Fluorouracil

What it is

Fluorouracil is a synthetic fluorinated relative of uracil, one of the building blocks of RNA. Inside cells it is converted to three main active metabolites that block the enzyme thymidylate synthase and get built into RNA and DNA in place of the normal bases. It is used in two very different ways: as an intravenous chemotherapy for several solid cancers, and as a cream or solution painted onto sun-damaged skin. More than 80% of a dose is broken down by an enzyme called dihydropyrimidine dehydrogenase (DPD), and people with little or no DPD activity can be severely harmed by ordinary doses.

What the research says

The evidence for fluorouracil is strong but use-specific. For sun-damaged skin, a randomised head-to-head trial found 5% fluorouracil cream the most effective of four field treatments for actinic keratosis, and a separate randomised trial found it non-inferior to photodynamic therapy for superficial basal cell carcinoma. For bowel cancer after surgery, a large randomised trial found a real but small survival gain. Where it has been tested and failed, it failed clearly: it did not improve photoaged skin, and in the one trial that looked over four years it did not reduce overall skin-cancer risk. Harms are common and sometimes fatal, and the US injection label now carries a boxed warning about people with complete DPD deficiency.

Evidence grade: Well established.

How it works

Drug class: Fluoropyrimidine antimetabolite (nucleoside metabolic inhibitor; thymidylate synthase inhibitor)

Fluorouracil is a nucleoside metabolic inhibitor. It is turned inside the body into three main active metabolites which jam the enzyme thymidylate synthase and are built into RNA and DNA in place of the normal bases, so DNA and RNA cannot be made properly. Fast-dividing cells are hit hardest, which is why it damages tumours, and also why it damages the lining of the mouth and gut, the bone marrow and treated skin. (Source 1)

Boxed warning

WARNING: SERIOUS ADVERSE REACTIONS OR DEATH IN PATIENTS WITH COMPLETE DPD DEFICIENCY

(Source 2)

What it is used for

• In a four-arm randomised trial in 624 people, 74.7% of those given 5% fluorouracil cream were still free from treatment failure 12 months after treatment ended, against 53.9% with imiquimod, 37.7% with photodynamic therapy and 28.9% with ingenol mebutate. In a separate placebo-controlled trial a single course left 3.0 lesions per person at 6 months against 8.1 in the control group. Evidence: established. (Source 3)
• In a randomised non-inferiority trial of 601 people, 80.1% treated with fluorouracil cream were tumour-free at both 3 and 12 months, against 72.8% with photodynamic therapy and 83.4% with imiquimod. Fluorouracil was non-inferior to photodynamic therapy but imiquimod did better than photodynamic therapy, and the trialists named imiquimod the preferred option. Evidence: established. (Source 4)
• In the QUASAR randomised trial of 3239 patients, mostly with stage II disease, the relative risk of death from any cause with chemotherapy versus observation was 0.82 (95% CI 0.70-0.95; p=0.008). The trialists translated that into an absolute survival improvement of 3.6% (95% CI 1.0-6.0), which they themselves described as small. Evidence: established. (Source 5)
• The US label lists these three cancers alongside colorectal cancer as approved uses. That is a regulatory position, not evidence: we did not retrieve outcome trials for these three indications in this run, so we record the label's list and nothing more. Evidence: unknown. (Source 6)
• In the 932-person Veterans Affairs chemoprevention trial, a single course cut surgically treated squamous cell carcinoma in the first year (5 participants, 1%, versus 20, 4%, a 75% risk reduction, P = .002), but over the whole study there was no difference between groups in time to first keratinocyte, basal cell or squamous cell carcinoma, and the 11% reduction in basal cell carcinoma in year 1 was not statistically significant. Evidence: disputed. (Source 7)
• A Cochrane review of twelve trials, which randomised 1319 participants, found regular-dose postoperative 5-FU injections reduced surgical failure at one year (risk ratio 0.44, 95% CI 0.29 to 0.68 in eyes at high risk of failure), a number needed to treat of 4.1, but low-dose injections showed no difference (RR 0.93, 95% CI 0.70 to 1.24) and the reviewers rated some of the evidence very low using GRADE. Evidence: limited. (Source 8)
• A systematic review of eighteen papers covering 482 patients found 5-FU treatment effective in 45-96% of patients, but concluded that only the combination with triamcinolone acetonide may perform better than triamcinolone alone and that the level of evidence was poor. Evidence: limited. (Source 9)
• A secondary analysis of 3042 photographs from 281 of the 932 randomised participants found no statistically significant change in photodamage at 6, 12 or 18 months on any of four validated photonumeric scales. Evidence: not-supported. (Source 10)

