival sometimes fails as a surrogate of overall survival, and differences among results obtained with various progression-free survival definitions can be large. Overall survival should be used as primary endpoint in studies evaluating preoperative therapy.

A Randomized Controlled Trial Comparing Primary Tumour Resection Plus Systemic Therapy With Systemic Therapy Alone in Metastatic Breast Cancer (PRIM-BC): Japan Clinical Oncology Group Study JCOG1017

This trial is being conducted to confirm the superiority, in terms of overall survival, of primary tumour resection plus systemic therapy to systemic therapy alone in patients with Stage IV breast cancer who are not refractory to primary systemic therapy. The inclusion criteria for the study are as follows: untreated patients with histologically confirmed invasive breast cancer with one or more measurable metastatic lesions diagnosed by radiological examination. All patients receive primary systemic therapy according to the estrogen receptor and human epidermal growth factor receptor type-2 status of the primary breast cancer after the first registration. After 3 months, the patients without disease progression are randomized to the primary tumour resection plus systemic therapy arm or the systemic therapy alone arm. The primary endpoint is the overall survival, and the secondary endpoints are proportion of patients without tumour progression at the metastatic sites, yearly local recurrence-free survival, proportion of local ulcer/local bleeding, yearly primary tumour resection-free survival, adverse events of chemotherapy, operative morbidity and serious adverse events. The patient recruitment was commenced in May 2011. Enrolment of 410 patients for randomization is planned over a 5 year recruitment period. We hereby report the details of the study.

Phase II study of cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) therapy for newly diagnosed patients with low- and low–intermediate risk, aggressive non-Hodgkin’s lymphoma: final results of the Japan Clinical Oncology Group Study, JCOG9508

The regimen of cyclophosphamide, doxorubicin, vincristine, and prednisolone, known as CHOP therapy, has been established as the standard treatment for aggressive non-Hodgkin's lymphoma (NHL). Although patients categorized as low (L) and low-intermediate (L-I) risk using the International Prognostic Index have favorable prognoses in Western countries, the efficacy and safety of CHOP therapy has not been prospectively evaluated in Japan. We conducted a phase II study of CHOP in L and L-I risk Japanese patients, evaluating overall survival (OS) as the primary endpoint. A total of 213 patients were enrolled and treated with eight courses of CHOP. Efficacy was evaluated in 168 eligible patients (L risk, 87; L-I risk, 81). Five-year OS rates in all eligible, L, and L-I risk patients were 68% [95% confidence interval (CI): 61-76%], 73% (95% CI: 63-82%), and 64% (95% CI: 53-74%), respectively. The major toxicity observed was grade 4 neutropenia (64%). Grade 4 non-hematological toxicities were observed as follows: one case each of paralytic ileus, convulsions, hypoxemia due to interstitial pneumonia, and reactivated fulminant hepatitis B. These results show reasonable efficacy and safety of the CHOP regimen in Japanese patients with lower risk aggressive NHL (UMIN-CTR Number C000000053).

Short-term clinical outcomes from a randomized controlled trial to evaluate laparoscopic versus open complete mesocolic excision for stage II,III colorectal cancer (CRC): Japan Clinical Oncology Group study JCOG0404 (NCT00147134).

3569 Background: The benefits of laparoscopic surgery (LAP) in comparison with open surgery (OP) have been suggested; however, the long-term survival of LAP for advanced CRC requiring complete mesocolic excision is still unclear. We conducted a study to confirm the non-inferiority of LAP to OP in terms of overall survival (OS)with less frequent post-operative morbidity. Short-term outcomes including post-operative complications are presented here. Methods: Only accredited surgeons from 30 Japanese institutions participated. Eligibility criteria included histologically proven CRC; tumor located in the cecum, ascending, sigmoid or rectosigmoid colon; T3 or deeper lesion without involvement of other organs; N0–2 and M0; tumor size =<8 cm; patient age 20-75 years. Patients were randomized preoperatively.Patients with pathological stage III received adjuvant chemotherapy with fluorouracil plus leucovorin. The primary endpoint is OS. and the planned sample size was 1050. Results: A total of 1057 patients were randomized (OP: 528, LAP: 529) between October 2004 and March 2009. Conversion to OP was needed for 29 (5.4%) patients in LAP arm (technical conversion; 2.3%, indicated conversion; 2.8%, complicated conversion; 0.4%). Patients assigned to LAP had less blood loss compared with those assigned to OP (median 30 ml vs 85 ml, p<0.001), although LAP lasted 52 minutes longer than did OP (p<0.001). Radicality of resection as assessed by number of resected lymph nodes did not differ between two groups. LAP was associated with earlier recovery of bowel function (p<0.001), and with a shorter hospital stay (p<0.001) compared with OP. Morbidity and mortality untill discharge did not differ between two groups, except for less wound-related complications in LAP (p=0.007). Conclusions: Laparoscopic complete mesocolic excision for stage II,III colorectal cancer can be performed safely and short-term clinical benefits was demonstrated. If the non-inferiority of LAP in OS is demonstrated in the primary analysis planned in 2014 , LAP will be the new standard procedure for CRC.

