Yasuo Hamamoto

Appearance of enhanced tissue features in narrow-band endoscopic imaging

This study was performed to examine the usefulness of medical endoscopic imaging utilizing narrow-band illumination. The contrast between the vascular pattern and the adjacent mucosa of the underside of the human tongue was measured using five narrow-band illuminations and three broadband illuminations. The results demonstrate that the pathological features of a vascular pattern are dependent on the center wavelength and the bandwidth of illumination. By utilizing narrow-band illumination of 415+/-30 nm, the contrast of the capillary pattern in the superficial layer was markedly improved. This is an important benefit that is difficult to obtain with ordinary broadband illumination. The appearances of capillary patterns on color images were evaluated for three sets of filters. The narrow, band imaging (NBI) filter set (415+/-30 nm, 445+/-30 nm, 500+/-30 nm) was selected to achieve the preferred appearance of the vascular patterns for clinical tests. The results of clinical tests in colonoscopy and esophagoscopy indicated that NBI will be useful as a supporting method for observation of the endoscopic findings of early cancer.

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.

Usefulness of narrow-band imaging endoscopy for diagnosis of Barrett's esophagus

BackgroundA newly developed endoscope lighting system called a narrow-band imaging system emphasizes certain histological features such as capillary and crypt patterns. The usefulness of NBI for the diagnosis of Barrett’s esophagus (BE) was evaluated.MethodsEleven patients with previously diagnosed BE were enrolled in this study. Magnifying endoscopy was performed by an experienced endoscopist, using both a conventional system and an NBI system. All images were recorded by video and by a digital still image filing system. Differences in images were evaluated by another experienced endoscopist. The quality of images for the visualization of the esophagogastric junction, capillary vessels, and columnar-lined esophagus (CLE) was judged as: optimal (score of 4), diagnostic (3), suboptimal (2), or nondiagnostic (1).ResultsIn contrast to the low rate of visualization of the esophagogastric junction by conventional endoscopy, visualization of this area endoscopy was better by NBI. Net-like blood vessels were more clearly seen on images obtained by NBI endoscopy. Visualization of the CLE was better by NBI endoscopy than by conventional endoscopy. In contrast to conventional endoscopy, NBI endoscopy captured the optimal view of Barrett’s epithelium. The relationship between the endoscopic and histopathologic diagnoses was more accurate by NBI endoscopy than by conventional endoscopy.ConclusionsMagnifying endoscopy by NBI is more useful than conventional magnifying endoscopy for the diagnosis of BE.

Multicenter Phase II Study of Everolimus in Patients With Previously Treated Metastatic Gastric Cancer

PURPOSE Everolimus, an oral inhibitor of the mammalian target of rapamycin, has shown antitumor activity in gastric cancer in preclinical and phase I studies. This phase II study evaluated the efficacy and safety of everolimus in pretreated patients with advanced gastric cancer. PATIENTS AND METHODS Patients with advanced gastric cancer who experienced progression despite prior chemotherapy received everolimus 10 mg orally daily until disease progression or study discontinuation. The primary end point was disease control rate (DCR; ie, complete response, partial response, or stable disease). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. RESULTS Fifty-three patients were assessable (median age, 63 years; 51% and 49% received one or two prior chemotherapy regimens, respectively). Although no complete or partial response was obtained, a decrease in tumor size from baseline was observed in 45% of patients by central review. The DCR was 56.0% (95% CI, 41.3% to 70.0%); median PFS was 2.7 months (95% CI, 1.6 to 3.0 months). At a median follow-up time of 9.6 months, median OS was 10.1 months (95% CI, 6.5 to 12.1 months). Common grade 3 or 4 adverse events included anemia, hyponatremia, increased gamma-glutamyltransferase, and lymphopenia. Grade 1 or 2 pneumonitis was reported in eight patients (15.1%). CONCLUSION Everolimus monotherapy resulted in a promising DCR in patients with previously treated advanced gastric cancer. Adverse events are consistent with the reported safety profile of everolimus. These results warrant further evaluation in patients with advanced gastric cancer.

