Minoru Kurihara

Phase II Study of S-1, a Novel Oral Derivative of 5-Fluorouracil, in Advanced Gastric Cancer

Purpose: To assess the efficacy and safety of S-1, a novel oral fluoropyrimidine derivative, we conducted a multicenter late phase II study in patients with advanced gastric cancer. Patients and Methods: Fifty-one patients who had received no previous chemotherapy were enrolled. Fifty patients were eligible for efficacy and safety analyses. The overall response was evaluated for the 43 patients who had metastatic lesions. S-1 was administered orally after breakfast and dinner for 28 days, followed by a 14-day break. The dosages were assigned according to the patients’ body surface area (BSA): BSA <1.25 m2, 40 mg; 1.25–1.5 m2, 50 mg, and BSA ≥1.5 m2, 60 mg, twice daily. Results: The overall response to treatment was evaluated as partial response in 19 of the 43 patients (44%; 95% confidence interval 30–59%). The median survival time in all patients was 207 days with 1- and 2-year survival rates of 36.0 and 14.0%, respectively. Grade 3 adverse reactions included decreased hemoglobin values in 2 patients, leukopenia, neutropenia and diarrhea in 1 patient each. No other grade 4 or unexpected adverse reactions were seen. Conclusions: S-1 is effective against advanced gastric cancer. This oral treatment is suitable for outpatients because of its mild toxicity. Further therapeutic benefits are likely to be obtained by combining S-1 with other chemotherapeutic agents.

Development of quality of life questionnaire in Japan: quality of life assessment of cancer patients receiving chemotherapy.

The Japanese Quality of Life Research Group has developed a general questionnaire suitable for assessing the Quality of Life (QOL) in patients undergoing chemotherapy. The questionnaire covers four major categories: (1) daily activities, (2) physical condition, (3) social activities, and (4) mental and psychological status. The State–Trait Anxiety Inventory (STAI), Self‐Rating Depression Scale (SDS), and Performance Status (PS) were used as external measures of quality of life and for the validation of our tool. On the basis of two basic surveys and two studies we selected 22 questions from a larger set of items. Validity and reliability were verified for the final 22‐question form. This questionnaire, named the QOL Questionnaire for Cancer Patients Treated with Anticancer Drugs (QOL‐ACD), can be used to detect changes in QOL over time. Its use as an additional outcome measure in Phase III chemotherapy trials should be encouraged. Copyright

Phase II study of protracted infusional 5-fluorouracil combined with cisplatinum for advanced gastric cancer: Report from the Japan Clinical Oncology Group (JCOG)

A phase II study of protracted infusional 5-fluorouracil (5FU) combined with cisplatin (CDDP) was conducted in patients with advanced gastric carcinoma. 55 previously untreated patients, including 40 patients with measurable disease, were treated with 5FU (800 mg/m2, days 1-5, protracted infusion) and CDDP (20 mg/m2, days 1-5, drip infusion). Objective tumour responses were observed in 17/40 (43%) patients with measurable disease. Median survival was 7 months. WHO grade 3 or 4 leucopenia occurred in 10/55 patients (18%) and grade 3/4 thrombocytopenia was observed in 4 patients (7%). A randomised trial including this regimen is now underway in a JCOG study.

Sialosyl-Tn, antigen as a marker of gastric cancer progression: An international study

Sialosyl‐Tn, a mucin‐associated carbohydrate antigen, is not expressed by normal mucus‐producing cells of the stomach but becomes expressed in metaplastic, pre‐malignant and malignant gastric tissues. Reports vary as to the frequency of STn expression and its prognostic role in gastric cancer. To determine whether these differences might be due to inter‐country variations in gastric cancer biology, we immunohistochemically analyzed 340 gastric cancers from 2 countries at high‐risk (high incidence) for gastric cancer (Japan and Chile), one with intermediate risk (Brazil) and one with low‐risk (USA). Expression of STn was correlated with clinico‐pathological features of the tumors and with cancer‐related survival. Regardless of country, the frequency of STn‐positive tumors was lower in non‐invasive (“early”) than in advanced gastric cancer. Consequently, high‐risk countries where early gastric cancer is more common demonstrated a lower overall frequency of STn‐positive tumors. In all 4 countries, STn expression directly correlated with depth of invasion, stage, and lymph node involvement. In addition, STn expression correlated with a poor prognosis in all 4 countries, but the effect of STn on survival was not independent of tumor stage. Our findings indicate the need to consider the inherent gastric cancer risk and prevalence of early gastric cancer in the study population when reporting frequency of STn expression in gastric cancer. Regardless of country, however, STn expression is a marker of gastric cancer progression suggesting that cancer‐associated mucins play a role in the malignant behavior of this tumor.

