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A novel irradiation stent versus conventional irradiation stent for malignant dysphagia: A prospective randomized controlled trial.
Zhu, GY, Lu, J, Wang, C, Guo, JH
Journal of cancer research and therapeutics. 2021;(5):1261-1268
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Abstract
AIM: To evaluate whether a novel irradiation stent (NIS) could decrease the rate of recurrent dysphagia, compared to the conventional irradiation stent (CIS) in patients with malignant dysphagia. MATERIALS AND METHODS We performed an open-label randomized controlled trial of participants with malignant dysphagia. A total of 94 participants were parallelly allocated into the NIS group or the NIS group between April 2019 and April 2020. The primary endpoint was the rate of recurrent dysphagia. The secondary endpoints included technical success, clinical success, overall survival, and adverse events. RESULTS The technical success rate and the clinical success rate was 100.0% (47/47) in both groups. The median follow-up period was 189 days (range 14-422 days). Recurrent dysphagia was observed in 12.8% (6/47) of patients in the NIS group and 31.9% (15/47) in the CIS group (P = 0.026). Tissue/tumor growth occurred in 4 patients (8.5%) after NIS placement and 12 (25.5%) after CIS placement (P = 0.028). Stent migration occurred in 2 patients (4.3%) after NIS placement and 3 (6.4%) after CIS placement (P = 0.646). No food obstruction was found in both groups. The median overall survival was 177 days (95% confidence interval [CI] 139-214) in the NIS group and 168 days (95% CI 153-183) in the CIS group (P = 0.932). The incidence of severe adverse events was comparable between the two groups (21.3% vs. 17.0%, P = 0.600). CONCLUSIONS In patients with malignant dysphagia, compared with CIS, NIS could decrease the rate of tissue/tumor growth without increase the rate of stent migration and therefore decrease the rate of recurrent dysphagia.
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FOLFIRINEC: a randomized phase II trial of mFOLFIRINOX vs platinum-etoposide for metastatic neuroendocrine carcinoma of gastroenteropancreatic or unknown origin.
Hadoux, J, Afchain, P, Walter, T, Tougeron, D, Hautefeuille, V, Monterymard, C, Lorgis, V, Thuillier, F, Baudin, E, Scoazec, JY, et al
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2021;(7):824-829
Abstract
BACKGROUND Poorly differentiated neuroendocrine carcinomas (NEC) are rare diseases with a poor prognosis. Platinum-etoposide (PE) has been the recommended first-line treatment for decades. FOLFIRINEC (NCT04325425) is a national multicenter randomized phase II study which aims to challenge this standard regimen. METHODS The primary objective is to compare the median progression-free survival (PFS) under mFOLFIRINOX versus PE. The secondary objectives are to evaluate the objective response rates (ORR), median overall survival (OS), safety and quality of life. The associated real-time translational study will establish a molecular profile for each patient enrolled. MAIN INCLUSION CRITERIA ARE NEC of gastroenteropancreatic (GEP) or unknown origin, metastatic and RECIST 1.1 evaluable disease, tumor sample available and no contraindication to chemotherapy. Patients will be randomized 1:1 between PE every 21 days for 6-8 cycles and mFOLFIRINOX every 14 days for up to 12 cycles and stratified according to center, performance status, Ki67 and pathological subtype. This trial will randomize 218 patients (24 months of follow-up) to have 80% power to detect an improvement of the median PFS from 5 months under PE to 7.5 months under mFOLFIRINOX (HR of 0.67, α =5%, two-sided). An intermediate analysis is planned at 50% of events. Recruitment started on October 20, 2020.
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Effect of Aprepitant for the Prevention of Chemotherapy-Induced Nausea and Vomiting in Women: A Randomized Clinical Trial.
