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Liposomal irinotecan in metastatic pancreatic adenocarcinoma in Asian patients: Subgroup analysis of the NAPOLI-1 study.
Bang, YJ, Li, CP, Lee, KH, Chiu, CF, Park, JO, Shan, YS, Kim, JS, Chen, JS, Shim, HJ, Rau, KM, et al
Cancer science. 2020;(2):513-527
Abstract
The global, randomized NAPOLI-1 phase 3 trial reported a survival benefit with liposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (nal-IRI+5-FU/LV) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) after previous gemcitabine-based therapy. Median overall survival (OS) with nal-IRI+5-FU/LV was 6.1 vs 4.2 months with 5-FU/LV alone (unstratified hazard ratio [HR] = 0.67, P = .012). Herein, we report efficacy and safety results from a post-hoc subgroup analysis of Asian patients treated at Asian centers. Primary study endpoint was OS; secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. Patients receiving nal-IRI+5-FU/LV (n = 34) had significantly longer median OS versus 5-FU/LV (n = 35) (8.9 vs 3.7 months; unstratified HR = 0.51, P = .025). Patients had significantly increased median PFS with nal-IRI+5-FU/LV versus 5-FU/LV (4.0 vs 1.4; unstratified HR = 0.48, P = .011), and increased ORR (8.8% vs 0; P = .114). nal-IRI monotherapy (n = 50) numerically improved efficacy endpoints versus 5-FU/LV (n = 48): median OS was 5.8 versus 4.3 months (HR = 0.83, P = .423) and median PFS was 2.8 versus 1.4 months (HR = 0.69, P = .155). Grade ≥3 neutropenia was reported more frequently with nal-IRI+5-FU/LV versus 5-FU/LV (54.5% vs 3.4%), and incidence of grade ≥3 diarrhea was comparable between the two arms (3.0% vs 6.9%). This subgroup analysis confirms nal-IRI+5-FU/LV as an efficacious treatment option that improves survival in Asian patients with mPDAC that progressed after gemcitabine-based therapy, with a safety profile agreeing with previous findings. The nal-IRI+5-FU/LV regimen should represent a new standard of care for these patients in Asia. (Clinicaltrials.gov: NCT01494506).
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S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin as first-line therapy in patients with advanced gastric cancer (SOLAR): a randomised, open-label, phase 3 trial.
Kang, YK, Chin, K, Chung, HC, Kadowaki, S, Oh, SC, Nakayama, N, Lee, KW, Hara, H, Chung, IJ, Tsuda, M, et al
The Lancet. Oncology. 2020;(8):1045-1056
Abstract
BACKGROUND S-1 plus leucovorin and oxaliplatin showed promising efficacy for treatment of advanced gastric cancer in a randomised phase 2 study. We aimed to evaluate the efficacy and safety of oral TAS-118 (S-1 plus leucovorin) and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer. METHODS We did a randomised, open-label, phase 3 trial in 62 centres across Japan and South Korea. Patients aged 20 years or older, with a histologically confirmed advanced gastric cancer with negative or unknown HER2 status, with Eastern Cooperative Oncology Group performance status of 0 or 1, measurable or evaluable metastatic lesions, and no previous treatment were randomly assigned (1:1) via an interactive web response system using the minimisation method, stratified by performance status, presence of a measurable lesion, and country, to receive TAS-118 (S-1 40-60 mg and leucovorin 25 mg orally twice daily for 7 days) plus oxaliplatin (85 mg/m2 intravenously on day 1) every 2 weeks, or S-1 (40-60 mg orally twice daily) for 21 days plus cisplatin (60 mg/m2 intravenously on day 1 or 8) every 5 weeks. The primary endpoint was overall survival in patients who had advanced gastric cancer with measurable or evaluable metastatic lesions and who received the study drug. Safety was assessed in all patients who received the study drug. This study was registered at ClinicalTrials.gov, NCT02322593. FINDINGS Between Jan 28, 2015, and Dec 5, 2016, 711 patients were randomised to TAS-118 plus oxaliplatin (n=356) or S-1 plus cisplatin (n=355). 11 untreated patients and 19 ineligible patients were excluded from the primary analysis (TAS-118 plus oxaliplatin group n=347, S-1 plus cisplatin group n=334) following recommendation from the independent data monitoring committee. After median follow-up of 26·0 months (IQR 22·0-32·8), median overall survival was 16·0 months (95% CI 13·8-18·3) in the TAS-118 plus oxaliplatin group and 15·1 months (95% CI 13·6-16·4) in the S-1 plus cisplatin group (hazard ratio 0·83, 95% CI 0·69-0·99; p=0·039). The most common grade 3 or higher adverse events in the 352 patients in the TAS-118 plus oxaliplatin group and the 348 patients in the S-1 plus cisplatin group were anaemia (56 [16%] vs 64 [18%]), neutropenia (54 [15%] vs 88 [25%]), decreased appetite (53 [15%] vs 46 [13%]), diarrhoea (33 [9%] vs 15 [4%]), and peripheral sensory neuropathy (30 [9%] vs one [<1%]). Serious adverse events were observed in 155 (44%) of 352 patients in the TAS-118 plus oxaliplatin group and 159 (46%) of 348 patients in the S-1 plus cisplatin group. Two treatment-related deaths occurred in the TAS-118 plus oxaliplatin group (pulmonary tuberculosis and viral pneumonia). INTERPRETATION TAS-118 plus oxaliplatin showed a clinically meaningful improvement in efficacy compared with S-1 plus cisplatin, and could be considered a new first-line treatment option for advanced gastric cancer in Asian patients. FUNDING Taiho Pharmaceutical and Yakult Honsha.
