Michitaka Nagase

Randomized, Open-Label, Phase III Study Comparing Irinotecan With Paclitaxel in Patients With Advanced Gastric Cancer Without Severe Peritoneal Metastasis After Failure of Prior Combination Chemotherapy Using Fluoropyrimidine Plus Platinum: WJOG 4007 Trial

PURPOSE This phase III study compared treatment with weekly paclitaxel and biweekly irinotecan in patients with advanced gastric cancer refractory to treatment with fluoropyrimidine plus platinum. PATIENTS AND METHODS Patients were randomly assigned to receive either paclitaxel (80 mg/m(2) on days 1, 8, and 15, every 4 weeks) or irinotecan (150 mg/m(2) on days 1 and 15, every 4 weeks). Primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), response rate, adverse events, and proportion of patients who received third-line chemotherapy. RESULTS Of 223 patients, 219 were eligible for analysis. Median OS was 9.5 months in 108 patients allocated to the paclitaxel group and 8.4 months in 111 patients allocated to the irinotecan group (hazard ratio [HR], 1.13; 95% CI, 0.86 to 1.49; P = .38). Median PFS was 3.6 months in the paclitaxel group and 2.3 months in the irinotecan group (HR, 1.14; 95% CI, 0.88 to 1.49; P = .33). Response rate was 20.9% in the paclitaxel group and 13.6% in the irinotecan group (P = .24). Common grade 3 to 4 adverse events were neutropenia (paclitaxel group, 28.7%; irinotecan group, 39.1%), anemia (21.3%; 30.0%), and anorexia (7.4%; 17.3%). Treatment-related deaths occurred in two patients (1.8%) in the irinotecan group. Third-line chemotherapy was administered in 97 patients (89.8%) after paclitaxel treatment and in 80 patients (72.1%) after irinotecan treatment (P = .001). CONCLUSION No statistically significant difference was observed between paclitaxel and irinotecan for OS. Both are reasonable second-line treatment options for advanced gastric cancer.

Phase II Study of Radiotherapy Employing Proton Beam for Hepatocellular Carcinoma

4024 Background: Proton beam radiotherapy (PRT) has an excellent depth-dose profile that can deliver high dose to the liver tumor without debilitating liver function compared to photon beam radiotherapy. It is reasonable to evaluate the safety and efficacy of PRT prospectively for hepatocellular carcinoma (HCC). METHODS Eligibility criteria for this study were: solitary HCC; neither surgery nor local ablation therapy were indicated; no ascites; age ≥20 years; Zubord performance status is 0∼2; no serious co-morbidities other than liver cirrhosis; written informed consent. Tumor close to the stomach or intestinal loop was not considered as a subject for this study. Clinical target volume (CTV) was defined as gross tumor volume plus 5 mm of lateral and cranio-caudal margin. PRT administering 76 GyE/20 fractions/5 weeks to the CTV was done using respiration-gated irradiation system (ReGIS) with 150∼190 MeV proton beam. Relative biological effectiveness of our proton beam was defined as 1.1. No patients received transarterial chemoembolization or local ablation in combination with PRT. RESULTS Thirty patients were enrolled between May 1999 and Feb. 2003. There were 20 male and 10 female with a median age of 70 years (range: 48∼87 years). Maximum tumor diameter ranged from 25 ∼ 82 mm (median 45 mm). All patients had liver cirrhosis of which the degree was Child class A in 9, B in 19, and C in 2. Acute reactions of PRT were well tolerated, and PRT were completed as planned in all patients. After a median follow-up period of 31 months (14∼54 months), only 1 patient experienced tumor recurrence within the CTV and 2-year actuarial local control rate was as 96% (95% confidence interval: 88%∼100%). Actuarial overall survival rate at 2 years was 64% (46∼83%). Pretreatment liver function that was evaluated with indocyanin green clearance at 15 minutes (ICG 15), and liver volume that received 30 GyE or more (V30) significantly correlated with overall survival. CONCLUSIONS Since PRT showed minimal acute toxicity and excellent tumor control within CTV, it is expected as one of the convincing non-surgical treatment options for HCC. ICG 15 and V30 were considered as useful indicators of patient prognosis. No significant financial relationships to disclose.