Randomized phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations: NEJ005/TCOG0902

BACKGROUND The first-line combination of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) and platinum-based doublet chemotherapy has not been sufficiently evaluated for patients with EGFR-mutant non-small cell lung cancer (NSCLC). This randomized phase II study was designed to select a combination regimen for phase III evaluation. PATIENTS AND METHODS Chemotherapy-naïve patients with advanced non-squamous, EGFR-mutant NSCLC were randomly assigned to receive either a concurrent or a sequential alternating regimen with gefitinib (250 mg) and carboplatin/pemetrexed [area under the curve (AUC) = 6 and 500 mg/m(2); 3-weekly]. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), response, and safety. RESULTS All 80 patients enrolled were eligible and assessable for efficacy (41 and 39 patients in the concurrent and sequential alternating regimen groups, respectively). Median PFS was 18.3 months for the concurrent regimen and 15.3 months for the sequential alternating regimen [hazard ratio (HR) 0.71 (0.42-1.20), P = 0.20]. Although OS data are immature (16 and 24 death events), median survival times were 41.9 and 30.7 months in the concurrent and sequential alternating regimen groups, respectively [HR 0.51 (0.26-0.99); P = 0.042]. Response rates were similar in both groups (87.8% and 84.6%). Hematological and non-hematological adverse events were common and reversible; interstitial lung disease was neither frequent nor fatal (two cases in each group; 5% of all patients). CONCLUSION This is the first randomized study to investigate the efficacy of combinational EGFR-TKI and chemotherapy in the EGFR-mutated setting. Both regimens had promising efficacy with predictable toxicities, although concurrent regimens might provide better OS. The concurrent regimen was chosen to compare with gefitinib monotherapy in our ongoing phase III study. CLINICAL TRIALS REGISTRATION University Hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN C000002789).

A phase II study of combination therapy with 5'-deoxy-5-fluorouridine and cisplatin in the treatment of advanced gastric cancer with primary foci

Background. 5′‐Deoxy‐5‐fluorouridine (5′‐DFUR, doxifluridine) is a recently developed prodrug of oral 5‐fluorouracil (5‐FU), which is used clinically in Japan for the treatment of gastric, colorectal, and breast cancer. 5‐FU has been reported to act synergistically with cisplatin (CDDP) in experimental and clinical studies. The authors conducted a multicenter Phase II study of combination therapy with 5′‐DFUR and CDDP to evaluate the therapeutic usefulness of this regimen in the treatment of unresectable and advanced gastric cancers with primary foci. None of the patients had previously undergone chemotherapy. Their ages ranged from 27 to 75 years and performance status was grade 0 to 3.

A Cooperative Randomized Study on Tegafur plus Mitomycin C versus Combined Tegafur and Uracil plus Mitomycin C in the Treatment of Advanced Gastric Cancer

A randomized controlled trial involving 13 institutions in Japan was conducted in order to compare the efficacy of tegafur plus mitomycin C (MMC) (Regimen A) and UFT (a combination of uracil and tegafur at a molar ratio of 4 to 1) plus MMC (Regimen B) for patients with advanced gastric cancer, who had not received any prior cancer chemotherapy. Regimen A (tegafur+MMC) consisted of 5 mg of MMC/m2/week given intravenously, and 500 mg of tegafur/m2/day given orally. Regimen B consisted of the same schedule of MMC and 375 mg of UFT/m2/day given orally. One hundred and eighty‐six patients with primary gastric cancer were entered; 183 were eligible and 3 were ineligible for the study. A total of 169 were evaluable for efficacy of the treatment, including 90 patients with Regimen A and 79 with Regimen B. A response rate of 7.8% (7/90 cases) for Regimen A and one of 25.3% (20/79 cases) for Regimen B were obtained, indicating a significantly higher response rate for Regimen B according to the Criteria for Evaluating Efficacy of Chemotherapy /Radiation Therapy in the Treatment of Gastric Cancer (P= 0.004), Regarding side effects, no marked differences in either severity or incidence were observed between the two groups. The group assigned to Regimen B showed a significant survival advantage after adjustment for major prognostic factors using a proportional hazards model (P=0.0398). Moreover, a close correlation of antitumor effect and survival duration was found when the above criteria were used.