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Efficacy of prolonged elemental diet therapy after pancreaticoduodenectomy for pancreatic ductal adenocarcinoma: A pilot prospective randomized trial (UMIN000004108).
Mori, R, Matsuyama, R, Taniguchi, K, Goto, K, Miyake, K, Hiratani, S, Homma, Y, Ohta, Y, Kumamoto, T, Morioka, D, et al
Clinical nutrition ESPEN. 2019;:116-124
Abstract
BACKGROUNDS AND AIMS This randomized clinical trial examined efficacy of prolonged elemental diet (ED) therapy after pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC), which often causes postoperative malnutrition leading to worsened short- and long-term outcomes. METHODS Thirty-nine patients with PDAC receiving PD was randomly assigned to prolonged ED group (PEDG) and control group (CG). Fat-free ED (Elental®, EA Pharma CO., Ltd., Tokyo, Japan) via tube jejunostomy was initiated on postoperative day 1 and increased to maintain with 600 kcal/day in addition to oral intake. ED was discontinued if sufficient oral intake was achieved in CG but continued during 3 postoperative months in PEDG. Primary outcome was complication necessitating readmission. Secondary outcomes were nutritional parameters, relative dose intensity (RDI) in cases of adjuvant chemotherapy, and survival outcomes. RESULTS Twenty patients were assigned to CG and 19 to PEDG. Cumulative post-discharge readmission rate was significantly lower in PEDG than in CG (PEDG vs CG; 12.6% vs 43.7% at 12-post-discharge-month; p = 0.018). Total calorie and ED-derived protein intakes were significantly larger in PEDG than in CG up to 3-postoperative-month but thereafter similar among groups. Lymphocyte counts were significantly increased and neutrophil-to-lymphocyte-ratio (NLR) was significantly reduced in PEDG than in CG at 2-, 3-, and 6-postoperative-month. However, other outcome measures did not differ among groups. CONCLUSION This trial failed to show survival benefit of prolonged ED therapy but demonstrated its favorable effect on increased lymphocyte counts, reduced NLR, and prevention of complications necessitating readmission, those which may lead to survival benefit with some modifications.
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Effect of First-line S-1 Plus Oxaliplatin With or Without Ramucirumab Followed by Paclitaxel Plus Ramucirumab on Advanced Gastric Cancer in East Asia: The Phase 2 RAINSTORM Randomized Clinical Trial.
