Chemotoxicity and pre-treatment dihydropyrimidine dehydrogenase analysis in patients on fluoropyrimidine based chemotherapy at a tertiary care hospital in South India

Fluoropyrimidine-based chemotherapy is widely used in the treatment of various solid tumors. The drugs, 5-Fluorouracil and its oral prodrug, capecitabine, are widely used in the treatment of colorectal, gastric, pancreatic, breast and head & neck cancers. These drugs inhibit cancer cell growth by interfering with DNA  and RNA  synthesis and form the backbone of many chemotherapy regimens These drugs are metabolized by the enzyme, Dihydropyrimidine Dehydrogenase . This is the rate limiting step in the metabolism of the drugs. It has been reported that patients with certain homozygous or compound heterozygous variants in the DPYD gene, are known to suffer from complete or near complete absence of DPD activity . A deficiency or reduced activity of DPD leads to drug accumulation, and the risk of toxicity. DPD is coded by the DPYD gene, and this promotes the first step of the drug degradation pathway. This pathway helps to convert  fluorouracil to its inactive metabolite. The remaining 5FU is excreted in urine. One of the key factors influencing fluoropyrimidine toxicity is the individual variation in drug metabolism. This affects the treatment outcomes. The most common toxicities are myelosuppression, cardiac toxicity, mucositis, hand-foot syndrome, and diarrhea. These leads to treatment discontinuation or serious life-threatening complications. Recently, many countries are advocating a mandatory screening before initiating the therapy.