Kazumasa Fujitani

Prospective randomized trial of preoperative enteral immunonutrition followed by elective total gastrectomy for gastric cancer.

Perioperative enteral immunonutrition is thought to reduce postoperative morbidity in patients undergoing major gastrointestinal surgery. This study assessed the clinical effects of preoperative enteral immunonutrition in well nourished patients with gastric cancer undergoing total gastrectomy.

Randomized controlled trial comparing gastrectomy plus chemotherapy with chemotherapy alone in advanced gastric cancer with a single non-curable factor: Japan Clinical Oncology Group Study JCOG 0705 and Korea Gastric Cancer Association Study KGCA01.

A randomized controlled trial has started in both Japan and Korea to evaluate the role of gastrectomy in the management of incurable advanced gastric cancer (AGC). Patients with AGC diagnosed as having a single non-curable factor are randomized to gastrectomy plus chemotherapy or chemotherapy alone. Surgeons at 33 specialized centers in Japan and at 15 high-volume hospitals in Korea will recruit 330 patients. Primary end-point is overall survival, and secondary end-points are progression-free survival and adverse events associated with either gastrectomy or chemotherapy.

Phase II Study of a Combination of Irinotecan and S-1 in Patients with Advanced Gastric Cancer (OGSG0002)

Background/Aims: To investigate the efficacy and safety of the combination therapy of irinotecan (CPT-11) plus S-1 in patients with advanced gastric cancer at the dose recommended by a previous phase I study. Methods: A total of 23 patients received 80 mg/m2 of CPT-11 on days 1 and 15, and S-1 at a dose level set on the basis of the body surface area (BSA): 40 (BSA <1.25 m2), 50 (BSA ≧1.25 to <1.5 m2) or 60 mg (BSA ≧1.5 m2) b.i.d. was given from days 1–21. Results: The overall response rate was 47.8% (11 of 23, 95% confidence interval, CI: 27.4–68.2%). The median time to progression (TTP) was 210 days (95% CI: 145–322 days) and the median survival time was 394 days (95% CI: 241–484 days). The incidence of grade 3 or 4 hematological and non-hematological toxicity was 17.4 and 8.7%. The most common hematological toxicity was anemia and the most common non-hematological toxicity was diarrhea. Conclusion: The combination therapy of CPT-11 and S-1 provided prolonged TTP with low toxicity, and the results warrant a further phase III study to define the efficacy in improvement of survival in patients with advanced gastric cancer.

Multi-Center Phase II Study for Combination Therapy with Paclitaxel/Doxifluridine to Treat Advanced/Recurrent Gastric Cancer Showing Resistance to S-1 (OGSG 0302)

BACKGROUNDnA pre-clinical study demonstrated that paclitaxel induced thymidine phosphorylase in the tumor tissues. The combination of paclitaxel and doxifluridine is expected to exert extra anti-tumor effects. We evaluated the efficacy of this combination in patients with unresectable or recurrent gastric cancer who had been previously treated with S-1.nnnMETHODSnRegistration was started to enroll 35 patients with advanced/recurrent gastric cancer, who were selected among those with measurable lesions fitting to response evaluation criteria in solid tumors, and with resistant to S-1 treatment. This regimen is consisted of paclitaxel, 80 mg/m(2), iv on days 1 and 8; and doxifluridine, 600 mg/m(2), po on days 1-14. The treatment was repeated every three weeks. Primary endpoint was response rate (RR); and secondary endpoints were overall survival (OS), progression free survival (PFS) and onset rate of adverse events.nnnRESULTSnFrom September 2003 to March 2005, 35 patients were registered: including 28 men; 7 women; median age of 66 years (range, 49-75 years); and performance status (PS) levels were, zero with 21 and one with 14 patients. In 33 eligible patients, except two, clinical usefulness was evaluated resulting in RR of 18.2% (partial response, 6; stable disease, 15; progressive disease, 10; and not evaluable, 2 patients). Median survival time was 321 days and median PFS was 119 days. Severe adverse events were found in three patients to discontinue the present treatment.nnnCONCLUSIONSnThe combination of paclitaxel and doxifluridine might be a treatment of choice as a second line chemotherapy for patient undergone S-1 treatment.