Wang, DS, Hu, MT, Wang, ZQ, Ren, C, Qiu, MZ, Luo, HY, Jin, Y, Fong, WP, Wang, SB, Peng, JW, et al
JAMA network open. 2021;(4):e215250
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IMPORTANCE The prevention of chemotherapy-induced nausea and vomiting has an important role in the overall management of cancer treatment. OBJECTIVE To evaluate whether adding aprepitant to palonosetron and dexamethasone can further prevent the incidence and severity of nausea and vomiting caused by FOLFIRI (fluorouracil, leucovorin, and irinotecan) or FOLFOX (fluorouracil, leucovorin, and oxaliplatin) chemotherapy regimens among women with gastrointestinal cancer at higher risk. DESIGN, SETTING, AND PARTICIPANTS This phase 3, double-blind, placebo-controlled randomized clinical trial recruited young women (age ≤50 years) who drank little or no alcohol and had gastrointestinal cancer for which they received FOLFOX or FOLFIRI chemotherapy. A total of 248 women were enrolled and assigned in the ratio 1:1 to intervention and control groups from August 4, 2015, to March 31, 2020. Intention-to-treat analysis was used to evaluate patient baseline characteristics and efficacy. The analysis was conducted on October 30, 2020. INTERVENTIONS Patients were randomly assigned to the aprepitant group (aprepitant, 125 mg, orally 60 minutes before initiation of chemotherapy on day 1 and 80 mg orally each morning of days 2 and 3; palonosetron, 0.25 mg, intravenously; and dexamethasone, 6 mg, orally 30 minutes before chemotherapy initiation on day 1) or the placebo group (placebo, 125 mg, orally 60 minutes before initiation of chemotherapy on day 1 and 80 mg orally on each morning of days 2 and 3; palonosetron, 0.25 mg, intravenously; and dexamethasone, 12 mg, orally 30 minutes before chemotherapy initiation on day 1). MAIN OUTCOMES AND MEASURES The primary end point was the complete response (CR) rate, defined as the proportion of patients without emesis episodes or rescue medication use during the overall phase of the first cycle. Other efficacy indicators, such as no vomiting and no nausea, were measured as the secondary and exploratory end points. RESULTS A total of 248 women from 4 clinical centers in China entered this study, and 243 patients (aprepitant regimen, 125 patients [51.4%]; placebo regimen, 118 patients [48.5%]) were evaluable for efficacy and safety; mean (SD) age of the total population was 40.1 (7.3) years. The CR rate was significantly higher in the aprepitant group vs the control group overall (107 [87.0%] vs 80 [66.7%]; P < .001) and in the acute (114 [92.7%] vs 91 [75.8%]; P = .001) and delayed (109 [88.6%] vs 84 [70.0%]; P = .001) phases of the trial. The incidence of adverse events was similar between the 2 groups (100 [80.0%] vs 96 [81.3%]; P = .79), and no grade 3 or 4 aprepitant treatment-related adverse events were observed. Multivariable analysis revealed that aprepitant use was the only independent factor associated with CR during the overall phase. CONCLUSIONS AND RELEVANCE The combination of aprepitant with palonosetron and dexamethasone provided increased antiemetic efficacy in the FOLFOX or FOLFIRI chemotherapy regimen and was well tolerated by younger women with gastrointestinal cancer who have a history of little or no alcohol consumption. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03674294.
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FOLFIRINOX for the Treatment of Advanced Gastroesophageal Cancers: A Phase 2 Nonrandomized Clinical Trial.
