Akira Fukutomi

Randomized Phase III Study of Gemcitabine Plus S-1, S-1 Alone, or Gemcitabine Alone in Patients With Locally Advanced and Metastatic Pancreatic Cancer in Japan and Taiwan: GEST Study

PURPOSE The present phase III study was designed to investigate the noninferiority of S-1 alone and superiority of gemcitabine plus S-1 compared with gemcitabine alone with respect to overall survival. PATIENTS AND METHODS The participants were chemotherapy-naive patients with locally advanced or metastatic pancreatic cancer. Patients were randomly assigned to receive only gemcitabine (1,000 mg/m(2) on days 1, 8, and 15 of a 28-day cycle), only S-1 (80, 100, or 120 mg/d according to body-surface area on days 1 through 28 of a 42-day cycle), or gemcitabine plus S-1 (gemcitabine 1,000 mg/m(2) on days 1 and 8 plus S-1 60, 80, or 100 mg/d according to body-surface area on days 1 through 14 of a 21-day cycle). RESULTS In the total of 834 enrolled patients, median overall survival was 8.8 months in the gemcitabine group, 9.7 months in the S-1 group, and 10.1 months in the gemcitabine plus S-1 group. The noninferiority of S-1 to gemcitabine was demonstrated (hazard ratio, 0.96; 97.5% CI, 0.78 to 1.18; P < .001 for noninferiority), whereas the superiority of gemcitabine plus S-1 was not (hazard ratio, 0.88; 97.5% CI, 0.71 to 1.08; P = .15). All treatments were generally well tolerated, although hematologic and GI toxicities were more severe in the gemcitabine plus S-1 group than in the gemcitabine group. CONCLUSION Monotherapy with S-1 demonstrated noninferiority to gemcitabine in overall survival with good tolerability and presents a convenient oral alternative for locally advanced and metastatic pancreatic cancer.

Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan.

Background:A British randomised study of gemcitabine plus cisplatin (GC) combination showed promising results in biliary tract cancer (BTC) patients. In our study, we evaluated the efficacy and safety of this combination compared with gemcitabine alone (G) in Japanese BTC patients.Methods:Overall, 84 advanced BTC patients were randomised to either cisplatin 25 mg m−2 plus gemcitabine 1000 mg m−2 on days 1, 8 of a 21-day cycle (GC-arm), or single-agent gemcitabine 1000 mg m−2 on days 1, 8 and 15 of a 28-day cycle (G-arm). Treatments were repeated for at least 12 weeks until disease progression or unacceptable toxicity occurred, up to a maximum of 48 weeks.Results:A total of 83 patients were included in the analysis. For the GC and G-arms, respectively, the 1-year survival rate was 39.0 vs 31.0%, median survival time 11.2 vs 7.7 months, median progression-free survival time 5.8 vs 3.7 months and overall response rate 19.5 vs 11.9%. The most common grade 3 or 4 toxicities (GC-arm/G-arm) were neutropenia (56.1%/38.1%), thrombocytopenia (39.0%/7.1%), leukopenia (29.3%/19.0%), haemoglobin decrease (36.6%/16.7%) and γ-GTP increase (29.3%/35.7%).Conclusions:Gemcitabine plus cisplatin combination therapy was found to be effective and well tolerated, suggesting that it could also be a standard regimen for Japanese patients.

Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01)