Interactions

• Warfarin and other CYP2C9 substrates (label): Clotting times go up when fluorouracil is taken with warfarin, which raises bleeding risk. The label says pharmacokinetic data are not available for fluorouracil itself and suggests the effect may come from fluorouracil or its metabolites blocking the enzyme CYP2C9. (Source 11)
• Folinic acid (leucovorin, a folate) (clinical trial): Folinic acid is given with fluorouracil on purpose, to increase its anticancer effect; it is not a hazard to be avoided but part of the regimen. In QUASAR the fluorouracil was always paired with high-dose or low-dose L-folinic acid. (Source 12)
• Oxaliplatin (clinical trial): Adding oxaliplatin to fluorouracil and leucovorin after colon cancer surgery improved disease-free survival but added nerve damage: grade 3 sensory neuropathy occurred in 12.4 percent during treatment, falling to 1.1 percent a year later. (Source 13)

Stopping it

• Topical fluorouracil is used as a defined course, not continuously. The label says to stop when the inflammatory response reaches the erosion stage, usually after 2 to 4 weeks, and that complete healing may take a further 1 to 2 months after the drug is stopped. (Source 14)
• Treatment is also meant to be stopped early if signs of DPD enzyme deficiency appear. One case of life-threatening systemic toxicity has been reported after topical 5% fluorouracil cream in a person with DPD deficiency, with severe abdominal pain, bloody diarrhoea, vomiting, fever and chills. (Source 15)
• Intravenous fluorouracil is given as timed courses rather than continuously, and we found no withdrawal syndrome described. In QUASAR the comparison group simply had no chemotherapy, with chemotherapy considered only if the cancer came back. (Source 12)

What goes wrong

Across 211 studies of 63,186 patients, cardiotoxicity of any grade was reported in a pooled 5.04% of people given fluoropyrimidines, and 0.29% died of severe cardiotoxicity. (Source 16)

• Meta-analysis, Moderate certainty.
• Size: 211 studies, 63,186 patients across 31 countries or regions.
• Who: cancer patients receiving fluoropyrimidines (fluorouracil or capecitabine)
• How long: varies by study.
• Result: Pooled incidence 5.04% all grades and 1.5% grade 3 or higher; 0.29% of patients died due to severe cardiotoxicities; cardiac ischemia 2.24% and arrhythmia 1.85% most frequent.
• Funding: not stated in the abstract.

The pooled incidence of FAC, by meta-analytic, was 5.04% for all grades and 1.5% for grade 3 or higher. A total of 0.29% of patients died due to severe cardiotoxicities. More than 38 cardiac AEs were identified, with cardiac ischemia (2.24%) and arrhythmia (1.85%) being the most frequent.

Specific DPYD gene variants multiply the risk of severe fluoropyrimidine toxicity, especially gut and blood toxicity. (Source 17)

• Meta-analysis, Moderate certainty.
• Size: 7365 patients from eight studies (individual patient data)
• Who: patients treated with fluoropyrimidines alone, with other anticancer drugs, or with radiotherapy.
• How long: treatment course.
• Result: Adjusted RR for severe toxicity 4·40 (95% CI 2·08-9·30, p<0·0001) for c.1679T>G and 1·59 (1·29-1·97, p<0·0001) for c.1236G>A/HapB3; c.1601G>A not significant at 1·52 (95% CI 0·86-2·70, p=0·15). DPYD*2A 2·85 (1·75-4·62) and c.2846A>T 3·02 (2·22-4·10)
• Funding: none, per the paper.

