Background: The efficacy and safety of oxaliplatin combined with S-1 (SOX regimen) for unresectable advanced or recurrent gastric cancer were investigated.
Patients and methods: Oxaliplatin was ...administered i.v. (100 mg/m2) on day 1, while S-1 was administered orally (80 mg/m2/day, b.i.d.) for 14 days followed by a 7-day rest. This schedule was repeated every 3 weeks.
Results: Among 55 patients enrolled, one patient received oxaliplatin for the other study, and three patients were considered unsuitable against the inclusion criteria. Accordingly, 51 patients were assessable for efficacy. The response rate was 59%, and the disease control rate was 84%. The median progression-free survival time was 6.5 months, the 1-year survival rate was 71%, and the median survival time was 16.5 months. In 54 patients assessed for safety, the major grade 3/4 toxic effects were neutropenia (22%), thrombocytopenia (13%), anemia (9%), anorexia (6%), fatigue (6%), and sensory neuropathy (4%).
Conclusion: These findings indicate that SOX regimen with oxaliplatin at a dose of 100 mg/m2 is feasible and shows promising efficacy against advanced gastric cancer.
The Adjuvant Chemotherapy Trial of TS-1 for Colon Cancer (ACTS-CC) is a phase III trial designed to validate the non-inferiority of S-1 to UFT/leucovorin (LV) as postoperative adjuvant chemotherapy ...for stage III colon cancer. We report the results of a planned safety analysis.
Patients aged 20-80 years with curatively resected stage III colon cancer were randomly assigned to receive UFT/LV (UFT, 300 mg m(-2) per day as tegafur; LV, 75 mg per day on days 1-28, every 35 days, 5 courses) or S-1 (80, 100, or 120 mg per day on days 1-28, every 42 days, 4 courses). Treatment status and safety were evaluated.
Of 1535 enrolled patients, a total of 1504 (756 allocated to S-1 and 748 to UFT/LV) were analysed. The completion rate of protocol treatment was 77% in the S-1 group and 73% in the UFT/LV group. The overall incidence of adverse events (AEs) were 80% in S-1 and 74% in UFT/LV. Stomatitis, anorexia, hyperpigmentation, and haematological toxicities were common in S-1, whereas increased alanine aminotransferase and aspartate aminotransferase were common in UFT/LV. The incidences of grade 3 AEs were 16% and 14%, respectively.
Although AE profiles differed between the groups, feasibility of the protocol treatment was good. Both S-1 and UFT/LV could be safely used as adjuvant chemotherapy.
Abstract Background The aim of this study was to evaluate the efficacy and feasibility of preoperative chemotherapy with S-1 plus cisplatin in patients with initially unresectable locally advanced ...gastric cancer. Methods We enrolled patients with initially unresectable locally advanced gastric cancer because of severe lymph node metastases or invasion of adjacent structures. Preoperative chemotherapy consisted of S-1 at 80 mg/m2 divided in two daily doses for 21 days and cisplatin at 60 mg/m2 intravenously on day 8, repeated every 35 days. If a tumor decreased in size, patients received 1 or 2 more courses. Surgery involved radical resection with D2 lymphadenectomy. Results Between December 2000 and December 2007, 27 patients were enrolled on the study. No CR was obtained, but PR was seen in 17 cases, and the response rate was 63.0%. Thirteen patients (48.1%) had R0 resections. There were no treatment related deaths. The median overall survival time (MST) and the 3-year overall survival (OS) of all patients were 31.4 months and 31.0%, respectively. Among the 13 patients who underwent curative resection, the median disease-free survival (DFS) and the 3-year DFS were 17.4 months and 23.1%, respectively. The MST and the 3-year OS were 50.1 months and 53.8%, respectively. The most common site of initial recurrence after the R0 resection was the para-aortic lymph nodes. Conclusions Preoperative S-1 plus cisplatin can be safely delivered to patients undergoing radical gastrectomy. This regimen is promising as neoadjuvant chemotherapy for resectable gastric cancer. For initially unresectable locally advanced gastric cancer, new trials using more effective regimens along with extended lymph node dissection are necessary.
