Study protocol of the TRICOLORE trial: a randomized phase III study of oxaliplatin-based chemotherapy versus combination chemotherapy with S-1, irinotecan, and bevacizumab as first-line therapy for metastatic colorectal cancer.

BACKGROUND: Metastatic colorectal cancer carries a poor prognosis and cannot be cured by currently available therapy. Chemotherapy designed to prolong survival and improve the quality of life (QOL) of patients is the mainstay of treatment. Standard regimens of FOLFOX/bevacizumab and CapeOX/bevacizumab can cause neurotoxicity, potentially disrupting treatment. The results of 3 phase II studies of combination therapy with S-1, irinotecan, and bevacizumab showed comparable efficacy to mFOLFOX6/bevacizumab and CapeOX/bevacizumab, without severe neurotoxicity. Therefore, the establishment and evaluation of S-1-containing irinotecan-based regimens for first-line treatment are expected to become more important. METHODS: The TRICOLORE trial is a multicenter, randomized, open-label, controlled phase III study which aims to evaluate the non-inferiority of combination therapy with S-1/irinotecan/bevacizumab (a 3-week regimen [SIRB] or 4-week regimen [IRIS/bevacizumab]) to oxaliplatin-based standard treatment (mFOLFOX6/bevacizumab or CapeOX/bevacizumab) in patients with metastatic colorectal cancer who had not previously received chemotherapy. Patients will be randomly assigned to either the control group (mFOLFOX6/bevacizumab or CapeOX/bevacizumab) or study group (SIRB or IRIS/bevacizumab). The target sample size is 450 patients. The primary endpoint is progression-free survival (PFS), and the secondary endpoints are overall survival (OS), response rate (RR), time to treatment failure (TTF), relative dose intensity (RDI), the incidence and severity of adverse events, quality of life (QOL), quality-adjusted life years (QALY), health care costs, and relations between biomarkers and treatment response (translational research, TR). DISCUSSION: The results of this study will provide important information that will help to improve the therapeutic strategy for metastatic colorectal cancer, and we believe that this study is very meaningful from the perspective of comparative effectiveness research. TRIAL REGISTRATION: UMIN000007834.

Primary Salvage Survey of the Interference of Radiowaves Emitted by Smartphones on Medical Equipment.

Use of mobile phones has become a standard reality of everyday living for many people worldwide, including medical professionals, as data sharing has drastically helped to improve quality of care. This increase in the use of mobile phones within hospitals and medical facilities has raised concern regarding the influence of radio waves on medical equipment. Although comprehensive studies have examined the effects of electromagnetic interference from 2G wireless communication and personal digital cellular systems on medical equipment, similar studies on more recent wireless technologies such as Long Term Evolution, wideband code division multiple access, and high-speed uplink access have yet to be published. Numerous tests targeting current wireless technologies were conducted between December 2012 and March 2013 in an anechoic chamber, shielded from external radio signals, with a dipole antenna to assess the effects of smartphone interference on several types of medical equipment. The interference produced by electromagnetic waves across five frequency bands from four telecommunication standards was assessed on 49 components from 22 pieces of medical equipment. Of the 22 pieces of medical equipment tested, 13 experienced interference at maximum transmission power. In contrast, at minimum transmission power, the maximum interference distance varied from 2 to 5 cm for different wireless devices. Four machines were affected at the minimum transmission power, and the maximum interference distance at the maximum transmission power was 38 cm. Results show that the interference from smartphones on medical equipment is very controllable.

Silazanes/catalytic bases: mild, powerful and chemoselective agents for the preparation of enol silyl ethers from ketones and aldehydes.

We have developed an efficient method for the preparation of enol silyl ethers using novel agents, silazanes together with NaH or DBU catalyst, wherein TMS and TBDMS groups were smoothly and chemoselectively introduced into ketones and aldehydes under mild conditions.

Sequence-dependence of cisplatin and 5-fluorouracil in advanced and recurrent gastric cancer.