DPYD c.1679T>G was significantly associated with fluoropyrimidine-associated toxicity (adjusted RR 4·40, 95% CI 2·08-9·30, p<0·0001), as was c.1236G>A/HapB3 (1·59, 1·29-1·97, p<0·0001). The association between c.1601G>A and fluoropyrimidine-associated toxicity was not significant (adjusted RR 1·52, 95% CI 0·86-2·70, p=0·15).

Even with up-front DPYD genotyping and dose reduction, people carrying a DPYD variant still had more severe toxicity than people without one. (Source 18)

• Cohort study, Moderate certainty.
• Size: 1103 evaluable patients of 1181 enrolled, at 17 hospitals in the Netherlands.
• Who: adults with cancer starting fluoropyrimidine-based therapy; 85 (8%) heterozygous DPYD variant carriers and 1018 (92%) wild type.
• How long: entire treatment duration.
• Result: Severe (grade ≥3) toxicity in 33 of 85 (39%) variant carriers versus 231 of 1018 (23%) wild-type patients, p=0·0013. Relative risk of severe toxicity with genotype-guided dosing 1·31 (95% CI 0·63-2·73) for DPYD*2A carriers versus 2·87 (2·14-3·86) in the historical cohort.
• Funding: Dutch Cancer Society, per the paper.

Overall, fluoropyrimidine-related severe toxicity was higher in DPYD variant carriers (33 [39%] of 85 patients) than in wild-type patients (231 [23%] of 1018 patients; p=0·0013).

Adding oxaliplatin to fluorouracil and leucovorin caused grade 3 sensory nerve damage in about one in eight patients during treatment. (Source 13)

• Randomized trial, High certainty.
• Size: 1123 patients randomly assigned to each group.
• Who: patients after curative resection for stage II or III colon cancer.
• How long: six months of treatment, with follow-up to one year.
• Result: Grade 3 sensory neuropathy 12.4 percent during treatment, falling to 1.1 percent at one year; febrile neutropenia 1.8 percent; six deaths during treatment in each group (death rate 0.5 percent)
• Funding: not stated in the abstract.

the incidence of grade 3 sensory neuropathy was 12.4 percent during treatment, decreasing to 1.1 percent at one year of follow-up. Six patients in each group died during treatment (death rate, 0.5 percent).

Topical fluorouracil causes local skin reactions in most people treated, and occasionally wound infection needing extra treatment. (Source 4)

• Randomized trial, Moderate certainty.
• Size: 601 patients randomised; 198 analysed in the fluorouracil group.
• Who: adults with superficial basal cell carcinoma.
• How long: 4 weeks of twice-daily cream, followed to 12 months.
• Result: Local skin redness most often reported as moderate or severe in all groups; cream-treated patients more often reported moderate to severe local swelling, erosion, crust formation and itching than photodynamic-therapy patients; two patients treated with fluorouracil developed a local wound infection needing additional outpatient treatment.
• Funding: independent (Netherlands Organization for Scientific Research grant, per the paper)

For other local adverse reactions, local skin redness was most often reported as moderate or severe in all treatment groups. Patients treated with creams more often reported moderate to severe local swelling, erosion, crust formation, and itching of the skin than patients treated with MAL-PDT. In the MAL-PDT group no serious adverse events were reported. One patient treated with imiquimod and two patients treated with fluorouracil developed a local wound infection and needed additional treatment in the outpatient setting.