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).

Randomized phase II study of gemcitabine plus S‐1 versus S‐1 in advanced biliary tract cancer: A Japan Clinical Oncology Group trial (JCOG 0805)

The oral fluoropyrimidine, S‐1, combined with or without gemcitabine is considered to be a promising agent for treating advanced biliary tract cancer; gemcitabine plus cisplatin is the current standard regimen. This randomized phase II trial was designed to evaluate the safety and efficacy of two regimens: gemcitabine plus S‐1 (GS) (gemcitabine: 1000 mg/m2, day 1 and day 8; S‐1: 60 mg/m2, twice daily on days 1–14, repeated every 3 weeks); and S‐1 (80 mg/m2, days 1–28, given orally twice daily for 4 weeks, followed by a 2‐week rest, repeated every 6 weeks). The regimen with a higher 1‐year survival would be selected for a subsequent phase III trial. Between February 2009 and April 2010, 101 patients were randomized. For the GS (n = 51) and S‐1 (n = 50) arms, the 1‐year survival was 52.9% (95% confidence interval, 38.5–65.5) and 40.0% (95% confidence interval, 26.5–53.1), and the median survival times were 12.5 and 9.0 months, respectively. Grade 3/4 hematological toxicities were more frequent in the GS arm (leucocytes 29.4%, neutrophils 60.8%, hemoglobin 11.8%, platelets 11.8%) than in the S‐1 arm (leucocytes 2.0%, neutrophils 4.0%, hemoglobin 4.0%, platelets 4.0%). Although two treatment‐related deaths occurred in the GS arm, all other grade 3/4 non‐hematological toxicities were reversible. In conclusion, GS was considered to be more promising and was selected as the test regimen for a subsequent phase III trial comparing GS with gemcitabine plus cisplatin combination therapy. This study was registered at the UMIN Clinical Trials Registry as UMIN 000001685 (http://www.umin.ac.jp/ctr/index.htm).

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.

A Phase 2 Clinical Trial of Panitumumab Monotherapy in Japanese Patients with Metastatic Colorectal Cancer

OBJECTIVE Panitumumab, a fully human monoclonal antibody targeting epidermal growth factor receptor (EGFR), has antitumor activity and an acceptable safety profile in patients with metastatic colorectal cancer (mCRC). This Phase 2 study evaluated efficacy, pharmacokinetics and safety of panitumumab in Japanese patients with mCRC who developed progressive disease during or after fluoropyrimidine, irinotecan and oxaliplatin chemotherapy. METHODS Eligible patients had histologically proven colorectal adenocarcinoma and EGFR tumor expression in > or =1% of tumor cells by immunohistochemistry. Patients received panitumumab 6 mg/kg every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) per modified Response Evaluation Criteria in Solid Tumors (RECIST) by independent central review. Secondary endpoints included progression-free survival (PFS), overall survival (OS), pharmacokinetic parameters and incidence of adverse events. RESULTS Fifty-two patients received at least one dose of panitumumab. Seven patients had partial responses for a confirmed ORR of 13.5% (95% CI: 5.6, 25.8). Median PFS was 8.0 weeks (95% CI: 7.4, 11.4) and median OS was 9.3 months (95% CI: 7.1, 12.8). Panitumumab pharmacokinetics were consistent with prior studies in Japanese and non-Japanese patients. The most common treatment-related adverse events (all, worst grade 3) were acne (81%, 2%), dry skin (62%, 0%), rash (46%, 2%), paronychia (33%, 2%), pruritus (33%, 0%) and hypomagnesemia (33%, 0%). No adverse event of infusion reaction was reported by the investigators. CONCLUSIONS Panitumumab monotherapy was active in Japanese patients with chemotherapy-refractory mCRC, with pharmacokinetic and safety profiles similar to those seen in prior studies.

