Continuing Education Activity

5-Fluorouracil (5-FU) is a medication used to treat various neoplasms. It is in the chemotherapy class of drugs. This activity outlines the indications, mechanism of action, and contraindications for 5-FU as a valuable agent in treating various visceral and dermatologic malignancies. This activity will also highlight the adverse event profile and other key factors (e.g., off-label uses) of 5-FU, including the importance of the interprofessional team.

Objectives:

• Identify the mechanism of action of fluorouracil.
• Describe the adverse effects of fluorouracil.
• Summarize the appropriate monitoring strategies for fluorouracil.
• Review interprofessional team strategies for improving care coordination and communication to advance the appropriate use of fluorouracil and improve patient outcomes.

Indications

Fluorouracil (5-FU) is a chemotherapeutic agent used in the treatment of a wide variety of malignancies. Systemic use of 5-FU is FDA-indicated for treating gastric adenocarcinoma, pancreatic adenocarcinoma, breast carcinoma, and colorectal adenocarcinoma.[1] In addition to systemic use, 5-FU is FDA-approved for topical use in the treatment of many dermatologic conditions, including multiple actinic or solar keratoses, as well as superficial basal cell carcinomas when other treatment methods are impractical.[2]

In addition to the FDA-approved indications for 5-FU, clinicians often use it topically to treat various other skin conditions, including metastatic cutaneous lesions from melanoma, keratoacanthomas, and treatment-resistant vitiligo. Evidence suggests that a conventional four-week course of 5-FU applied to the face and ears can be considered for reducing squamous cell carcinoma in high-risk individuals. Other dermatologic uses of 5-FU include the reduction of keloids and hypertrophic scars.[3][4]

Mechanism of Action

After ingestion or topical application, 5-FU enters cells via a facilitated transport mechanism and is converted to fluorodeoxyuridine monophosphate (FdUMP). FdUMP complexes with the enzyme thymidylate synthase (TS), inhibiting the production of the compound deoxythymidine monophosphate (dTMP). dTMP is essential for DNA replication and repair, and depletion of this compound results in an imbalance of intracellular nucleotides leading to double-stranded breaks in DNA by the enzyme endonuclease.[5] In addition to inhibiting thymidylate synthase, 5-FU also serves as a pyrimidine analog by misincorporating into RNA and DNA in place of uracil or thymine. The overwhelming damage of DNA repair machinery caused by these mechanisms ultimately results in cell death of rapidly proliferating cells. The topical use of 5-FU has been shown to have a selective cytotoxic effect for actinic skin, leaving normal skin unaffected. The proposed mechanism for this phenomenon is selective inhibition of TS in actinic skin and only partial inhibition in normal skin.[6]

5-FU exhibits other mechanisms of action that include interference with RNA processing and increasing p53 expression.[1] The mechanism by which 5-FU increases p53 expression may be concomitantly responsible for its efficacy in treating dermatologic conditions with altered p53 expression, including actinic keratosis and squamous cell carcinoma.[6]

Administration

5-FU exhibits poor absorption in the gastrointestinal tract when administered orally. Parenteral administration of 5-FU is preferable when treating visceral malignancies to optimize systemic bioavailability. 5-FU can be administered via intravenous bolus, continuous intravenous infusion over several days, and by ‘protracted’ infusion via an ambulatory pump for one to two weeks. When given intravenously, the terminal half-life of 5-FU is around 8 to 20 minutes due to rapid catabolism in the liver.[7]

5-FU can also be applied topically in solutions or cream with strengths varying from 0.5% to 5% when the desired clinical use is for dermatologic conditions. Systemic absorption of topical 5-FU has been studied to range from less than 2% to 6% but can be up to 75 times greater if applied to diseased skin. In addition to topical 5-FU for dermatologic conditions, intralesional delivery is also useful for various conditions. Further studies are needed to determine the systemic absorption of intralesionally delivered 5-FU.[4][6]

Some general dosing regimens follow based on indications. However, clinicians should refer to institutional protocols and the package inserts for specific dosing, including toxicity-related dose adjustments. There are also alternative regimens for some of the following conditions not covered here.

• Breast cancer: 500 mg/m^2/dose IV for a single dose on days 1 and 8 of a 28-day cycle.
• Gastric cancer: 
  • Resectable disease: 200 mg/m^2/24 hours IV infusion on days 1 to 21 of a 21-day cycle. Use with cisplatin as part of a multi-drug chemotherapy regimen.
  • Advanced disease: 750 to 1000 mg/m^2/24 hours IV infusion on days 1 to 4 of a 28-day cycle. Use with cisplatin.
• Colorectal cancer: 
  • Bolus regimen: 
  • Infusion regimen: 400 mg/m^2/dose IV for a single dose on day 1, then 1200 to 1500 mg/m^2/24 hour IV infusion on days 1 and 2 of a 14-day regimen. Use with leucovorin with or without irinotecan or oxaliplatin.
• Pancreatic cancer: 400 mg/m^2/dose IV on the first day, then 1200 mg/m^2/24 hours IV infusion on days 1 and 2 of a 14-day cycle. Give for 12 cycles as part of a multi-drug chemotherapy regimen.