In a retrospective review of medical records, people already taking warfarin who started fluorouracil had very large rises in INR and needed large warfarin dose reductions. (Source 19)

• Cohort study, Low certainty.
• Size: 24 eligible patients; 15 in the primary analysis (9 on fluorouracil, 6 on capecitabine)
• Who: patients taking therapeutic doses of warfarin before starting a fluoropyrimidine, identified by retrospective medical record review in one large academic Veterans Affairs health care system.
• How long: 90-day study period.
• Result: Mean change in INR 4.62 with fluorouracil versus 5.11 with capecitabine (p=0.87); INR above 9 in 22% of the fluorouracil group and 17% of the capecitabine group; warfarin dose reduced by 38% and 41% respectively.
• Funding: not stated in the abstract.

Limit of this finding: This is a retrospective look back through records on a very small number of people, not a trial. The 4.62 and 5.11 figures are the average rise in INR within each group, and the p=0.87 compares fluorouracil with capecitabine, not either drug with no chemotherapy. A non-significant difference between two fluoropyrimidines on 15 patients is not evidence that fluorouracil leaves warfarin alone; the rises themselves are the finding.

The mean change in INR for patients taking warfarin before fluoropyrimidine use was 4.62 in the 5-fluorouracil group compared with 5.11 in the capecitabine group (p=0.87). The capecitabine group had a similar proportion of patients achieving an INR above 9 while taking warfarin compared with the 5-fluorouracil group (17% vs 22%). In those patients who required a warfarin dosage reduction, the dose was reduced by 38% and 41% in the 5-fluorouracil and capecitabine groups, respectively.

The topical label records burning, crusting, allergic contact dermatitis, itching, scarring, soreness and ulceration as the most frequent adverse reactions, and leukocytosis as the most frequent blood effect. (Source 20)

• Official position, Certainty not rated.
• Size: not stated.
• Who: people using fluorouracil cream or solution on the skin.
• How long: not stated.
• Result: No rates are given in this section of the label; reactions are listed without frequencies.
• Funding: manufacturer label (Bausch Health US, LLC)

The most frequent adverse reactions to EFUDEX occur locally and are often related to an extension of the pharmacological activity of the drug. These include burning, crusting, allergic contact dermatitis, pruritus, scarring, rash, soreness, and ulceration.

Topical fluorouracil has caused life-threatening systemic toxicity in at least one person with DPD enzyme deficiency. (Source 15)

• Official position, Very low certainty.
• Size: one reported case.
• Who: a person with DPD enzyme deficiency using 5% fluorouracil cream.
• How long: not stated.
• Result: Severe abdominal pain, bloody diarrhoea, vomiting, fever and chills, with stomatitis, erythematous skin rash, neutropenia, thrombocytopenia and inflammation of the oesophagus, stomach and small bowel.
• Funding: manufacturer label (Bausch Health US, LLC)

One case of life-threatening systemic toxicity has been reported with the topical use of EFUDEX in a patient with DPD enzyme deficiency. Symptoms included severe abdominal pain, bloody diarrhea, vomiting, fever, and chills. Physical examination revealed stomatitis, erythematous skin rash, neutropenia, thrombocytopenia, inflammation of the esophagus, stomach, and small bowel.

The US fluorouracil injection label carries a boxed warning about serious adverse reactions or death in people with complete DPD deficiency. (Source 2)

• Official position, Certainty not rated.
• Size: not applicable.
• Who: people prescribed intravenous fluorouracil.
• How long: not applicable.
• Result: The label instructs testing for DPYD genetic variants before starting unless immediate treatment is necessary, and avoiding fluorouracil in people with certain homozygous or compound heterozygous DPYD variants.
• Funding: manufacturer label (Fresenius Kabi USA, LLC)

Test patients for genetic variants of DPYD prior to initiating fluorouracil unless immediate treatment is necessary. Avoid use of fluorouracil in patients with certain homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency [see Warnings and Precautions (5.1)].

