Seiichiro Yamamoto

Daily Total Physical Activity Level and Premature Death in Men and Women: Results From a Large-Scale Population-Based Cohort Study in Japan (JPHC Study)

PURPOSE The impact of daily total physical activity level on premature deaths has not been fully clarified in non-Western, relatively lean populations. We prospectively examined the association between daily total physical activity level (METs/day) and subsequent risk of all-cause mortality and mortalities from cancer, heart disease, and cerebrovascular disease. METHODS A total of 83,034 general Japanese citizens ages 45-74 years who responded to the questionnaire in 1995-1999 were followed for any cause of death through December 2005. Mutlivariate-adjusted hazard ratios were calculated with a Cox proportional hazards model controlling for potential confounding factors. RESULTS During follow-up, a total of 4564 deaths were recorded. Compared with subjects in the lowest quartile, increased daily total physical activity was associated with a significantly decreased risk of all-cause mortality in both sexes (hazard ratios for the second, third, and highest quartiles were: men, 0.79, 0.82, 0.73 and women, 0.75, 0.64, 0.61, respectively). The decreased risk was observed regardless of age, frequency of leisure-time sports or physical exercise, or obesity status, albeit with a degree of risk attenuation among those with a high body mass index. A significantly decreased risk was similarly observed for death from cancer and heart disease in both sexes, and from cerebrovascular disease in women. CONCLUSION Greater daily total physical activity level, either from occupation, daily life, or leisure time, may be of benefit in preventing premature death.

Epidermal Growth Factor Receptor Gene Mutations and Increased Copy Numbers Predict Gefitinib Sensitivity in Patients With Recurrent Non–Small-Cell Lung Cancer

PURPOSE To evaluate epidermal growth factor receptor (EGFR) mutations and copy number as predictors of clinical outcome in patients with non-small-cell lung cancer (NSCLC) receiving gefitinib. PATIENTS AND METHODS Sixty-six patients with NSCLC who experienced relapse after surgery and received gefitinib were included. Direct sequencing of exons 18 to 24 of EGFR and exons 18 to 24 of ERBB2 was performed using DNA extracted from surgical specimens. Pyrosequencing and quantitative real-time polymerase chain reaction were performed to analyze the allelic pattern and copy number of EGFR. RESULTS Thirty-nine patients (59%) had EGFR mutations; 20 patients had deletional mutations in exon 19, 17 patients had missense mutations (L858R) in exon 21, and two patients had missense mutations (G719S or G719C) in exon 18. No mutations were identified in ERBB2. Response rate (82% [32 of 39 patients] v 11% [three of 27 patients]; P < .0001), time to progression (TTP; median, 12.6 v 1.7 months; P < .0001), and overall survival (median, 20.4 v 6.9 months; P = .0001) were significantly better in patients with EGFR mutations than in patients with wild-type EGFR. Increased EGFR copy numbers (> or = 3/cell) were observed in 29 patients (44%) and were significantly associated with a higher response rate (72% [21 of 29 patients] v 38% [14 of 37 patients]; P = .005) and a longer TTP (median, 9.4 v 2.6 months; P = .038). High EGFR copy numbers (> or = 6/cell) were caused by selective amplification of mutant alleles. CONCLUSION EGFR mutations and increased copy numbers were significantly associated with better clinical outcome in gefitinib-treated NSCLC patients.

Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study

BACKGROUND The best chemotherapy regimen for metastatic gastric cancer is uncertain, but promising findings have been reported with irinotecan plus cisplatin and S-1 (tegafur, 5-chloro-2,4-dihydropyrimidine, and potassium oxonate). We aimed to investigate the superiority of irinotecan plus cisplatin and non-inferiority of S-1 compared with fluorouracil, with respect to overall survival, in patients with metastatic gastric cancer. METHODS We undertook a phase 3 open label randomised trial in 34 institutions in Japan. We enrolled patients aged 20-75 years or younger, who had histologically proven gastric adenocarcinoma, and randomly assigned them by minimisation to receive either: a continuous infusion of fluorouracil (800 mg/m(2) per day, on days 1-5) every 4 weeks (n=234); intravenous irinotecan (70 mg/m(2), on days 1 and 15) and cisplatin (80 mg/m(2), on day 1) every 4 weeks (n=236); or oral S-1 (40 mg/m(2), twice a day, on days 1-28) every 6 weeks (n=234). The primary endpoint was overall survival. Analyses were done by intention to treat. This study is registered with Clinicaltrials.gov, number NCT00142350, and with UMIN-CTR, number C000000062. FINDINGS All randomised patients were included in the primary analysis. Median overall survival was 10.8 months (IQR 5.7-17.8) for individuals assigned fluorouracil, 12.3 months (8.1-19.5) for those allocated irinotecan plus cisplatin (hazard ratio 0.85 [95% CI 0.70-1.04]; p=0.0552), and 11.4 months (6.4-21.3) for those assigned S-1 (0.83 [0.68-1.01]; p=0.0005 for non-inferiority). Three treatment-related deaths occurred in the irinotecan plus cisplatin group and one was recorded in the S-1 group. INTERPRETATION S-1 is non-inferior to fluorouracil and, in view of the convenience of an oral administration, could replace intravenous fluorouracil for treatment of unresectable or recurrent gastric cancer, at least in Asia. Irinotecan plus cisplatin is not superior to fluorouracil in this setting.

Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer : The Japan Clinical Oncology Group Study (JCOG9205)

PURPOSE To compare fluorouracil (FU) alone with FU plus cisplatin (FP) and with uracil and tegafur plus mitomycin (UFTM) for patients with advanced gastric cancer in a prospective, randomized, controlled trial. PATIENTS AND METHODS A total of 280 patients with advanced gastric cancer were randomly allocated and analyzed for survival, response, and toxicity. The survival curves were compared between groups by log-rank test on an intent-to-treat basis. RESULTS At the interim analysis, the UFTM arm showed a significantly inferior survival with higher incidences of hematologic toxic effects than did control arm FU alone, and the registration to UFTM was terminated. Both investigational regimens, FP and UFTM, had a significantly higher incidence of hematologic toxic effects than FU alone, although the effects were manageable. The overall response rates of the FU-alone, FP, and UFTM arms were 11%, 34%, and 9%, respectively. The median progression-free survival was 1.9 months with FU alone, 3.9 months with FP, and 2.4 months with UFTM, respectively. Although FP demonstrated a higher response rate (P <.001) and longer progression-free survival than did FU alone (P <.001), no differences in overall survival were observed between the arms. The median survival times and 1-year survival rates were 7.1 months and 28% with FU, 7.3 months and 29% with FP, and 6.0 months and 16% with UFTM, respectively. CONCLUSION Neither investigational regimen, FP nor UFTM, showed a survival advantage as compared with FU alone. FU alone will remain a reference arm in our future trial for advanced gastric cancer.

Identification of Genes Upregulated in ALK-Positive and EGFR/KRAS/ALK-Negative Lung Adenocarcinomas

Activation of the EGFR, KRAS, and ALK oncogenes defines 3 different pathways of molecular pathogenesis in lung adenocarcinoma. However, many tumors lack activation of any pathway (triple-negative lung adenocarcinomas) posing a challenge for prognosis and treatment. Here, we report an extensive genome-wide expression profiling of 226 primary human stage I-II lung adenocarcinomas that elucidates molecular characteristics of tumors that harbor ALK mutations or that lack EGFR, KRAS, and ALK mutations, that is, triple-negative adenocarcinomas. One hundred and seventy-four genes were selected as being upregulated specifically in 79 lung adenocarcinomas without EGFR and KRAS mutations. Unsupervised clustering using a 174-gene signature, including ALK itself, classified these 2 groups of tumors into ALK-positive cases and 2 distinct groups of triple-negative cases (groups A and B). Notably, group A triple-negative cases had a worse prognosis for relapse and death, compared with cases with EGFR, KRAS, or ALK mutations or group B triple-negative cases. In ALK-positive tumors, 30 genes, including ALK and GRIN2A, were commonly overexpressed, whereas in group A triple-negative cases, 9 genes were commonly overexpressed, including a candidate diagnostic/therapeutic target DEPDC1, that were determined to be critical for predicting a worse prognosis. Our findings are important because they provide a molecular basis of ALK-positive lung adenocarcinomas and triple-negative lung adenocarcinomas and further stratify more or less aggressive subgroups of triple-negative lung ADC, possibly helping identify patients who may gain the most benefit from adjuvant chemotherapy after surgical resection.

