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Page Created: 21 July 2021

 

 

NCCN Guideline Recommendation

 

Submitted by:  Gabriel A. Brooks, MD, MPH, Assistant Professor, Geisel School of Medicine/Norris Cotton Cancer Center, and Kenneth E. Surprenant, Patient Advocate

 

Email: gabriel.a.brooks@hitchcock.org;  kesbc6@gmail.com

 

With Support of Those Appended to the End of the Recommendation

 

Date of request: July 5, 2021; revision 1, July 6, 2021 (revision – add Dr. Elias as supporter).

 

We respectfully request the NCCN Panel for Colon/Rectal/Anal Cancer review the enclosed data for inclusion in the initial diagnostic evaluation of patients preparing to receive fluoropyrimidine chemotherapy treatment (5-fluorouracil or capecitabine). 

 

 

 

Specific Changes:  Revise the current NCCN guidelines for Colon Cancer Treatment (page MS-41 and MS-42) to recommend screening for Dihydropyrimidine Dehydrogenase (DPD) deficiency prior to the start of fluoropyrimidine chemotherapy. Recommended tests for DPD deficiency screening include genotypic or phenotypic tests (i.e., DPYD genotyping or measurement of the plasma uracil concentration), as recommended by the European Medicines Agency (see EMA communique). For patients with a positive screening test for DPD deficiency, use and dosing of fluoropyrimidine agents should follow the expert consensus recommendations from the Clinical Pharmacogenetics Implementation Consortium (CPIC, see Amstutz, 2018). 

 

 

 

FDA Clearance: The current FDA label for 5-fluorouracil states: “Increased Risk of Serious or Fatal Adverse Reactions in Patients with Low or Absent Dipyrimidine Dehydrogenase Activity: Withhold or permanently discontinue fluorouracil in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of dipyrimidine dehydrogenase (DPD) activity. No fluorouracil dose has been proven safe in patients with absent DPD activity. (5.1)”

 

 

 

The FDA Table of Pharmacogenetic Associations identifies intermediate and poor metabolizers of 5-FU and capecitabine have a “higher adverse reaction risk (severe, life threatening, or fatal toxicities). (https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations)

 

 

 

The FDA’s Patient Counseling Information for Fluorouracil advises: “Patients to notify their healthcare provider if they have a known DPD deficiency. Advise patients if they have complete or near complete absence of DPD activity, they are at an increased risk of severe and life-threatening mucositis, diarrhea, neutropenia and neurotoxicity. (17)”

 

 

 

The FDA is currently evaluating a citizen’s petition that seeks to revise fluoropyrimidine drug labels to indicate screening for DPD deficiency prior to fluoropyrimidine chemotherapy use. (https://www.regulations.gov/document/FDA-2020-P-2213-0001)

 

 

 

Although not FDA cleared, the NCBI Genetic Testing Registry (Link) lists 61 CLIA-approved laboratories in the United States that offer DPYD targeted polymorphism genotyping and/or sequencing, including from commonly used laboratories such as Quest Diagnostics (Link) and LabCorp (Link).

 

 

 

Rationale: The NCCN Colon Cancer Guideline discussion section acknowledges that prospective studies have demonstrated that pre-treatment DPYD screening to guide fluoropyrimidine treatment is feasible, improves treatment outcomes, and is cost-effective, confirming that this strategy has demonstrated clinical utility. The guideline states that “Pretreatment DPYD testing of all patients has the potential to identify the estimated 1% to 2% of the population with truncating alleles”, but then recommends against this practice because “it is not known with certainty that given DPYD variants are necessarily associated with this risk” (MS-41, 42).

 

 

 

Well-conducted retrospective analyses of prospective NCTN clinical trials and meta-analyses confirm that at least four DPYD variants increase risk of severe toxicity. The estimated proportion of the U.S. population carrying one of these variants is approximately 6%. Prospective studies demonstrate the feasibility, clinical benefit, and cost-effectiveness of pre-treatment genotyping of these alleles to inform fluoropyrimidine dosing, based on expert consensus guidelines. Finally, screening for DPD deficiency has become the standard of care in large segments of the medically advanced world, following the European Medicines Agency’s April 2020 recommendation in favor of pre-treatment DPD deficiency screening.  Some U.S. cancer centers are taking note and are already screening or planning to screen most patients for DPD deficiency prior to fluoropyrimidine chemotherapy (including the University of Michigan and Norris Cotton Cancer Center at Dartmouth).

 

·         The well-conducted, pre-specified pharmacogenetic analysis of the prospective Alliance N0147 trial found that when treated with standard fluorouracil dosing, patients carrying DPYD variants c.1905+1G>A (*2A) and c.2846A>T had 88% and 82% risk of grade ³3 fluorouracil-related toxicity, respectively.

 

o   Lee AM, Shi Q, Pavey E, et al. DPYD variants as predictors of 5-fluorouracil toxicity in adjuvant colon cancer treatment (NCCTG N0147). J Natl Cancer Inst. 2014;106.

 

·         Meta-analyses have confirmed that four DPYD variants significantly increase risk of severe fluoropyrimidine toxicity ((c.1905+1G>A [*2A], c.1679T>G [*13], c.2846A>T, and c.1129-5923G>A [HapB3]). 

