Evaluation of the Association of Perioperative UGT1A1 Genotype–Dosed gFOLFIRINOX With Margin-Negative Resection Rates and Pathologic Response Grades Among Patients With Locally Advanced Gastroesophageal Adenocarcinoma
Daniel V.T. CatenacciLeah M. ChaseSamantha LomnickiTheodore KarrisonRobert de Wilton MarshMurtuza RampurwalaSunil NarulaLindsay AlpertNamrata SetiaShu‐Yuan XiaoJohn HartUzma D. SiddiquiBryan PetersonKelly L. MooreKristin Kipping-JohnsonUgne MarkeviciusBarbara GordonKenisha AllenChristine RacetteSteven B. MaronChih‐Yi LiaoBlasé N. PoliteHedy L. KindlerKiran K. TuragaVivek N. PrachandKevin K. RogginMark K. FergusonMitchell C. Posner
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Abstract:
Importance
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, andUGT1A1genotype–directed irinotecan) to optimize efficacy while limiting toxic effects may have value.Objective
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.Design, Setting, and Participants
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.Interventions
Patients received biweekly gFOLFIRINOX (fluorouracil, 2400 mg/m2over 46 hours; oxaliplatin, 85 mg/m2; irinotecan, 180 mg/m2forUGT1A1genotype 6/6, 135 mg/m2forUGT1A1genotype 6/7, or 90 mg/m2forUGT1A1genotype 7/7; and prophylactic peg-filgrastim, 6 mg) for 4 cycles before and after surgery. Patients with tumors positive forERBB2also received trastuzumab (6-mg/kg loading dose, then 4 mg/kg).Main Outcomes and Measures
Margin-negative resection rate and PRG.Results
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%] withERBB2-positive tumors; 19 [53%] withUGT1A1 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 byUGT1A1genotype 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%]).Conclusions and Relevance
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.Trial Registration
ClinicalTrials.gov Identifier:NCT02366819Treatment of colorectal cancer is considered to be a major oncological problem. Colorectal cancer is the second most common cause of cancer-related mortality in Europe and North America. Chemotherapy improves overall survival in patients with metastatic colorectal cancer when compared to the best supportive care. The introduction of irinotecan, oxaliplatin, and molecularly targeted agents has broadened the treatment options available for patients with metastatic colorectal cancer and prolonged median survival to 20–24 months. A case of female patients with relapse of metastatic colorectal cancer after 10 years of follow-up is presented.
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Colorectal cancer is one of the most common cancers worldwide. The prognosis of patients with metastatic colorectal cancer in recent years has increased from 5 months with best supportive care to nearly 2 years with chemotherapy combined with bevacizumab, an antivascular endothelial growth factor monoclonal antibody. New prognostic and predictive biomarkers have been identified to guide chemotherapy in metastatic colorectal cancer, such as KRAS and BRAF oncogenes. However, the status of these oncogenes does not affect the efficacy of bevacizumab, and biomarkers predicting response to treatment with bevacizumab are still lacking. Addition of bevacizumab to regimens based on fluoropyrimidines or irinotecan has been shown to improve overall survival in treatment-naïve patients with metastatic colorectal cancer. Similarly, a significant increase in overall survival rate is achieved by adding bevacizumab to fluoropyrimidines and oxaliplatin in patients with disease progression. Bevacizumab has been found to be effective even when used as third-line therapy and later. In addition, cohort studies have shown that bevacizumab improves survival significantly despite disease progression. Finally, bevacizumab therapy in the neoadjuvant setting for the treatment of liver metastasis is well tolerated, safe, and effective.
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