Akira Sawaki

Bevacizumab in Combination With Chemotherapy As First-Line Therapy in Advanced Gastric Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase III Study

PURPOSE The Avastin in Gastric Cancer (AVAGAST) trial was a multinational, randomized, placebo-controlled trial designed to evaluate the efficacy of adding bevacizumab to capecitabine-cisplatin in the first-line treatment of advanced gastric cancer. PATIENTS AND METHODS Patients received bevacizumab 7.5 mg/kg or placebo followed by cisplatin 80 mg/m(2) on day 1 plus capecitabine 1,000 mg/m(2) twice daily for 14 days every 3 weeks. Fluorouracil was permitted in patients unable to take oral medications. Cisplatin was given for six cycles; capecitabine and bevacizumab were administered until disease progression or unacceptable toxicity. The primary end point was overall survival (OS). Log-rank test was used to test the OS difference. RESULTS In all, 774 patients were enrolled; 387 were assigned to each treatment group (intention-to-treat population), and 517 deaths were observed. Median OS was 12.1 months with bevacizumab plus fluoropyrimidine-cisplatin and 10.1 months with placebo plus fluoropyrimidine-cisplatin (hazard ratio 0.87; 95% CI, 0.73 to 1.03; P = .1002). Both median progression-free survival (6.7 v 5.3 months; hazard ratio, 0.80; 95% CI, 0.68 to 0.93; P = .0037) and overall response rate (46.0% v 37.4%; P = .0315) were significantly improved with bevacizumab versus placebo. Preplanned subgroup analyses revealed regional differences in efficacy outcomes. The most common grade 3 to 5 adverse events were neutropenia (35%, bevacizumab plus fluoropyrimidine-cisplatin; 37%, placebo plus fluoropyrimidine-cisplatin), anemia (10% v 14%), and decreased appetite (8% v 11%). No new bevacizumab-related safety signals were identified. CONCLUSION Although AVAGAST did not reach its primary objective, adding bevacizumab to chemotherapy was associated with significant increases in progression-free survival and overall response rate in the first-line treatment of advanced gastric cancer.

Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial.

BACKGROUND Patients with advanced gastric cancer have a poor prognosis and few efficacious treatment options. We aimed to assess the addition of cetuximab to capecitabine-cisplatin chemotherapy in patients with advanced gastric or gastro-oesophageal junction cancer. METHODS In our open-label, randomised phase 3 trial (EXPAND), we enrolled adults aged 18 years or older with histologically confirmed locally advanced unresectable (M0) or metastatic (M1) adenocarcinoma of the stomach or gastro-oesophageal junction. We enrolled patients at 164 sites (teaching hospitals and clinics) in 25 countries, and randomly assigned eligible participants (1:1) to receive first-line chemotherapy with or without cetuximab. Randomisation was done with a permuted block randomisation procedure (variable block size), stratified by disease stage (M0 vs M1), previous oesophagectomy or gastrectomy (yes vs no), and previous (neo)adjuvant (radio)chemotherapy (yes vs no). Treatment consisted of 3-week cycles of twice-daily capecitabine 1000 mg/m(2) (on days 1-14) and intravenous cisplatin 80 mg/m(2) (on day 1), with or without weekly cetuximab (400 mg/m(2) initial infusion on day 1 followed by 250 mg/m(2) per week thereafter). The primary endpoint was progression-free survival (PFS), assessed by a masked independent review committee in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. This study is registered at EudraCT, number 2007-004219-75. FINDINGS Between June 30, 2008, and Dec 15, 2010, we enrolled 904 patients. Median PFS for 455 patients allocated capecitabine-cisplatin plus cetuximab was 4.4 months (95% CI 4.2-5.5) compared with 5.6 months (5.1-5.7) for 449 patients who were allocated to receive capecitabine-cisplatin alone (hazard ratio 1.09, 95% CI 0.92-1.29; p=0.32). 369 (83%) of 446 patients in the chemotherapy plus cetuximab group and 337 (77%) of 436 patients in the chemotherapy group had grade 3-4 adverse events, including grade 3-4 diarrhoea, hypokalaemia, hypomagnesaemia, rash, and hand-foot syndrome. Grade 3-4 neutropenia was more common in controls than in patients who received cetuximab. Incidence of grade 3-4 skin reactions and acne-like rash was substantially higher in the cetuximab-containing regimen than in the control regimen. 239 (54%) of 446 in the cetuximab group and 194 (44%) of 436 in the control group had any grade of serious adverse event. INTERPRETATION Addition of cetuximab to capecitabine-cisplatin provided no additional benefit to chemotherapy alone in the first-line treatment of advanced gastric cancer in our trial. FUNDING Merck KGaA.

Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study

BACKGROUND The best chemotherapy regimen for metastatic gastric cancer is uncertain, but promising findings have been reported with irinotecan plus cisplatin and S-1 (tegafur, 5-chloro-2,4-dihydropyrimidine, and potassium oxonate). We aimed to investigate the superiority of irinotecan plus cisplatin and non-inferiority of S-1 compared with fluorouracil, with respect to overall survival, in patients with metastatic gastric cancer. METHODS We undertook a phase 3 open label randomised trial in 34 institutions in Japan. We enrolled patients aged 20-75 years or younger, who had histologically proven gastric adenocarcinoma, and randomly assigned them by minimisation to receive either: a continuous infusion of fluorouracil (800 mg/m(2) per day, on days 1-5) every 4 weeks (n=234); intravenous irinotecan (70 mg/m(2), on days 1 and 15) and cisplatin (80 mg/m(2), on day 1) every 4 weeks (n=236); or oral S-1 (40 mg/m(2), twice a day, on days 1-28) every 6 weeks (n=234). The primary endpoint was overall survival. Analyses were done by intention to treat. This study is registered with Clinicaltrials.gov, number NCT00142350, and with UMIN-CTR, number C000000062. FINDINGS All randomised patients were included in the primary analysis. Median overall survival was 10.8 months (IQR 5.7-17.8) for individuals assigned fluorouracil, 12.3 months (8.1-19.5) for those allocated irinotecan plus cisplatin (hazard ratio 0.85 [95% CI 0.70-1.04]; p=0.0552), and 11.4 months (6.4-21.3) for those assigned S-1 (0.83 [0.68-1.01]; p=0.0005 for non-inferiority). Three treatment-related deaths occurred in the irinotecan plus cisplatin group and one was recorded in the S-1 group. INTERPRETATION S-1 is non-inferior to fluorouracil and, in view of the convenience of an oral administration, could replace intravenous fluorouracil for treatment of unresectable or recurrent gastric cancer, at least in Asia. Irinotecan plus cisplatin is not superior to fluorouracil in this setting.

EUS-guided choledochoduodenostomy for palliative biliary drainage in patients with malignant biliary obstruction: Results of long-term follow-up

Five patients with obstructive jaundice caused by malignant periampullary biliary stenosis underwent EUS-guided choledochoduodenostomy (EUS-CDS) from the first portion of the duodenum using a convex echoendoscope and a needle knife. All the steps of the procedure including passage dilatation and the plastic stent placement were performed through the accessory channel of the echoendoscope over the guide wire. Stent insertion was technically successful in all five patients. The procedure was also clinically effective in relieving jaundice in all cases. One patient developed pneumoperitoneum, which resolved with conservative management. Stent exchange was successful in seven of eight attempts in patients with stent occlusion. One failure was due to tumor invasion to the choledochoduodenal fistula. Stent patency was maintained in the remaining patients throughout their survival period. The average stent patency was 211.8 days. EUS-CDS from the first portion of the duodenum appears to be feasible and safe in cases of obstructive jaundice caused by distal bile duct obstruction.

Diagnostic utility of EUS-guided FNA in patients with gastric submucosal tumors

BACKGROUND Submucosal tumors (SMTs) comprise both benign and malignant lesions, and most of the gastric lesions tend to be malignant. The addition of EUS-guided FNA (EUS-FNA) has the potential to improve this distinction, but published series are limited. OBJECTIVE To evaluate the yield of EUS-FNA in gastric SMTs with referral to a criterion standard final diagnosis. DESIGN Retrospective study. SETTING Tertiary-care referral center. PATIENTS This study involved 141 consecutive patients with gastric SMTs, who underwent EUS-FNA from January 2000 to December 2008. Immunohistochemical staining with c-kit, CD34, actin, and S-100 antibodies was done if a spindle cell tumor was found. Based on FNA sample adequacy, and whether a specific diagnosis could be established, EUS-FNA results were categorized as diagnostic, suggestive, or nondiagnostic. The criterion standards for final diagnosis were the surgical histopathological results or the follow-up course for malignant, inoperable cases. INTERVENTION EUS-FNA. MAIN OUTCOME MEASUREMENTS Diagnostic yield of EUS-FNA and factors related to sampling adequacy for cytological and immunohistochemical evaluation. RESULTS A total of 141 patients (52% female, mean age 56.7 years) underwent EUS-FNA (range 1-5 passes). The overall results of EUS-FNA were diagnostic, suggestive, and nondiagnostic in 43.3%, 39%, and 17.7% of cases, respectively. Adequate specimens were obtained in 83% of cases, and 69 cases (48.9%) had a definitive final diagnosis. The most common gastric SMT was GI stromal tumor (59.5%). EUS-FNA results were 95.6% accurate (95% confidence interval [CI], 87.5%-99%) for the final diagnosis and 94.2% (95% CI, 85.6%-98.1%) accurate for differentiating potentially malignant lesions. A heterogeneous echo pattern was the only independent predictor for sampling adequacy (adjusted odds ratio 6.15; P = .002). There were no procedure-related complications. LIMITATIONS Possibility of selection bias. CONCLUSION EUS-FNA is an accurate method for diagnosis of gastric SMTs and for differentiating malignant lesions.