Topical fluorouracil is contraindicated in pregnancy and in people with DPD enzyme deficiency. (Source 21)

• Official position, Certainty not rated.
• Size: not applicable.
• Who: people who are or may become pregnant, and people with DPD enzyme deficiency.
• How long: not applicable.
• Result: Contraindicated; DPD deficiency can shunt fluorouracil into the anabolic pathway, leading to cytotoxic activity and potential toxicities.
• Funding: manufacturer label (Bausch Health US, LLC)

EFUDEX should not be used in patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency. A large percentage of fluorouracil is catabolized by the DPD enzyme. DPD enzyme deficiency can result in shunting of fluorouracil to the anabolic pathway, leading to cytotoxic activity and potential toxicities. EFUDEX is contraindicated in women who are or may become pregnant during therapy. If this drug is used during pregnancy, or if the patient becomes pregnant while using this drug, the patient should be apprised of the potential hazard to the fetus.

What the evidence supports

Twelve months after treatment ended, the cumulative probability of remaining free from treatment failure was higher with 5% fluorouracil cream than with imiquimod, photodynamic therapy or ingenol mebutate; that is the trial's time-to-failure outcome, not its primary outcome, which was the proportion of patients with a reduction of 75% or more in lesion count. (Source 3)

• Randomized trial, High certainty.
• Size: 624 patients.
• Who: adults with five or more actinic keratosis lesions on the head in one continuous area, at four Dutch hospitals.
• How long: 12 months after the end of treatment.
• Result: Free from treatment failure: fluorouracil 74.7% (95% CI 66.8 to 81.0), imiquimod 53.9% (45.4 to 61.6), MAL-PDT 37.7% (30.0 to 45.3), ingenol mebutate 28.9% (21.8 to 36.3); hazard ratios for treatment failure versus fluorouracil 2.03, 2.73 and 3.33 (P<=0.001 for all comparisons)
• Funding: independent (Netherlands Organization for Health Research and Development, per the paper)

At 12 months after the end of treatment, the cumulative probability of remaining free from treatment failure was significantly higher among patients who received fluorouracil (74.7%; 95% confidence interval [CI], 66.8 to 81.0) than among those who received imiquimod (53.9%; 95% CI, 45.4 to 61.6), MAL-PDT (37.7%; 95% CI, 30.0 to 45.3), or ingenol mebutate (28.9%; 95% CI, 21.8 to 36.3).

A single course of 5% fluorouracil cream reduced actinic keratosis counts and raised complete clearance compared with a vehicle control cream. (Source 22)

• Randomized trial, Moderate certainty.
• Size: 932 veterans.
• Who: veterans with two or more keratinocyte carcinomas in the previous 5 years, at 12 Veterans Affairs medical centres.
• How long: study visits every 6 months through the trial.
• Result: Lesions per person 3.0 versus 8.1 at 6 months (P < .001); complete clearance 38% versus 17% at 6 months; hazard ratio 0.69 (95% CI 0.60-0.79) for time to first spot treatment.
• Funding: not stated in the abstract.

After randomization, the fluorouracil group had fewer AKs compared with the control group at 6 months (3.0 vs 8.1, P < .001) and for the overall study duration (P < .001). The fluorouracil group also had higher complete AK clearance rates (38% vs 17% at 6 months)

Adjuvant fluorouracil with folinic acid after bowel cancer surgery reduced death from any cause and recurrence compared with observation. (Source 5)

• Randomized trial, High certainty.
• Size: 3239 patients from 150 centres in 19 countries.
• Who: patients after apparently curative resection of colon or rectal cancer, 91% stage II.
• How long: median follow-up 5.5 years (range 0-10.6)
• Result: 311 versus 370 deaths; relative risk of death 0.82 (95% CI 0.70-0.95; p=0.008). 293 versus 359 recurrences; relative risk of recurrence 0.78 (0.67-0.91; p=0.001)
• Funding: not stated in the abstract.