 

o   Meulendijks D, Henricks LM, Sonke GS, et al. Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data. Lancet Oncol. 2015;16:1639-1650.

 

o   Lee AM, Qian Shi, et al. Association between DPYD c.1129-5923 C>G/hapB3 and

 

severe toxicity to 5-fluorouracil-based chemotherapy in stage III

 

colon cancer patients: NCCTG N0147 (Alliance). Pharmacogenetics and Genomics 2016, 26:133–137

 

·         The 1-2% incidence of DPYD variant carriers cited in the NCCN Guideline is an underestimation, based on a study reporting the incidence of carriers of a single variant (c.1905+1G>A [*2A]). Any one of the four validated variants above is carried by 5% to 7% of patients with European ancestry, while another putative diminished activity variant, DPYD c.557A>G (p.Y186C), is carried by 3-5% of patients of African ancestry. These frequencies are documented within the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, co-authored by medical oncologists and clinical pharmacologists, which provide regularly updated recommendations for fluoropyrimidine dosing in carriers of DPYD variants.

 

o   Amstutz U, Henricks LM, Offer SM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther. 2018;103:210-216.  See updates here: https://cpicpgx.org/guidelines/guideline-for-fluoropyrimidines-and-dpyd/  

 

·         Prospective clinical studies demonstrate that pre-treatment DPYD genotyping to guide dosing of fluoropyrimidine chemotherapy is feasible, cost-effective, and reduces severe toxicity. Based on the U.S. prevalence of DPYD gene variants, and using literature-based estimates of attributable deaths and hospitalizations, we conservatively estimate a number needed to test (NNT) of 952 patients to prevent 1 treatment-related fatality and 140 patients to prevent 1 toxicity-related hospitalization.

 

o   Deenen MJ, Meulendijks D, Cats A, et al: Upfront Genotyping of DPYD*2A to Individualize Fluoropyrimidine Therapy: A Safety and Cost Analysis. J Clin Oncol 34:227-34, 2016

 

o   Henricks LM, Lunenburg C, de Man FM, et al: DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol 19:1459-1467, 2018

 

·         DPD deficiency screening is no longer considered investigational by many global authorities. Pretreatment DPD deficiency screening has been recommended by the European Medicines Agency since April of 2020 and has become the standard of care in France, Switzerland, the Netherlands, the United Kingdom and the province of Quebec.

 

o   European Medicines Agency. 2020. '5-Fluorouracil (i.v.), capecitabine and tegafur containing products: Pre-treatment testing to identify DPD-deficient patients at increased risk of severe toxicity'.  https://www.ema.europa.eu/en/medicines/dhpc/5-fluorouracil-iv-capecitabine-tegafur-containing-products-pre-treatment-testing-identify-dpd

 

o   5-fluorouracil (intravenous), capecitabine, tegafur: DPD testing recommended before initiation to identify patients at increased risk of severe and fatal toxicity. Gov.UK. https://www.gov.uk/drug-safety-update/5-fluorouracil-intravenous-capecitabine-tegafur-dpd-testing-recommended-before-initiation-to-identify-patients-at-increased-risk-of-severe-and-fatal-toxicity

 

 

 

In closing, we note that the grassroots, word-of-mouth patient advocacy network that we are members of has learned of at least two additional deaths related to DPD deficiency since our prior petition to this committee in 2019. Both of those deaths occurred at NCI-designated comprehensive cancer centers, including the deaths of David McIntyre (OHSU Knight Cancer Center) and Carol Rosen (Dana-Farber Cancer Institute). These deaths were uncovered by unsystematic networking within a patient advocacy network, and likely represent a small fraction of U.S. deaths related to DPD deficiency within the last two years. We believe that an NCCN recommendation in favor of routine pre-treatment screening for DPD deficiency will serve to prevent similar avoidable fatalities. By adopting the practice of screening for DPD deficiency prior to fluoropyrimidine chemotherapy, fluoropyrimidines may safely remain a pillar of CRC therapy with improved outcomes for patients. 

 

 

 

 

 

 

 

Respectfully,

 

Gabriel A. Brooks, MD, MPH

 

Kenneth E. Surprenant, patient advocate

 

 

 

Supported by:

 

·         Daniel L. Hertz, PharmD PhD, Assistant Professor of Pharmacy at the University of Michigan, dlhertz@med.umich.edu

 

·         Sheheryar Kabraji, MD, Dana Farber Cancer Institute, Boston MA, Sheheryar_Kabraji@dfci.harvard.edu

 

·         Sara Rogers, PharmD, BCPS, Director of Clinical Affairs, American Society of Pharmacovigilance, sara@stopadr.org 

 

·         Rawad Elias, MD, Hartford HealthCare, Hartford CT, Rawad.Elias@hhchealth.org

 

·         Lindsay Murray, lindsaymurray522@gmail.com, and Joanne McIntyre, joannemci@comcast.net, both patient advocates who lost loved ones at NCI designated cancer centers.

 

·         Glenn Prettitore, patient advocate, surviving spouse, gprett@yahoo.com

 

·         Sue Sheridan, Director of Patient Engagement Emeritus, Society to Improve Diagnosis in Medicine (SIDM)¸ Sue.Sheridan@improvediagnosis.org