Naoki Ishizuka

Phase I/II Study of Concurrent Chemoradiotherapy for Localized Nasal Natural Killer/T-Cell Lymphoma: Japan Clinical Oncology Group Study JCOG0211

PURPOSE To explore a more effective treatment for localized nasal natural killer (NK)/T-cell lymphoma, we conducted a phase I/II study of concurrent chemoradiotherapy. PATIENTS AND METHODS Treatments comprised concurrent radiotherapy (50 Gy) and 3 courses of dexamethasone, etoposide, ifosfamide, and carboplatin (DeVIC). Patients with a newly diagnosed stage IE or contiguous IIE disease with cervical node involvement and a performance status (PS) of 0 to 2 were eligible for enrollment. The primary end point of the phase II portion was a 2-year overall survival in patients treated with the recommended dose. RESULTS Of the 33 patients enrolled, 10 patients were enrolled in the phase I portion and a two thirds dose of DeVIC was established as the recommended dose. Twenty-seven patients (range, 21 to 68; median, 56 years) treated with the recommended dose showed the following clinical features: male:female, 17:10; stage IE, 18; stage IIE, 9; B symptoms present, 10; elevated serum lactate dehydrogenase, 5; and PS 2, 2. With a median follow-up of 32 months, the 2-year overall survival was 78% (95% CI, 57% to 89%). This compared favorably with the historical control of radiotherapy alone (45%). Of the 26 patients assessable for a response, 20 (77%) achieved a complete response, with one partial response. The overall response rate was 81%. The most common grade 3 nonhematologic toxicity was mucositis related to radiation (30%). No treatment-related deaths were observed. CONCLUSION Concurrent chemoradiotherapy using multidrug resistance-nonrelated agents and etoposide is a safe and effective treatment for localized nasal NK/T-cell lymphoma and warrants further investigation.

Low-dose aspirin for primary prevention of cardiovascular events in japanese patients 60 years or older with atherosclerotic risk factors: A randomized clinical trial

IMPORTANCE Prevention of atherosclerotic cardiovascular diseases is an important public health priority in Japan due to an aging population. OBJECTIVE To determine whether daily, low-dose aspirin reduces the incidence of cardiovascular events in older Japanese patients with multiple atherosclerotic risk factors. DESIGN, SETTING, AND PARTICIPANTS The Japanese Primary Prevention Project (JPPP) was a multicenter, open-label, randomized, parallel-group trial. Patients (N = 14,464) were aged 60 to 85 years, presenting with hypertension, dyslipidemia, or diabetes mellitus recruited by primary care physicians at 1007 clinics in Japan between March 2005 and June 2007, and were followed up for up to 6.5 years, with last follow-up in May 2012. A multidisciplinary expert panel (blinded to treatment assignments) adjudicated study outcomes. INTERVENTIONS Patients were randomized 1:1 to enteric-coated aspirin 100 mg/d or no aspirin in addition to ongoing medications. MAIN OUTCOMES AND MEASURES Composite primary outcome was death from cardiovascular causes (myocardial infarction, stroke, and other cardiovascular causes), nonfatal stroke (ischemic or hemorrhagic, including undefined cerebrovascular events), and nonfatal myocardial infarction. Secondary outcomes included individual end points. RESULTS The study was terminated early by the data monitoring committee after a median follow-up of 5.02 years (interquartile range, 4.55-5.33) based on likely futility. In both the aspirin and no aspirin groups, 56 fatal events occurred. Patients with an occurrence of nonfatal stroke totaled 114 in the aspirin group and 108 in the no aspirin group; of nonfatal myocardial infarction, 20 in the aspirin group and 38 in the no aspirin group; of undefined cerebrovascular events, 3 in the aspirin group and 5 in the no aspirin group. The 5-year cumulative primary outcome event rate was not significantly different between the groups (2.77% [95% CI, 2.40%-3.20%] for aspirin vs 2.96% [95% CI, 2.58%-3.40%] for no aspirin; hazard ratio [HR], 0.94 [95% CI, 0.77-1.15]; P = .54). Aspirin significantly reduced incidence of nonfatal myocardial infarction (0.30 [95% CI, 0.19-0.47] for aspirin vs 0.58 [95% CI, 0.42-0.81] for no aspirin; HR, 0.53 [95% CI, 0.31-0.91]; P = .02) and transient ischemic attack (0.26 [95% CI, 0.16-0.42] for aspirin vs 0.49 [95% CI, 0.35-0.69] for no aspirin; HR, 0.57 [95% CI, 0.32-0.99]; P = .04), and significantly increased the risk of extracranial hemorrhage requiring transfusion or hospitalization (0.86 [95% CI, 0.67-1.11] for aspirin vs 0.51 [95% CI, 0.37-0.72] for no aspirin; HR, 1.85 [95% CI, 1.22-2.81]; P = .004). CONCLUSIONS AND RELEVANCE Once-daily, low-dose aspirin did not significantly reduce the risk of the composite outcome of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction among Japanese patients 60 years or older with atherosclerotic risk factors. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00225849.

