Recommendations from the EGAPP working group

Can UCT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan?

Alfred O. Berg, Katrina Armstrong, Jeffrey Botkin, Ned Calonge, James Haddow, Maxine Hayes, Celia Kaye, Kathryn A. Phillips, Margaret Piper, Carolyn (Sue) Richards, Joan A. Scott, Ora L. Strickland, Steven Teutsch

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

Summary of Recommendations: The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found that the evidence is currently insufficient to recommend for or against the routine use of UGT1A1 genotyping in patients with metastatic colorectal cancer who are to be treated with irinotecan, with the intent of modifying the dose as a way to avoid adverse drug reactions (severe neutropenia). Rationale: The EGAPP Working Group (EWG) found no intervention trials showing that targeted dosing of irinotecan based on UGT1A1 genotyping could reduce the rates of two specific adverse drug events, severe (Grade 3-4) neutropenia or diarrhea. Observational studies indicate a significant association between UGT1A1 genotypes, particularly *28/*28 and *1/*28, and the occurrence of severe neutropenia. Observational studies also indicate a possible association between severe diarrhea and these UGT1A1 genotypes, but the association is not statistically significant. An additional finding was the suggestion that reducing irinotecan dose may result in patient harms due to diminished effectiveness of treatment in highest risk individuals (*28/*28 homozygotes), and that a higher dose might be warranted among individuals at lower risk of adverse drug events (*1/*1 and *1/*28 genotypes). This review did not consider higher risk patients (e.g., having previous adverse reactions to irinotecan or additional risk factors for neutropenia). Analytic Validity: The EWG found adequate evidence to conclude that analytic sensitivity and specificity were high for the commonly tested alleles, but evidence was inadequate for rarer alleles. Clinical Validity: The EWG found adequate evidence of a significant association between UGT1A1 genotype and the incidence of severe neutropenia at standard doses of irinotecan. The EWG found adequate evidence of a possible association between genotype and severe diarrhea, but the effect was smaller and not statistically significant. The EWG found adequate evidence of a significantly higher rate of tumor response to standard irinotecan dosing among individuals with the genotype at highest risk of adverse drug events (*28/*28). Clinical Utility: The EWG found no evidence to support clinical utility in the proposed clinical scenario. Preliminary modeling suggests that, even if targeted dosing were to be highly effective, it is not clear that benefits (reduced adverse drug events) outweigh harms (unresponsive tumors). Contextual Issues: Addressing patient preferences regarding risk of side effects and quality of life, versus aggressive treatment to potentially improve effectiveness, is expected practice. In addition, a recent study reported that risk for neutropenia was lower at lower irinotecan doses. For treatment regimens utilizing lower irinotecan doses, UGT1A1 genotype may not be a useful indicator of risk for adverse drug events. Further rigorous evaluation of UGT1A1 genotyping using current and promising irinotecan treatment protocols is warranted. Genet Med 2009:11(1):15-20. This recommendation statement is a product of the independent EGAPP Working Group. Although the Centers for Disease Control and Prevention (CDC) provides support to the EGAPP Working Group, including staff support in the preparation of this document, recommendations made by the EGAPP Working Group should not be construed as official positions of the CDC or the US Department of Health and Human Services.

Original languageEnglish (US)
Pages (from-to)15-20
Number of pages6
JournalGenetics in Medicine
Volume11
Issue number1
DOIs
StatePublished - Jan 2009

Fingerprint

irinotecan
Colorectal Neoplasms
Neutropenia
Drug-Related Side Effects and Adverse Reactions
Morbidity
Mortality
Genotype
Diarrhea
Centers for Disease Control and Prevention (U.S.)
Observational Studies
Alleles
United States Dept. of Health and Human Services
Patient Harm
Viverridae
Patient Preference

Keywords

  • Chemotherapy
  • Irinotecan
  • Metastatic colorectal cancer
  • UGT1A1 geno-typing

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Recommendations from the EGAPP working group : Can UCT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? / Berg, Alfred O.; Armstrong, Katrina; Botkin, Jeffrey; Calonge, Ned; Haddow, James; Hayes, Maxine; Kaye, Celia; Phillips, Kathryn A.; Piper, Margaret; Richards, Carolyn (Sue); Scott, Joan A.; Strickland, Ora L.; Teutsch, Steven.

