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The combination of platinum-based chemotherapy and an antibody to PD-1 or to its ligand PD-L1, with or without an antibody to CTLA-4, has improved the survival of individuals with metastatic non-small-cell lung cancer (NSCLC). However, no randomised controlled trial has evaluated the survival benefit of adding a CTLA-4 inhibitor to platinum-based chemotherapy plus a PD-1 or PD-L1 inhibitor.

Although segmentectomy was better than lobectomy in terms of overall survival for patients with non-small-cell lung cancer (NSCLC) with a pure-solid tumour appearance on thin-section CT in the open-label, multicentre, randomised, controlled, phase 3 JCOG0802/WJOG4607L trial, the reasons why segmentectomy was associated with better overall survival were unclear. We aimed to compare the survival, cause of death, and recurrence patterns after segmentectomy versus lobectomy in trial participants with NSCLC with a pure-solid appearance

Although segmentectomy is a widely used surgical procedure, lobectomy is the standard procedure for resectable non-small-cell lung cancer (NSCLC). This study aimed to evaluate the efficacy and safety of segmentectomy for NSCLC up to 3 cm in size, including ground-glass opacity (GGO) and predominant GGO.

Lobectomy is the standard of care for early-stage non-small-cell lung cancer (NSCLC). The survival and clinical benefits of segmentectomy have not been investigated in a randomised trial setting. We aimed to investigate if segmentectomy was non-inferior to lobectomy in patients with small-sized peripheral NSCLC.

The JCOG0802/WJOG4607L trial revealed superior overall survival in segmentectomy compared with lobectomy for small-peripheral NSCLC. Nevertheless, locoregional relapse (LR) is a major issue for segmentectomy. An ad hoc supplementary analysis aimed to determine the risk factors for LR and the degree of advantages of segmentectomy on the basis of primary tumor sites.

We investigated the superiority of docetaxel plus cisplatin and S-1 compared with cisplatin and S-1 in chemotherapy-naive patients with advanced gastric cancer.

Postoperative adjuvant chemotherapy with S-1 for 1 year (corresponding to eight courses) is standard care for stage II gastric cancer. Whether the duration of S-1 could be shortened to 6 months (corresponding to four courses) without worsening survival is unclear. The aim of this study was to investigate the non-inferiority of four courses of S-1 compared with eight courses of S-1 for patients with stage II gastric cancer.

Adjuvant chemotherapy with oral fluoropyrimidine alone after D3/D2 lymph node dissection improves disease-free survival and overall survival in patients with stage III colon cancer. Adjuvant S-1 has been shown to be non-inferior to uracil and tegafur plus leucovorin in terms of disease-free survival. This study aims to confirm the non-inferiority of S-1 compared with capecitabine as adjuvant treatment in patients with stage III colorectal cancer.

The performance of scientifically and ethically valid prospective clinical trials is the only means by which to obtain reliable clinical evidence that can improve clinical practice and thus the outcome of patients with lung cancer. The efficacy of treatment for advanced lung cancer remains limited; many cooperative study groups for lung cancer have been established in Japan since 1990s, and they have completed several landmark investigator-initiated clinical trials. This review highlights eight active Japanese cooperative study groups for lung cancer and summarizes their achievements made through clinical trials. In addition to their benefits, the existence of multiple study groups for a single disease such as lung cancer presents several challenges including the provision of infrastructure to ensure the scientific integrity of trial results, the unnecessary duplication of effort and the wasting of limited resources, and the accrual and completion of large-scale phase III trials in the shortest possible time. Collaboration among Japanese cooperative groups has recently increased in order to overcome these challenges. Although institutional barriers to the performance of such large intergroup trials remain, further harmonization and collaboration among cooperative groups will be vital in allowing Japanese investigators to make further important contributions for the development of new lung cancer therapies.