Genotype-directed, dose-finding study of irinotecan in cancer patients with UGT1A1*28 and/or UGT1A1*6 polymorphisms.

Irinotecan‐induced severe neutropenia is associated with homozygosity for the UGT1A1*28 or UGT1A1*6 alleles. In this study, we determined the maximum‐tolerated dose (MTD) of irinotecan in patients with UGT1A1 polymorphisms. Patients who had received chemotherapy other than irinotecan for metastatic gastrointestinal cancer were enrolled. Patients were divided into three groups according to UGT1A1 genotypes: wild‐type (*1/*1); heterozygous (*28/*1, *6/*1); or homozygous (*28/*28, *6/*6, *28/*6). Irinotecan was given every 2 weeks for two cycles. The wild‐type group received a fixed dose of irinotecan (150 mg/m2) to serve as a reference. The MTD was guided from 75 to 150 mg/m2 by the continual reassessment method in the heterozygous and homozygous groups. Dose‐limiting toxicity (DLT) and pharmacokinetics were evaluated during cycle 1. Of 82 patients enrolled, DLT was assessable in 79 patients (wild‐type, 40; heterozygous, 20; and homozygous, 19). Dose‐limiting toxicity occurred in one patient in the wild‐type group, none in the heterozygous group, and six patients (grade 4 neutropenia) in the homozygous group. In the homozygous group, the MTD was 150 mg/m2 and the probability of DLT was 37.4%. The second cycle was delayed because of neutropenia in 56.3% of the patients given the MTD. The AUC0–24 h of SN‐38 was significantly greater (P < 0.001) and more widely distributed in the homozygous group. Patients homozygous for the UGT1A1*28 or UGT1A1*6 allele can receive irinotecan in a starting dose of 150 mg/m2, but many required dose reductions or delayed treatment in subsequent cycles. UMIN Clinical Trial Registration number: UMIN000000618. (Cancer Sci 2011; 102: 1868–1873)

A community intervention trial of multimodal suicide prevention program in Japan: A Novel multimodal Community Intervention program to prevent suicide and suicide attempt in Japan, NOCOMIT-J

BackgroundTo respond to the rapid surge in the incidence of suicide in Japan, which appears to be an ongoing trend, the Japanese Multimodal Intervention Trials for Suicide Prevention (J-MISP) have launched a multimodal community-based suicide prevention program, NOCOMIT-J. The primary aim of this study is to examine whether NOCOMIT-J is effective in reducing suicidal behavior in the community.Methods/DesignThis study is a community intervention trial involving seven intervention regions with accompanying control regions, all with populations of statistically sufficient size. The program focuses on building social support networks in the public health system for suicide prevention and mental health promotion, intending to reinforce human relationships in the community. The intervention program components includes a primary prevention measures of awareness campaign for the public and key personnel, secondary prevention measures for screening of, and assisting, high-risk individuals, after-care for individuals bereaved by suicide, and other measures. The intervention started in July 2006, and will continue for 3.5 years. Participants are Japanese and foreign residents living in the intervention and control regions (a total of population of 2,120,000 individuals).DiscussionThe present study is designed to evaluate the effectiveness of the community-based suicide prevention program in the seven participating areas.Trial registrationUMIN Clinical Trials Registry (UMIN-CTR) UMIN000000460.

