colorectal cancer and preparing for chemotherapy? ask about your risk of serious side effects

Petition to NCCN

Appeal to the National Comprehensive Cancer Network (NCCN) to Change Guidelines on the Treatment of Patients with Colon/Rectal/Anal Cancer


The NCCN's Colon Cancer Panel met in June of 2014 and rejected the proposed revision (see below) to the guideline as it concluded: 


"Impaired dihydropyrimidine dehydrogenase (DPD) activity is a rare

occurrence and the test is not done routinely. Therefore, the panel consensus

was to not revise the Guidelines to recommend pre-screening of patients to

measure the dihydrouracil/uracil ratio. "


Pasted from <http://www.nccn.org/professionals/drug_compendium/content/pdf/28_6_9_2014.pdf>


NCCN Guideline Recommendation

Submitted by:  Ken Surprenant

Organization: unaffiliated (surviving spouse)

Date of request: 23 March 2014

NCCN Guideline Panel: Colon/Rectal/Anal Cancer


I respectfully request the NCCN Panel for Colon Cancer review the enclosed data for inclusion in the initial diagnostic evaluation of patients preparing to receive treatment with a fluoropyrimidine. 


Specific Changes:  Revise the guidelines to recommend  pre-screening of patients  using a “functional” test that measures the dihydrouracil/uracil ratio to identify  individuals with impaired dihydropyrimidine dehydrogenase (DPD) activity for whom the fluoropyrimidine dosage should be reduced to avoid severe toxic reactions; treatments should also rely upon pharmacokinetic follow-up to indicate more precisely recommended dosage levels.


FDA Clearance: not applicable


Rationale:  Pre-screening of patients for impaired DPD activity (due to genetic and non-genetic factors) will improve patient care, treatment efficacy, and significantly reduce grade 3 and 4 toxic reactions and fatalities that occur much more frequently than common treatment practices acknowledge (instances of severe toxicity range from 10-40%).


The following articles are submitted to support this proposed change:  These studies show that severe reactions are far from rare (estimated 500-1000 fatalities/year in the US) and demonstrate that pre-treatment screening and dose management of fluoropyrimidine can effectively reduce the incidence of severe toxic and fatal reactions.


Zhu, Andrew; Puchalski, Thomas; et al. Dihydropyrimidine Dehydrogenase and Thymidylate Synthase Polymorphisms and Their Association with 5-Fluorouracil/Leucovorin Chemotherapy in Colorectal Cancer, Clinical Colorectal Cancer, 2004 (Vol 3, No. 4): 225-234.  This paper indicates that toxicity is not a rare condition: 15-20% suffer grade 3, 3-10% grade 4 toxic reactions to 5-FU treatment; between 500-1000 US patients die annually due to 5-FU toxicity. 

Caudle, KE; Diasio, RB; et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for Dihydropyrimidine Dehydrogenase Genotype and Fluoroupyrimidine Dosing, Clinical Pharmacology & Therapeutics, (29 August 2013), doi:10.1038/clpt.2013.172.  This study reports 10-40% of patients with 5-FU suffer severe and sometimes life threatening toxic reactions and recommends starting dosage at 50%, in order to minimize toxicities, followed by an assessment of the patient’s tolerance before increasing dose levels.


Ciccolini, Joseph; Mercier, Cedric; et al. Routine Dihydropyrimidine Dehydrogenase Testing for Anticipating 5-Fluorouracil-Related Severe Toxicities: Hype or Hope?, Clinical Colorectal Cancer, 2010 (Vol 9, No. 4): 224-228.  This study indicates non-genetic factors  may lower DPD levels and put patients at risk; it reports that  functional techniques (uracil/dihydrouracil plasma tests and uracil breath tests) are available to identify patients who have a limited ability to metabolize 5-FU; and it asserts that pre-screening and dose tailoring systematically improved clinical outcomes of 5-FU patients.


Piper, Margaret; Aronson, Naomi; et al. Pharmacogenetic Testing to Predict Serious Toxicity From 5-Fluorouracil (5-FU) for Patients Administered 5-FU-Based Chemotherapy for Cancer, Technology Evaluation Center, Assessment Program Vol 24, No. 13, Aug 2010.  This study reports 30% of patients receiving this treatment regimen suffer severe toxic reactions; genetic testing has poor predictive value.


Saif, M. Wasif, et al. Pharmacokinetically Guided Dose Adjustment of 5-Fluorouracil: A Rational Approach to Improving Therapeutic Outcomes, Journal National Cancer Institute, 2009, 101: 1543-1552.  The authors offer that dose management may lead to substantial costs savings and better patient outcomes.


Gamelin, Erick, et al. Individual Fluorouracil Dose Adjustment Based on Pharmacokinetic Follow-up Compared With Conventional Dosage: Results of a Multi-Center Randomized Trial of Patients With Metastatic Colorectal Cancer, Journal of Clinical Oncology, 2008, 26: 2099-2105.  This study found that plasma-level measurements of 5-FU is the optimal means of minimizing toxicity while ensuring the proper dose intensity; it also offered that this practice can be easily integrated into clinical practice.