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Fluorouracil


Fluorouracil

Article Author:
Jarett Casale
Article Editor:
Jonathan Crane
Updated:
3/28/2020 1:52:54 PM
For CME on this topic:
Fluorouracil CME
PubMed Link:
Fluorouracil

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 the treatment of gastric adenocarcinoma, pancreatic adenocarcinoma, breast carcinoma, and colorectal adenocarcinoma. 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.[1][2]

In addition to the FDA-approved indications for 5-FU, it is often used topically for the treatment of various other skin conditions, including cutaneous metastatic lesions from melanoma, keratoacanthomas, and treatment-resistant vitiligo. There is evidence to suggest that a conventional four-week course of 5-FU applied to the face and ears can be considered for the reduction of 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. In addition to inhibition of 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.[5][6]

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

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, which can lead to ulceration and predispose 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 the degradation of 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 it can be performed safely with intermittent therapy. The topical use of 5-FU on the breast is not a contraindication with breastfeeding, but steps must be taken to avoid direct contact between 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. Some studies suggest that DPD is inducible in deficient patients by the use of capecitabine, leading to new methods of 5-FU chemotherapy titration in these individuals.[10][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 is unknown whether to be 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%-15% and only 40%-50% when combined with other chemotherapeutic agents. Many potential mechanisms of resistance to systemic 5-FU treatment have been identified. They include alteration of drug influx and efflux pumps, drug target mutations, and alterations in enzyme activity that all reduce its clinical efficacy. Alterations in enzyme activity reducing clinical efficacy include overexpression of the target enzyme TS, as well as 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 broad use in the dermatological setting for the treatment of various skin conditions. It is best known for its use as field therapy for the treatment of multiple actinic or solar keratoses to prevent progression to squamous cell carcinoma. 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 the reduction of actinic keratoses, including combination tretinoin, salicylic acid, and cryotherapy. Topical 5-FU has also been proposed to be efficacious for the improvement of photodamage in individuals. However, some studies found no significant aesthetic improvement when a conventional course was used in an elderly male population.[1][14][3]

Intralesional 5-FU has been studied as an effective method for the treatment of 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. Intralesional 5-FU can merit consideration when cutaneous malignancy is present in an anatomic area with poor wound healing capacity and, surgical intervention is not desirable, such as the lower leg in elderly individuals.[4][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 assisting in therapy choices, to verify dosing, check for interactions, and counsel on adverse effects. Oncology specialized nurses may be administering the drug, and can also monitor for treatment effectiveness as well as adverse reactions. All members of the team 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]


References

[1] Prince GT,Cameron MC,Fathi R,Alkousakis T, Topical 5-fluorouracil in dermatologic disease. International journal of dermatology. 2018 Oct;     [PubMed PMID: 30187924]
[2] Gupta AK,Weiss JS,Jorizzo JL, 5-fluorouracil 0.5% cream for multiple actinic or solar keratoses of the face and anterior scalp. Skin therapy letter. 2001 Jun;     [PubMed PMID: 11550079]
[3] Weinstock MA,Thwin SS,Siegel JA,Marcolivio K,Means AD,Leader NF,Shaw FM,Hogan D,Eilers D,Swetter SM,Chen SC,Jacob SE,Warshaw EM,Stricklin GP,Dellavalle RP,Sidhu-Malik N,Konnikov N,Werth VP,Keri JE,Robinson-Bostom L,Ringer RJ,Lew RA,Ferguson R,DiGiovanna JJ,Huang GD, Chemoprevention of Basal and Squamous Cell Carcinoma With a Single Course of Fluorouracil, 5%, Cream: A Randomized Clinical Trial. JAMA dermatology. 2018 Feb 1;     [PubMed PMID: 29299592]
[4] Prince GT,Cameron MC,Fathi R,Alkousakis T, Intralesional and Laser-Assisted 5-Fluorouracil in Dermatologic Disease: A Systematic Review. Journal of drugs in dermatology : JDD. 2018 Mar 1;     [PubMed PMID: 29537445]
[5] Zhang N,Yin Y,Xu SJ,Chen WS, 5-Fluorouracil: mechanisms of resistance and reversal strategies. Molecules (Basel, Switzerland). 2008 Aug 5;     [PubMed PMID: 18794772]
[6] Ceilley RI, Mechanisms of action of topical 5-fluorouracil: review and implications for the treatment of dermatological disorders. The Journal of dermatological treatment. 2012 Apr;     [PubMed PMID: 21034289]
[7] Diasio RB,Harris BE, Clinical pharmacology of 5-fluorouracil. Clinical pharmacokinetics. 1989 Apr;     [PubMed PMID: 2656050]
[8] Kadoyama K,Miki I,Tamura T,Brown JB,Sakaeda T,Okuno Y, Adverse event profiles of 5-fluorouracil and capecitabine: data mining of the public version of the FDA Adverse Event Reporting System, AERS, and reproducibility of clinical observations. International journal of medical sciences. 2012;     [PubMed PMID: 22211087]
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[10] Lee JJ,Beumer JH,Chu E, Therapeutic drug monitoring of 5-fluorouracil. Cancer chemotherapy and pharmacology. 2016 Sep;     [PubMed PMID: 27217046]
[11] Yoshida Y,Ogura K,Hiratsuka A,Aisu N,Yamada T,Kojima D,Tanimura S,Ogata K,Hara S,Mogi A,Takamatsu Y,Tamura K,Mishima H,Yamashita Y, 5-Fluorouracil Chemotherapy for Dihydropyrimidine Dehydrogenase-deficient Patients: Potential of the Dose-escalation Method. Anticancer research. 2015 Sep;     [PubMed PMID: 26254383]
[12] Traynor K, FDA approves therapy to treat overdose of fluorouracil, capecitabine. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 2016 Feb 1;     [PubMed PMID: 26796900]
[13] Ma WW,Saif MW,El-Rayes BF,Fakih MG,Cartwright TH,Posey JA,King TR,von Borstel RW,Bamat MK, Emergency use of uridine triacetate for the prevention and treatment of life-threatening 5-fluorouracil and capecitabine toxicity. Cancer. 2017 Jan 1;     [PubMed PMID: 27622829]
[14] Korgavkar K,Lee KC,Weinstock MA, Effect of Topical Fluorouracil Cream on Photodamage: Secondary Analysis of a Randomized Clinical Trial. JAMA dermatology. 2017 Nov 1;     [PubMed PMID: 28877312]
[15] Metterle L,Nelson C,Patel N, Intralesional 5-fluorouracil (FU) as a treatment for nonmelanoma skin cancer (NMSC): A review. Journal of the American Academy of Dermatology. 2016 Mar;     [PubMed PMID: 26577512]
[16] Srivastava S,Patil A,Prakash C,Kumari H, Comparison of Intralesional Triamcinolone Acetonide, 5-Fluorouracil, and Their Combination in Treatment of Keloids. World journal of plastic surgery. 2018 May;     [PubMed PMID: 30083505]