Randomized phase III study of adjuvant chemotherapy with oral uracil and tegafur plus leucovorin versus intravenous fluorouracil and levofolinate in patients (pts) with stage III colon cancer (CC): Final results of Japan Clinical Oncology Group study (JCOG0205).

3524 Background: NSABP C-06 reported the non-inferiority of oral adjuvant uracil and tegafur plus leucovorin (UFT/LV) to weekly fluorouracil and folinate (5-FU/LV) in disease-free survival (DFS) in stage II/III CC. Although adjuvant FOLFOX for stage III is standard care in US or EU, its toxicity and cost is major problem. This is the first report of JCOG0205, which compared UFT/LV to standard 5-FU/levofoloinate (l-LV) in stage III CC. Methods: Pts were randomized to 3 courses of 5-FU/l-LV (5-FU 500 mg/m2, l-LV 250 mg/m2, on days 1, 8, 15, 22, 29, 36, q8w), or 5 courses of UFT/LV (UFT 300 mg/m2/day, LV 75 mg/day, on days 1–28, q5w). Primary endpoint was DFS. Sample size was 1,100, determined with one-sided alpha of 0.05, power of 0.78, and non-inferiority margin of hazard ratio (HR) of 1.27. Owing to interim analyses, the multiplicity-adjusted alpha and confidence coefficient of CI in the final analysis were 0.0433 and 91.3%. Results: Between Feb 2003 and Nov 2006, 1,101 pts (1,092 eligible) were randomized to 5-FU/l-LV (n=550) or UFT/LV (n=551). Median follow-up was 72.0 months, median age: 61, colon/rectum: 67%/33%, number of positive nodes <3/4<: 73%/27%, stage IIIa/IIIb: 75%/25%. The HR of DFS was 1.02 (91.3% CI, 0.84–1.23) and non-inferiority of UFT/LV was demonstrated (P=0.0236). Incidences of G3/4 toxicities were 8.4% neutropenia in 5-FU/l-LV and 8.7% ALT elevation in UFT/LV. In the 2 arms (5-FU/l-LV, UFT/LV), diarrhea (9.6%, 8.5%) and anorexia (4.0%, 3.7%) were similar. G3/4 diarrhea was one-third less and G3/4 ALT elevation was three times more common than those in C-06. No treatment-related death was reported. Conclusions: Adjuvant UFT/LV is demonstrated to be non-inferior to standard 5-FU/l-LV in DFS. Five-year OS (87.5%) is favorable to 69.6% in C-06, possibly due to D3 dissection and stage migration. UFT/LV should be an oral treatment option for stage III CC. [Table: see text]

Phase II trial of chemoradiotherapy concurrent with S-1 plus cisplatin in patients with unresectable, locally advanced squamous cell carcinoma of the head and neck (SCCHN): Results of the Japan Clinical Oncology Group study, JCOG 0706.

