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Thymidylate synthase genotype-directed neoadjuvant chemoradiation for patients with rectal adenocarcinoma.

ABSTRACT: Downstaging (DS) of rectal cancers is achieved in approximately 45% of patients with neoadjuvant fluorouracil (FU) -based chemoradiotherapy (CRT). Polymorphisms in the thymidylate synthase gene (TYMS) had previously defined two risk groups associated with disparate tumor DS rates (60% v 22%). We conducted a prospective single-institution phase II study using TYMS genotyping to direct neoadjuvant CRT for patients with rectal cancer.Patients with T3/T4, N0-2, M0-1 rectal adenocarcinoma were evaluated for germline TYMS genotyping. Patients with TYMS *2/*2, *2/*3, or *2/*4 (good risk) were treated with standard chemoradiotherapy using infusional FU at 225 mg/m²/d. Patients with TYMS *3/*3 or *3/*4 (poor risk) were treated with FU/RT plus weekly intravenous irinotecan at 50 mg/m². The primary end point was pathologic DS. Secondary end points included complete tumor response (ypT0), toxicity, recurrence rates, and overall survival.Overall, 135 patients were enrolled, of whom 27.4% (37 of 135) were considered poor risk. The prespecified statistical goals were achieved, with DS and ypT0 rates reaching 64.4% and 20% for good-risk and 64.5% and 42% for poor-risk patients, respectively.To our knowledge, this is the first study to prospectively use TYMS genotyping to direct neoadjuvant CRT in patients with rectal cancer. High rates of DS and ypT0 were achieved among both risk groups when personalized treatment was based on TYMS genotype. These results are encouraging, and further evaluation of this genotype-based strategy using a randomized study design for locally advanced rectal cancer is warranted.

SUBMITTER: Tan BR

PROVIDER: S-EPMC3068061 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Thymidylate synthase genotype-directed neoadjuvant chemoradiation for patients with rectal adenocarcinoma.

Tan Benjamin R BR Thomas Fabienne F Myerson Robert J RJ Zehnbauer Barbara B Trinkaus Kathryn K Malyapa Robert S RS Mutch Matthew G MG Abbey Elliot E EE Alyasiry Amer A Fleshman James W JW McLeod Howard L HL

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20110104 7

<h4>Purpose</h4>Downstaging (DS) of rectal cancers is achieved in approximately 45% of patients with neoadjuvant fluorouracil (FU) -based chemoradiotherapy (CRT). Polymorphisms in the thymidylate synthase gene (TYMS) had previously defined two risk groups associated with disparate tumor DS rates (60% v 22%). We conducted a prospective single-institution phase II study using TYMS genotyping to direct neoadjuvant CRT for patients with rectal cancer.<h4>Patients and methods</h4>Patients with T3/T4, ...[more]

PMID: 21205745

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Project description:Background:There is recent interest in treating locally advanced rectal cancer (LARC) patients with total neoadjuvant therapy (TNT). However, whether TNT is associated with improved overall survival (OS) remains unknown. This study compares outcomes following TNT and following neoadjuvant chemoradiation therapy (nCRT) in patients with LARC, clinically defined cT3/4 or node positive disease, using the National Cancer Database. Methods:LARC patients diagnosed between 2004-2015 were included. TNT was defined as multi-agent chemotherapy given at least 2 months before RT followed by pre-operative chemoradiation therapy and definitive surgery without adjuvant chemotherapy. nCRT was defined as pre-operative RT and chemotherapy started within 2 weeks from each other followed by definitive surgery with or without adjuvant chemotherapy. Kaplan-Meier curve with logrank test and multivariable Cox proportional hazards regression modelling were used to analyse the primary endpoint of overall survival (OS). Multivariable logistic regression modelling was used for secondary outcomes to determine if TNT is associated with pathological complete response (pCR), defined as ypT0N0, and negative circumferential resection margin (CRM). Findings:Data from 372 TNT patients and 707 nCRT patients were analysed after a 2:1 propensity matching with replacement. Kaplan-Meier curve showed that OS with TNT was comparable to that with nCRT (p = 0•16). The 5-year OS rates for TNT and nCRT were 73•6% vs. 78•5% (p = 0•20). Multivariable Cox proportional hazards regression modelling confirmed no difference in OS between TNT and nCRT (HR = 1•21, p = 0•25). With TNT, 16•9% patients achieved pCR, whereas 13•1% patients achieved pCR with nCRT (p = 0•12). TNT was not found to be significantly associated with pCR (OR = 1•36, p = 0•13) or negative CRM (OR = 1•77, p = 0•19) in multivariable logistic regression modelling. Interpretation:With results from current clinical trials pending, our data suggested that TNT and nCRT resulted in similar survival, while TNT led to higher pCR and CRM negative rate, albeit not statistically significant.

Dataset Information

Thymidylate synthase genotype-directed neoadjuvant chemoradiation for patients with rectal adenocarcinoma.

Publications

Thymidylate synthase genotype-directed neoadjuvant chemoradiation for patients with rectal adenocarcinoma.

Similar Datasets

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