BACKGROUND Although adjuvant chemotherapy with gemcitabine is standard care for resected pancreatic cancer, S-1 has shown non-inferiority to gemcitabine for advanced disease. We aimed to investigate the non-inferiority of S-1 to gemcitabine as adjuvant chemotherapy for pancreatic cancer in terms of overall survival. METHODS We did a randomised, open-label, multicentre, non-inferiority phase 3 trial undertaken at 33 hospitals in Japan. Patients who had histologically proven invasive ductal carcinoma of the pancreas, pathologically documented stage I-III, and no local residual or microscopic residual tumour, and were aged 20 years or older were eligible. Patients with resected pancreatic cancer were randomly assigned (in a 1:1 ratio) to receive gemcitabine (1000 mg/m(2), intravenously administered on days 1, 8, and 15, every 4 weeks [one cycle], for up to six cycles) or S-1 (40 mg, 50 mg, or 60 mg according to body-surface area, orally administered twice a day for 28 days followed by a 14 day rest, every 6 weeks [one cycle], for up to four cycles) at the data centre by a modified minimisation method, balancing residual tumour status, nodal status, and institutions. The primary outcome was overall survival in the two treatment groups, assessed in the per-protocol population, excluding ineligible patients and those not receiving the allocated treatment. The protocol prespecified that the superiority of S-1 with respect to overall survival was also to be assessed in the per-protocol population by a log-rank test, if the non-inferiority of S-1 was verified. We estimated overall and relapse-free survival using the Kaplan-Meier methods, and assessed non-inferiority of S-1 to gemcitabine using the Cox proportional hazard model. The expected hazard ratio (HR) for mortality was 0.87 with a non-inferiority margin of 1.25 (power 80%; one-sided type I error 2.5%). This trial is registered at UMIN CTR (UMIN000000655). FINDINGS 385 patients were randomly assigned to treatment between April 11, 2007, and June 29, 2010 (193 to the gemcitabine group and 192 to the S-1 group). Of these, three were exlcuded because of ineligibility and five did not receive chemotherapy. The per-protocol population therefore consisted of 190 patients in the gemcitabine group and 187 patients in the S-1 group. On Sept 15, 2012, following the recommendation from the independent data and safety monitoring committee, this study was discontinued because the prespecified criteria for early discontinuation were met at the interim analysis for efficacy, when all the protocol treatments had been finished. Analysis with the follow-up data on Jan 15, 2016, showed HR of mortality was 0.57 (95% CI 0.44-0.72, pnon-inferiority<0.0001, p<0.0001 for superiority), associated with 5-year overall survival of 24.4% (18.6-30.8) in the gemcitabine group and 44.1% (36.9-51.1) in the S-1 group. Grade 3 or 4 leucopenia, neutropenia, aspartate aminotransferase, and alanine aminotransferase were observed more frequently in the gemcitabine group, whereas stomatitis and diarrhoea were more frequently experienced in the S-1 group. INTERPRETATION Adjuvant chemotherapy with S-1 can be a new standard care for resected pancreatic cancer in Japanese patients. These results should be assessed in non-Asian patients. FUNDING Pharma Valley Center, Shizuoka Industrial Foundation, Taiho Pharmaceutical.

Weekly paclitaxel as second-line chemotherapy for advanced or recurrent gastric cancer

BackgroundPaclitaxel scheduled every 3 weeks has shown a response rate of ∼20% for gastric cancer, with modest hematological toxicity. Weekly administration of paclitaxel in patients with breast or ovarian cancer has shown equivalent efficacy and milder toxicity compared with an every-3 week schedule. We investigated, retrospectively, the antitumor effects and toxicity profiles of weekly paclitaxel for patients with metastatic or recurrent gastric cancer in clinical practice.MethodsIn 38 patients who had metastatic or recurrent histologically confirmed gastric cancer and a history of one prior chemotherapy regimen, other than paclitaxel or docetaxel, paclitaxel (8mg/m2) was administered weekly, three times every 4 weeks, with short-term premedication.ResultsAll 38 patients had had prior chemotherapy that included 5-fluorouracil, the fluoropyrimidine anticancer drug S-1, or cisplatin. The median number of courses in the present regimen was 6 (range, 1–44+). Dose intensity was 5mg/m2 per week, corresponding to 92% of the planned dose (6mg/m2 per week). The overall response rate was 24% (6/25) in measurable lesions, and pleural effusion and ascites disappeared in 2 of 7 patients (29%) and in 3 of 21 patients (14%), respectively. Median survival time was 151 days from the commencement of this treatment, with a median follow-up period of 260 days. Grade 3 or 4 leukopenia and neutropenia were observed in 11 (29%) and 12 (32%) patients, respectively. Seven patients (18%) died within 30 days of the last administration of paclitaxel.ConclusionWeekly paclitaxel seems to be active as second-line chemotherapy against metastatic and recurrent gastric cancer. Further study is needed to confirm the efficacy and safety of weekly paclitaxel.