The genetic polymorphisms of aldehyde dehydrogenase-2 (ALDH2), alcohol dehydrogenase-2 (ADH2), ADH3, and glutathione S-transferase M1 (GSTM1) influence the metabolism of alcohol and other carcinogens. The ALDH2*1/2*2 genotype, which encodes inactive ALDH2, and ADH2*1/2*1, which encodes the low-activity form of ADH2, enhance the risk for esophageal cancer in East Asian alcoholics. This case–control study of whether the enzyme-related vulnerability for esophageal cancer can be extended to a general population involved 234 Japanese men with esophageal squamous cell carcinoma and 634 cancer-free Japanese men who received annual health checkups. The GSTM1 genotype was not associated with the risk for this cancer. Light drinkers (1–8.9 units/week) with ALDH2*1/2*2 had an esophageal cancer risk 5.82 times that of light drinkers with ALDH2*1/2*1 (reference category), and their risk was similar to that of moderate drinkers (9–17.9 units/week) with ALDH2*1/2*1 (odds ratio = 5.58). The risk for moderate drinkers with ALDH2*1/2*2 (OR = 55.84) exceeded that for heavy drinkers (18+ units/week) with ALDH2*1/2*1 (OR = 10.38). Similar increased risks were observed for those with ADH2*1/2*1. A multiple logistic model including ALDH2, ADH2, and ADH3 genotypes showed that the ADH3 genotype does not significantly affect the risk for esophageal cancer. For individuals with both ALDH2*1/2*2 and ADH2*1/2*1, the risk of esophageal cancer was enhanced in a multiplicative fashion (OR = 30.12), whereas for those with either ALDH2*1/2*2 or ADH2*1/2*1 alone the ORs were 7.36 and 4.11. In comparison with the estimated population-attributable risks for preference for strong alcoholic beverages (30.7%), smoking (53.6%) and for lower intake of green and yellow vegetables (25.7%) and fruit (37.6%), an extraordinarily high proportion of the excessive risk for esophageal cancer in the Japanese males can be attributed to drinking (90.9%), particularly drinking by persons with inactive heterozygous ALDH2 (68.5%). Education regarding these risky conditions in connection with ALDH2 and ADH2 is vitally important in a new strategic approach aimed at preventing esophageal cancer in East Asians.

The genetic polymorphisms of aldehyde dehydrogenase-2 (ALDH2), alcohol dehydrogenase-2 (ADH2), ADH3, and glutathione S-transferase M1 (GSTM1) influence the metabolism of alcohol and other carcinogens. The ALDH2*1/2*2 genotype, which encodes inactive ALDH2, and ADH2*1/2*1, which encodes the low-activity form of ADH2, enhance the risk for esophageal cancer in East Asian alcoholics. This case-control study of whether the enzyme-related vulnerability for esophageal cancer can be extended to a general population involved 234 Japanese men with esophageal squamous cell carcinoma and 634 cancer-free Japanese men who received annual health checkups. The GSTM1 genotype was not associated with the risk for this cancer. Light drinkers (1-8.9 units/week) with ALDH2*1/2*2 had an esophageal cancer risk 5.82 times that of light drinkers with ALDH2*1/2*1 (reference category), and their risk was similar to that of moderate drinkers (9-17.9 units/week) with ALDH2*1/2*1 (odds ratio = 5.58). The risk for moderate drinkers with ALDH2*1/2*2 (OR = 55.84) exceeded that for heavy drinkers (18+ units/week) with ALDH2*1/2*1 (OR = 10.38). Similar increased risks were observed for those with ADH2*1/2*1. A multiple logistic model including ALDH2, ADH2, and ADH3 genotypes showed that the ADH3 genotype does not significantly affect the risk for esophageal cancer. For individuals with both ALDH2*1/2*2 and ADH2*1/2*1, the risk of esophageal cancer was enhanced in a multiplicative fashion (OR = 30.12), whereas for those with either ALDH2*1/2*2 or ADH2*1/2*1 alone the ORs were 7.36 and 4.11. In comparison with the estimated population-attributable risks for preference for strong alcoholic beverages (30.7%), smoking (53.6%) and for lower intake of green and yellow vegetables (25.7%) and fruit (37.6%), an extraordinarily high proportion of the excessive risk for esophageal cancer in the Japanese males can be attributed to drinking (90.9%), particularly drinking by persons with inactive heterozygous ALDH2 (68.5%). Education regarding these risky conditions in connection with ALDH2 and ADH2 is vitally important in a new strategic approach aimed at preventing esophageal cancer in East Asians.

Background:Mucosal iodine staining is known to improve the endoscopic visualization of esophageal squamous dysplasia and cancer. However, it often causes mucosal irritation leading to retrosternal discomfort. The clinical usefulness of sodium thiosulfate solution (STS) for easing symptoms induced by mucosal staining with Lugol's solution was evaluated in this study. Methods:One hundred twenty healthy men over 50 years of age were enrolled in the study. They each underwent esophagogastroscopy including the spraying of Lugol's iodine solution (10 mL) on the mid and distal esophagus and were subsequently randomized into three groups: (I) no treatment (n = 40), (II) spraying of 20 mL of aluminum-magnesium hydroxide gel (Maalox) by means of endoscopic catheter (n = 40), and (III) spraying of 20 mL of 5% sodium thiosulfate solution by means of endoscopic catheter (n = 40). An hour after the endoscopic examination the subjects were asked to complete a questionnaire that addressed adverse symptoms induced by Lugol's iodine staining. Results:Sodium thiosulfate solution spray substantially reduced adverse symptoms that lasted more than 30 minutes after chromoendoscopy, compared with the no-treatment group. There was no significant difference in the proportion of subjects with symptoms between the Maalox and no-treatment groups. Cost of sodium thiosulfate solution spray per use was $0.15 (15 yen). Conclusions:Sodium thiosulfate solution is recommended for routine use after Lugol's staining. (Gastrointest Endosc 2001;53:199-202).