After a median follow-up of 5.5 (range 0-10.6) years, there were 311 deaths in the chemotherapy group and 370 in the observation group; the relative risk of death from any cause with chemotherapy versus observation alone was 0.82 (95% CI 0.70-0.95; p=0.008). There were 293 recurrences in the chemotherapy group and 359 in the observation group; the relative risk of recurrence with chemotherapy versus observation alone was 0.78 (0.67-0.91; p=0.001).

The trialists put the absolute survival benefit of adjuvant fluorouracil in stage II colorectal cancer at about 3.6%, and called the improvement small. (Source 23)

• Randomized trial, High certainty.
• Size: 3239 patients.
• Who: patients after curative resection of colon or rectal cancer at low risk of recurrence.
• How long: 5-year mortality framing.
• Result: Assuming 5-year mortality without chemotherapy of 20%, an absolute improvement in survival of 3.6% (95% CI 1.0-6.0)
• Funding: not stated in the abstract.

although the absolute improvements are small: assuming 5-year mortality without chemotherapy is 20%, the relative risk of death seen here translates into an absolute improvement in survival of 3.6% (95% CI 1.0-6.0).

Adding oxaliplatin to fluorouracil and leucovorin improved three-year disease-free survival after colon cancer surgery. (Source 13)

• Randomized trial, High certainty.
• Size: 1123 patients randomly assigned to each group.
• Who: patients after curative resection for stage II or III colon cancer.
• How long: median follow-up 37.9 months.
• Result: Cancer-related events 21.1 percent versus 26.1 percent; hazard ratio for recurrence 0.77 (P=0.002). Three-year disease-free survival 78.2 percent (95 percent confidence interval, 75.6 to 80.7) versus 72.9 percent (70.2 to 75.7), P=0.002.
• Funding: not stated in the abstract.

After a median follow-up of 37.9 months, 237 patients in the group given FL plus oxaliplatin had had a cancer-related event, as compared with 293 patients in the FL group (21.1 percent vs. 26.1 percent; hazard ratio for recurrence, 0.77; P=0.002). The rate of disease-free survival at three years was 78.2 percent (95 percent confidence interval, 75.6 to 80.7) in the group given FL plus oxaliplatin and 72.9 percent (95 percent confidence interval, 70.2 to 75.7) in the FL group (P=0.002 by the stratified log-rank test).

What the evidence does not support

In a secondary analysis of trial photographs, a standard course of topical fluorouracil did not improve photoaging on any of four validated photonumeric scales. (Source 10)

• Randomized trial, Moderate certainty.
• Size: 281 participants whose photographs were graded, out of the 932 randomised in the parent trial.
• Who: US veterans with a recent history of 2 or more keratinocyte carcinomas; predominantly male (274 [97.5%]) and white (281 [100%]), mean age 71.5 years.
• How long: assessments at baseline, 6, 12 and 18 months.
• Result: No statistically significant changes at 6 months (Griffiths scale P = .93; forehead lines P = .67; melomental fold P = .87; crow's feet P = .12), 12 months or 18 months (Griffiths P = .08; forehead lines P = .34; melomental fold P = .20; crow's feet P = .50)
• Funding: not stated in the abstract.

Limit of this finding: The 281 people described here are the subset of the trial whose photographs were graded, not the whole trial: the Veterans Affairs Keratinocyte Carcinoma Chemoprevention Trial randomised 932 veterans, and 3042 photographs from 281 of them were scored. Read the 281 as the size of this photo analysis, not of the trial. The journal also prints the age as "mean (SD) age of 71.5 (0.57) years"; a standard deviation of 0.57 years across 281 older men is not credible and is almost certainly a standard error mislabelled in the source, so it should not be read as the spread of ages.