Assertive case management versus enhanced usual care for people with mental health problems who had attempted suicide and were admitted to hospital emergency departments in Japan (ACTION-J): a multicentre, randomised controlled trial

BACKGROUND Non-fatal suicide attempt is the most important risk factor for later suicide. Emergency department visits for attempted suicide are increasingly recognised as opportunities for intervention. However, no strong evidence exists that any intervention is effective at preventing repeated suicide attempts. We aimed to investigate whether assertive case management can reduce repetition of suicide attempts in people with mental health problems who had attempted suicide and were admitted to emergency departments. METHODS In this multicentre, randomised controlled trial in 17 hospital emergency departments in Japan, we randomly assigned people aged 20 years and older with mental health problems who had attempted suicide to receive either assertive case management (based on psychiatric diagnoses, social risks, and needs of the patients) or enhanced usual care (control), using an internet-based randomisation system. Interventions were provided until the end of the follow-up period (ie, at least 18 months and up to 5 years). Outcome assessors were masked to group allocation, but patients and case managers who provided the interventions were not. The primary outcome was the incidence of first recurrent suicidal behaviour (attempted suicide or completed suicide); secondary outcomes included completed suicide and all-cause mortality. This study is registered at ClinicalTrials.gov (NCT00736918) and UMIN-CTR (C000000444). FINDINGS Between July 1, 2006, and Dec 31, 2009, 914 eligible participants were randomly assigned, 460 to the assertive case management group and 456 to the enhanced usual care group. We noted no significant difference in incidence of first recurrent suicidal behaviour between the assertive case management group and the enhanced usual care group over the full study period (log-rank p=0·258). Because the proportional hazards assumption did not hold, we did ad-hoc analyses for cumulative incidence of the primary outcome at months 1, 3, 6, 12, and 18 after randomisation, adjusting for multiplicity with the Bonferroni method. Assertive case management significantly reduced the incidence of first recurrent suicidal behaviour up to the 6-month timepoint (6-month risk ratio 0·50, 95% CI 0·32-0·80; p=0·003), but not at the later timepoints. Prespecified subgroup analyses showed that the intervention had a greater effect in women (up to 18 months), and in participants younger than 40 years and those with a history of previous suicide attempts (up to 6 months). We did not identify any differences between the intervention and control groups for completed suicide (27 [6%] of 460 vs 30 [7%] of 454, log-rank p=0·660) or all-cause mortality (46 [10%] of 460 vs 42 [9%] of 454, log-rank p=0·698). INTERPRETATION Our results suggest that assertive case management is feasible in real-world clinical settings. Although it was not effective at reducing the incidence of repetition of suicide attempts in the long term, the results of our ad-hoc analyses suggested that it was effective for up to 6 months. This finding should be investigated in future research. FUNDING The Ministry of Health, Labour, and Welfare of Japan.

Long-term follow-up of patients with unresectable locally advanced non-small cell lung cancer treated with chemoradiotherapy: A retrospective analysis of the data from the Japan Clinical Oncology Group trials (JCOG0003A)

To clarify the long‐term survival data and factors that are correlated with survival outcome of unresectable locally advanced non‐small cell lung cancer (NSCLC) following chemoradiotherapy, we analyzed patients who entered the Japan Clinical Oncology Group (JCOG) clinical trials for unresectable locally advanced NSCLC. Between October 1989 and August 1997, 240 patients (male 207, female 33; PS (performance status) 0 58, PS 1 172, PS 2 9, unknown 1; stage IIB 2, IIIA 62, IIIB 175, unknown 1) entered the 6 trials. All patients received chemotherapy and radiotherapy. The associations between survival outcome and treatment‐related factors were analyzed using Cox regression analysis. Median survival times and 5‐year survival rates in the trials were 11.9–19.7 months and 0–17.6%, respectively. Median survival time was 16.1 months and the 5‐ and 7‐year survival rates of all 240 patients were 14.4% and 12.0%, respectively. No deaths were observed 7 years after initiation of the treatment or later. For stage IIIA and IIIB patients, the 5‐year survival rates were 16.3% and 13.4%, respectively. Node status and age were significantly associated with survival, but no factors of the treatment were associated with survival of patients with unresectable locally advanced NSCLC. The present retrospective analysis showed that approximately 12% of patients with unresectable locally advanced NSCLC could be cured by various chemoradiotherapy regimens.