This randomized controlled clinical trial was designed to compare the safety and effectiveness of different sequences of treatment with cisplatin (CDDP) and 5-fluorouracil (5-FU) in patients with unresectable advanced and post-operative recurrent gastric cancer. Patients with unresectable advanced or post-operative recurrent gastric cancer were randomly assigned by a registration center to group A or B. Group A received CDDP (80 mg/m(2)) as a continuous 2-h intravenous infusion on day 1 and 5-FU (700 mg/m(2)) as a continuous intravenous infusion on days 2-5. Group B was given 5-FU (700 mg/m(2)) as a continuous intravenous infusion on days 1-4, followed by CDDP (80 mg/m(2)) as a continuous 2-h intravenous infusion on day 5. Each course of chemotherapy was repeated every 28 days. A total of 74 patients were enrolled. One patient died accidentally, and 5 could not be evaluated. Response was assessable in 68 patients. The response rate was 31.3% (10/32) in group A as compared with 13.9% (5/36) in group B. Although the response rate was higher in Group A, the difference was not significant (p=0.085). The response rate in patients with diffuse type tumors was significantly lower in group B. There was no difference between the groups in response among patients with intestinal type tumors. The median overall survival was 239 and 174 days and time to progression was 175 and 140 days in group A and group B, respectively. Although there were trends toward longer survival and time to progression in group A, the differences between the groups were not statistically significant. There was also no difference in the type or incidence of adverse reactions. The results of this controlled study indicate that the overall response rate was slightly but not significantly higher in patients who received CDDP before 5-FU. Among patients with diffuse type tumors, the response rate was significantly lower when 5-FU was administered before CDDP. Our results suggest that CDDP should be given before 5-FU in patients with gastric cancer when treated with a combination of CDDP and 5-FU.

Long-term results for patients with unresectable gastric cancer who received chemotherapy in the Japan Clinical Oncology Group (JCOG) trials.

BACKGROUND: Despite recent developments in chemotherapeutic trials, the long-term results of chemotherapy remain to be clarified. We evaluated the impact of chemotherapy on long-term survival in patients with unresectable gastric cancer.METHODS: Between 1985 and 1991, a total of 363 patients with gastric cancer were enrolled into a single randomized phase II study and into three series of phase II studies of the Japan Clinical Oncology Group. The chemotherapy regimens consisted of tegafur + mitomycin C (FTM), uracil-tegafur + mitomycin C (UFTM), 5'deoxy-flurorouridine + cisplatin (5'P), etoposide + doxorubicin + cisplatin (EAP), and 5-fluorouracil + cisplatin (FP). After a review of the 363 patients' case records, 226 patients who fulfilled the criteria of having "unresectable" factors prior to chemotherapy became the subjects for this analysis. Of the 226 patients, 50 were in the FTM regimen group, 39, in the UFTM; 49, in the 5'P; 42, in the EAP; and 46, in the FP group. Survival was updated continually.RESULTS: Of the 226 patients, 22 (10%) survived longer than 2 years, and 8 (4%) have survived longer than 5 years. The 8 5-year survivors consisted of 6 patients who had para-aortic node metastases alone as an "unresectable factor", 1 who had para-aortic and cervical node metastases, and the remaining patient who had liver metastasis alone. Twenty-nine patients with para-aortic node metastasis alone had a significantly longer survival than the other 197 patients ( P < 0.001).CONCLUSION: Systemic chemotherapy may offer some hope of achieving long-term survival in patients with unresectable gastric cancer, particularly when the patient has metastasis only to para-aortic nodes.

Randomized phase II study comparing mitomycin, cisplatin plus doxifluridine with cisplatin plus doxifluridine in advanced unresectable gastric cancer.

UNLABELLED: Various chemotherapies have been used to treat inoperable gastric cancer. Most combination therapies include cisplatin (CDDP) and fluoropyrimidine (5-FUs), which are thought of as key drugs. In the present study, we randomly compared mitomycin (MMC) and CDDP plus doxifluridine (5'-DFUR), which is an oral 5-FU and an intermediate metabolite of capecitabine (Xeloda), with CDDP plus 5'-DFUR in advanced unresectable gastric cancer. Regimen A was CDDP (70 mg/m2, by 2-hour intravenous drip infusion on day 1), MMC (7 mg/m2, injected intravenously on day 2), and oral 5'-DFUR (1200 mg/m2, on days 4 to 7, 11 to 14, 18 to 21 and 25 to 28; 3 days rest and 4 days administration). Regimen B was identical to regimen A without MMC. RESULTS: The response rate was 25.0% (8/32 patients) in Regimen A, 17.2% (5/29) in Regimen B (p=0.541). The median survival time was 241 days in Regimen A and 179 days in Regimen B (p=0.498). In Regimen A, although no significant difference was observed, end points such as response rate and suvival improved. Thus, we concluded that a randomized controlled phase III study with more subjects should be conducted.

Advantages of Japanese response criteria for estimating the survival of patients with primary gastric cancer.