No statistically significant changes were found in photodamage between baseline and 6 months (Griffiths scale: χ2 = 0.01, P = .93; Allergan forehead lines scale: χ2 = 0.18, P = .67; melomental fold scale: χ2 = 0.03, P = .87; crow's feet scale: χ2 = 2.41, P = .12)

Where the evidence is mixed

Fluorouracil cream was non-inferior to photodynamic therapy for superficial basal cell carcinoma, but imiquimod was better than photodynamic therapy and fluorouracil was not. (Source 4)

• Randomized trial, Moderate certainty.
• Size: 601 patients randomised.
• Who: adults with histologically proven superficial basal cell carcinoma at seven Dutch hospitals.
• How long: follow-up at 3 and 12 months.
• Result: Tumour-free at both 3 and 12 months: 80.1% (95% CI 74.7-85.9) fluorouracil, 72.8% (66.8-79.4) MAL-PDT, 83.4% (78.2-88.9) imiquimod; fluorouracil versus MAL-PDT difference 7.3% (-1.9 to 16.5; p=0.120), imiquimod versus MAL-PDT 10.6% (1.5-19.5; p=0.021)
• Funding: independent (Netherlands Organization for Scientific Research grant, per the paper)

Limit of this finding: Two different numbers in this paper answer two different questions. The 72.8%, 83.4% and 80.1% figures are the proportions tumour-free at BOTH the 3-month and the 12-month check. The separate "52 of 196", "31 of 189" and "39 of 198" counts are the 12-month check alone, so they do not divide back into those percentages. The published abstract also prints the last confidence interval with a missing closing bracket ("p=0.435."); that is the journal's own typesetting, not a corrupted quote.

The proportion of patients tumour-free at both 3 and 12 month follow-up was 72.8% (95% CI 66.8-79.4) for MAL-PDT, 83.4% (78.2-88.9) for imiquimod cream, and 80.1% (74.7-85.9) for fluorouracil cream.

Postoperative 5-FU injections at regular dose reduced trabeculectomy failure at one year, but the low-dose schedule did not and parts of the evidence were rated very low certainty. (Source 8)

• Systematic review, Low certainty.
• Size: Twelve trials, which randomised 1319 participants.
• Who: people having glaucoma filtration surgery; mean age 61 to 75 years, 83% white, 40% male.
• How long: all studies at least one year.
• Result: Regular-dose postoperative 5-FU: RR 0.44 (95% CI 0.29 to 0.68) in eyes at high risk of failure and 0.21 (0.06 to 0.68) in first surgery; number needed to treat 4.1 and 5.0. Low-dose postoperative 5-FU in primary trabeculectomy: RR 0.93 (95% CI 0.70 to 1.24)
• Funding: not stated in the abstract.

A significant reduction in surgical failure in the first year after trabeculectomy was detected in eyes at high risk of failure and those undergoing surgery for the first time receiving regular-dose 5-FU postoperative injections (RR 0.44, 95% confidence interval (CI) 0.29 to 0.68 and 0.21, 0.06 to 0.68, respectively). No surgical failures were detected in studies assessing combined surgery. No difference was detected in the low-dose postoperative 5-FU injection group in patients undergoing primary trabeculectomy (RR 0.93, 95% CI 0.70 to 1.24). Peroperative 5-FU in patients undergoing primary trabeculectomy significantly reduced risk of failure (RR 0.67, 95% CI 0.51 to 0.88). This translates to a number needed to treat for an additional beneficial outcome of 4.1 for the high risk of failure patients, and 5.0 for primary trabeculectomy patients receiving postoperative 5-FU.

Over four years a single course of topical fluorouracil did not reduce the risk of keratinocyte, basal cell or squamous cell carcinoma, despite a first-year reduction in squamous cell carcinoma. (Source 7)

• Randomized trial, Moderate certainty.
• Size: 932 participants.
• Who: veterans with a history of at least two keratinocyte carcinomas in the past 5 years; 98% men, 99% white, median age 70.
• How long: 4 years, median follow-up 2.8 years.
• Result: Year 1 squamous cell carcinoma 5 (1%) versus 20 (4%), a 75% (95% CI 35%-91%) risk reduction (P = .002). Year 1 basal cell carcinoma 45 (10%) versus 50 (11%), an 11% reduction, not significant (95% CI 39% reduction to 31% increase). Over the entire study, no difference in time to first cancer of any of the three types.
• Funding: not stated in the abstract.