Differential diagnosis of pancreatic cancer and focal pancreatitis by using EUS-guided FNA

BACKGROUND Despite advances in diagnostic imaging techniques, the differentiation between pancreatic cancer and focal pancreatitis remains difficult. This study evaluated the effectiveness of EUS-guided FNA in the differential diagnosis between pancreatic cancer and focal pancreatitis, with particular reference to detection of the K-ras point mutation. METHODS The study included 62 consecutive patients with pancreatic ductal cancer and 15 patients with focal pancreatitis demonstrated as a pancreatic mass lesion by EUS. RESULTS Sensitivity, specificity, overall accuracy, positive predictive value, and negative predictive value of cytopathologic diagnosis were 82%, 100%, 86%, 100%, and 58%, respectively. Sensitivity, specificity, overall accuracy, positive predictive value, and negative predictive value of histopathologic diagnosis were 44%, 100%, 55%, 100%, and 32%, respectively. The K-ras point mutation was found in 74% of pancreatic cancers and 0% of focal pancreatitis lesions. No complication of EUS-guided FNA was observed. CONCLUSIONS EUS-guided FNA is useful for the differential diagnosis of pancreatic mass lesions caused by pancreatic cancer and focal pancreatitis. Analysis for the K-ras point mutation in specimens obtained by EUS-guided FNA may enhance diagnostic accuracy in indeterminate cases.

Development of pancreatic cancers during long-term follow-up of side-branch intraductal papillary mucinous neoplasms

BACKGROUND AND STUDY AIMS Side-branch intraductal papillary mucinous neoplasms (SB-IPMNs), and associated synchronous and metachronous pancreatic cancers are increasingly detected as imaging modalities become more sensitive. We investigated the natural history of SB-IPMN, and the incidence and characteristics of pancreatic cancers among patients undergoing long-term follow-up. PATIENTS AND METHODS We reviewed the clinical, imaging, and pathological features in 103 patients, diagnosed at the Aichi Cancer Center between September 1988 and September 2006 as having SB-IPMN, and conservatively followed up for ≥ 2 years (median 59 months) based on an endoscopic ultrasonography (EUS) database. RESULTS 74 (71.8 %) patients had nonprogressive lesions. Overall, six patients (5.8 %) developed pancreatic cancers during follow-up, with intraductal papillary mucinous (IPM) carcinoma in four, and ductal carcinoma of pancreas that was not IPMN in two patients. Of the six pancreatic cancers, five were diagnosed at a resectable stage. The 5-year and 10-year actuarial rates of development of pancreatic cancer were 2.4 % and 20.0 %, respectively. Although, at the last follow-up, cyst size, main pancreatic duct (MPD) diameter, mural nodule size, and frequency of metachronous and/or synchronous cancers of other organs were significantly higher in patients who developed IPM carcinoma, resected SB-IPMNs without mural nodules and dilated MPDs had no IPM carcinomas. CONCLUSIONS The frequency of pancreatic cancers is high on long-term follow-up of SB-IPMN. Although conservative management is appropriate for selected patients, regular and long-term imaging, especially by EUS is essential, even if SB-IPMN remains unchanged for 2 years. Presence of mural nodule and dilated MPD seem to be more appropriate indicators for resection than cyst size alone for SB-IPMNs.

Prospective clinical study of EUS-guided choledochoduodenostomy for malignant lower biliary tract obstruction.

OBJECTIVES:Endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) has recently been reported as an alternative to percutaneous transhepatic biliary drainage (PTBD) in cases of biliary obstruction, when endoscopic biliary drainage (EBD) is unsuccessful. However, prospective studies of EUS-CDS have not yet been performed. We conducted a prospective study to evaluate the safety, feasibility, and efficacy of EUS-CDS in patients with malignant lower biliary tract obstruction.METHODS:A prospective study to confirm the safety of EUS-CDS was carried out in 6 patients, followed by a trial to evaluate the feasibility and efficacy of EUS-CDS in 12 additional patients. We placed a plastic stent from the duodenal bulb into the extrahepatic bile duct under EUS guidance using an oblique viewing echoendoscope, needle knife, guidewire, and biliary dilators.RESULTS:The site of extrahepatic bile duct puncture was the common hepatic duct in 15 patients and the common bile duct in 3 patients. Mean diameter of the punctured extrahepatic bile ducts was 10 mm (range: 6–20 mm). Technical and functional success rates were 94% (17/18) and 100% (17/17), respectively. Median procedure time was 30 min (range: 10–52 min). Median duration to first oral intake after the procedure was 1 day (range: 1–3 days). Early complications were encountered in three (17%) patients, including focal peritonitis in two patients and hemobilia in one patient. During the follow-up period (median: 163 days; range: 46–484 days), 12 stent occlusion events were observed in nine patients. Re-intervention with exchange of the occluded stent was successful in 8 of 12 (66%) times. Severe early and late complications were not encountered in any patients in this study. Median duration of stent patency by Kaplan–Meier analysis was 272 days.CONCLUSIONS:EUS-CDS is safe, feasible, and effective as an alternative to PTBD and EBD in cases of malignant distal biliary tract obstruction. Prospective randomized studies are needed to compare the safety and efficacy of various kinds of endoscopic devices used in EUS-CDS and to compare EUS-CDS with PTBD or EBD.