BACKGROUND: We conducted a retrospective study to investigate the adequacy of the Efficacy Criteria for Primary Lesions in the Japanese Classification of Gastric Cancer (Japanese criteria) for evaluating the anti-tumor efficacy of chemotherapies and the relationship between tumor regression and the prognosis of gastric cancer.METHODS: The data for 90 patients with inoperable ad-vanced gastric cancer who received various chemotherapies, consisting of fluorinated pyrimidines and cisplatin, were retrospectively analyzed. Based on the Japanese criteria, we investigated the efficacy of the chemotherapies and the relationship between the response in primary lesions and survival. We also compared the efficacy of chemotherapies evaluated by the Japanese criteria to that evaluated by the WHO criteria.RESULTS: All 90 patients were evaluable by the Japanese criteria. The overall response rate was 53.3% (Partial response [PR] in 48 patients and no change + progressive disease [NC + PD] in 42 patients). The primary lesions were classified as measurable (a-lesions) in 27 patients, evaluable but not measurable (b-lesions) in 31 patients, and diffusely infiltrating (c-lesions) in 32 patients. Overall median survival time (MST) was 9.4 months. The MSTs of the responders and non-responders were 12.6 and 7.8 months, respectively. In contrast, by the WHO criteria, 49 patients (54.4%) were evaluable; the other 41 patients had gastric primary lesions alone but were not measurable by WHO criteria. The overall response rate was 67.3% (33/49), and overall MST was 9.4 months. The MSTs of the responders evaluated by both sets of criteria were both 12.6 months.CONCLUSIONS: We suggest that the Japanese criteria are useful for evaluating the anti-tumor effect of gastric cancer chemotherapies and that prospective studies to reconfirm their usefulness are warranted in Japan, and in Western countries.

[Development of a Japanese version of the FLIE].

Nausea and vomiting induced by chemotherapy have an impact on cancer patients' quality of life (QOL). The Functional Living Index-Emesis (FLIE), which is designed to assess the change in QOL from the influence of nausea and vomiting is rarely used in Japan, regardless of its utility, because it is written in English. We investigated the use by cancer patients with the main object of designing a reliable and valid Japanese version of the FLIE. We also verified the validity of a Japanese translation and improved part to design a highly precise Japanese version FLIE. Consequently, we found a correlation between the FLIE Japanese version and the QOL questionnaire Quality of Life Assessment of Cancer Patients Receiving Chemotherapy (QOL-ACPRC), which was the external standard. Furthermore, we improved the questionnaire to raise the rate of patient response, and improve reliability and validity. We think that this FLIE Japanese version will become useful in assessing the change in patient QOL due to the influence of nausea and vomiting.

Phase II study of S-1 as first-line treatment for elderly patients over 75 years of age with advanced gastric cancer: the Tokyo Cooperative Oncology Group study.

PURPOSE: This prospective multicenter phase II study was carried out to investigate the efficacy, safety and pharmacokinetics of S-1 monotherapy in elderly patients over 75 years of age, with unresectable advanced or recurrent gastric cancer. METHODS: Patients had measurable or evaluable lesions according to the Japanese Classification of Gastric Carcinoma. S-1 (25-60 mg determined by the body surface area and creatinine clearance) was given orally, twice daily. A course of treatment consisted of 4-week administration followed by a 2-week rest period, and the patients received repeated courses. RESULTS: Thirty-three patients were enrolled. Pharmacokinetics of S-1 was studied in six patients, and the maximum plasma concentrations of respective metabolites after S-1 administration were found to be similar to those reported for younger cancer patients. The overall response rate in 33 patients was 21.2% (95% CI, 10.7-37.8%), and median progression-free survival was 3.9 months, with a median overall survival of 15.7 months. Frequently noted adverse events include leukopenia, neutropenia, anemia, anorexia, and fatigue. As for serious adverse events, relatively higher frequencies of anemia (9%) and anorexia (12%) of grade 3 severity were found, but there were no grade 4 episodes. CONCLUSIONS: The results suggest that S-1 monotherapy is safe and useful for elderly patients with unresectable advanced or recurrent gastric cancer when the dose is selected with caution, taking into account renal function.

Effectiveness of doxifluridine (5'-DFUR)/docetaxel against advanced/recurrent gastric cancer showing resistance to various anticancer drug regimens.

