S4394 Toxicity Unveiled: The Critical Role of DPD Deficiency in 5-Fluorouracil Chemotherapy

Introduction: Dihydropyrimidine dehydrogenase (DPD) deficiency is a rare but clinically significant genetic disorder that impairs the metabolism of 5-fluorouracil (5-FU), a cornerstone chemotherapeutic agent in gastrointestinal (GI) cancers. DPD normally inactivates 5-FU for safe excretion; deficiency can result in drug accumulation and potentially fatal toxicity. While most patients tolerate 5-FU, 10–40% experience grade ≥3 toxicities, primarily hematologic and gastrointestinal and 1% suffer fatal outcomes. Case Description/Methods: A 76-year-old woman with a history of gastric banding, gastroesophageal reflux disease, and Barrett’s esophagus was diagnosed with poorly differentiated esophageal adenocarcinoma during an diagnostic esophagogastroduodenoscopy for weight loss and anorexia. Imaging showed no metastasis, likely stage T2N0M0 and she began neoadjuvant FOLFOX chemotherapy (5-FU, leucovorin, oxaliplatin) in preparation for surgical resection. Ten days after the first cycle, she presented with generalized weakness and profuse diarrhea. Symptoms began on day 3 post-chemotherapy with severe mucositis, nausea, vomiting, and diarrhea. By day 11, she was in shock and required ICU care. She was found to have grade 4 mucositis, leukopenia (WBC 0.3 K/µL, ANC 0), and thrombocytopenia (platelets 25 K/µL). She was treated with vasopressors, G-CSF, transfusions, and broad-spectrum antibiotics. Infectious workup, including C. difficile and other enteric pathogens, was negative and sepsis was ultimately ruled out. Given the extreme toxicity after a single dose of 5-FU, DPD deficiency was suspected. Genetic testing confirmed heterozygosity for the non-functional DPYD*13 variant (activity score 1), indicating an intermediate metabolizer phenotype and increased risk for fluoropyrimidine toxicity. Her hospital course was further complicated by Hand-Foot-Mouth disease and a small bowel obstruction, both managed conservatively. She was discharged after 25 days. This case highlights the importance of DPD testing before 5-FU therapy. Discussion: GI cancers make up 25% of U.S. cancer cases and 35% of related deaths. Fluoropyrimidines like 5-FU and capecitabine remain key treatments, but can cause severe toxicity in patients with DPD deficiency. While European countries mandate cost-effective DPYD testing, U.S. guidelines currently suggest only shared decision-making. DPYD testing is a simple blood test. Gastroenterologists, often first to diagnose GI cancers and manage related toxicities, are uniquely positioned to advocate for testing.