Seiichi Takagi

S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial

BACKGROUND Phase I/II clinical trials of S-1 plus cisplatin for advanced gastric cancer have yielded good responses and the treatment was well tolerated. In this S-1 Plus cisplatin versus S-1 In RCT In the Treatment for Stomach cancer (SPIRITS) trial, we aimed to verify that overall survival was better in patients with advanced gastric cancer treated with S-1 plus cisplatin than with S-1 alone. METHODS In this phase III trial, chemotherapy-naive patients with advanced gastric cancer were enrolled between March 26, 2002, and Nov 30, 2004, at 38 centres in Japan, and randomly assigned to S-1 plus cisplatin or S-1 alone. In patients assigned to S-1 plus cisplatin, S-1 (40-60 mg depending on patients body surface area) was given orally, twice daily for 3 consecutive weeks, and 60 mg/m(2) cisplatin was given intravenously on day 8, followed by a 2-week rest period, within a 5-week cycle. Those assigned to S-1 alone received the same dose of S-1 twice daily for 4 consecutive weeks, followed by a 2-week rest period, within a 6-week cycle. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportions of responders, and safety. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00150670. FINDINGS 305 patients were enrolled; seven patients were ineligible or withdrew consent, therefore, 148 patients were assigned to S-1 plus cisplatin and 150 patients were assigned to S-1 alone. Median overall survival was significantly longer in patients assigned to S-1 plus cisplatin (13.0 months [IQR 7.6-21.9]) than in those assigned to S-1 alone (11.0 months [5.6-19.8]; hazard ratio for death, 0.77; 95% CI 0.61-0.98; p=0.04). Progression-free survival was significantly longer in patients assigned to S-1 plus cisplatin than in those assigned to S-1 alone (median progression-free survival 6.0 months [3.3-12.9] vs 4.0 months [2.1-6.8]; p<0.0001). Additionally, of 87 patients assigned S-1 plus cisplatin who had target tumours, one patient had a complete response and 46 patients had partial responses, ie, a total of 54% (range 43-65). Of 106 patients assigned S-1 alone who had target tumours, one patient had a complete response and 32 had partial responses, ie, a total of 31% (23-41). We recorded more grade 3 or 4 adverse events including leucopenia, neutropenia, anaemia, nausea, and anorexia, in the group assigned to S-1 plus cisplatin than in the group assigned to S-1 alone. There were no treatment-related deaths in either group. INTERPRETATION S-1 plus cisplatin holds promise of becoming a standard first-line treatment for patients with advanced gastric cancer.

Endoscopic submucosal dissection (two-point fixed ESD) for early esophageal cancer.

Background:  We have been attempting to improve the safety, reliability and simplicity of endoscopic submucosal dissection for the treatment of early esophageal cancer and to shorten the time needed for this operation.

A multicenter, phase I dose-escalating study of docetaxel, cisplatin and S-1 for advanced gastric cancer (KDOG0601).

Objective: This dose-escalation study of a combination of docetaxel, cisplatin and S-1 investigated the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), recommended dose (RD) and antitumor activity in advanced gastric cancer. Patients and Methods: Patients received docetaxel (40 mg/m2), cisplatin (DIV on day 1) and S-1 (40 mg/m2 p.o., twice daily, on days 1–14 every 28 days). The starting dose of cisplatin was 60 mg/m2 (level 1); the dose was escalated to 70 (level 2) and 80 mg/m2 (level 3) in a stepwise fashion. Results: Fourteen patients were enrolled. The MTD of cisplatin was 80 mg/m2 (level 3). DLT was grade 3 diarrhea, febrile neutropenia and delayed resumption of treatment. The RD of cisplatin was considered to be 70 mg/m2 (level 2). DLT was liver dysfunction, occurring in only 1 patient at level 2. The response rate was 69.2% (9/13). Conclusions: For combined treatment with docetaxel, cisplatin and S-1 in patients with advanced gastric cancer, RD were docetaxel 40 mg/m2, cisplatin 70 mg/m2 and S-1 80 mg/m2/day. This regimen yields a high rate of tumor response and can be administered safely. Phase II studies of this regimen are under way.

Phase II Study of Bolus 5-Fluorouracil and Leucovorin Combined with Weekly Paclitaxel as First-Line Therapy for Advanced Gastric Cancer

Objective: We evaluated the efficacy and safety of bolus 5-fluorouracil (5-FU) and leucovorin combined with weekly paclitaxel (FLTAX) in advanced gastric cancer (GC) patients. Methods: Patients with untreated stage IV GC received paclitaxel 80 mg/m2 as a 1-hour infusion, followed by 5-FU 600 mg/m2 as a bolus infusion and L-leucovorin 250 mg/m2 as a 2-hour infusion on days 1, 8 and 15. Treatment cycles were repeated every 28 days. The primary endpoint was response rate. Results: Thirty-five patients were enrolled. The median age was 62 years (range 34–75). Twenty-one patients (60%) had diffuse-type cancer and 11 had peritoneal metastasis. The confirmed response rate was 43% (95% CI 26–61) with 15 partial responses. Stable disease was observed in 16 (46%) patients. Median progression-free survival and overall survival were 6.8 months (95% CI 5.8–7.4) and 16.2 months (95% CI 10.0–22.8), respectively. Grade 3–4 adverse events were: neutropenia (54%), febrile neutropenia (3%), diarrhea (6%) and sensory neuropathy (11%). Conclusion: FLTAX showed a desirable safety profile, and the efficacy against advanced GC was encouraging. FLTAX may be a good option for GC patients with deteriorated general condition, and a randomized clinical trial in such patients is currently underway.

A Survey of Regenerating Capacity in Patchy Liver and in Nodular Liver—with Special Reference to DNA Synthesis Estimated by BrdU Labeling Index—

Abstract: Laparoscopically, patchy liver and nodular liver were considered as features of regeneration of liver cells. In this study, the regenerating capacity of liver cells obtained by a liver biopsy from laparoscopically identified patchy liver and nodular liver was estimated by Bromodeoxvuridine (BrdU)‐anti‐BrdU method. BrdU labeling indices (L. I.), of liver cells in biopsy specimens from 6 normal livers, 12 patchy livers, and from 15 nodular livers were examined using an in‐vitro labeling technique. Liver biopsy specimens obtained by a Tru‐cut needle were immediately incubated for 45 min. in 0.1% BrdU solution in RPMI 1640 at 37°C under a pressure of 3 atmospheres in a mixture of 95% O2 and 5% CO2. Immunohistochemical detection of BrdU was performed by the Avidin‐Biotin‐Peroxidase Complex (ABC) method. The mean BrdU L. I. (±SE) of normal liver, patchy liver, and of nodular liver was 0.25±0.09%, 1.4±0.2%, and 1.7±0.4% respectively. Among the nodular liver, flat shaped ones showed a low level (0.5±0.1%), in contrast to the high level (2.4±0.7%) in the semispherical nodular liver. The BrdU L. I. of both the patchy liver and the nodular liver was significantly higher than that in the normal liver (p<0.001, p<0.01 respectively).