Dataset Information

Pharmacogenetic predictors of adverse events and response to chemotherapy in metastatic colorectal cancer: results from North American Gastrointestinal Intergroup Trial N9741.

ABSTRACT:

Purpose

With three available chemotherapy drugs for advanced colorectal cancer (CRC), response rate (RR) and survival outcomes have improved with associated morbidity, accentuating the need for tools to select optimal individualized treatment. Pharmacogenetics identifies the likelihood of adverse events or response based on variants in genes involved in drug transport, metabolism, and cellular targets.

Patients and methods

Germline DNA was extracted from 520 patients on the North American Gastrointestinal Intergroup N9741 study. Three study arms were evaluated: IFL (fluorouracil [FU] + irinotecan [IRN]), FOLFOX (FU + oxaliplatin), and IROX (IRN + oxaliplatin). Information on adverse events, response, and disease-free survival was available. Thirty-four variants in 15 candidate genes for analysis based on previous associations with adverse events or outcome were assessed. Genotyping was performed using pyrosequencing.

Results

All variants were polymorphic. The homozygous UGT1A1*28 allele observed in 9% of patients was associated with risk of grade 4 neutropenia in patients on IROX (55% v 15%; P = .002). Deletion in GSTM1 was associated with grade 4 neutropenia after FOLFOX (28% v 16%; P = .02). Patients with a homozygous variant genotype for GSTP1 were more likely to discontinue FOLFOX because of neurotoxicity (24% v 10%; P = .01). The presence of a CYP3A5 variant was significantly associated with RR on IFL (29% v 60%; P = .0074). Most previously published genotype-toxicity or -efficacy relationships were not validated in this study.

Conclusion

This study provides a platform to evaluate pharmacogenetic predictors of response or severe adverse events in advanced CRC. Pharmacogenetic studies can be conducted in multicenter trials, and our findings demonstrate that with continued research, clinical application is practical.

SUBMITTER: McLeod HL

PROVIDER: S-EPMC2903324 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Publications

Pharmacogenetic predictors of adverse events and response to chemotherapy in metastatic colorectal cancer: results from North American Gastrointestinal Intergroup Trial N9741.

McLeod Howard L HL Sargent Daniel J DJ Marsh Sharon S Green Erin M EM King Cristi R CR Fuchs Charles S CS Ramanathan Ramesh K RK Williamson Stephen K SK Findlay Brian P BP Thibodeau Stephen N SN Grothey Axel A Morton Roscoe F RF Goldberg Richard M RM

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20100607 20

<h4>Purpose</h4>With three available chemotherapy drugs for advanced colorectal cancer (CRC), response rate (RR) and survival outcomes have improved with associated morbidity, accentuating the need for tools to select optimal individualized treatment. Pharmacogenetics identifies the likelihood of adverse events or response based on variants in genes involved in drug transport, metabolism, and cellular targets.<h4>Patients and methods</h4>Germline DNA was extracted from 520 patients on the North ...[more]

PMID: 20530282

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Project description:BackgroundAdverse events of chemotherapy may be caused by pharmacodynamics or psychological factors such as negative expectations, which constitute nocebo effects. In a randomized controlled trial, we examined whether educating patients about the nocebo effect is efficacious in reducing the intensity of self-reported adverse events.MethodsIn this proof-of-concept study, N = 100 outpatients (mean age: 60.2 years, 65% male, 54% UICC tumour stage IV) starting first-line, de novo chemotherapy for gastrointestinal cancers were randomized 1:1 to a nocebo education (n = 49) or an attention control group (n = 51). Our primary outcome was patient-rated intensity of four chemotherapy-specific and three non-specific adverse events (rated on 11-point Likert scales) at 10-days and 12-weeks after the first course of chemotherapy. Secondary outcomes included perceived control of adverse events and tendency to misattribute symptoms.ResultsGeneral linear models indicated that intensity of adverse events differed at 12-weeks after the first course of chemotherapy (mean difference: 4.04, 95% CI [0.72, 7.36], p = .02, d = 0.48), with lower levels in the nocebo education group. This was attributable to less non-specific adverse events (mean difference: 0.39, 95% CI [0.04, 0.73], p = .03, d = 0.44) and a trend towards less specific adverse events in the nocebo education group (mean difference: 0.36, 95% CI [- 0.02, 0.74], p = .07, d = 0.37). We found no difference in adverse events at 10-days follow-up, perceived control of adverse events, or tendency to misattribute non-specific symptoms to the chemotherapy.ConclusionsThis study provides first proof-of-concept evidence for the efficacy of a brief information session in preventing adverse events of chemotherapy. However, results regarding patient-reported outcomes cannot rule out response biases. Informing patients about the nocebo effect may be an innovative and clinically feasible intervention for reducing the burden of adverse events.Trial registrationRetrospectively registered on March 27, 2018 to the German Clinical Trial Register (ID: DRKS00009501).

Dataset Information

Pharmacogenetic predictors of adverse events and response to chemotherapy in metastatic colorectal cancer: results from North American Gastrointestinal Intergroup Trial N9741.

Purpose

Patients and methods

Results

Conclusion

Publications

Pharmacogenetic predictors of adverse events and response to chemotherapy in metastatic colorectal cancer: results from North American Gastrointestinal Intergroup Trial N9741.

Similar Datasets

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