In: Genetics in Medicine, Vol. 11, No. 1, 01.2009, p. 15-20.

Research output: Contribution to journalArticle

Berg, AO, Armstrong, K, Botkin, J, Calonge, N, Haddow, J, Hayes, M, Kaye, C, Phillips, KA, Piper, M, Richards, CS, Scott, JA, Strickland, OL & Teutsch, S 2009, 'Recommendations from the EGAPP working group: Can UCT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan?', Genetics in Medicine, vol. 11, no. 1, pp. 15-20. https://doi.org/10.1097/GIM.0b013e31818efd9d
Berg, Alfred O. ; Armstrong, Katrina ; Botkin, Jeffrey ; Calonge, Ned ; Haddow, James ; Hayes, Maxine ; Kaye, Celia ; Phillips, Kathryn A. ; Piper, Margaret ; Richards, Carolyn (Sue) ; Scott, Joan A. ; Strickland, Ora L. ; Teutsch, Steven. / Recommendations from the EGAPP working group : Can UCT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan?. In: Genetics in Medicine. 2009 ; Vol. 11, No. 1. pp. 15-20.
@article{273fd28731e54fe2b3fc123b875e69bf,
title = "Recommendations from the EGAPP working group: Can UCT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan?",
abstract = "Summary of Recommendations: The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found that the evidence is currently insufficient to recommend for or against the routine use of UGT1A1 genotyping in patients with metastatic colorectal cancer who are to be treated with irinotecan, with the intent of modifying the dose as a way to avoid adverse drug reactions (severe neutropenia). Rationale: The EGAPP Working Group (EWG) found no intervention trials showing that targeted dosing of irinotecan based on UGT1A1 genotyping could reduce the rates of two specific adverse drug events, severe (Grade 3-4) neutropenia or diarrhea. Observational studies indicate a significant association between UGT1A1 genotypes, particularly *28/*28 and *1/*28, and the occurrence of severe neutropenia. Observational studies also indicate a possible association between severe diarrhea and these UGT1A1 genotypes, but the association is not statistically significant. An additional finding was the suggestion that reducing irinotecan dose may result in patient harms due to diminished effectiveness of treatment in highest risk individuals (*28/*28 homozygotes), and that a higher dose might be warranted among individuals at lower risk of adverse drug events (*1/*1 and *1/*28 genotypes). This review did not consider higher risk patients (e.g., having previous adverse reactions to irinotecan or additional risk factors for neutropenia). Analytic Validity: The EWG found adequate evidence to conclude that analytic sensitivity and specificity were high for the commonly tested alleles, but evidence was inadequate for rarer alleles. Clinical Validity: The EWG found adequate evidence of a significant association between UGT1A1 genotype and the incidence of severe neutropenia at standard doses of irinotecan. The EWG found adequate evidence of a possible association between genotype and severe diarrhea, but the effect was smaller and not statistically significant. The EWG found adequate evidence of a significantly higher rate of tumor response to standard irinotecan dosing among individuals with the genotype at highest risk of adverse drug events (*28/*28). Clinical Utility: The EWG found no evidence to support clinical utility in the proposed clinical scenario. Preliminary modeling suggests that, even if targeted dosing were to be highly effective, it is not clear that benefits (reduced adverse drug events) outweigh harms (unresponsive tumors). Contextual Issues: Addressing patient preferences regarding risk of side effects and quality of life, versus aggressive treatment to potentially improve effectiveness, is expected practice. In addition, a recent study reported that risk for neutropenia was lower at lower irinotecan doses. For treatment regimens utilizing lower irinotecan doses, UGT1A1 genotype may not be a useful indicator of risk for adverse drug events. Further rigorous evaluation of UGT1A1 genotyping using current and promising irinotecan treatment protocols is warranted. Genet Med 2009:11(1):15-20. This recommendation statement is a product of the independent EGAPP Working Group. Although the Centers for Disease Control and Prevention (CDC) provides support to the EGAPP Working Group, including staff support in the preparation of this document, recommendations made by the EGAPP Working Group should not be construed as official positions of the CDC or the US Department of Health and Human Services.",
keywords = "Chemotherapy, Irinotecan, Metastatic colorectal cancer, UGT1A1 geno-typing",
author = "Berg, {Alfred O.} and Katrina Armstrong and Jeffrey Botkin and Ned Calonge and James Haddow and Maxine Hayes and Celia Kaye and Phillips, {Kathryn A.} and Margaret Piper and Richards, {Carolyn (Sue)} and Scott, {Joan A.} and Strickland, {Ora L.} and Steven Teutsch",
year = "2009",
month = "1",
doi = "10.1097/GIM.0b013e31818efd9d",
language = "English (US)",
volume = "11",
pages = "15--20",
journal = "Genetics in Medicine",
issn = "1098-3600",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