Phase II trial of preoperative S-1 plus cisplatin followed by surgery for initially unresectable locally advanced gastric cancer

BACKGROUNDnThe 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.nnnMETHODSnWe 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/m(2) divided in two daily doses for 21 days and cisplatin at 60 mg/m(2) 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.nnnRESULTSnBetween 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.nnnCONCLUSIONSnPreoperative 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.

Three-year outcomes of a phase II study of adjuvant chemotherapy with S-1 plus docetaxel for stage III gastric cancer after curative D2 gastrectomy

BackgroundWe have previously reported the superior feasibility and safety of adjuvant S-1 plus docetaxel in patients with stage III gastric cancer during a prospective phase II study. We report 3-year follow-up data on patients enrolled in this study.Patients and methodsFifty-three patients with histologically confirmed stage III gastric cancer who underwent gastrectomy with D2 lymphadenectomy were enrolled into this study. They received oral S-1 (80xa0mg/m2/day) for 2 consecutive weeks and intravenous docetaxel (40xa0mg/m2) on day 1, repeated every 3xa0weeks (one cycle). Treatment was initiated within 45xa0days after surgery and repeated for four cycles, followed by S-1 monotherapy (4xa0weeks on, 2xa0weeks off) until 1xa0year after surgery. Three-year overall survival (OS) and disease-free survival (DFS) were evaluated.ResultsThe OS rate at 3xa0years was 78.4xa0% [95xa0% confidence interval (CI), 67.9–90.6xa0%] and the DFS rate at 3xa0years was 66.2xa0% (95xa0% CI, 54.4–80.7xa0%). Subgroup analyses according to disease stage showed a 3-year OS and DFS rate of 85.7xa0% (95xa0% CI, 74.9–98.1xa0%) and 70.8xa0% (95xa0% CI, 57.1–87.8xa0%) for stage IIIA, and 62.5xa0% (95xa0% CI, 42.8–91.4xa0%) and 56.2xa0% (95xa0% CI, 36.5–86.7xa0%) for stage IIIB, respectively.ConclusionsOn the basis of 3-year follow-up data, postoperative adjuvant therapy with S-1 plus docetaxel yielded promising OS and DFS in stage IIIA gastric cancer patients who had undergone D2 gastrectomy. We believe that this regimen is a candidate for future phase III trials studying the optimal adjuvant chemotherapy regimen for stage III gastric cancer.

A Phase I Study of Triplet Combination Chemotherapy of Paclitaxel, Cisplatin and S-1 in Patients with Advanced Gastric Cancer

OBJECTIVEnS-1 and cisplatin combination therapy is a standard regimen for patients with advanced gastric cancer in Japan. The primary objective of this study was to determine the maximum tolerated dose and dose-limiting toxicities of a triplet regimen adding paclitaxel to S-1 and cisplatin combination therapy.nnnMETHODSnPatients with previously untreated metastatic or recurrent gastric cancer were enrolled. Patients received S-1 (40 mg/m(2) p.o., twice daily, on days 1-21 every 35 days), cisplatin (30 mg/m(2) divided, on days 1 and 15) and paclitaxel (divided on days 1 and 15). The starting dose of paclitaxel was 50 mg/m(2) (level 1); the dose was escalated to 60 (level 2), 70 (level 3) and 80 mg/m(2) (level 4) in a stepwise fashion. Dose-limiting toxicity was determined during the first treatment cycle.nnnRESULTSnEighteen patients enrolled. During the first cycle, no dose-limiting toxicity was observed at dose levels 1 and 2. At dose level 3, one of the six patients had dose-limiting toxicity (one patient had grade 4 neutropenia) and at dose level 4, one of the six patients had dose-limiting toxicity (one patient had febrile neutropenia, hypoalbuminemia and fatigue of grade 3). The maximum tolerated dose was not reached at level 4; however, grade 3 hyponatremia and hypokalemia in two of the six patients occurred during the second treatment course at level 4. From the point of view of safety in the outpatient setting, the recommended dose of paclitaxel was determined at 70 mg/m(2). The overall response rate was 50%.nnnCONCLUSIONSnThe recommended dose of paclitaxel added to S-1 (80 mg/m(2) days 1-21) plus cisplatin (30 mg/m(2) days 1 and 15) was 70 mg/m(2) on days 1 and 15 of a 5-week cycle.