This phase I first-in-human study was conducted in Japanese patients to investigate the safety, pharmacokinetics (PKs), and determine the maximum tolerated dose (MTD) of oral TAK-285, a novel dual ...erbB protein kinase inhibitor that specifically targets human epidermal growth factor receptor (EGFR) and HER2.
The TAK-285 dose was escalated until MTD was determined. A second patient cohort received TAK-285 at the MTD for at least 4 weeks.
In all, 26 patients received TAK-285 at doses ranging from 50 to 400 mg once daily (q.d.) or twice daily (b.i.d.); 20 patients made up the dose escalation cohort and the remaining 6 patients were the repeated administration cohort. TAK-285 was well tolerated. Dose-limiting toxicities noted in two patients who received 400 mg b.i.d. were grade 3 increases in aminotransferases and grade 3 decreased appetite. Consequently, the MTD was determined to be 300 mg b.i.d. Absorption of TAK-285 was rapid after oral dosing, and plasma exposure at steady-state increased in a dose-proportional fashion for doses ranging from 50 to 300 mg b.i.d. A partial response was observed for one patient with parotid cancer who received 300 mg b.i.d.
The toxicity profile and PK properties of oral TAK-285 warrant further evaluation.
The aims of this phase I/II study of docetaxel and S-1 were to determine the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and recommended dose (RD) in the phase I part and to explore ...the tumour response, survival and safety in the phase II part. Patients with histologically- or cytologically confirmed unresectable or recurrent gastric cancer were eligible. Treatment consisted of intravenous docetaxel on day 1 (starting dose 50 mg m(-2)) and oral S-1 at a fixed dose of 40 mg m(-2) twice daily on days 1-14, every 4 weeks up to six cycles. Nine patients took part in the phase I portion of the study. The MTD of docetaxel was determined to be 50 mg m(-2), with the DLTs of grade 3 infection associated with grade 3 neutropenia and grade 4 neutropenia during S-1 administration. The RD of docetaxel was 40 mg m(-2) in combination with S-1 40 mg m(-2) b.i.d. The efficacy and safety of this regimen was therefore assessed in 46 patients with at least one measurable lesion. The overall response rate and estimated median overall survival were 46% (95% CI, 31-61%) and 14.0 months (8.3-17.3 months), respectively. The most common grade 3/4 toxicity was neutropenia (67% of patients), which was predictable and manageable. This regimen showed promising activity with moderate toxicities in advanced gastric cancer.
Objective Cetuximab is a chimeric IgG1 monoclonal antibody that specifically blocks the epidermal growth factor receptor. We evaluated the efficacy and safety of cetuximab in combination with ...irinotecan in patients with metastatic colorectal cancer (CRC) refractory to irinotecan, oxaliplatin and fluoropyrimidines. Methods Cetuximab was administered initially at a dose of 400 mg/m2 followed by weekly infusions at 250 mg/m2. Irinotecan was administered either weekly at a dose of 100 mg/m2 or every 2 weeks at 150 mg/m2. Results Between October 2005 and February 2006, 39 consecutive patients were enrolled. The response and disease control rates (complete or partial response, or stable disease) were 30.8% (95% CI, 17.0–47.6) and 64.1% (95% CI, 47.2–78.8), respectively. With a median follow-up of 14.4 months, median time to progression was 4.1 months (95% CI, 2.7–5.1) and median survival time was 8.8 months (95% CI, 5.9–12.8). Patients (5.1%) developed Grade 3 acne-like rash. Conclusions Combination therapy of cetuximab and irinotecan is effective and well-tolerated in patients with metastatic CRC refractory to irinotecan, oxaliplatin and fluoropyrimidines.