TY - JOUR

T1 - Recommendations from the EGAPP working group

T2 - Can UCT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan?

AU - Berg, Alfred O.

AU - Armstrong, Katrina

AU - Botkin, Jeffrey

AU - Calonge, Ned

AU - Haddow, James

AU - Hayes, Maxine

AU - Kaye, Celia

AU - Phillips, Kathryn A.

AU - Piper, Margaret

AU - Richards, Carolyn (Sue)

AU - Scott, Joan A.

AU - Strickland, Ora L.

AU - Teutsch, Steven

PY - 2009/1

Y1 - 2009/1

N2 - Summary of Recommendations: The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found that the evidence is currently insufficient to recommend for or against the routine use of UGT1A1 genotyping in patients with metastatic colorectal cancer who are to be treated with irinotecan, with the intent of modifying the dose as a way to avoid adverse drug reactions (severe neutropenia). Rationale: The EGAPP Working Group (EWG) found no intervention trials showing that targeted dosing of irinotecan based on UGT1A1 genotyping could reduce the rates of two specific adverse drug events, severe (Grade 3-4) neutropenia or diarrhea. Observational studies indicate a significant association between UGT1A1 genotypes, particularly *28/*28 and *1/*28, and the occurrence of severe neutropenia. Observational studies also indicate a possible association between severe diarrhea and these UGT1A1 genotypes, but the association is not statistically significant. An additional finding was the suggestion that reducing irinotecan dose may result in patient harms due to diminished effectiveness of treatment in highest risk individuals (*28/*28 homozygotes), and that a higher dose might be warranted among individuals at lower risk of adverse drug events (*1/*1 and *1/*28 genotypes). This review did not consider higher risk patients (e.g., having previous adverse reactions to irinotecan or additional risk factors for neutropenia). Analytic Validity: The EWG found adequate evidence to conclude that analytic sensitivity and specificity were high for the commonly tested alleles, but evidence was inadequate for rarer alleles. Clinical Validity: The EWG found adequate evidence of a significant association between UGT1A1 genotype and the incidence of severe neutropenia at standard doses of irinotecan. The EWG found adequate evidence of a possible association between genotype and severe diarrhea, but the effect was smaller and not statistically significant. The EWG found adequate evidence of a significantly higher rate of tumor response to standard irinotecan dosing among individuals with the genotype at highest risk of adverse drug events (*28/*28). Clinical Utility: The EWG found no evidence to support clinical utility in the proposed clinical scenario. Preliminary modeling suggests that, even if targeted dosing were to be highly effective, it is not clear that benefits (reduced adverse drug events) outweigh harms (unresponsive tumors). Contextual Issues: Addressing patient preferences regarding risk of side effects and quality of life, versus aggressive treatment to potentially improve effectiveness, is expected practice. In addition, a recent study reported that risk for neutropenia was lower at lower irinotecan doses. For treatment regimens utilizing lower irinotecan doses, UGT1A1 genotype may not be a useful indicator of risk for adverse drug events. Further rigorous evaluation of UGT1A1 genotyping using current and promising irinotecan treatment protocols is warranted. Genet Med 2009:11(1):15-20. This recommendation statement is a product of the independent EGAPP Working Group. Although the Centers for Disease Control and Prevention (CDC) provides support to the EGAPP Working Group, including staff support in the preparation of this document, recommendations made by the EGAPP Working Group should not be construed as official positions of the CDC or the US Department of Health and Human Services.