5542 Background: To evaluate the efficacy and safety of chemoradiotherapy (CRT) concurrent with S-1 plus cisplatin in patients with unresectable locally advanced SCCHN. Methods: Eligibility criteria included histologically proven SCCHN with unresectable locally advanced lesions, PS 0-1, aged 20 to 75 years old, adequate organ function, and no prior treatment. Chemotherapy consisted of administration of S-1 twice daily on days 1-14 at 60 mg/m2/day, and cisplatin at 20 mg/m2/day on days 8-11, repeated twice at a 5-week interval. Single daily radiation of 70 Gy in 35 fractions was given concurrently startingon day 1. For patients achieving an objective response after CRT, two additional cycles of chemotherapy wereadministered. The primary endpoint was clinical complete response rate (%CR), which was the proportion of complete response (CR) and good partial response (good PR). Good PR was defined as remaining tissue with tumor shrinkage, which was not regarded as residual tumor but rather as scar material.The planned sample size was 45 patients, which was calculated by SWOG's two-stage attained design based on an expected %CR of 60% and a threshold of 45%, with a one-sided alpha of 0.1 and a power of 0.9. Results: From July 2008 to July 2010, 45 eligible subjects were accrued, including 43 males, with median age 63 years, ECOG PS 0/1 (36/9), oropharynx/ hypopharynx/larynx (26/15/4), T1/T2/T3/T4a/T4b (1/11/7/17/9) and N0/N2a/N2b/N2c/N3 (2/3/10/24/6). %CR was 64.4% (8 CR, 21 good PR) on central review. After a median follow-up of 1.56 years, 1-year local progression-free survival was 77.8%, with 1-year progression-free survival of 70.9%, 1-year overall survival of 93.3% and 1-year time to treatment failure of 57.6%. Grade 3 or 4 toxicity included mucositis (46.7%), dysphagia (46.7%), anorexia (42.2%), radiation dermatitis (26.7%), neutropenia (26.7%) and febrile neutropenia (4.4%). No treatment-related deaths were observed. Conclusions: This combination showed promising efficacy with acceptable toxicities. Further investigation in a phase III trial is planned.

Randomized phase II trial of gemcitabine plus S−1 combination therapy versus S−1 in advanced biliary tract cancer: Results of the Japan Clinical Oncology Group study (JCOG0805).

4031 Background: Gemcitabine plus cisplatin combination (GC) therapy is the standard therapy for advanced biliary tract cancer (BTC). In previous trials, gemcitabine plus S-1 combination (GS) therapy and S-1 mono-therapy had shown considerable efficacy in patients with BTC. The aim of this trial is to evaluate the efficacy and safety of the two regimens and to determine which is more promising as a test arm regimen for a subsequent phase III trial. Methods: Chemotherapy-naive patients with recurrent or unresectable BTC (gallbladder [GB], intrahepatic biliary duct [IHBD], extrahepatic biliary duct [EHBD], ampulla of Vater [AV]), an ECOG PS of 0 - 1, and adequate organ function were randomly assigned to receive GS (gemcitabine: 1,000 mg/m2, iv, days 1 and 8; S-1: 60 mg/m2, p.o., days 1 - 14, every 3 weeks) or S-1 (80 mg/m2, p.o., days 1 - 28, every 6 weeks). We assumed that %1-year survival of one regimen is 30% and that of the other regimen is more than 40%. To ensure at least 85% probability of correct selection, 98 eligible pts are required. The decision rule was that the regimen with higher %1-year survival will be considered as more promising regimen. Results: From February 2009 to April 2010, 101 pts (GB, n=38; IHBD, n=35; EHBD, n=20; AV, n=8) were randomized (GS, n=51; S-1, n=50). For the GS arm and S-1 arm, %1-year survivals were 52.9% and 40.0%, the median survival time were 12.5 and 9.0 months (hazard ratio 0.86 [95%CI 0.54-1.36]; p=0.52), and the median progression-free survival time were 7.1 and 4.2 months (0.44 [0.29-0.67]; p<0.0001). Grade 3/4 hematological toxicities were more frequent in the GS arm than in the S-1 arm, (percentage in GS/S-1 arms): neutropenia, 60.8/4.0; leukocytopenia, 29.4/2.0; hemoglobin, 11.8/4.0; and thrombocytopenia, 11.8/4.0; respectively. Although two treatment-related deaths occurred in the GS arm (pneumonitis, acute myocardial infarction), other grade 3/4 non-hematological toxicities were infrequent and reversible in both arms. Conclusions: The GS arm was superior in %1-year survival to S-1. Here we consider GS to be more promising as the test arm for a subsequent phase III trial comparing with GC.

A Phase II Study of Systemic Chemotherapy with Docetaxel, Cisplatin, and S-1 (DCS) Followed by Surgery in Gastric Cancer Patients with Extensive Lymph Node Metastasis: Japan Clinical Oncology Group Study JCOG1002

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.