Renal impairment does not require any dosing adjustments, although hemodialysis patients should reduce their dose by 50% on dialysis days. In hepatic impairment, caution is advised.

For topical 5-FU, dosing regimens include:

• Actinic keratosis: Apply the solution or 5% cream twice daily for 2 to 4 weeks.
• Superficial basal cell carcinoma: Apply 5% cream twice daily for 3 to 6 weeks.

Adverse Effects

5-FU has many adverse drug effects when used systemically. The most common adverse effect reported in patients receiving systemic 5-FU treatment was diarrhea. Other common adverse effects include vomiting, nausea, and dehydration. More concerning side effects that require monitoring in patients receiving systemic 5-FU chemotherapy include neutropenia, pyrexia, pulmonary embolism, thrombocytopenia, and leukopenia. Leukopenia, leading to an immunocompromised state in these patients, can result in secondary pneumonia or sepsis.[8]

The systemic side effect profile of topically applied 5-FU is minimal due to limited absorption. The most common adverse effect of the topical application of 5-FU is localized skin irritation, leading to ulceration and predisposing patients to infection. Other side effects of topical 5-FU therapy include pruritis, pain, erythema, crusting, and eczematous skin reactions.[1][2]

Contraindications

Contraindications to treatment with 5-FU include patients with a documented deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD). This enzyme is responsible for degrading over 80% of 5-FU to biologically inactive metabolites, and deficiency can result in life-threatening toxicity.[6]

Breastfeeding is also a contraindication to systemic 5-FU treatment. However, some studies suggest that intermittent therapy can be performed safely. The topical use of 5-FU on the breast is not a contraindication with breastfeeding, but steps are necessary to avoid direct contact between the treated skin and the infant’s skin.[9]

5-FU has been shown to interact with many other pharmaceutical agents. Therefore, drug interactions should be checked before beginning treatment with 5-FU.[7]

Monitoring

Therapeutic drug monitoring of 5-FU can be performed using high-performance liquid chromatography, gas chromatography-mass spectrometry, or immunoassay to measure plasma drug levels to reduce toxicity and improve efficacy. Therapeutic drug monitoring is especially important for patients with DPD deficiency, in which 5-FU treatment is the mainstay of treatment for their condition with no clinically efficacious alternatives.[10] Some studies suggest that DPD is inducible in deficient patients by using capecitabine, leading to new methods of 5-FU chemotherapy titration in these individuals.[11]

Toxicity

Patients experiencing severe adverse effects of 5-FU treatment can be administered the drug uridine triacetate within four days of 5-FU 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 5-FU metabolites for binding sites in the body. Uridine triacetate is administered orally, but it is unknown whether it is safe or efficacious after four days following 5-FU administration.[12][13]

Enhancing Healthcare Team Outcomes

Clinical utilization of systemic 5-FU therapy for the treatment of visceral malignancies has been shown to have low efficacy due to various mechanisms of drug resistance. The overall response rate of advanced colorectal cancer to 5-FU monotherapy is only 10% to 15% and only 40% to 50% when combined with other chemotherapeutic agents. Many potential mechanisms of resistance to systemic 5-FU 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 TS and increased DPD activity, resulting in increased drug catabolism. Identification and targeting of genes responsible for these resistance patterns using microarray technology can help to guide future treatment strategies and improve the clinical efficacy of systemic 5-FU chemotherapy. Some studies suggest that many common mechanisms for 5-FU resistance can be overcome with new encapsulated formulation technologies that alter drug absorption and bioavailability.[5]

Topical 5-FU has a broad array of uses in the dermatological setting to treat various skin conditions. It 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 topical 5% 5-FU has been shown to reduce the incidence of squamous cell carcinomas in high-risk individuals and ultimately reduce the need for Mohs micrographic surgery in these patients. In addition to 5-FU monotherapy, several topical combination therapies have been studied to increase its clinical efficacy for reducing actinic keratoses, including combination tretinoin, salicylic acid, and cryotherapy. Topical 5-FU has also been proposed to be efficacious for improving photodamage in individuals. However, some studies found no significant aesthetic improvement when a conventional course was used in an elderly male population.[14][3]

Intralesional 5-FU has been studied as an effective method for treating keloids, hypertrophic scars, and keratoacanthomas. Studies suggest that combination therapy for keloids with intralesional 5-FU and intralesional triamcinolone offers a fast and efficacious treatment with a reduced adverse effect profile compared to each drug delivered individually.[4] Intralesional 5-FU can merit consideration when cutaneous malignancy is present in an anatomic area with poor wound healing capacity and where surgical intervention is not desirable, such as the lower leg in elderly individuals.[15][16]

Therapy with 5-FU requires the efforts of an interprofessional team. The clinician or specialist will prescribe the drug but would do well to have an oncology board-certified pharmacist assist in therapy choices, verify dosing, check for interactions, and counsel on adverse effects. Oncology specialized nurses may administer the drug and monitor for treatment effectiveness and adverse reactions. All team members need to have open lines of communication so that any issues encountered can be shared with everyone on the team and the matter addressed promptly. This interprofessional healthcare team paradigm will lead to optimal patient therapeutic outcomes. [Level 5]