Yoshikawa, T, Muro, K, Shitara, K, Oh, DY, Kang, YK, Chung, HC, Kudo, T, Chin, K, Kadowaki, S, Hamamoto, Y, et al
JAMA network open. 2019;(8):e198243
Abstract
IMPORTANCE Ramucirumab, a human IgG 1 antibody against vascular endothelial growth factor receptor 2, has been shown to improve progression-free survival and overall survival in patients with advanced gastric cancer in the second-line setting. OBJECTIVE To compare progression-free survival for S-1 and oxaliplatin plus ramucirumab with that for S-1 and oxaliplatin plus placebo in patients with advanced gastric cancer. DESIGN, SETTING, AND PARTICIPANTS This phase 2, double-blind randomized clinical trial (RAINSTORM [First-line S-1 Plus Oxaliplatin With or Without Ramucirumab Followed by Paclitaxel Plus Ramucirumab in Patients With Advanced Gastric Cancer]) was conducted from October 12, 2015, to April 11, 2018, at 36 sites in Japan, South Korea, and Taiwan. Participants were chemotherapy-naive patients (n = 189) with metastatic gastric or gastroesophageal adenocarcinoma. Analyses of the full analysis set and safety population were conducted between November 27, 2017, and June 4, 2018. INTERVENTIONS Patients randomized to the ramucirumab plus S-1 and oxaliplatin arm received S-1, 80 to 120 mg/d twice daily, on days 1 to 14 and oxaliplatin, 100 mg/m2, on day 1 with ramucirumab, 8 mg/kg, on days 1 and 8 in part A (21-day cycle). Patients randomized to the placebo plus S-1 and oxaliplatin arm received the same S-1 and oxaliplatin dosage as well as placebo on days 1 and 8 in part A. Eligible patients received second-line paclitaxel, 80 mg/m2, on days 1, 8, and 15 and ramucirumab, 8 mg/kg, on days 1 and 15 in part B (28-day cycle). MAIN OUTCOMES AND MEASURES The primary end point was progression-free survival, analyzed using the stratified log-rank test; the hazard ratio (HR) was estimated using the stratified Cox proportional hazards regression model. Secondary end points included overall survival and adverse events. RESULTS In total, 189 patients were randomized and received treatment: 96 to the ramucirumab plus S-1 and oxaliplatin arm and 93 to the placebo plus S-1 and oxaliplatin arm. Among the 189 patients, 121 (64.0%) were male, and the median (range) age was 62.0 (26-84) years. Median progression-free survival was not prolonged in the ramucirumab plus S-1 and oxaliplatin arm compared with the placebo plus S-1 and oxaliplatin arm (6.34 [80% CI, 5.65-6.93] vs 6.74 [80% CI, 5.75-7.13] months; HR, 1.07; 80% CI, 0.86-1.33; P = .70). Median overall survival was 14.65 (80% CI, 12.39-15.67) months in the ramucirumab plus S-1 and oxaliplatin arm and 14.26 (80% CI, 13.83-17.31) months in the placebo plus S-1 and oxaliplatin arm (HR, 1.11; 80% CI, 0.89-1.40; P = .55). The most commonly reported grade 3 or higher treatment-emergent adverse events in the ramucirumab plus S-1 and oxaliplatin arm in part A were decreased neutrophil count (14 patients [14.6%]), hypertension (10 patients [10.4%]), and anemia (10 patients [10.4%]). CONCLUSIONS AND RELEVANCE In this randomized clinical trial, the addition of ramucirumab to first-line S-1 and oxaliplatin treatment did not prolong progression-free survival or overall survival compared with S-1 and oxaliplatin alone among East Asian patients with advanced gastric cancer; no new safety signals for ramucirumab were identified. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02539225.
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Combination of arginine, glutamine, and omega-3 fatty acid supplements for perioperative enteral nutrition in surgical patients with gastric adenocarcinoma or gastrointestinal stromal tumor (GIST): A prospective, randomized, double-blind study.
Ma, C, Tsai, H, Su, W, Sun, L, Shih, Y, Wang, J
Journal of postgraduate medicine. 2018;(3):155-163
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Abstract
BACKGROUND Perioperative enteral nutrition (EN) enriched with immune-modulating substrates is preferable for patients undergoing major abdominal cancer surgery. In this study, perioperative EN enriched with immune-modulating nutrients such as arginine, glutamine, and omega-3 fatty acids was evaluated for its anti-inflammatory efficacy in patients with gastric adenocarcinoma or gastrointestinal stromal tumor (GIST) receiving curative surgery. MATERIALS AND METHODS This prospective, randomized, double-blind study recruited 34 patients with gastric adenocarcinoma or gastric GIST undergoing elective curative surgery. These patients were randomly assigned to the study group, receiving immune-modulating nutrient-enriched EN, or the control group, receiving standard EN from 3 days before surgery (preoperative day 3) to up to postoperative day 14 or discharge. Laboratory and inflammatory parameters were assessed on preoperative day 3 and postoperative day 14 or at discharge. Adverse events (AEs) and clinical outcomes were documented daily and compared between groups. RESULTS No significant differences were observed between the two groups in selected laboratory and inflammatory parameters, or in their net change, before and after treatment. AEs and clinical outcomes, including infectious complications, overall complications, time to first bowel action, and length of hospital stay after surgery, were comparable between treatment groups (all P > 0.05). CONCLUSION Immune-modulating nutrient-enriched EN had no prominent immunomodulation effect compared with that of standard EN.
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Roux-en-Y or Billroth II Reconstruction After Radical Distal Gastrectomy for Gastric Cancer: A Multicenter Randomized Controlled Trial.