Phase II feasibility study of preoperative chemotherapy with docetaxel, cisplatin, and fluorouracil for esophageal squamous cell carcinoma

The combination of docetaxel, cisplatin, and 5‐fluorouracil (DCF) as preoperative treatment for esophageal squamous cell carcinoma (ESCC) has not been investigated. We carried out a multicenter phase II feasibility study of preoperative chemotherapy with DCF for ESCC. Patients with clinical stage II/III ESCC (International Union Against Cancer TNM classification system, 6th edition) were eligible. Chemotherapy consisted of i.v. docetaxel (70–75 mg/m2) and cisplatin (70–75 mg/m2) on day 1, and continuous infusion of fluorouracil (750 mg/m2/day) on days 1–5. Antibiotic prophylaxis on days 5–15 was mandatory. This regimen was repeated every 3 weeks with a maximum of three cycles allowed. After completion of chemotherapy, esophagectomy with extended lymphadenectomy was carried out. The primary endpoint was the completion rate of protocol treatment. Forty‐two eligible patients were enrolled. During chemotherapy, the most common grade 3 or 4 toxicities were neutropenia (83%), anorexia (7%), and stomatitis (5%). Forty‐one (98%) patients underwent surgery. The completion rate of protocol treatment was 90.5% (38/42). No treatment‐related death was observed and the incidence of operative morbidity was tolerable. According to RECIST, the overall response rate after the completion of DCF was 64.3%. Pathological complete response was achieved in 17%. The estimated 2‐year progression‐free survival and overall survival were 74.5% and 88.0%, respectively. Although these data are preliminary, preoperative DCF was well tolerated. Antitumor activity was highly promising and warrants further investigation. This trial was registered with University Hospital Medical Information Network (no. UMIN000002396).

Evaluation of Contrast Enhancement Patterns in Pancreatic Tumors by Coded Harmonic Sonographic Imaging With a Microbubble Contrast Agent

Objective. The purpose of the study was to assess patterns of primary pancreatic lesions by contrast‐enhanced sonography for differentiating ductal carcinomas from other pancreatic tumors. Methods. One hundred six consecutive patients with pancreatic masses, consisting of 83 ductal carcinomas, 7 endocrine carcinomas, 5 intraductal papillary mucinous tumors, 3 cases of autoimmune‐related pancreatitis, 3 solid pseudopapillary tumors, 2 cases of chronic pancreatitis, 1 serous cystadenoma, 1 osteoclastoid giant cell tumor, and 1 follicular lymphoma, were examined by contrast‐enhanced sonography with coded harmonic imaging in a phase inversion harmonic technique. The contrast enhancement patterns were assessed, and specimens removed during pancreatectomy were subjected to pathologic examination. Results. Internal tumoral vascularity was detected in 47 (56.6%) of the 83 ductal carcinomas. Vascular image spreading and homogeneous staining throughout the tumors were observed in all endocrine carcinomas. Two of the 5 intraductal papillary mucinous tumors were positive for enhancement effects. Enhancement effects were observed in all 3 cases of autoimmune‐related pancreatitis, but the degree varied. There was a significant correlation between the intensity of enhancement effects and the ratio of patent vessels in the tumors (P < .05). Conclusions. Vascularity was detected by contrast‐enhanced sonography in only about half of the ductal carcinomas, confirming the difficulty in distinguishing those tumors from other pancreatic tumors. There was a correlation between the patency of the vessels in the tumors and their vascularity.

A Phase I Study of Combination Chemotherapy with Gemcitabine and Oral S-1 for Advanced Pancreatic Cancer

Objective: The aim of this study was to determine the maximum-tolerated dose and dose-limiting toxicity (DLT) of combination therapy with gemcitabine and S-1 in patients with advanced pancreatic cancer. Methods: Chemotherapy-naive patients with histologically or cytologically proven unresectable or metastatic pancreatic cancer were enrolled. The patients received gemcitabine intravenously over 30 min on days 1 and 8 and S-1 orally twice daily from days 1 to 14. Cycles were repeated every 21 days until disease progression. Patients were scheduled to receive gemcitabine (mg/m2/week) and S-1 (mg/m2/day) at four dose levels: 800/60 (level 1), 1,000/60 (level 2), 1,000/70 (level 3) and 1,000/80 (level 4). Results: Eighteen patients were enrolled in this study. The maximum-tolerated dose was not reached even at the highest dose level (level 4) because only 2 of the 6 patients at this level experienced DLT. The DLTs were neutropenia and rash. Six (33%) of the 18 patients achieved a partial response and median overall survival time was 7.6 months. Conclusions: Combination chemotherapy with gemcitabine and S-1 was well tolerated and showed good antitumor activity in the treatment of pancreatic cancer. We recommend a gemcitabine dose of 1,000 mg/m2/week and an S-1 dose of 80 mg/m2/day in further studies with this schedule.