Left thoracoabdominal approach versus abdominal-transhiatal approach for gastric cancer of the cardia or subcardia: a randomised controlled trial

BACKGROUND Because of the inaccessibility of mediastinal nodal metastases, the left thoracoabdominal approach (LTA) has often been used to treat gastric cancer of the cardia or subcardia. In a randomised phase III study, we aimed to compare LTA with the abdominal-transhiatal approach (TH) in the treatment of these tumours. METHODS Between July, 1995, and December, 2003, 167 patients were enrolled from 27 Japanese hospitals and randomly assigned to TH (n=82) or LTA (n=85). The primary endpoint was overall survival, and secondary endpoints were disease-free survival, postoperative morbidity and hospital mortality, and postoperative symptoms and change of respiratory function. The projected sample size was 302. After the first interim analysis, the predicted probability of LTA having a significantly better overall survival than TH at the final analysis was only 3.65%, and the trial was closed immediately. Analysis was by intention to treat. This study is registered with , number NCT00149266. FINDINGS 5-year overall survival was 52.3% (95% CI 40.4-64.1) in the TH group and 37.9% (26.1-49.6) in the LTA group. The hazard ratio of death for LTA compared with TH was 1.36 (0.89-2.08, p=0.92). Three patients died in hospital after LTA but none after TH. Morbidity was worse after LTA than after TH. INTERPRETATION Because LTA does not improve survival after TH and leads to increased morbidity in patients with cancer of the cardia or subcardia, LTA cannot be justified to treat these tumours.

Nonrandomized comparison between definitive chemoradiotherapy and radical surgery in patients with T2–3Nany M0 squamous cell carcinoma of the esophagus

PURPOSE To compare the treatment results between radical surgery and definitive chemoradiotherapy for resectable squamous cell carcinoma of the esophagus and to identify useful clinicopathologic and biologic markers to select better treatment. METHODS AND MATERIALS Between August 1992 and April 1999, 98 consecutive patients were selected for this study; 53 were treated with chemoradiotherapy and 45 with surgery. The patients in the chemoradiotherapy group received 5-fluorouracil combined with cisplatin plus 60 Gy of radiation, and those in the surgery group received an esophagectomy with radical node dissection. Biologic markers were investigated immunohistochemically using pretreatment biopsy specimens. RESULTS The baseline clinical TNM stage was more advanced in the chemoradiotherapy group than in the surgery group. With a median follow-up period of 43 months, the 5-year survival rate was 46% in the chemoradiotherapy and 51% in the surgery group, without statistical significance (p = 0.47, log-rank test). Cox regression analysis for prognosis revealed that epidermal growth factor receptor positivity, high microvessel density, and cyclin D1 positivity yielded a low value for relative risk (0.66, 0.54, and 0.62, respectively), which favored chemoradiotherapy over surgery, without statistical significance. CONCLUSION This nonrandomized study showed a trend for the chemoradiotherapy in the treatment of esophageal carcinoma, but the results need to be confirmed by additional study.

EGFR Mutations Predict Survival Benefit From Gefitinib in Patients With Advanced Lung Adenocarcinoma: A Historical Comparison of Patients Treated Before and After Gefitinib Approval in Japan