Rationale, design, and baseline data of the Japanese Primary Prevention Project (JPPP)—A randomized, open-label, controlled trial of aspirin versus no aspirin in patients with multiple risk factors for vascular events

BACKGROUND Prevention of atherosclerotic disease has become an important public health priority in Japan due to the aging of the population and changes in diet and lifestyle factors. METHODS The Japanese Primary Prevention Project (JPPP) is a multicenter, open-label, randomized, parallel-group trial that is evaluating primary prevention with low-dose aspirin in Japanese patients aged 60 to 85 years with hypertension, dyslipidemia, or diabetes mellitus. The study cohort will be followed for a mean of 4 years. The primary end point is a composite of death from cardiovascular causes (including fatal myocardial infarction [MI], fatal stroke, and other cardiovascular death), nonfatal stroke (ischemic or hemorrhagic), and nonfatal MI. Key secondary end points include a composite of cardiovascular death, nonfatal stroke, nonfatal MI, transient ischemic attack, angina pectoris, or arteriosclerotic disease requiring surgery or intervention; each component of the primary end point; noncerebrovascular and noncardiovascular death; and extracranial hemorrhage requiring transfusion or hospitalization. End point assessment is done by a central adjudication committee that is blinded to treatment assignments. RESULTS Enrollment began in March 2005 and was completed in June 2007. A total of 14,466 patients were randomly allocated to receive enteric-coated aspirin, 100 mg/d, or no aspirin. At randomization, the study cohort had a mean (SD) age of 70.6 (6.2) years; 57.8% were women, 85.0% had hypertension, 71.7% had dyslipidemia, and 33.9% had diabetes. In the study cohort, 80.4% of patients had > or =3 risk factors. CONCLUSION The JPPP is the largest primary prevention trial of aspirin in a Japanese population that is investigating whether the benefit of aspirin in reducing risk of vascular events outweighs any bleeding risk in elderly patients with multiple risk factors.

A Randomized Controlled Trial Investigating the Survival Benefit of Dose-Intensified Multidrug Combination Chemotherapy (LSG9) for Intermediate- or High-Grade Non-Hodgkin's Lymphoma : Japan Clinical Oncology Group Study 9002

The effect of enhancing the dose intensity (DI) of the key drugs in multidrug combination chemotherapy for malignant lymphoma is uncertain. We investigated the survival benefit of dose-intensified multidrug combination chemotherapy for intermediate- or high-grade non-Hodgkin’s lymphoma (NHL). Patients without any prior chemotherapy were randomly assigned either to dose-intensified multidrug combination chemotherapy, LSG9 (VEPA-B/FEPP-AB/M-FEPA, treated 3 times every 10 weeks for 28 weeks total), or to control-arm combination chemotherapy, mLSG4 (VEPA-B/FEPP-B/M-FEPA, treated 4 times every 14 weeks for 54 weeks total). The planned DI of doxorubicin and cyclophosphamide were 1.96 and 1.47 times higher, respectively, in LSG9 than in mLSG4. Overall survival, complete response (CR) rate, and toxicities were evaluated. The 447 patients (230 for LSG9 and 217 for mLSG4) were enrolled between February 1991 and March 1995.The 5-year overall survival rates were 56.8% for LSG9 patients and 55.1% for mLSG4 patients (log-rank P =.42).The rates for CR plus uncertain CR were 70.0% for LSG9 and 64.5% for mLSG4. The toxicities of both regimens were similar and tolerable. The median actual DI of doxorubicin and cyclophosphamide were 1.56 and 1.17 times higher, respectively, in LSG9 than in mLSG4. Compared with the control regimen mLSG4, the dose-intensified regimen LSG9 did not show significant survival benefit. An increase in the DI of doxorubicin in multidrug combination chemotherapy did not improve the survival of patients with intermediate- or high-grade NHL.

Glucocorticoid Therapy and the Risk of Infection in Patients With Newly Diagnosed Autoimmune Disease.