So, JB, Rao, J, Wong, AS, Chan, YH, Pang, NQ, Tay, AYL, Yung, MY, Su, Z, Phua, JNS, Shabbir, A, et al
Annals of surgery. 2018;(2):236-242
Abstract
OBJECTIVE The aim of the study was to compare the clinical symptoms between Billroth II (B-II) and Roux-en-Y (R-Y) reconstruction after distal subtotal gastrectomy (DG) for gastric cancer. BACKGROUND Surgery is the mainstay of curative treatment for gastric cancer. The technique for reconstruction after DG remains controversial. Both B-II and R-Y are popular methods. METHODS This is a prospective multicenter randomized controlled trial. From October 2008 to October 2014, 162 patients who underwent DG were randomly allocated to B-II (n = 81) and R-Y (n = 81) groups. The primary endpoint is Gastrointestinal (GI) Symptoms Score 1 year after surgery. We also compared the nutritional status, extent of gastritis on endoscopy, and quality of life after surgery between the 2 procedures at 1 year. RESULTS Operative time was significantly shorter for B-II than for R-Y [mean difference 21.5 minutes, 95% confidence interval (95% CI) 3.8-39.3, P = 0.019]. The B-II and R-Y groups had a peri-operative morbidity of 28.4% and 33.8%, respectively (P = 0.500) and a 30-day mortality of 2.5% and 1.2%, respectively (P = 0.500). GI symptoms score did not differ between R-Y versus B-II reconstruction (mean difference -0.45, 95% CI -1.21 to 0.31, P = 0.232). R-Y resulted in a lower median endoscopic grade for gastritis versus B-II (mean difference -1.32, 95% CI -1.67 to -0.98, P < 0.001). We noted no difference in nutritional status (R-Y versus B-II mean difference -0.31, 95% CI -3.27 to 2.65, P = 0.837) and quality of life at 1 year between the 2 groups too. CONCLUSION Although BII is associated with a higher incidence of heartburn symptom and higher median endoscopic grade for gastritis, BII and RY are similar in terms of overall GI symptom score and nutritional status at 1 year after distal gastrectomy.
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Pancreatic enzyme supplementation after gastrectomy for gastric cancer: a randomized controlled trial.
Catarci, M, Berlanda, M, Grassi, GB, Masedu, F, Guadagni, S
Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association. 2018;(3):542-551
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BACKGROUND Gastrectomy for gastric cancer is a significant cause of secondary exocrine pancreatic insufficiency. Pancreatic enzyme replacement therapy may influence nutritional status and quality of life after gastrectomy, but the pertinent clinical research to date remains controversial. A randomized controlled trial to test this hypothesis was carried out. METHODS After gastrectomy, 43 patients with gastric cancer were randomly assigned to a normal diet (Normal-d; n = 21) or to a pancreatic enzyme supplementation diet (PES-d; n = 22) and were followed up during a 12-month period, assessing nutritional status and quality of life through body mass index (BMI), instant nutritional assessment (INA) class status, serum pre-albumin (SPA) values, and GastroiIntestinal Quality of Life Index (GIQLI). RESULTS BMI was not significantly influenced by the type of diet; INA class status was significantly improved in the PES-d arm, particularly during the first 3 months after gastrectomy; SPA levels increased in both arms at 6 months after gastrectomy, reaching significantly higher values in the PES-d arm at 12 months. GIQLI was not significantly influenced by the type of diet throughout the follow-up period; however, this index significantly improved in the PES-d arm between the first and third month after gastrectomy. CONCLUSIONS PES-d improves nutritional status and quality of life after gastrectomy for gastric cancer, particularly within 3 months from the operation. A larger, multicenter trial is necessary to address the potential influence of several confounding variables such as disease stage and adjuvant treatments.
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Multicentre factorial randomized clinical trial of perioperative immunonutrition versus standard nutrition for patients undergoing surgical resection of oesophageal cancer.
Mudge, LA, Watson, DI, Smithers, BM, Isenring, EA, Smith, L, Jamieson, GG, ,
The British journal of surgery. 2018;(10):1262-1272
Abstract
BACKGROUND Preoperative immunonutrition has been proposed to reduce the duration of hospital stay and infective complications following major elective surgery in patients with gastrointestinal malignancy. A multicentre 2 × 2 factorial RCT was conducted to determine the impact of preoperative and postoperative immunonutrition versus standard nutrition in patients with oesophageal cancer. METHODS Patients were randomized before oesophagectomy to immunonutrition (IMPACT® ) versus standard isocaloric/isonitrogenous nutrition, then further randomized after operation to immunonutrition versus standard nutrition. Clinical and quality-of-life outcomes were assessed at 14 and 42 days after operation on an intention-to-treat basis. The primary outcome was the occurrence of infective complications. Secondary outcomes were other complications, duration of hospital stay, mortality, nutritional and quality-of-life outcomes (EuroQol EQ-5D-3 L™, European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and EORTC QLQ-OES18). Patients and investigators were blinded until the completion of data analysis. RESULTS Some 278 patients from 11 Australian sites were randomized; two were excluded and data from 276 were analysed. The incidence of infective complications was similar for all groups (37 per cent in perioperative standard nutrition group, 51 per cent in perioperative immunonutrition group, 34 per cent in preoperative immunonutrition group and 40 per cent in postoperative immunonutrition group; P = 0·187). There were no significant differences in any other clinical or quality-of-life outcomes. CONCLUSION Use of immunonutrition before and/or after surgery provided no benefit over standard nutrition in patients undergoing oesophagectomy. Registration number: ACTRN12611000178943 ( https://www.anzctr.org.au).