PURPOSE This study evaluated whether the presence of epidermal growth factor receptor (EGFR) mutations is a predictive marker for survival benefit from gefitinib and/or a prognostic marker in patients with advanced lung adenocarcinoma. PATIENTS AND METHODS Overall survival (OS) was compared between patients with advanced lung adenocarcinoma who began first-line systemic therapy before and after gefitinib approval in Japan (January 1999 to July 2001 and July 2002 to December 2004, respectively). Deletional mutations in exon 19 or the L858R mutation in exon 21 of EGFR were evaluated using high-resolution melting analysis. RESULTS EGFR mutations were detected in 136 (41%) of the 330 patients included in this study. OS was significantly longer among the EGFR-mutant patients treated after gefitinib approval compared with the OS of patients treated before gefitinib approval (median survival time [MST], 27.2 v 13.6 months, respectively; P < .001), whereas no significant survival improvement was observed in patients without EGFR mutations (MST, 13.2 v 10.4 months, respectively; P = .13). A significant interaction between the presence of EGFR mutations and a survival improvement was seen (P = .045). Among patients treated before gefitinib approval, those with EGFR mutations lived longer than those without EGFR mutations (MST, 13.6 v 10.4 months, respectively; P = .034). The response rates to first-line cytotoxic chemotherapy were not significantly different between patients with and without EGFR mutations (31% v 28%, respectively; P = .50). CONCLUSION EGFR mutations significantly predict both a survival benefit from gefitinib and a favorable prognosis in patients with advanced lung adenocarcinoma.

Randomized controlled trial of laparoscopic versus open colectomy for advanced colorectal cancer

Background: After confirming a favorable outcome of laparoscopic surgery for early colorectal cancer, we conducted a randomized controlled trial to compare short-term outcomes of laparoscopic and open colectomy for advanced colorectal cancer. Methods: Fifty-nine patients with T2 or T3 colorectal cancer were randomized to undergo laparoscopic (n = 29) or open (n = 30) colectomy. Median follow-up was 20 months (range, 6–34 months). Results: Operative time was longer (p <0.0001) and blood loss (p = 0.0034) and postoperative analgesic requirement were less in the laparoscopic group than in the open group. An earlier return of bowel motility and earlier discharge from the hospital (p = 0.0164) were observed after laparoscopic surgery. Serum C-reactive protein levels on postoperative days 1 (p <0.0001) and 4 (p = 0.0039) were lower in the laparoscopic group than in the open group. Postoperative complications did not differ between the two groups. Conclusion: Laparoscopic surgery for advanced colorectal cancer is feasible, with favorable short-term outcome.

Randomized Trial of Adjuvant Chemotherapy With Mitomycin, Fluorouracil, and Cytosine Arabinoside Followed by Oral Fluorouracil in Serosa-Negative Gastric Cancer: Japan Clinical Oncology Group 9206–1

PURPOSE To evaluate the survival benefit of adjuvant chemotherapy after curative resection in serosa-negative gastric cancer patients (excluding patients who were T1N0), we conducted a multicenter phase III clinical trial in which 13 cancer centers in Japan participated. PATIENTS AND METHODS From January 1993 to December 1994, 252 patients were enrolled into the study and allocated randomly to adjuvant chemotherapy or surgery alone. The chemotherapy comprised intravenous mitomycin 1.33 mg/m2, fluorouracil (FU) 166.7 mg/m2, and cytarabine 13.3 mg/m2 twice weekly for the first 3 weeks after surgery, and oral FU 134 mg/m2 daily for the next 18 months for a total dose of 67 g/m2. The primary end point was relapse-free survival. Overall survival and the site of recurrence were secondary end points. RESULTS Ninety-eight percent of patients underwent gastrectomy with D2 or greater lymph node dissection. There were no treatment-related deaths and few serious adverse events. There was no significant difference in relapse-free and overall survival between the arms (5-year relapse-free survival 88.8% chemotherapy v 83.7% surgery alone; P =.14 and 5-year survival 91.2% chemotherapy v 86.1% surgery alone; P =.13, respectively). Nine patients (7.1%) in the chemotherapy arm and 17 patients (13.8%) in the surgery-alone arm had cancer recurrence. CONCLUSION There was no statistically significant relapse-free or overall survival benefit with this adjuvant chemotherapy for patients with macroscopically serosa-negative gastric cancer after curative resection, and there was no statistical difference between the two arms relating to the types of cancer recurrence. We do not recommend adjuvant chemotherapy with this regimen for this population in clinical practice.