Park, H, Jin, RU, Wang-Gillam, A, Suresh, R, Rigden, C, Amin, M, Tan, BR, Pedersen, KS, Lim, KH, Trikalinos, NA, et al
JAMA oncology. 2020;(8):1231-1240
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IMPORTANCE Standard first-line regimens for patients with metastatic gastroesophageal adenocarcinomas have an approximate 40% objective response rate (ORR). The combination of leucovorin, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) has been efficacious as first-line therapy for other gastrointestinal cancers, such as pancreatic and colon cancers. OBJECTIVE To evaluate the clinical activity and safety of FOLFIRINOX as first-line treatment for patients with advanced gastroesophageal adenocarcinoma. DESIGN, SETTING, AND PARTICIPANTS This is an open-label, single-arm phase 2 study of first-line FOLFIRINOX in patients with advanced gastroesophageal adenocarcinoma. Estimated sample size included 41 patients with ERBB2-negative disease with 90% power to detect an ORR of 60% or greater with α of .10. No enrollment goal was planned for ERBB2-positive patients, but they were allowed to receive trastuzumab in combination with FOLFIRINOX. INTERVENTIONS Starting doses were fluorouracil, 400 mg/m2 bolus, followed by 2400 mg/m2 over 46 hours; leucovorin, 400 mg/m2; irinotecan, 180 mg/m2; and oxaliplatin, 85 mg/m2. Trastuzumab was administered as a 6 mg/kg loading dose, followed by 4 mg/kg every 14 days in patients with ERBB2-positive disease. MAIN OUTCOMES AND MEASURES The primary end point was ORR by the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included safety profile, progression-free survival (PFS), overall survival (OS), and duration of response. RESULTS From November 2013 to May 2018, 67 patients were enrolled (median [range] age, 59.0 [34-78] years; including 56 [84%] men), and 26 of 67 (39%) had ERBB2-positive disease. Median follow-up was 17.4 months. The ORR was 61%(95% CI, 44.5%-75.8%) (25 of 41) in the ERBB2-negative group and 85% (95% CI, 65.1%-95.6%) (22 of 26) in the ERBB2-positive group, including 1 patient with complete response. For ERBB2-negative patients, median PFS was 8.4 months and median OS was 15.5 months; for ERBB2-positive patients, median PFS was 13.8 months and median OS was 19.6 months. Fifty-six patients (84%) had dose modifications or treatment delays. The most common toxic effects were neutropenia (91%, n = 61), diarrhea (63%, n = 42), peripheral sensory neuropathy (61%, n = 41), and nausea (48%, n = 32), with no unexpected toxic effects. CONCLUSIONS AND RELEVANCE The FOLFIRINOX regimen with or without trastuzumab was associated with improved ORR and PFS in patients with advanced gastroesophageal adenocarcinoma in the first-line setting. This regimen may be a reasonable therapeutic option for patients with preserved performance status. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01928290.
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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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A Phase II Study of Modified FOLFOX6 for Advanced Gastric Cancer Refractory to Standard Therapies.
Mitani, S, Kadowaki, S, Komori, A, Kondoh, C, Oze, I, Kato, K, Masuishi, T, Honda, K, Narita, Y, Taniguchi, H, et al
Advances in therapy. 2020;(6):2853-2864
Abstract
INTRODUCTION In patients with advanced gastric cancer refractory to chemotherapy, the treatment options are limited. Via this phase II study, we aimed to assess the efficacy and safety of oxaliplatin in combination with 5-fluorouracil and l-leucovorin (modified FOLFOX6). METHODS Patients who had histologically confirmed metastatic gastric cancer refractory to ≥ two previous chemotherapy regimens were included. The primary endpoint was the overall response rate (ORR) by an independent central review. According to an assumption of a threshold ORR of 10% and expected ORR of 25%, with α = 0.05 and β = 0.20, at least 33 patients were required. The secondary endpoints included overall survival (OS), progression-free survival (PFS), quality of life measured by EQ-5D, and safety. RESULTS Among the 35 enrolled patients, 33 were included in the primary analysis. All patients previously received fluoropyrimidines, cisplatin, and taxanes, and 24 (73%) were pretreated with irinotecan. The confirmed ORR was 27% [95% confidence interval (CI) 13-46]. The median PFS and OS were 2.2 (95% CI 1.2-3.2) and 5.6 (95% CI 4.1-7.0) months, respectively. In the multivariate analyses, immunotherapy within 90 days and a Glasgow Prognostic Score of 0 were associated with better treatment outcomes. The most common grade ≥ 3 adverse event was neutropenia (36%), and no febrile neutropenia was observed. The median EQ-5D scores did not change from baseline at 2, 4, and 8 weeks (p value = 0.38, 0.79, and 0.98, respectively). CONCLUSION Modified FOLFOX6 (mFOLFOX6) showed substantial activity and acceptable toxicity for chemotherapy-refractory advanced gastric cancer. TRIAL REGISTRATION UMIN Clinical Trial Registry (UMIN000016416).
