Year: 2020
Type: article
Abstract: Perioperative chemotherapy remains critical in improving long-term disease-free and overall survival outcomes among patients with locally advanced yet surgically resectable gastroesophageal adenocarcinoma (GEA).Fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) is a recognized standard treatment from the phase 3 FLOT4 trial, 1 but toxic effects limit its application to select patients such that doublet chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) is also recommended in national guidelines. 2 Catenacci et al 3 present a single-group phase 2 trial exploring an alternative triplet chemotherapy regimen of fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX), in which all 3 cytotoxic agents have demonstrable activity in the metastatic setting.Thus, the report by Catenacci et al 3 presents a unique first application of this combination among patients with GEA that can be surgically resected with curative intent.Furthermore, the authors pursued a personalized pharmacogenomic approach in dosing the irinotecan (gFOLFIRINOX) based on the UGT1A1 genotype (OMIM 191740), using standardized assays for detection of germline polymorphisms in the promoter region or first coding exon of UGT1A1.Common polymorphisms include variations in the number of TA repeats in the promoter region, which influence the activity of the UGT1A1 enzyme (ie, genotype 6/6 harbors 6 repeats and has normal enzyme activity; genotype 7/7 equates to 7 repeats and reduced activity), which is relevant to the elimination of the active metabolite of irinotecan, SN-38.Patients with homozygous germline polymorphisms (ie, genotype 7/7) exhibit a more severe phenotype, susceptible to increased toxic effects from irinotecan.Building on their work in the metastatic setting, Catenacci et al 3 pursued an up-front dose reduction of irinotecan for patients with genotyping results associated with diminished activity of the UGT1A1 enzyme.In enrolling patients at 2 US centers, it is not surprising that 31 of 38 patients were white individuals, with 3 patients exhibiting the higher risk of toxic effects of the 7/7 genotype.Only 2 patients were of Asian descent, with 1 patient in the 7/7 genotype group.Although the known polymorphism in exon 1 of the UGT1A1 gene, which is also associated with diminished enzyme activity, was included in their assay platform, it was not found in any patients enrolled in the trial.However, the pharmacogenomic dosing used in this study can still serve as a framework in Asian countries, where GEA has higher incidence and both TA promoter repeats and exon 1 coding polymorphisms encompass the differing UGT1A1 genotypes.Regarding their observed efficacy outcomes, Catenacci et al 3 used the feasible and clinically relevant coprimary end points of margin-negative resection rate and pathologic response grade (PRG, also commonly referred to as tumor regression grade [TRG]) to power their single-group statistical analysis of 36 evaluable patients.For their intention-to-treat population, 33 of 36 patients (92%) met the investigators' goal of at least 30 patients achieving a margin-negative resection, although 3 patients (8%) achieving a complete pathologic response (ie, PRG 1a) fell short of their target of 4 patients to reject the null hypothesis.While this study had a small sample, it is interesting to draw comparisons with the FLOT4 trial data set, 1 which reported that 6% of patients achieved PRG 1a with the triplet of epirubicin, cisplatin, and fluorouracil (ECF) and 16% achieved PRG 1a with FLOT.With median follow up being relatively early (ie, approximately 20 months), median diseasefree survival appeared promising at 30.1 months and median overall survival had yet to be reached.For the adjuvant phase of therapy, 5 patients (14%) were prescribed regimens other than gFOLFIRINOX, including 4 patients (11%) who received FLOT, which may skew interpretation of longterm survival outcomes.However, the consequences of the change in adjuvant therapy may be minimal, given that, across the spectrum of perioperative trials, dose intensity is 80% to 90% in neoadjuvant courses of therapy versus 50% to 60% in adjuvant courses of therapy, leading some to +
Source: JAMA Network Open
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,000
OpenAlex ID: W3006040758