Background:The main form of cytotoxic treatment for multiple myeloma (MM) is conventional dose chemotherapy at present.Method:Between November 1989 and December 1991, a multicenter phase II study of alternating conventional dose combination chemotherapy (CCT) with COP (cyclophosphamide, vincristine, prednisone) and MP (melphalan and prednisone) to evaluate its clinical usefulness for overt MM patients was conducted by the Lymphoma Study Group of the Japan Clinical Oncology Group (JCOG).Results:Eighty-one previously untreated patients were enrolled in the study. For 69 eligible patients, the response rate was 50.7% [95% confidence interval (CI) 38.4–63.0%]. The median survival time was 38.5 (95% CI 32.0–44.4) months. The survival rate at 3 and 5 years was 50.7 and 27.3%, respectively. Grade 4 toxicity by the criteria of the World Health Organization consisted of anemia in eight patients, leucocytopenia in three, cardiac in one and hepatic in two, but there was no treatment-related death.Conclusion:The COP—MP regimen for overt MM is thought to be one of the effective CCTs according to the results of the present phase II study.

Background:Patients with acute lymphocytic leukemia (ALL) and those with lymphoblastic lymphoma (LBL) have overlapping clinical and immunophenotypic features and they have been treated with the same or very similar chemotherapy regimens. The goal of this multi-institutional phase II trial was to evaluate the therapeutic efficacy of a short-term, six-drug chemotherapy regimen for adult patients with untreated ALL or LBL.Methods:Forty-six eligible patients, 41 with ALL and five with LBL, were treated with a short-term (planned total therapy duration; 36–38 weeks), simplified chemotherapy program; two courses of VEPA-L (vincristine, cyclophosphamide, prednisolone, doxorubicin, l-asparaginase plus intrathecal methotrexate and prednisolone) followed by four courses of M-VEPA (methotrexate plus VEPA), without the traditional maintenance therapy using daily 6-mercaptopurine and weekly methotrexate.Results:Thirty-six (78%; 95% confidence interval 64–89%) of the 46 eligible patients achieved complete remission (CR). Among the 36 patients who achieved CR, four (11%) died of treatment complications, 26 (72%) relapsed and six (17%) remain alive in continuous CR. The median survival for all 46 eligible patients is 14 months and the median disease-free survival (DFS) for the 36 patients who achieved CR is 11 months. The estimate of the proportion of survival at 7 years of all 46 eligible patients is 15% at a median follow-up time of 96 months and that of DFS of the 36 patients achieving CR is 17% at a median follow-up time of 93 months. Subgroup analysis showed that an elevated serum C-reactive protein (CRP) level, age of 30 years or older, the presence of B-symptom and T-cell phenotype were likely to be associated with shortened survival. Although the observed CR rate (78%) is within the range of satisfaction, the long-term survival rate (15%) is inferior to those of published programs incorporating maintenance therapy.Conclusions:A fraction of adult patients with ALL or LBL are curable with a short-term, six-drug chemotherapy regimen. However, this simplified therapy of shorter duration cannot be recommended.

As the geriatric population is growing, it is increasingly important to be familiar with chemotherapy for the elderly. Age-related changes in pharmacokinetics are documented for doxorubicin, etoposide, ifosfamide, daunorubicin, mitomycin, cisplatin and methotrexate. The hematological toxicity of most standard-dose chemotherapy is not affected by age in patients with normal organic functions and good performance status, although increased toxicity with aging is suggested in the use of actinomycin-D, etoposide, vinblastin, methotrexate, methyl-CCNU, doxorubicin and mitomycin, and in dose-intensive chemotherapy. Among non-hematological toxicities, only doxorubicin-induced cardiomyopathy and bleomycin-induced pulmonary toxicity are demonstrated to be accelerated in the elderly. There is no evidence that advanced age decreases the efficacy of chemotherapy for tumors, except for Hodgkin's disease and acute leukemia. These results suggest that advanced chronological age alone is not always associated with severe toxicity and poor prognosis, and that many elderly patients with cancer will benefit from chemotherapy. To answer questions regarding the optimal chemotherapy regimen, dose and intensity in this population, the influence of age should be analyzed in a multivariate approach in future studies.