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Efficacy of vonoprazan in prevention of bleeding from endoscopic submucosal dissection-induced gastric ulcers: a prospective randomized phase II study.
Hamada, K, Uedo, N, Tonai, Y, Arao, M, Suzuki, S, Iwatsubo, T, Kato, M, Shichijo, S, Yamasaki, Y, Matsuura, N, et al
Journal of gastroenterology. 2019;(2):122-130
Abstract
BACKGROUND Vonoprazan, potassium-competitive acid blocker, is expected to reduce incidence of delayed bleeding after gastric endoscopic submucosal dissection (ESD); however, preliminary data to design a large-scale comparative study are lacking. This study aimed to assess the efficacy of vonoprazan in preventing delayed bleeding after gastric ESD. METHODS In this single-center randomized phase II trial, a modified screened selection design was used with a threshold non-bleeding rate of 89% and an expected rate of 97%. In this design, Simon's optimal two-stage design was first applied for each parallel group, and efficacy was evaluated in comparison with the threshold rate using binomial testing. Patients were randomly assigned in a 1:1 ratio to receive either vonoprazan 20 mg (VPZ group) or lansoprazole 30 mg (PPI group) for 8 weeks from the day before gastric ESD. The primary endpoint was the incidence of delayed bleeding, defined as endoscopically confirmed bleeding accompanied by hematemesis, melena, or a decrease in hemoglobin of ≥ 2 g/dl. RESULTS Delayed bleeding occurred in three of 69 patients (4.3%, 95% CI 0.9-12.2%, p = 0.047) in the VPZ group, and four of 70 (5.7%, 95% CI 1.6-14.0%, p = 0.104) in the PPI group. As only vonoprazan showed significant reduction in delayed bleeding compared with the threshold rate, it was determined to be efficacious treatment. CONCLUSIONS Vonoprazan efficaciously reduced the delayed bleeding rate in patients with an ESD-induced gastric ulcer. A large-scale, randomized, phase III study is warranted to definitively test the effectiveness of vonoprazan compared with proton pump inhibitors.
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Preoperative weight loss program involving a 20-day very low-calorie diet for obesity before laparoscopic gastrectomy for gastric cancer.
Inoue, K, Yoshiuchi, S, Yoshida, M, Nakamura, N, Nakajima, S, Kitamura, A, Mouri, K, Michiura, T, Mukaide, H, Ozaki, T, et al
Asian journal of endoscopic surgery. 2019;(1):43-50
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INTRODUCTION The increased visceral fat in patients with obesity can increase the technical difficulty of surgery. This study was performed to evaluate a preoperative 20-day very low-calorie diet for obesity before laparoscopic gastrectomy for gastric cancer. METHODS This prospective single-center study involved patients with obesity who were planning to undergo laparoscopic gastrectomy for gastric cancer. Obesity was defined according to the Japanese criteria: BMI ≥25 kg/m2 or waist circumference ≥85 cm in men and ≥90 cm in women. The patients underwent a preoperative 20-day very low-calorie diet and received nutritional counseling. Weight loss, body composition, visceral fat mass, and operative outcomes were evaluated. RESULTS Thirty-three patients were enrolled from September 2013 to August 2015. Their median age was 71 years, and 78.8% were men. Their median bodyweight and BMI were 72.3 kg (range, 53.8-82.5 kg) and 26.0 kg/m2 (range, 23.5-31.0 kg/m2 ), respectively. The patients achieved a mean weight loss of 4.5% (95% confidence interval [CI]: 3.8-5.1), corresponding to 3.2 kg (95%CI: 2.7-3.7 kg). Body fat mass was significantly decreased by a mean of 2.5 kg (95%CI: 1.9-3.1), whereas skeletal muscle mass was unaffected (mean: -0.20 kg [95%CI: -0.55-0.15]). The visceral fat mass reduction rate was high as 16.8% (range, 11.6%-22.0%). All patients underwent laparoscopic gastrectomy as planned. Severe postoperative morbidity (Clavien-Dindo grade ≥III) was seen in only one patient (3.0%). CONCLUSION The preoperative 20-day very low-calorie diet weight loss program is promising for the treatment of obesity before laparoscopic gastrectomy for gastric cancer.