Risk factors for vitamin D deficiency in patients with Crohn’s disease

BackgroundAlthough the pathogenesis of osteopenia in Crohn’s disease is not established, vitamin D deficiency is thought to be an important risk factor. However, little is known about the prevalence of vitamin D deficiency in patients with Crohn’s disease in Japan. This study aimed to clarify the prevalence of vitamin D deficiency in patients with Crohn’s disease in Japan and to examine the possible causes of the deficiency.MethodsWe investigated serum 25-hydroxyvitamin D (25-OHD) levels, various laboratory parameters, and patient histories in 33 outpatients (25 men, 8 women; median age, 37 years; range, 26–57 years) and 15 age- and sex-matched healthy controls (8 men, 7 women; median age, 37 years; range, 24–57 years) and assessed risk factors for vitamin D deficiency.ResultsAlthough patients with Crohn’s disease did not have significantly lower serum concentrations of 25-OHD than controls, 9 of 33 patients (27.3%) were considered vitamin D deficient (serum 25-OHD level ≤10 ng/ml) compared with only 1 of 15 (6.7%) controls. Serum 25-OHD levels were significantly related to disease duration (r = 0.46, P = 0.003), Crohn’s Disease Activity Index (CDAI) score (r = 0.44, P = 0.005), International Organization for the Study of Inflammatory Bowel Disease score (r = 0.30, P < 0.05), and serum values of ferritin (r = 0.34, P = 0.03), C-reactive protein (r = 0.34, P = 0.03), total cholesterol (r = 0.31, P = 0.04), and intact parathyroid hormone (r = 0.23, P < 0.05). A logistic regression analysis was performed to investigate the ability of variables to predict low or normal 25-OHD values. Results showed that disease duration (P = 0.03) and CDAI score (P = 0.04) could predict the occurrence of vitamin D deficiency (r2 = 0.472, P = 0.0004).ConclusionsVitamin D deficiency exists in patients with Crohn’s disease in Japan. 25-OHD levels should be assessed in patients who have had Crohn’s disease for a long time (>15 years) and who have been in the active stage of the disease for long periods.

Endoscopic ultrasound-guided fine-needle aspiration biopsy for the diagnosis of gastrointestinal stromal tumors in the stomach.

BackgroundFor the diagnosis of gastric submucosal tumors (SMTs), endoscopic ultrasound (EUS) alone does not reveal the complete pathology, such as the degree of malignancy, and EUS-guided fine-needle aspiration biopsy (EUS-FNAB) has been reported to be more useful. Recently, most cases initially diagnosed as leiomyosarcomas have received further study with immunohistochemical staining and have been given the new diagnosis of gastrointestinal stromal tumors (GISTs). The degree of malignancy of GISTs differs widely in clinical aspects. In this study, we examined whether EUS-FNAB was useful in diagnosing GISTs and differentiating their degrees of malignancy.MethodsFrom January 1997 to March 2002, 21 cases of gastric GISTs were diagnosed from the immunohistochemical staining of specimens resected at Aichi Cancer Center Hospital. Of these 21 patients, 14 (5 with high-grade malignancy and 9 with low-grade malignancy) underwent EUS-FNAB preoperatively, and were examined further: their EUS-FNAB specimens were submitted for additional immunohistochemical testing.ResultsThe EUS-FNAB specimens from all patients were positive for c-kit and CD34 immunohistochemical testing, coinciding with the staining results of the resected specimens. The MIB-1 labeling indices in specimens of high-grade malignancy were significantly higher than those of low-grade malignancy. If we assumed that a tumor with an MIB-1 labeling index of more than 5% was a high-grade malignancy, the diagnostic accuracy was 85.7%.ConclusionsThe EUS-FNAB procedure is a useful tool for diagnosing GISTs of the stomach with immunohistochemical staining. When used with MIB-1 staining, the procedure may indicate GIST prognosis and influence decisions regarding therapeutic strategies.