Impact of pretreatment systemic inflammatory response on survival in AGC patients receiving first-line chemotherapy.

88 Background: Systemic inflammatory response plays an important role in cancer progression. However, little is known about how it affects the advanced gastric cancer (AGC) patients receiving first-line chemotherapy. We assessed the impact of pre-treatment systemic inflammatory response on survival in AGC patients receiving S-1 based first-line chemotherapy. Methods: OGSG 0402 multi-institutional phase II trial randomly assigned 102 patients with previously untreated, locally advanced and/or metastatic measurable gastric adenocarcinoma to receive S-1 plus irinotecan (SI arm) (n=51) or S1 plus paclitaxel (SP arm) (n=51) to evaluate these two S-1 based regimens as first-line treatment for AGC [ASCO-GI 2009: abstract 9.]. Among these patients, 99 patients were identified in this study excluding 2 patients who had died before receiving the allocated treatment and one patient who was lost to follow-up. All patients had performance status (PS) of 0-1 except for one with PS of 2. Pre-treatment clinical findings,...

Multicenter phase II study of triplet combination chemotherapy with paclitaxel, cisplatin, and S-1 for advanced gastric cancer (OGSG 0703).

124 Background: Docetaxel combined with cisplatin and 5-fluorouracil is active in advanced gastric cancer, but not generally accepted because of its substantial toxicities. We conducted a multicenter phase II study of triplet combination using paclitaxel, cisplatin and S-1 (PCS) as first-line treatment for advanced gastric cancer.nnnMETHODSnPatients with previously untreated, locally advanced or metastatic measurable gastric cancer, a performance status < 2, age of 20-75 years, and adequate organ functions were given intravenous paclitaxel at 70 mg/m2 and cisplatin at 30 mg/m2 on days 1 and 15, plus oral S-1 at 40 mg/m2 b.i.d. on days 1 to 21, followed by 2-week rest, repeated every 5 weeks. Treatment was continued until disease progression or unacceptable toxicity occurred, or the patient refused the therapy. Study endpoints included overall response rate (ORR) as primary, progression free survival (PFS), overall survival (OS), and toxicity. Sample size of 40 patients was determined to reject the ORR of 55% under the expectation of 75% with a power of 80% and a one-sided α of 5%.nnnRESULTSnA total of 52 patients were enrolled in this study, among whom 49 were assessable for efficacy and 51 assessable for toxicity. ORR was 46.9% (95% CI: 32.5-61.7%). The median PFS and median OS were 5.4 months (95% CI: 4.1-7.0) and 11.5 months (95% CI: 7.3-16.1), respectively. Frequent grade 3/4 toxicities were neutropenia (51%), leucopenia (25%), anemia (20%), hyponatremia (16%), anorexia (14%), diarrhea (8%) and fatigue (8%). There was no treatment-related death.nnnCONCLUSIONSnTriplet combination chemotherapy with PCS demonstrated superior feasibility with promising antitumor activity, though which did not meet the statistical hypothesis, for advanced gastric cancer.

THE ACCURACY OF CT IMAGING DIAGNOSIS OF LYMPH NODES METASTASIS OF GASTRIC CANCER

In surgical resection of gastric cancer, upper abdominal CT scan is usually performed, but the diagnosing method of the presence of abdominal lymph node metastasis has not been established as yet. The purpose of this study was to evaluate the accuracy of diagnosing criteria for the lymph nodes metastasis that was designed based on CT imagings of cases of gastric cancer. Subjects were 72 cases of advanced gastric cancer who underwent gastrectomy with lymph noede dissection at the hospital. In our criteria, lymph node with the diameter of 1cm or more and smooth circumference on CT imaging was designated positive lymph node. The dissected lymph nodes from the 72 cases were analyzed according to our criteria, and compared with histological findings for the accuracy of CT imaging diagnosis. The corect diagnosing rates by locations were as low as 56.5%, 47.8%, and 75.0% at the lesser curvature area, greater curvature area, and celiac artery area, respectively. In conclusion, the diagnosing ability of metastasis of gastric cancer to lymph nodes by CT is poor at present, and examinations other than CT are required for more accurate assessment.