A 58-year-old man was diagnosed as having type 3 gastric cancer (poorly differentiated adenocarcinoma). He underwent total gastrectomy with splenectomy, as well as D3 dissection, and received postoperative chemotherapy combining oral uracil and futrafur (UFT) with cisplatin (CDDP), but results showed recurrence of multiple abdominal lymph node metastases around the aorta. He therefore received various anticancer drug regimens (irinotecan [CPT-11]/CDDP; 1 M tegafur-0.4 M gimeracil-1 M oteracil potassium [TS-1], methotrexate (MTX)/5-fluorouracil); however, final results showed growth of lymph node metastasis and simultaneous worsening of his general condition. The patient then received combined administration of doxifluridine (5'-DFUR)/docetaxel (5'-DFUR, 1000 mg/body [666.7 mg/m(2)], given by consecutive daily administration, orally, for days 1-14; and docetaxel, 80 mg/body [60 mg/m(2)], on day 8, by venous drip, every 3 weeks). Three courses of this regimen resulted in approximately 90% reduction of the abdominal lymph node size, disappearance of the right cervical lymph node metastasis, reductions of the levels of two tumor markers (carcinoembryonic antigen [CEA] and carbohydrate antigen [CA]19-9), and improvement of his general condition. In total, seven courses of the regimen were carried out. The patient died on day 298 after starting this combined regimen and showed a response period of 126 days. The primary toxicity identified was neutropenia (grade 4), as well as other low-grade (grade 1, 2) hematological and nonhematological toxicities. In the field of gastric cancer treatment, especially for patients showing multiple resistance to anticancer drugs, an effective therapy is critically needed.

The Effects of the Hepatitis B Virus and Occupational and Lifestyle Factors on Liver Function Among Workers in Shanghai.

The hepatitis B virus (HBV) infection is a major health problem in China. This study examined liver function in relation to HBV infection, and the occupational and lifestyle factors among workers in Shanghai. The study included 690 male workers aged 20-59 employed at a steel manufacturing company. The occupational and lifestyle factors were evaluated by self-administered questionnaire addressing worksite, exposure to dust or chemicals, history of cigarette smoking and habitual alcohol consumption. The prevalence of hepatitis B surface antigen(HBsAg) seropositivity was 21.4%. Elevated values of aspartate aminotransferase (AST, >30IU/liter) appeared in HBsAg-positive and current alcohol drinking groups but statistically on the borderline. There was a positive linear trend in the odds ratios(ORs) among age groups and ethanol consumption levels for elevated values of g-glutamyl transferase (GGT, >50IU/liter). There was no clear association between occupational exposure and liver functions. When the effects of HBsAg and the current alcohol drinking status on the elevated value of AST were examined simultaneously, OR for cases with HBsAg-positive and current alcohol drinking rose to 2.85(95%CI.98-8.28) against reference cases with HBsAg-negative and non-alcohol drinking, although this association was statistically on the borderline. The results indicated that some interventional attempts including educational strategy for alcohol drinking would be important among the HBsAg-positive cases to reduce the risk of liver dysfunction and further, hepatocellular carcinoma.

Long-term survival and prognostic factors in patients with metastatic gastric cancers treated with chemotherapy in the Japan Clinical Oncology Group (JCOG) study.

BACKGROUND: The long-term survival of patients after chemotherapy for advanced gastric cancer remains unclear. The aim of this analysis was to investigate prognostic factors for patients with metastatic gastric cancer treated by chemotherapy, and to identify the characteristics of long-term survivors. METHODS: Six hundred and forty three patients were enrolled in four phase II studies and one phase III study by the Japan Clinical Oncology Group between January 1985 and April 1997. By adjusting patients' eligibility between the five studies, 497 patients (77%) were selected for the analysis. Univariate and multivariate analyses were performed using log-rank tests and Cox's proportional hazard model, respectively. RESULTS: Of the 497 patients analyzed, 39 (8%) and 11 (2%) patients have survived longer than 2 and 5 years, respectively. By multivariate analysis, better performance status, a small number of metastatic sites and macroscopically non-scirrhous type tumors were significantly associated with better prognosis. Characteristics of the 11 5-year survivors revealed eight with para-aortic node metastases alone. Eight of these patients received gastrectomy; four underwent it before chemotherapy, and the other four patients received it after achieving downstaging with successful chemotherapy. CONCLUSIONS: These results demonstrated that better performance status, a small number of metastatic sites and macroscopically non-scirrhous type tumors are independent favorable factors for survival. There were a few 5-year survivors with unresectable gastric cancers, most of whom had only abdominal lymph node metastases and received gastrectomy before or after chemotherapy.