AbstractGlucocorticoid (GC) therapy is associated with the risk of life-threatening adverse events in patients with autoimmune disease. To determine accurately the incidence and predictors of GC-related adverse events during initial GC treatment, we conducted a cohort study. Patients with autoimmune disease who were initially treated with GCs in Japan National Hospital Organization (NHO) hospitals were enrolled. Cox proportional hazard regression was used to determine the independent risks for GC-related serious adverse events and mortality. Survival was analyzed according to the Kaplan-Meier method and was assessed with the log-rank test.The 604 patients had a total follow-up of 1105.8 person-years (mean, 1.9 year per patient). One hundred thirty-six patients had at least 1 infection with objective confirmation, and 71 patients had serious infections. Twenty-two cardiovascular events, 55 cases of diabetes, 30 fractures, 23 steroid psychosis events, and 4 avascular bone necrosis events occurred during the follow-up period. The incidence of serious infections was 114.8 (95% confidence interval, 95.7–136.6) per 1000 person-years. After adjustment for covariates, the following independent risk factors for serious infection were found: elderly age (hazard ratio [HR], 1.25/10-yr age increment; p = 0.016), presence of interstitial lung disease (HR, 2.01; p = 0.011), high-dose GC use (≥29.9 mg/d) (HR, 1.71; p = 0.047), and low performance status (Karnofsky score, HR, 0.98/1-score increment; p = 0.002). During the follow-up period, 73 patients died, 35 of whom died of infection. Similarly, elderly age, the presence of interstitial lung disease, and high-dose GC use were found to be significant independent risk factors for mortality. The incidence of serious and life-threatening infection was higher in patients with autoimmune disease who were initially treated with GCs. Although the primary diseases are important confounding factors, elderly age, male sex, the presence of interstitial lung diseases, high-dose GCs, and low performance status were shown to be risk factors for serious infection and mortality.Abstract Glucocorticoid (GC) therapy is associated with the risk of life-threatening adverse events in patients with autoimmune disease. To determine accurately the incidence and predictors of GC-related adverse events during initial GC treatment, we conducted a cohort study. Patients with autoimmune disease who were initially treated with GCs in Japan National Hospital Organization (NHO) hospitals were enrolled. Cox proportional hazard regression was used to determine the independent risks for GC-related serious adverse events and mortality. Survival was analyzed according to the Kaplan-Meier method and was assessed with the log-rank test. The 604 patients had a total follow-up of 1105.8 person-years (mean, 1.9 year per patient). One hundred thirty-six patients had at least 1 infection with objective confirmation, and 71 patients had serious infections. Twenty-two cardiovascular events, 55 cases of diabetes, 30 fractures, 23 steroid psychosis events, and 4 avascular bone necrosis events occurred during the follow-up period. The incidence of serious infections was 114.8 (95% confidence interval, 95.7–136.6) per 1000 person-years. After adjustment for covariates, the following independent risk factors for serious infection were found: elderly age (hazard ratio [HR], 1.25/10-yr age increment; p = 0.016), presence of interstitial lung disease (HR, 2.01; p = 0.011), high-dose GC use (≥29.9 mg/d) (HR, 1.71; p = 0.047), and low performance status (Karnofsky score, HR, 0.98/1-score increment; p = 0.002). During the follow-up period, 73 patients died, 35 of whom died of infection. Similarly, elderly age, the presence of interstitial lung disease, and high-dose GC use were found to be significant independent risk factors for mortality. The incidence of serious and life-threatening infection was higher in patients with autoimmune disease who were initially treated with GCs. Although the primary diseases are important confounding factors, elderly age, male sex, the presence of interstitial lung diseases, high-dose GCs, and low performance status were shown to be risk factors for serious infection and mortality.

Prognostic biomarkers in patients with localized natural killer/T-cell lymphoma treated with concurrent chemoradiotherapy

Concurrent chemoradiotherapy has become one of the standard management approaches for newly diagnosed localized nasal natural killer (NK)/T‐cell lymphoma (NKTCL). Few data are available on the prognostic biomarkers of NKTCL among patients treated with concurrent chemoradiotherapy. To evaluate the prognostic significance of immunophenotypic biomarkers for patients treated with concurrent chemoradiotherapy, latent membrane protein 1 (LMP1), cutaneous lymphocyte antigen (CLA) and cell origin were examined in samples from 32 patients who were enrolled in the Japan Clinical Oncology Group 0211 trial and treated with concurrent chemoradiotherapy. LMP1 and CLA were positive in 66% (19/29) and 29% (9/31) of the cases examined, respectively. The median follow‐up duration was 68 months (range, 61–94). The patients with LMP1‐positive tumors showed a better overall survival (OS) than the patients with LMP1‐negative tumors (hazard ratio, 0.240; 95% confidence interval [CI], 0.057–1.013; 80% CI, 0.093–0.615; P = 0.035). All five patients with LMP1‐negative tumors who experienced disease progression died of lymphoma, and both patients with local failure had LMP1‐negative tumors. There was no significant difference in OS according to CLA expression. A total of 27 (84%) cases were of NK‐cell origin, two were of αβ T‐cell origin and three were of γδ T‐cell origin. In contrast to those with tumors of NK‐cell origin, all five patients with NKTCL of T‐cell origin were alive without relapse at the last follow up. Our results indicate that LMP1 expression is a favorable prognostic marker and suggest that a T‐cell origin of the tumor may be a favorable prognostic marker for patients with localized NKTCL treated with concurrent chemoradiotherapy.