The Japan Clinical Oncology Group (JCOG) is a cooperative oncology group with the aims of conducting, developing, coordinating and stimulating clinical research in Japan on the treatment of cancer and related problems. The purpose of JCOG is to establish and improve the standard of cancer treatment, mainly in solid cancer, through the testing of new therapeutic regimens or combined modalities, using drugs that are newly-approved or already commercially available. Research sponsored by JCOG is accomplished mainly through the execution of large, prospective, randomized, multicenter, clinical trials. In this way, JCOG facilitates the passage of new clinical trial discoveries into state-of-the-art treatment.

The paper gives guidelines to authors on the use of statistics, including statistical considerations when designing studies. Information on this article plus a list of other recommended books is available on the World Wide Web (http://wwwinfo.ncc.go.jp/jjco/) in Japanese as well as English.

A study was conducted to examine whether or not the histopathological therapeutic effects of preoperative chemotherapy could be useful for determining prognosis in women with locally advanced breast cancer. The patients were 37 women with locally advanced breast cancer who received preoperative chemotherapy between 1977 and 1987. The histological grade of malignancy (HGM) and histopathological therapeutic effects of chemotherapy (TEf) were examined in resected specimens. Patients with HGM 3 showed a poorer 10-year overall survival (38%) than those with HGM 1 or 2 (62%). Patients showing a better histopathological response (TEf 1b plus 2) had a poorer 10-year overall survival (20%) than those with a poorer response (TEf 0 plus 1a) (60%). Therapeutic effects were significantly related to histological grade, nuclear atypia and mitotic index (P=0.03, 0.005 and 0.002, respectively). Histopathological therapeutic effects were not directly correlated with patient prognosis. Cox proportional hazard regression analysis revealed that mitotic index was the most significant prognostic factor related to 10-year overall survival.

An early phase II study was conducted to evaluate the anti-tumor effects and toxicity of etoposide in patients with unresectable or relapsed advanced gastric cancer. From April 1991 to December 1992, 13 patients were enrolled into this study; one was subsequently considered ineligible. Before enrollment, all the patients had been treated with chemotherapy which did not include etoposide. Etoposide (100 mg/m2/day) was administered as an intravenous infusion over 120 min for five consecutive days and was repeated every four weeks. Seven patients received one course of this therapy and the remaining five received two. No patient showed a complete or a partial response. No change and progressive disease were observed in three and nine patients, respectively. The clinical toxicities (grade 3–4; WHO) of leukocytopenia, anemia and alopecia occurred in 50, 42, and 42% of the patients, respectively. We conclude that this dose of etoposide administered according to the present schedule is ineffective in previously treated patients with advanced gastric cancer.

Maruyama: Takeda: Honoraria; Janssen: Honoraria. Tobinai:Chugai Pharma: Research Funding; Ono Pharmaceutical: Research Funding; Abbvie: Research Funding; Takeda: Honoraria, Research Funding; Kyowa Hakko Kirin: Research Funding; Eisai: Honoraria, Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding; Celgene: Research Funding; HUYA Bioscience: Honoraria; Mundipharma KK: Honoraria, Research Funding; SERVIER: Research Funding; Zenyaku Kogyo: Honoraria; GlaxoSmithKline: Research Funding; Daiichi Sankyo Co., Ltd.: Consultancy. Tsukasaki:Daiichi Sankyo Co., Ltd.: Consultancy; Takeda: Research Funding.

Introduction:The International Workshop Criteria (IWC) has been used for response evaluation in malignant lymphoma since 1999. In contrast, the Response Evaluation Criteria in Solid Tumors (RECIST) has been used for most solid tumors since 2000. The IWC is more complicated than RECIST, partly because it requires calculating the sum of the product of bidimensional diameters of the target lesions, whereas RECIST is based on unidimensional assessment of target lesions. If RECIST can be demonstrated to be more valid and precise than the IWC for malignant lymphoma, RECIST would be the substitute for IWC even for malignant lymphoma. The objective of this study was to evaluate whether RECIST could be substituted for the IWC using data from the JCOG0203 trial, a phase II/III study of R-CHOP-21 versus R-CHOP-14 in untreated, advanced-stage indolent B-cell lymphoma where the superiority of R-CHOP-14 in progression-free survival (PFS) was not shown (hazard ratio [HR], 0.92; 95% CI, 0.68-1.25; one-sided log-rank p = 0.30) (J Clin Oncol 2011;29:3990-8).