The History and Future of the Urologic Oncology Study Group (UOSG) of the Japan Clinical Oncology Group (JCOG)

The Urologic Oncology Study Group (UOSG) of the Japan Clinical Oncology Group was founded in 2001. At the beginning, 41 collaborative institutions participated, and the first group representative was Kenichi Tobisu, from the Shizuoka Cancer Center. In the last 10 years, three JCOG studies have been conducted. In two of them, patient registration has been closed and they are now in the follow-up period. The third study has just started registration in 2011. At present, we have not yet completed the final data analyses in any of the studies. In the meantime, however, we have performed a few retrospective analyses by collecting clinical data from each of the participating institutions, and the results were published as important Japanese data. All the activities of the investigation were supported by the Health and Labor Sciences Research Grants for Clinical Research in Japan. The UOSG encountered great difficulties in planning the prospective study, completing the sophisticated protocol and recruiting the expected number of patients. It usually took a longer time than expected to achieve the final goal. This was probably due to insufficient experience in conducting sophisticated protocol studies and immaturity in managing a study group. Now, the UOSG consists of 38 institutions and is gradually overcoming these problems. In 2011, the UOSG changed its group representative to Yoshiyuki Kakehi from Kagawa University and continues to strive to meet the challenge of becoming a more active group. In this review, we provide an overview of the history and achievements of the UOSG over the past 10 years, along with a list of participating institutions.

Phase II Study of Intensive Post-remission Chemotherapy and Stem Cell Transplantation for Adult Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma: Japan Clinical Oncology Group Study, JCOG9402

To evaluate the efficacy and safety of intensive post-remission chemotherapy for untreated patients aged 15-69 years with adult acute lymphoblastic leukemia and lymphoblastic lymphoma in a multicenter Phase II study. The chemotherapy regimen consisted of induction, post-remission and maintenance for 2 years. The primary endpoint was 5-year progression-free survival, and secondary endpoints included complete remission rate, overall survival and adverse events. Among 115 patients enrolled, 108 eligible patients [median age, 33.5 years (range, 15-69)] including 96 acute lymphoblastic leukemia and 12 lymphoblastic lymphoma were assessed. Other major characteristics were male 50%, T-cell phenotype 21%, Philadelphia chromosome 22%, B-symptom+ 35% and performance status 2/3 22%. Eighty-seven patients achieved complete remission (81%; 95% confidence interval 72-88%), while five (5%) died during the chemotherapy protocol. The median overall survival and progression-free survival were 1.8 years (95% confidence interval, 1.5-2.6) and 1.2 years (95% confidence interval, 0.8-1.6), respectively. Their 5-year overall survival and progression-free survival were 29 and 28%, respectively. The 5-year overall survival of 31 patients who underwent allogeneic (n = 19) or autologous (n = 12) stem cell transplantation during first complete response was 51%. Major non-hematologic toxicities of Grade 3 or greater were infections (21%) and pulmonary complications (6%). When compared with the investigators' previous Phase II trials, JCOG9402 improved progression-free survival and overall survival when compared with JCOG8702; however, it did not show improvement when compared with JCOG9004. Although the intensified induction and post-remission chemotherapy was feasible and 28% of the patients with adult acute lymphoblastic leukemia or lymphoblastic lymphoma achieved long-term progression-free survival, JCOG9402 did not show improvement.

The Role of Adjuvant Chemotherapy for Localized Squamous Cell Esophageal Cancer: Current Japanese Standard and the Unending Role of the Drawing Board

Esophageal cancer is the sixth most common cause of death for men and, among the various gastrointestinal malignancies, it is considered to possess a relatively high malignant potential. Major causes of the difficulties in the management of this clinical entity are largely related to its clinicopathological characteristics, particularly the high frequency of complex patterns of lymph node metastasis. As a result of intense discussion beginning approximately 30 years ago, radical esophagectomy with threefield lymphadenectomy has become established in leading institutes in Asia since the mid 1980 s. Although relatively acceptable long-term outcomes have been reported, one can claim by no means that substantial evidence of survival benefit has been proved by large-scale, randomized, controlled trials (RCT). Even in the high-volume centers in Asia, further improvement of 5-year survival rates by surgery alone appears to be extremely unlikely. Therefore, optimization of multimodal treatments for localized and resectable clinical stage II/III esophageal cancer is one of the most important topics in this field. Several clinical trials in the west have demonstrated the superiority of preoperative chemoradiation therapy compared with surgery alone. However, it must be admitted that one of the most conspicuous features, and one that in the minds of many constitutes a critical limitation of the above-mentioned western studies, has been the extremely poor outcome of the surgery-alone groups. On the other hand, Japanese surgeons believe that the relatively acceptable local tumor control by transthoracic radical esophagectomy obviates the need for preoperative radiation therapy, especially because the inevitable fibrotic changes induced by radiation would negatively affect the quality of the surgical approach. Therefore, many Asian physicians treating patients with esophageal squamous cell carcinoma hesitate to apply directly the presently available results of ‘‘Western evidence’’ to ‘‘Eastern’’ esophageal cancer, in which the environment of latter is different from the former. The Japan Clinical Oncology Group (JCOG) has conducted multicenter, multimodality, prospective, clinical trials for the treatment of esophageal cancer for more than 30 years, giving full regard to these considerations. Recently, a JCOG study (JCOG9907) demonstrated significantly better overall survival after preoperative chemotherapy with two courses of cisplatin plus 5-fluorouracil followed by surgery compared with postoperative chemotherapy for resectable cStageII/III thoracic squamous cell esophageal cancer. Since publication of the results of the JCOG9907 study, preoperative chemotherapy followed by radical esophagectomy has been accepted as the standard therapeutic approach to resectable cStage II/III esophageal cancer in Japan. On the other hand, it cannot be denied that the JCOG9907 study has aroused several controversies among some extremely knowledgeable experts who are seeking to examine and interpret the present study as much scientific rigor as possible. In a recent editorial article, Ajani et al. mentioned problems that they noted in the study design of JCOG9907. As representatives of the JCOG Esophageal Cancer Study Group, we would like to respond to their specific criticisms to encourage further understanding Society of Surgical Oncology 2012