Phase I study of TAS-102 treatment in Japanese patients with advanced solid tumours

Background:TAS-102 consists of α, α, α-trifluorothymidine (TFT) and an inhibitor of thymidine phosphorylase (TPI). We conducted a dose-escalation phase I study in Japanese patients with advanced solid tumours.Methods:TAS-102 was administered twice daily on days 1–5 and days 8–12 in a 28-day cycle to patients with solid tumours refractory to standard chemotherapy, to determine its maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics (PKs). MTD was evaluated in cycle 1.Results:Safety and PKs were evaluated in 21 patients treated with TAS-102 at 30, 40, 50, 60, or 70 mg m−2 per day. DLTs, such as grade 4 leucopenia, grade 4 neutropenia, and grade 4 thrombocytopenia, were observed in two patients at doses of 30 and 70 mg m−2. α, α, α-trifluorothymidine and TPI exposures increased dose dependently, and the percentage of decrease in neutrophil count and TFT exposure were significantly correlated. The disease control rate was 50.0% with a median progression-free survival of 2.4 months in 18 colorectal cancer patients. The dose of TAS-102 was not increased above 70 mg m−2 per day because of the increased tendency for grade 3 and 4 neutropenia, and 70 mg m−2 per day was the recommended dose for phase II studies.Conclusions:TAS-102 at 70 mg m−2 per day was tolerated in Japanese patients with advanced solid tumours. Phase II studies are ongoing in patients with colorectal cancer.

Randomized Phase III Trial of Adjuvant Chemotherapy with Gemcitabine versus S-1 in Patients with Resected Pancreatic Cancer: Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC-01)

A randomized controlled trial has begun in Japan to compare orally administered S-1 with intravenous gemcitabine (GEM) as adjuvant chemotherapy for patients with curatively resected pancreatic cancer. Patients are enrolled within 10 weeks after pancreatectomy to be treated for six months after assignment to either S-1 (80 mg/m(2)/day for four weeks, repeated similarly every six weeks for a total of four courses) or GEM (1000 mg/m(2) on days 1, 8 and 15, repeated similarly every four weeks for a total of six courses). The primary endpoint is overall survival; secondary endpoints include relapse-free survival, incidence of adverse events and health-related quality of life. Each treatment arm includes 180 patients, providing an expected hazard ratio of 0.87 and an upper margin of 1.25 (two-sided alpha-error, 0.05; power, 0.8). Follow-up abdominal computed tomography is repeated every three months during the first two years, then every six months for three years.

Phase II Study of Gemcitabine Chemotherapy Alone for Locally Advanced Pancreatic Carcinoma: JCOG0506

OBJECTIVE Chemoradiotherapy with 5-fluorouracil has been accepted as a standard care for locally advanced pancreatic cancer; however, it has not been shown to be superior to chemotherapy alone in the gemcitabine era. The present multicentre phase II study was conducted to evaluate the efficacy and safety of Gem monotherapy against locally advanced pancreatic cancer in comparison with the historical data of chemoradiotherapy with 5-fluorouracil. METHODS Eligibility criteria included patients with histologically proven locally advanced pancreatic cancer, all lesions encompassed by a square of 15 cm on one side, no prior treatment, good performance status and adequate organ function. Gemcitabine was given intravenously at a dose of 1000 mg/m(2) over 30 min on days 1, 8 and 15, repeated every 4 weeks. The primary endpoint was %1-year survival. Expected and threshold %1-year survival were 40 and 25%, respectively. RESULTS Between January 2006 and February 2007, 50 locally advanced pancreatic cancer patients were registered. The major grade 3-4 adverse events were neutropaenia (62%), thrombocytopaenia (18%), fatigue (12%) and infection-biliary tree (12%). Haematological toxicity was mostly transient and there was no episode of infection with grade 3-4 neutropaenia. Up to the final follow-up in February 2009, the median overall survival was 15.0 months with a %1-year survival of 64.0%. CONCLUSIONS Gemcitabine monotherapy demonstrated far better survival than historical data for chemoradiotherapy with 5-fluorouracil with mild toxicities. Gemcitabine could be consider as a standard treatment for locally advanced pancreatic cancer.