Chemotherapy in the treatment of advanced gallbladder cancer

Objective: To clarify the role of chemotherapy for advanced gallbladder cancer (GBC). Methods: We reviewed 89 GBC patients: 21 admitted before 1997 were treated with a combination of cisplatin, epirubicin, and 5-fluorouracil (CEF); 25, admitted subsequently, received a combination of 5-fluorouracil, doxorubicin and mitomycin (FAM), and the remaining 43, ineligible for these trials, received supportive care. We investigated the relation between pretreatment clinical variables and long-term survival in these 89 subjects, and analyzed whether chemotherapy could favor longer survival. Results: There were no significant differences in survival time between the chemotherapy groups, whereas the response rate to the CEF regimen was 4-fold higher than to the FAM regimen (32 vs. 8%). Subgroup analysis suggested that chemotherapy favored longer survival in patients with a performance status (PS) of 0 or 1, but not in patients with a PS of 2. Cox regression analysis suggested a significant hazard reduction by chemotherapy in patients with a PS of 0 or 1, but not in patients with a PS of 2. Conclusions: GBC patients with poor PS should not be treated with chemotherapy at present. It is essential to design good clinical trials and develop more effective chemotherapy regimens.

Intraoperative and conformal external-beam radiation therapy with protracted 5-fluorouracil infusion in patients with locally advanced pancreatic carcinoma

Chemoradiotherapy is widely used for patients with locally advanced pancreatic carcinoma. The purpose of this study was to clarify the efficacy and feasibility of chemoradiotherapy with more intensive radiotherapy in these patients, using a combination of intraoperative radiotherapy (IORT), conformal external‐beam radiaotherapy (EBRT), and protracted 5‐fluorouracil (5‐FU).

A multicenter phase II trial of S-1 with concurrent radiation therapy for locally advanced pancreatic cancer

PURPOSE The aim of this trial was to evaluate the efficacy and toxicity of S-1 and concurrent radiation therapy for locally advanced pancreatic cancer (PC). METHODS AND MATERIALS Locally advanced PC patients with histologically or cytologically confirmed adenocarcinoma or adenosquamous carcinoma, who had no previous therapy were enrolled. Radiation therapy was delivered through 3 or more fields at a total dose of 50.4 Gy in 28 fractions over 5.5 weeks. S-1 was administered orally at a dose of 80 mg/m2 twice daily on the day of irradiation during radiation therapy. After a 2- to 8-week break, patients received a maintenance dose of S-1 (80 mg/m2/day for 28 consecutive days, followed by a 14-day rest period) was then administered until the appearance of disease progression or unacceptable toxicity. The primary efficacy endpoint was survival, and the secondary efficacy endpoints were progression-free survival, response rate, and serum carbohydrate antigen 19-9 (CA19-9) response; the safety endpoint was toxicity. RESULTS Of the 60 evaluable patients, 16 patients achieved a partial response (27%; 95% confidence interval [CI], 16%-40%). The median progression-free survival period, overall survival period, and 1-year survival rate of the evaluable patients were 9.7 months (95% CI, 6.9-11.6 months), 16.2 months (95% CI, 13.5-21.3 months), and 72% (95%CI, 59%-82%), respectively. Of the 42 patients with a pretreatment serum CA19-9 level of ≥100 U/ml, 34 (81%) patients showed a decrease of greater than 50%. Leukopenia (6 patients, 10%) and anorexia (4 patients, 7%) were the major grade 3-4 toxicities with chemoradiation therapy. CONCLUSIONS The effect of S-1 with concurrent radiation therapy in patients with locally advanced PC was found to be very favorable, with only mild toxicity.

Adverse hepatic events caused by radiotherapy for advanced hepatocellular carcinoma.

Background:  Radiotherapy is often used to treat patients with unresectable advanced hepatocellular carcinoma (HCC). The present study examines the nature and frequency of adverse events with respect to liver function in such patients after radiotherapy.

Impact of gemcitabine on the treatment of metastatic pancreatic cancer

Background and Aim:  A previous randomized trial showed gemcitabine was superior to 5‐fluorouracil in overall patient survival. However, the incremental improvement in survival was minimal. It is 2.5 years since gemcitabine has become available for the treatment of pancreatic cancer in clinical practice in Japan. The current study was conducted to examine whether treatment outcomes have changed since the introduction of gemcitabine therapy.