Prediction of response to 5'-deoxy-5-fluorouridine (5'-DFUR) in patients with inoperable advanced gastric cancer by immunostaining of thymidine phosphorylase/platelet-derived endothelial cell growth factor.

Background: No reliable method is available for predicting the response to chemotherapy in patients with gastric cancer. The anticancer drug 5′-deoxy-5-fluorouridine (5′-DFUR) is converted into 5-fluorouracil (5-FU) by thymidine phosphorylase (dThdPase). We studied the relation between the expression of dThdPase in tumor tissue and the response to treatment with 5′-DFUR to determine if this enzyme can be used to predict the response to chemotherapy. Methods and Materials: We performed endoscopic biopsy and studied the expression of dThdPase by immunostaining with anti-dThdPase monoclonal antibody in 41 patients with inoperable advanced gastric carcinomas before they received multiple-drug chemotherapy, including 5′-DFUR. The relation between the expression of dThdPase and the response to chemotherapy was studied. We also studied the characteristics of positive cells against anti-dThdPase monoclonal antibody. Results: The response rate among patients whose tumors were positive for dThdPase expression (56.8%, 21/37) was higher than that among patients whose tumors were negative for dThdPase expression (0%, 0/4; p = 0.048). Spindle-shaped cells darkly expressing dThdPase were sporadically seen surrounding cancer nests in some patients. Multiple-antibody immunostaining suggested that these spindle-shaped cells were perivascular mesenchymal cells. The response rate was 82.4% (14/17) among patients with spindle-shaped cells strongly positive for dThdPase, as compared with 29.2% (7/24) among those with spindle-shaped cells weakly positive or negative for dThdPase (p = 0.00131). The expression of spindle-shaped cells darkly stained with dThdPase was the factor most strongly related to the response to chemotherapy (odds ratio = 35.513, p = 0.0027). Conclusions: The expression of dThdPase in stromal spindle-shaped cells may be a useful index in predicting the response to 5′-DFUR in patients with gastric cancer.

Active transepithelial transport of irinotecan (CPT-11) and its metabolites by human intestinal Caco-2 cells.

Irinotecan (CPT-11) is a camptothecin analog with low (about 10-20%) and variable oral bioavailability in animal models. Here, Caco-2 cells were used to evaluate the transepithelial transport of CPT-11 and its metabolites. Caco-2 cells demonstrated significant expression of P-glycoprotein (P-gp), multidrug resistance-associated protein and canalicular multispecific organic anion transporter. Both the lactone and carboxylate forms of CPT-11 and SN-38 were actively transported across the cell monolayers, mainly by the apical-localized P-gp pump. Cellular permeability of CPT-11 at a concentration of 17 μM converted from active to passive-diffusional transport between the 2 and 6 h exposure time points. Antiproliferative effects of CPT-11 were related to permeability of the lactone form, whereas for SN-38 efficacy was dependent on lactone accumulation. Exposure of CPT-11 with cyclosporin A significantly enhanced its efficacy, whereas this was not observed with verapamil and R101933. In contrast, SN-38 efficacy decreased in the presence of P-gp inhibitors due to active transport toward the basolateral side, thereby reducing drug accumulation. Hence, multiple-active transport systems could be demonstrated to be responsible for not only accumulation profiles but also cytotoxic efficacy of CPT-11 and SN-38 in the intestinal Caco-2 cells. It is suggested that CPT-11 might act in a time-dependent manner and that SN-38-mediated cytotoxicity relates to (dose-dependent) lactone kinetics. The results detailed in this report could contribute toward the development of a clinically useful oral formulation of CPT-11 with improved absorption characteristics and suggest that cyclosporin A is a suitable agent for further research of this concept.

MULTICENTRE COLLABORATIVE PROSPECTIVE STUDY OF ENDOSCOPIC TREATMENT OF EARLY GASTRIC CANCER

Aims:  The present study was conducted with the aims of elucidating the present state of endoscopic treatment, in particular endoscopic mucosal resection (EMR) of early gastric cancer, as well as any associated problems, and the prospects for further broadening of the indications for EMR.