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Evaluation of the Interaction of Amino Acid Infusion on 177Lu-Dotatate Pharmacokinetics in Patients with Gastroenteropancreatic Neuroendocrine Tumors.
Puszkiel, A, Bauriaud-Mallet, M, Bourgeois, R, Dierickx, L, Courbon, F, Chatelut, E
Clinical pharmacokinetics. 2019;(2):213-222
Abstract
BACKGROUND AND OBJECTIVE 177Lu-Dotatate is a radio-labeled analog of somatostatin used in the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. In order to prevent nephrotoxic effects of 177Lu-Dotatate a co-infusion of amino acids (AA) is administered, resulting in a decrease in tubular renal reabsorption of 177Lu-Dotatate. This study aimed to quantify the impact of AA co-infusion on the pharmacokinetics of 177Lu-Dotatate in cancer patients and to evaluate its relationship with toxicity during the first treatment cycle (C1). METHODS 7.4 GBq of 177Lu-Dotatate was administered to 42 patients over a 30-min intravenous infusion. Infusion of AA started 2 h before and continued for 6 h after the infusion of 177Lu-Dotatate. Radioactivity-time data (n = 346) were analyzed using NONMEM® (version 7.2.0). RESULTS 177Lu-Dotatate pharmacokinetics was best described by a three-compartment model with first-order elimination. AA co-infusion had a significant effect ('fixed effect') on 177Lu-Dotatate pharmacokinetics, with a mean value of 1.5-fold (95% confidence interval 1.03-1.97) increase in the elimination rate constant (k10) from 0.204 to 0.306 h-1, but this AA co-infusion effect was associated with a large inter-individual variability (IIV) of 104%. The individual k10 values increased during concomitant AA infusion by a factor ranging from 1.01 to 21.3 for 27 patients, whereas the opposite effect was observed in 15 patients (range 0.36-0.99) of whom seven had a k10 value lower than 0.85. This variability in AA effect contributed to the variability in 177Lu-Dotatate plasma exposure (area under the concentration-time curve from time zero to Day 15 for C1 [AUCDay15]) that correlated with lymphopenia observed at Day 15 (p = 0.004). CONCLUSIONS A substantial effect of AA co-infusion on 177Lu-Dotatate pharmacokinetics was shown but was associated with high IIV, contributing to IIV in hematological toxicity.
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The investigation of diet recovery after distal gastrectomy.
Kim, TH, Lee, YJ, Bae, K, Park, JH, Hong, SC, Jung, EJ, Ju, YT, Jeong, CY, Park, TJ, Park, M, et al
Medicine. 2019;(41):e17543
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This study aims to investigate the adaptation process of the alimentary tract after distal gastrectomy and understand the impact of remnant stomach volume (RSV) on diet recovery.One year after gastrectomy, although patients' oral intake had increased, the RSV was decreased and small bowel motility was enhanced. Patients with a larger RSV showed no additional benefits regarding nutritional outcomes.We prospectively enrolled patients who underwent distal gastrectomy with Billroth II reconstruction to treat gastric cancer at a tertiary hospital cancer center between September 2009 and February 2012. Demographic data, diet questionnaires, computed tomography (CT), and contrast fluoroscopy findings were collected. Patients were divided into 2 groups according to the RSV calculated using CT gastric volume measurements (large vs small). Dietary habits and nutritional status were compared between the groups.Seventy-eight patients were enrolled. Diet volume recovered to 90% of baseline by the 36 postoperative month, and RSV was 70% of baseline at 6 months after surgery and gradually decreased over time. One year after surgery, small bowel transit time was 75% compared to the 1st postoperative month (P < .05); however, transit time in the esophagus and remnant stomach showed no change in any studied interval. Compared to patients with a small RSV, those with a large RSV showed no differences in diet volume, habits, or other nutritional benefits (P > .05).Diet recovery for distal gastrectomy patients was achieved by increased small bowel motility. The size of the remnant stomach showed no positive impact on nutritional outcomes.