Phase I/II study of capecitabine plus oxaliplatin (XELOX) plus bevacizumab as first-line therapy in Japanese patients with metastatic colorectal cancer.

Objective The addition of bevacizumab to fluoropyrimidine-based combination chemotherapy as first-line therapy for metastatic colorectal cancer results in clinically significant improvements in patient outcome. However, clinical trials have been conducted primarily in Caucasian patients with only a small proportion of Asian patients. This Phase I/II study was designed to evaluate the efficacy and safety of XELOX (capecitabine plus oxaliplatin) plus bevacizumab in Japanese patients with metastatic colorectal cancer. Methods Patients with previously untreated, measurable metastatic colorectal cancer received bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m2 on day 1, plus capecitabine 1000 mg/m2 twice daily on days 1–14, every 3 weeks. A three-step design evaluated in: step 1, initial safety of XELOX in six patients; step 2, initial safety of XELOX plus bevacizumab in six patients; and step 3, efficacy and safety in a further 48 patients. The primary study endpoints were safety and response rate. Results No dose-limiting toxicity occurred during Steps 1 and 2. Fifty-eight patients were enrolled in Steps 2 and 3 and received XELOX plus bevacizumab. In the 57 patients assessed for response, the overall response rate was 72% (95% confidence interval, 58.5–83.0). Median progression-free survival was 11.0 months (95% confidence interval, 9.6–12.5) and median overall survival was 27.4 months (95% confidence interval, 22.0–not calculated). Eight patients (14%) underwent surgery with curative intent. The most common grade 3/4 adverse events were neurosensory toxicity (17%) and neutropenia (16%). Conclusions XELOX plus bevacizumab is effective and has a manageable tolerability profile when given to Japanese patients with metastatic colorectal cancer.

Randomized Phase III Study of 5-Fluorouracil Continuous Infusion vs. Sequential Methotrexate and 5-Fluorouracil Therapy in Far Advanced Gastric Cancer with Peritoneal Metastasis (JCOG0106)

OBJECTIVE Owing to the risks of serious and sustained toxicity, anticancer drugs such as cisplatin and irinotecan cannot be readily administered to patients with gastric cancer and severe peritoneal metastasis. Therefore, a standard chemotherapy regimen has yet to be established for these types of patients. This randomized study investigated the utility of sequential methotrexate and 5-fluorouracil therapy vs. 5-fluorouracil continuous infusion for gastric cancer with peritoneal metastasis. METHODS Eligible patients had radiologically confirmed peritoneal metastasis with intestinal stenosis, peritoneal tumor or ascites. Treatment with 5-fluorouracil continuous infusion (800 mg/m(2)/day, ci, d1-5, q4w) or methotrexate and 5-fluorouracil therapy (methotrexate, 100 mg/m(2), bolus infusion, followed 3 h later by 5-fluorouracil, 600 mg/m(2), bolus infusion, with leucovorin rescue, q1w) was continued until disease progression or unacceptable toxicity. The projected sample size was 236, providing 80% power to detect a 40% increase in median overall survival in methotrexate and 5-fluorouracil therapy with a one-sided α of 0.05. RESULTS All 237 randomized patients were included in the primary analysis. The methotrexate and 5-fluorouracil therapy arm was not superior to the 5-fluorouracil continuous infusion arm (median survival time, 9.4 months in the 5-fluorouracil continuous infusion arm, 10.6 months in the methotrexate and 5-fluorouracil therapy arm; hazard ratio, 0.94; 95% confidence interval, 0.72-1.22; one-sided P = 0.31). Frequencies of Grade 3 or higher neutropenia, Grade 3 or higher anorexia and treatment-related deaths were 0.9, 27.4 and 1.7%, respectively, in the 5-fluorouracil continuous infusion arm, and 31.9, 33.6 and 0.9%, respectively, in the methotrexate and 5-fluorouracil therapy arm. CONCLUSIONS Methotrexate and 5-fluorouracil therapy is not suitable for use as standard therapy for advanced gastric cancer with peritoneal metastasis.