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Observed benefit and safety of aflibercept in elderly patients with metastatic colorectal cancer: An age-based analysis from the randomized placebo-controlled phase III VELOUR trial.
Ruff, P, Van Cutsem, E, Lakomy, R, Prausova, J, van Hazel, GA, Moiseyenko, VM, Soussan-Lazard, K, Dochy, E, Magherini, E, Macarulla, T, et al
Journal of geriatric oncology. 2018;(1):32-39
Abstract
OBJECTIVES Aflibercept (ziv-aflibercept) significantly improves progression-free (PFS) and overall survival (OS) when added to 5-fluorouracil, leucovorin and irinotecan (FOLFIRI), compared with FOLFIRI alone, in patients with metastatic colorectal cancer previously treated with oxaliplatin-based therapy. This subset analysis of the VELOUR study investigates aflibercept plus FOLFIRI versus placebo plus FOLFIRI according to age. METHODS Efficacy and safety were analyzed by treatment arm and age (≥ or <65years). RESULTS Overall, 443 patients were ≥65years old (205 in aflibercept arm; 238 in placebo arm) and 783 were <65years old (407 in aflibercept arm; 376 in placebo arm). Median OS was 12.6 versus 11.3months (hazard ratio [HR]: 0.85; 95.34% CI 0.68-1.07) in patients ≥65years old and 14.5 versus 12.5months (HR: 0.80; 95.34% CI 0.67-0.95) in those patients <65years old, for patients receiving FOLFIRI plus aflibercept or placebo, respectively. There was no interaction between treatment and age. Treatment-emergent adverse events (AEs) were comparable for patients <65years and ≥65years old. The incidence of grade 3/4 AEs was higher for patients ≥65years old than for those <65years old in both the aflibercept (89.3% versus 80.5%) and placebo (67.4% versus 59.4%) arms. Interaction tests for grade 3/4 antiangiogenic agent-related AEs suggested no heterogeneity between the older and younger patient populations (p>0.1). CONCLUSION A limited but consistent benefit on both OS and PFS was associated with the addition of aflibercept to FOLFIRI compared with placebo in patients <65 and ≥65years old, with a marked but manageable increase in the toxicity profile in older patients. TRIAL REGISTRATION clinicaltrials.govNCT00561470.
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Effects of Preoperative Enteral Nutrition on Postoperative Recent Nutritional Status in Patients with Siewert II and III Adenocarcinoma of Esophagogastric Junction after Neoadjuvant Chemoradiotherapy.
Zhao, Q, Li, Y, Yu, B, Yang, P, Fan, L, Tan, B, Tian, Y
Nutrition and cancer. 2018;(6):895-903
Abstract
OBJECTIVE To study the effects of preoperative enteral nutrition (EN) on postoperative recent nutritional status (PRNS) in patients with Siewert II and III adenocarcinomas of esophagogastric junction (AEG) after neoadjuvant chemoradiotherapy (NCRT). METHODS A total of 66 patients with resectable AEG (Siewert II and III) were randomly divided into two groups. The trial group accepted oral nutrition supplementation (ONS) for 7 days before surgery while the control not. RESULTS Nutrition indexes were higher in trial group after surgery whereas the opposite was true for the diamine oxidase (DAO) and d-lactate (P < 0.05). The rate of malnutrition and nutritional risk became lower in trial group on the 8th day after surgery (P < 0.05). Injury levels of intestinal mucosa were more severe among control group. The recent prognosis was better in trial group. For patients with or without nutritional risks at admission, the PRNS and recent prognosis were improved by preoperative EN. Logistic regression analysis suggested that preoperative EN could be an independent protective factor of PRNS. CONCLUSIONS Preoperative EN may improve the PRNS and recent prognosis of patients with Siewert II and III AEG after NCRT.