Endoscopic ultrasonography-guided fine needle aspiration biopsy using 22-gauge needle in diagnosis of autoimmune pancreatitis

BACKGROUNDS The effectiveness of endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) has not been fully evaluated in the diagnosis of autoimmune pancreatitis (AIP). AIM To evaluate the effectiveness of EUS-FNA using 22-gauge needles in the diagnosis of AIP. METHODS EUS-FNA was examined in 85 patients with pancreatic mass, including 64 patients with pancreatic cancer and 21 patients with AIP. We investigated ability of EUS-FNA using 22-gauge needle for the differential diagnosis between AIP and pancreatic cancer. We also compared the factors concerning FNA procedures (number of needle passes, size of lesion, device, and amount of obtained pancreatic tissue) between two diseases. RESULTS Tissues obtained from 21 patients with AIP, although none of them demonstrated histology suspicious for malignancy, did not show histological evidence definitive for AIP. The amount of obtained pancreatic tissue was almost equal between two diseases in each pancreatic location. Sensitivity, specificity, overall accuracy, and negative predictive value of histological diagnosis of pancreatic cancer were 92.2%, 100%, 94.1%, and 80.8%, respectively. CONCLUSION EUS-FNA using 22-gauge needle distinguished benign from malignant pancreatic mass with >90% of accuracy, regardless of the location. Hence, it was helpful for the clinical diagnosis of AIP, however not providing satisfactory samples for the histological diagnosis of AIP.

Phase II study of FOLFIRINOX for chemotherapy-naïve Japanese patients with metastatic pancreatic cancer.

The FOLFIRINOX combination of chemotherapy drugs had not been fully evaluated for Japanese pancreatic cancer patients. Therefore, we carried out a phase II study to examine the efficacy and safety of FOLFIRINOX in chemotherapy‐naïve Japanese patients with metastatic pancreatic cancer. FOLFIRINOX (i.v. infusion of 85 mg/m2 oxaliplatin, 180 mg/m2 irinotecan, and 200 mg/m2 l‐leucovorin, followed by a bolus of 400 mg/m2 fluorouracil and a 46‐h continuous infusion of 2400 mg/m2 fluorouracil) was given every 2 weeks. The primary endpoint was the response rate. The 36 enrolled patients received a median of eight (range, 1–25) treatment cycles. The response rate was 38.9% (95% confidence interval [CI], 23.1–56.5); median overall survival, 10.7 months (95% CI, 6.9–13.2); and median progression‐free survival, 5.6 months (95% CI, 3.0–7.8). Major grade 3 or 4 toxicities included neutropenia (77.8%), febrile neutropenia (22.2%), thrombocytopenia (11.1%), anemia (11.1%), anorexia (11.1%), diarrhea (8.3%), nausea (8.3%), elevated alanine aminotransferase levels (8.3%), and peripheral sensory neuropathy (5.6%). Febrile neutropenia occurred only during the first cycle. There were no treatment‐related deaths. FOLFIRINOX can be a standard regimen showing favorable efficacy and acceptable toxicity profile in chemotherapy‐naïve Japanese patients with metastatic pancreatic cancer.

Weekly paclitaxel for heavily treated advanced or recurrent gastric cancer refractory to fluorouracil, irinotecan, and cisplatin

BackgroundAlthough triweekly administration of paclitaxel is approved for gastric cancer in Japan, currently, the drug is often delivered with a weekly schedule because of the equivalent efficacy and lesser toxicity of this dosing schedule as compared with the triweekly administration schedule. Weekly administration of paclitaxel as second-line or first-line chemotherapy for gastric cancer has been reported to yield a response rate of about 20%. Because there has been no report of the efficacy of weekly paclitaxel in the third-line setting, this retrospective study investigated the efficacy and toxicities of weekly paclitaxel used in the third-line setting for the treatment of gastric cancer refractory to all three key drugs, fluorouracil, irinotecan, and cisplatin, used in clinical practice.MethodsIn 85 patients with advanced or recurrent histologically confirmed gastric adenocarcinoma who had failed to respond to prior chemotherapy regimens containing fluorouracil, irinotecan, and cisplatin, paclitaxel (80 mg/m2) was administered weekly, three times, for 3 weeks out of 4.ResultsThe median number of courses was 3 (range, 1–38). The overall response rate was 23.2% (19/82) in the patients with measurable lesions, and ascites disappeared in 15 of 48 patients (31.3%). Progression-free survival was 105 days and the median survival time was 201 days from the initiation of paclitaxel administration. Grade 3 or 4 leukopenia, neutropenia, anemia, and thrombocytopenia were observed in 25 (29%), 25 (29%), 37 (44%), and 3 (4%) patients. Other, nonhematological, toxicities were nausea, vomiting, anorexia, sensory neuropathy, fatigue, and febrile neutropenia.ConclusionWeekly paclitaxel administration shows activity against advanced gastric cancer also in the third-line setting.