Abstract
Patients with locally advanced gastroesophageal adenocarcinoma (ie, stage ≥T3 and/or node positive) have high rates of recurrence despite surgery and adjunctive perioperative therapies, which also have high toxicity profiles. Evaluation of pharmacogenomically dosed perioperative gFOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and UGT1A1 genotype-directed irinotecan) to optimize efficacy while limiting toxic effects may have value. To evaluate the coprimary end points of margin-negative (R0) resection rates and pathologic response grades (PRGs) of gFOLFIRINOX therapy among patients with locally advanced gastroesophageal adenocarcinoma. This single-group phase 2 trial, conducted at 2 academic medical centers from February 2014 to March 2019, enrolled 36 evaluable patients with locally advanced adenocarcinoma of the esophagus, gastroesophageal junction, and gastric body. Data analysis was conducted in May 2019. Patients received biweekly gFOLFIRINOX (fluorouracil, 2400 mg/m2 over 46 hours; oxaliplatin, 85 mg/m2; irinotecan, 180 mg/m2 for UGT1A1 genotype 6/6, 135 mg/m2 for UGT1A1 genotype 6/7, or 90 mg/m2 for UGT1A1 genotype 7/7; and prophylactic peg-filgastrim, 6 mg) for 4 cycles before and after surgery. Patients with tumors positive for ERBB2 also received trastuzumab (6-mg/kg loading dose, then 4 mg/kg). Margin-negative resection rate and PRG. A total of 36 evaluable patients (27 [78%] men; median [range] age, 66 [27-85] years; 10 [28%] with gastric body cancer; 24 [67%] with intestinal-type tumors; 6 [17%] with ERBB2-positive tumors; 19 [53%] with UGT1A1 genotype 6/6; 16 [44%] with genotype 6/7; and 1 [3%] with genotype 7/7) were enrolled. Of these, 35 (97%) underwent surgery; 1 patient (3%) died after completing neoadjuvant chemotherapy while awaiting surgery. Overall, R0 resection was achieved in 33 of 36 patients (92%); 2 patients (6%) with linitis plastica achieved R1 resection. Pathologic response grades 1, 2, and 3 occurred in 13 patients (36%), 9 patients (25%), and 14 patients (39%), respectively, and PRG 1 was observed in 11 of 24 intestinal-type tumors (46%). Median disease-free survival was 30.1 months (95% CI, 15.0 months to not reached), and median overall survival was not reached (95% CI, 8.3 months to not reached). There were no differences in outcomes by UGT1A1 genotype group. A total of 38 patients, including 2 (5%) with antral tumors, were evaluable for toxic effects. Grade 3 or higher adverse events occurring in 5% or more of patients during the perioperative cycles included diarrhea (7 patients [18%]; 3 of 19 patients [16%] with genotype 6/6; 2 of 16 patients [13%] with genotype 6/7; 2 of 3 patients [67%] with genotype 7/7), anemia (2 patients [5%]), vomiting (2 patients [5%]), and nausea (2 patients [5%]). In this study, perioperative pharmacogenomically dosed gFOLFIRINOX was feasible, providing downstaging with PRG 1 in more than one-third of patients and an R0 resection rate in 92% of patients. ClinicalTrials.gov Identifier: NCT02366819.
Highlights
Gastroesophageal adenocarcinoma (GEA), which includes proximal esophagogastric junction (EGJ) and distal gastric adenocarcinomas, remains a global health problem with heterogeneous molecular features.[1,2,3] Esophagogastric junction adenocarcinomas are predominantly intestinal-subtype and chromosomally instable,[3] involving the distal esophagus, the gastroesophageal junction (GEJ), and the cardia.[4]
In Western countries, locally advanced GEA has a high rate of recurrence, and 5-year overall survival (OS) rates remain less than 50%, despite curative-intent surgery with perioperative chemotherapy and/or neoadjuvant chemoradiotherapy.[6]
The remaining 38 patients were evaluable for safety; per protocol, 2 (5%) were excluded from primary efficacy analyses given that they had primary antral tumors (1 [50%] mixed-type and 1 [50%] diffuse-type; both 7/7 genotype), and both achieved margin negative (R0) resection and demonstrated pathologic response grades (PRGs) 3
Summary
Gastroesophageal adenocarcinoma (GEA), which includes proximal esophagogastric junction (EGJ) and distal gastric adenocarcinomas, remains a global health problem with heterogeneous molecular features.[1,2,3] Esophagogastric junction adenocarcinomas are predominantly intestinal-subtype and chromosomally instable,[3] involving the distal esophagus, the gastroesophageal junction (GEJ), and the cardia (ie, so-called Siewert type I, II, and III tumors, respectively).[4] Esophagogastric junction adenocarcinoma is increasing in incidence in the Western world, while distal gastric adenocarcinoma, including the gastric body, incisura, antrum, and pylorus, is decreasing in incidence.[5] In Western countries, locally advanced GEA has a high rate of recurrence, and 5-year overall survival (OS) rates remain less than 50%, despite curative-intent surgery with perioperative chemotherapy and/or neoadjuvant chemoradiotherapy.[6] Adjunctive therapies increase 5-year survival 10% to 15% compared with surgery alone, at the cost of relatively high rates of toxic effects.[6,7,8,9] Standard therapy for distal gastric adenocarcinoma had been perioperative epirubicin, cisplatin, and fluorouracil (ie, the MAGIC regimen)[7] until recently, when fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) was shown to be superior.[9] Standard therapy for EGJ adenocarcinoma includes perioperative FLOT or neoadjuvant carboplatin and paclitaxel with radiotherapy (40.4 Gy; ie, the CROSS regimen).[8]
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