AB - Summary of Recommendations: The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found that the evidence is currently insufficient to recommend for or against the routine use of UGT1A1 genotyping in patients with metastatic colorectal cancer who are to be treated with irinotecan, with the intent of modifying the dose as a way to avoid adverse drug reactions (severe neutropenia). Rationale: The EGAPP Working Group (EWG) found no intervention trials showing that targeted dosing of irinotecan based on UGT1A1 genotyping could reduce the rates of two specific adverse drug events, severe (Grade 3-4) neutropenia or diarrhea. Observational studies indicate a significant association between UGT1A1 genotypes, particularly *28/*28 and *1/*28, and the occurrence of severe neutropenia. Observational studies also indicate a possible association between severe diarrhea and these UGT1A1 genotypes, but the association is not statistically significant. An additional finding was the suggestion that reducing irinotecan dose may result in patient harms due to diminished effectiveness of treatment in highest risk individuals (*28/*28 homozygotes), and that a higher dose might be warranted among individuals at lower risk of adverse drug events (*1/*1 and *1/*28 genotypes). This review did not consider higher risk patients (e.g., having previous adverse reactions to irinotecan or additional risk factors for neutropenia). Analytic Validity: The EWG found adequate evidence to conclude that analytic sensitivity and specificity were high for the commonly tested alleles, but evidence was inadequate for rarer alleles. Clinical Validity: The EWG found adequate evidence of a significant association between UGT1A1 genotype and the incidence of severe neutropenia at standard doses of irinotecan. The EWG found adequate evidence of a possible association between genotype and severe diarrhea, but the effect was smaller and not statistically significant. The EWG found adequate evidence of a significantly higher rate of tumor response to standard irinotecan dosing among individuals with the genotype at highest risk of adverse drug events (*28/*28). Clinical Utility: The EWG found no evidence to support clinical utility in the proposed clinical scenario. Preliminary modeling suggests that, even if targeted dosing were to be highly effective, it is not clear that benefits (reduced adverse drug events) outweigh harms (unresponsive tumors). Contextual Issues: Addressing patient preferences regarding risk of side effects and quality of life, versus aggressive treatment to potentially improve effectiveness, is expected practice. In addition, a recent study reported that risk for neutropenia was lower at lower irinotecan doses. For treatment regimens utilizing lower irinotecan doses, UGT1A1 genotype may not be a useful indicator of risk for adverse drug events. Further rigorous evaluation of UGT1A1 genotyping using current and promising irinotecan treatment protocols is warranted. Genet Med 2009:11(1):15-20. This recommendation statement is a product of the independent EGAPP Working Group. Although the Centers for Disease Control and Prevention (CDC) provides support to the EGAPP Working Group, including staff support in the preparation of this document, recommendations made by the EGAPP Working Group should not be construed as official positions of the CDC or the US Department of Health and Human Services.

KW - Chemotherapy

KW - Irinotecan

KW - Metastatic colorectal cancer

KW - UGT1A1 geno-typing

UR - http://www.scopus.com/inward/record.url?scp=59849117793&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=59849117793&partnerID=8YFLogxK

U2 - 10.1097/GIM.0b013e31818efd9d

DO - 10.1097/GIM.0b013e31818efd9d

M3 - Article

VL - 11

SP - 15

EP - 20

JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

IS - 1

ER -