Background Chemoradiotherapy (CRT) is currently performed for patients with esophageal squamous cell carcinoma (SCC). Some reports have revealed that patients who responded well to CRT had favorable ...outcomes, whereas poor responders conversely showed a worse prognosis. The aim of this study was to identify molecular markers predicting sensitivity to CRT. Methods We reviewed 62 patients with T3-4, N-any, and M-any esophageal SCC treated with definitive CRT. The regimen comprised protracted 5-fluorouracil infusion and a 2-h infusion of cisplatinum combined with radiation therapy (2 Gy/day) at a total radiation dose of 60 Gy. The expressions of epidermal growth factor receptor (EGFR), vascular endothelial growth factor, cyclin D1, and proliferating cell nuclear antigen were investigated immunohistochemically in biopsy specimens obtained before treatment from all 62 patients. The immunoreactivities were compared with responsiveness to CRT, as evaluated by endoscopy. Results The complete response rate of the primary tumor estimated by endoscopy was 62% (13/21) in patients in the EGFR-positive group. The difference in the CR rate between EGFR-positive and -negative groups was significant (p = 0.037). The immunoreactivities of the other molecular markers did not show a significant correlation with the responsiveness of the primary lesion to CRT. Multiple logistic regression analysis revealed that positive immunostaining for EGFR was significantly correlated with primary CR for CRT in esophageal SCC. Conclusion Among 62 patients with esophageal SCC, differences in the responsiveness of primary lesions to CRT were correlated with EGFR immunoreactivity assessed in the biopsy specimens. These results suggest that EGFR may help to predict the response of primary sites to definitive CRT in esophageal SCC, although the results should be confirmed in a larger, more homogeneous series.
The second-generation oral anticancer agent UFT, a combination of uracil and tegafur (TGF), results in a higher fluorouracil (5-FU) concentration in the tumor tissues than is achieved by TGF or ...comparable doses of intravenous 5-fluorouracil. UFT has been extensively studied in Japan and has been in use in the Orient for many years, particularly for patients with gastric carcinoma. UFT has recently entered extensive investigations in North America and Europe.
Relevant studies that have chronicled the establishment of UFT, its mechanism of action, preclinical toxicology, human pharmacokinetics, phase I studies, and activity against gastric carcinoma are described in detail.
The uracil in UFT slows degradation of 5-FU by dihydropyrimidine dehydrogenase (DPD), which results in sustained concentrations of 5-FU in blood and tumor tissues. UFT is well tolerated, but such toxic effects as nausea, vomiting, and diarrhea are dose- and schedule-dependent. In phase I pharmacokinetic studies, UFT given orally on a 28-day schedule resulted in blood concentrations comparable to those following low-dose continuous intravenous infusion of 5-FU. In patients with gastric carcinoma, UFT alone has a response rate of approximately 20%. In the adjuvant setting, UFT plus mitomycin appears superior to TGF plus mitomycin. In Japan, UFT is part of the standard adjuvant chemotherapy for gastric carcinoma.
UFT is one of the first second-generation oral 5-FU prodrugs under investigation in North America and Europe. The literature suggests UFT is well tolerated and has cellular pharmacokinetic superiority over the first-generation 5-FU prodrug TGF. UFT has a more favorable toxicity profile than intravenous 5-FU. The issues of efficacy, patient convenience, and quality of life need to be studied in controlled randomized trials.
Objectives: To conduct a phase I/II study of irinotecan with cisplatin to establish a recommended dose, and assess the safety,
efficacy and feasibility of this regimen in unresectable advanced or ...recurrent gastric cancer. Patients and Methods: In the
phase I portion of the study, patients received a fixed dose of cisplatin (30 mg/m 2 ) with escalating doses of irinotecan, ranging from 30 mg/m 2 to 70 mg/m 2 , on days 1 and 15. In the phase II portion of the study, 40 patients were evaluated for response and safety at the recommended
dose. Results: Eighteen patients were enrolled in the phase I study. Dose-limiting toxicity (diarrhea and neutropenia) appeared
at the irinotecan dose of 70 mg/m 2 . Therefore, the recommended irinotecan dose was 60 mg/m 2 . In the phase II study, 40 patients received cisplatin (30 mg/m 2 ) plus irinotecan (60 mg/m 2 ). Twenty-five out of 40 patients had received prior chemotherapy. The median number of cycles was 3.5. The response rate
was 32.5% (13/40) overall, and 53.3% (8/15) in patients without prior chemotherapy. The median time to tumor progression (TTP)
was 162 days. The median survival time was 288 days. Four patients (10%) developed grade 4 neutropenia and 3 patients (7.5%)
developed grade 4 anemia. The only observed non-hematological toxicity at grade 3 or higher was diarrhea, seen in 2.5% (1/40)
of the patients. Conclusion: Bi-weekly administration of irinotecan and cisplatin is safe and active for the management of
unresectable advanced or recurrent gastric cancer.
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