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Fluorouracil, also known as 5-fluorouracil or 5-FU, belongs to the class of chemotherapy drugs used to treat various neoplasms. Systemic fluorouracil is approved by the US Food and Drug Administration (FDA) for the treatment of gastric adenocarcinoma, pancreatic adenocarcinoma, breast adenocarcinoma, and colorectal adenocarcinoma. In addition, topical fluorouracil (5%) is FDA-approved for managing dermatologic conditions such as multiple actinic or solar keratoses and superficial basal cell carcinomas in cases where alternative methods are not feasible. Off-label uses of systemic fluorouracil include anal carcinoma, advanced biliary tract carcinoma, cervical cancer, and esophageal cancer. Upon ingestion or topical application, fluorouracil enters cells through a facilitated transport mechanism and undergoes conversion into fluorodeoxyuridine monophosphate (FdUMP). FdUMP then forms complexes with the enzyme thymidylate synthase, thereby inhibiting the production of deoxythymidine monophosphate (dTMP). As dTMP is crucial for DNA replication and repair, its depletion causes an imbalance in intracellular nucleotides, ultimately resulting in the generation of double-stranded DNA breaks facilitated by the enzyme endonuclease. This activity outlines the indications, mechanism of action, and contraindications of fluorouracil as a valuable agent for treating a spectrum of visceral and dermatologic malignancies. This activity particularly emphasizes the adverse event profile and other significant factors of fluorouracil, such as off-label uses, highlighting the crucial and collaborative efforts of the interprofessional healthcare team in the management of various malignancies. Objectives: Identify appropriate patient populations for fluorouracil therapy based on indications approved by the FDA. Implement proper dosage adjustments and administration techniques for fluorouracil based on individual patient factors. Apply evidence-based guidelines and clinical protocols to guide decision-making regarding the use of fluorouracil in various neoplastic conditions. Collaborate with interprofessional healthcare team members to optimize patient care and safety during fluorouracil treatment. Access free multiple choice questions on this topic.

As described above, cardiotoxicity and neurotoxicity can be severe, requiring immediate cessation of fluorouracil treatment. Patients experiencing severe adverse effects of fluorouracil treatment can be administered uridine triacetate within 4 days of fluorouracil treatment. Uridine triacetate is a pyrimidine analog composed of uridine triacetate. The mechanism of toxicity reversal is due to the high concentrations of uridine delivered by uridine triacetate that competes with fluorouracil metabolites for binding sites in the body. Uridine triacetate is administered orally, but whether it is safe or efficacious after 4 days following fluorouracil administration is unknown.[43][44]

Clinical utilization of systemic fluorouracil therapy for the treatment of visceral malignancies has shown low efficacy due to various mechanisms of drug resistance. The overall response rate of advanced colorectal cancer to fluorouracil monotherapy is only 10% to 15% and 40% to 50% when combined with other chemotherapeutic agents. Many potential mechanisms of resistance to systemic fluorouracil treatment have been identified. They include altering drug influx and efflux pumps, drug target mutations, and enzyme activity alterations that reduce its clinical efficacy. Alterations in enzyme activity reducing clinical efficacy include overexpression of the target enzyme thymidylate synthase and increased DPD activity, resulting in increased drug catabolism. Identifying and targeting genes responsible for these resistance patterns using microarray technology can help guide future treatment strategies and improve the clinical efficacy of systemic fluorouracil chemotherapy. Some studies suggest that new encapsulated formulation technologies that alter drug absorption and bioavailability can overcome many common mechanisms for fluorouracil resistance.[11] Topical fluorouracil has a broad array of uses in the dermatological setting to treat various skin conditions. This formulation is best known for its use as field therapy for treating multiple actinic or solar keratoses to prevent progression to squamous cell carcinoma.[1] Randomized clinical trials have shown that chemoprevention therapy with 5% topical fluorouracil has reduced the incidence of squamous cell carcinomas in high-risk individuals and ultimately reduces the need for Mohs micrographic surgery in these patients. In addition to fluorouracil monotherapy, several topical combination therapies, including combination tretinoin, salicylic acid, and cryotherapy, have been studied to increase their clinical efficacy for reducing actinic keratoses. Topical fluorouracil has been efficacious for improving photodamage in individuals. However, some studies found no significant aesthetic improvement when a conventional course was used in an older male population.[45][9]

In addition to fluorouracil monotherapy, several topical combination therapies, including combination tretinoin, salicylic acid, and cryotherapy, have been studied to increase their clinical efficacy for reducing actinic keratoses. Topical fluorouracil has been efficacious for improving photodamage in individuals. However, some studies found no significant aesthetic improvement when a conventional course was used in an older male population.[45][9] Intralesional fluorouracil has been studied as an effective method for treating keloids, hypertrophic scars, and keratoacanthomas. Studies suggest that combination therapy for keloids with intralesional fluorouracil and triamcinolone offers a prompt and productive treatment with a reduced adverse effect profile compared to each drug delivered individually.[10] Intralesional fluorouracil can merit consideration when cutaneous malignancy is present in an anatomic area with poor wound healing capacity and where surgical intervention is undesirable, such as in the lower leg in older individuals.[46][47] Therapy with fluorouracil requires the efforts of an interprofessional team. The clinician or specialist should work with an oncology board-certified pharmacist to choose therapy, verify dosing, check for interactions, and counsel on adverse effects when prescribing drugs. Oncology-specialized nurses may administer the medication and monitor for treatment effectiveness and adverse reactions. All team members must exercise open lines of communication so that any issues are addressed promptly. The interprofessional healthcare team of physicians, advanced practice practitioners, oncologists, board-certified oncology pharmacists, and oncology-specialized nurses can improve treatment efficacy, decrease preventable adverse drug reactions, and optimize outcomes related to fluorouracil therapy. Interprofessional coordination and collaboration among all team members, with shared decision-making, can enhance patient outcomes when using fluorouracil to treat cancers where it has efficacy.