North Central Cancer Treatment Group N0543 (Alliance): A phase 2 trial of pharmacogenetic‐based dosing of irinotecan, oxaliplatin, and capecitabine as first‐line therapy for patients with advanced small bowel adenocarcinoma. Issue 18 (10th May 2017)

• Record Type: Journal Article
• Authors: McWilliams, Robert R.; Foster, Nathan R.; Mahoney, Michelle R.; Smyrk, Thomas C.; Murray, Joseph A.; Ames, Matthew M.; Horvath, L. Elise; Schneider, Daniel J.; Hobday, Timothy J.; Jatoi, Aminah; Meyers, Jeffrey P.; Goetz, Matthew P.
• Is Part Of: Cancer. Volume 123:Issue 18(2017)
• Page Start: 3494
• Page End: 3501
• Publication Date: 2017-05-10
• Subjects: duodenal -- ileal -- jejunal -- small bowel adenocarcinoma -- UDP glucuronosyltransferase family 1 member A1 (UGT1A1); Cancer -- Periodicals; Cancer -- Cytopathology -- Periodicals; 616.99405
• DOI: 10.1002/cncr.30766
• Languages: English
• ISSNs: 0008-543X

Abstract

Abstract : BACKGROUND: Oxaliplatin in combination with either 5‐fluorouracil or capecitabine is commonly used as first‐line therapy for patients with small bowel adenocarcinoma. The addition of irinotecan improves survival in other gastrointestinal tumors but at the cost of hematologic toxicity. The authors performed a phase 2 cooperative group study (North Central Cancer Treatment Group N0543, Alliance) using genotype‐dosed capecitabine, irinotecan, and oxaliplatin (gCAPIRINOX), with dosing assigned based on UDP glucuronosyltransferase family 1 member A1 ( UGT1A1 ) genotype to test: 1) whether the addition of irinotecan would improve outcomes; and 2) whether UGT1A1 genotype‐based dosing could optimize tolerability. METHODS: Previously untreated patients with advanced small bowel adenocarcinoma received irinotecan (day 1), oxaliplatin (day 1), and capecitabine (days 2‐15) in a 21‐day cycle and were dosed with gCAPIRINOX according to UGT1A1*28 genotypes (6/6, 6/7, and 7/7). RESULTS: A total of 33 patients (17 with the 6/6 genotype, 10 with the 6/7 genotype, and 6 with the 7/7 genotype) were enrolled from October 2007 to November 2013; 73% were male, with a mean age of 64 years (range, 41‐77 years). Location of the primary tumor included the duodenum (58%), jejunum (30%), and ileum (9%). The regimen yielded a confirmed response rate of 37.5% (95% confidence interval, 21%‐56%), with a median progression‐free survival of 8.9 months and a median overall survival of 13.4 months. Neither hematologic toxicity (grade ≥3 in 52.9%, 30.0%, and 33.3%, respectively, of the 6/6, 6/7, and 7/7 genotype groups) nor tumor response rate (41.2%, 33%, and 33%, respectively) were found to differ significantly by UGT1A1 genotype. CONCLUSIONS: UGT1A1 genotype‐directed dosing (gCAPIRINOX) appears to be feasible with favorable rates of hematologic toxicity compared with prior 3‐drug studies in unselected patients. Larger studies would be needed to determine the regimen's comparability to oxaliplatin and capecitabine (CapeOx) alone or if response/toxicity differs among patients with different UGT1A1 genotypes. Cancer 2017;123:3494‐501. © 2017 American Cancer Society . Abstract : Dosing with irinotecan, oxaliplatin, and capecitabine in patients with small bowel adenocarcinoma appears to be tolerable, and substantial antitumor activity is noted in the current study. By dosing with a pharmacogenomic‐based regimen, the authors observe reasonable rates of toxicity and signs of activity in tumor response rates.