Phase II Study of Oral Etoposide and Intravenous Irinotecan for Patients with Platinum-resistant and Taxane-pretreated Ovarian Cancer: Japan Clinical Oncology Group Study 0503

A single-arm Phase II study evaluating combination chemotherapy utilizing oral etoposide and irinotecan for platinum-resistant and taxane-pretreated ovarian cancer has started. The aim of this study is to evaluate the efficacy and safety of this regimen as a test arm regimen in a subsequent Phase III trial. Patients with platinum-resistant and taxane-pretreated ovarian cancer are given etoposide at 50 mg/m(2) p.o. from days 1 to 21 and irinotecan 70 mg/m(2) i.v. at days 1 and 15, repeated every 28 days, up to six cycles. A total of 60 patients will be enrolled at 36 institutions. The primary endpoint is response rate. The secondary endpoints include adverse events and progression-free and overall survival.

Randomized phase II trial of gemcitabine plus S-1 combination therapy versus S-1 in advanced biliary tract cancer: Results of the Japan Clinical Oncology Group study (JCOG0805).

255 Background: Gemcitabine plus cisplatin combination (GC) therapy is the standard therapy for advanced biliary tract cancer (BTC). In previous trials, gemcitabine plus S-1 combination (GS) therapy and S-1 mono-therapy had shown considerable efficacy in patients with BTC. The aim of this trial is to evaluate the efficacy and safety of the two regimens and to determine which is more promising as a test arm regimen for a subsequent phase III trial. Methods: Chemotherapy-naive patients with recurrent or unresectable BTC (gallbladder [GB], intrahepatic biliary duct [IHBD], extrahepatic biliary duct [EHBD], ampulla of Vater [AV]), an ECOG PS of 0 - 1, and adequate organ function were randomly assigned to receive GS (gemcitabine: 1000 mg/m2, iv, days 1 and 8; S-1: 60 mg/m2, p.o., days 1 - 14, every 3 weeks) or S-1 (80 mg/m2, p.o., days 1 - 28, every 6 weeks). We assumed that %1-year survival of one regimen is 30% and that of the other regimen is more than 40%. To ensure at least 85% probability of correct selection, 98 eligible pts are required. The decision rule was that the regimen with higher %1-year survival will be considered as more promising regimen. Results: From February 2009 to April 2010, 101 pts (GB, n=38; IHBD, n=35; EHBD, n=20; AV, n=8) were randomized (GS, n=51; S-1, n=50). For the GS arm and S-1 arm, %1-year survivals were 52.9% and 40.0%, the median survival time were 12.5 and 9.0 months (hazard ratio 0.86 [95%CI 0.54-1.36]; p=0.52), and the median progression-free survival time were 7.1 and 4.2 months (0.44 [0.29-0.67]; p<0.0001). Grade 3/4 hematological toxicities were more frequent in the GS arm than in the S-1 arm, (percentage in GS/S-1 arms): neutropenia, 60.8/4.0; leukocytopenia, 29.4/2.0; hemoglobin, 11.8/4.0; and thrombocytopenia, 11.8/4.0; respectively. Although two treatment-related deaths occurred in the GS arm (pneumonitis, acute myocardial infarction), other grade 3/4 non-hematological toxicities were infrequent and reversible in both arms. Conclusions: The GS arm was superior in %1-year survival to S-1. Here we consider GS to be more promising as the test arm for a subsequent phase III trial comparing with GC.