Over the entire study, there was no difference between treatment groups in time to first keratinocyte, basal cell, or squamous cell carcinoma. During the first year, however, 5 participants (1%) in the fluorouracil group developed a squamous cell carcinoma vs 20 (4%) in the control group, a 75% (95% CI, 35%-91%) risk reduction (P = .002). The 11% reduction in basal cell carcinoma risk during year 1 (45 [10%] in the fluorouracil group vs 50 [11%] in the control group) was not statistically significant (95% CI, 39% reduction to 31% increase)

The evidence that intralesional 5-FU helps keloid scars rests on poor-quality studies, and only the combination with triamcinolone may beat triamcinolone alone. (Source 9)

• Systematic review, Very low certainty.
• Size: Eighteen papers, 482 patients.
• Who: people with keloid scars treated with intralesional 5-FU alone or combined with up to two other therapies.
• How long: not stated in the abstract.
• Result: 5-FU treatment effective in 45-96% of patients; only triamcinolone acetonide combined with 5-FU may perform better than triamcinolone alone.
• Funding: not stated in the abstract.

5-FU treatment was effective in 45-96% of patients, but only TAC:5-FU may perform better than TAC alone. Due to a poor level of evidence, further research should establish the superiority of repeated intralesional TAC:5-FU injections over TAC alone with several doses and injection schedules.

Where the research disagrees

Which topical agent should be first choice, and for which lesion. In actinic keratosis the four-arm trial put fluorouracil ahead of the other three field treatments; in superficial basal cell carcinoma the three-arm trial put imiquimod ahead of photodynamic therapy while fluorouracil was only non-inferior to it

• Jansen and colleagues (NEJM 2019 randomised trial, actinic keratosis), randomised controlled trial in 624 patients with actinic keratosis on the head; the figures are the time-to-treatment-failure outcome at 12 months: the cumulative probability of remaining free from treatment failure was significantly higher among patients who received fluorouracil (74.7%; 95% confidence interval [CI], 66.8 to 81.0) than among those who received imiquimod (53.9%; 95% CI, 45.4 to 61.6), MAL-PDT (37.7%; 95% CI, 30.0 to 45.3), or ingenol mebutate (28.9%; 95% CI, 21.8 to 36.3). (Source 3)
• Arits and colleagues (Lancet Oncology 2013 randomised trial, superficial basal cell carcinoma), randomised non-inferiority trial in 601 patients with superficial basal cell carcinoma; the source prints the last bracket unclosed: The difference between imiquimod and MAL-PDT was 10.6% (95% CI 1.5-19.5; p=0.021) and 7.3% (-1.9 to 16.5; p=0.120) between fluorouracil and MAL-PDT, and between fluorouracil and imiquimod was -3.3% (-11.6 to 5.0; p=0.435. (Source 4)

Whether a single course of topical fluorouracil prevents later skin cancers. The same trial reports a clear first-year reduction in squamous cell carcinoma and no difference over its full four years, so which result is quoted decides the answer

• Veterans Affairs chemoprevention trial, first-year result, randomised, double-blind, placebo-controlled trial in 932 veterans; first-year result: During the first year, however, 5 participants (1%) in the fluorouracil group developed a squamous cell carcinoma vs 20 (4%) in the control group, a 75% (95% CI, 35%-91%) risk reduction (P = .002). (Source 7)
• The same trial's four-year result, randomised, double-blind, placebo-controlled trial in 932 veterans; whole-study result over 4 years: Over the entire study, there was no difference between treatment groups in time to first keratinocyte, basal cell, or squamous cell carcinoma. (Source 7)

How much

• Reference intake: There is no reference intake for fluorouracil: it is a prescription cytotoxic medicine and the dose is set by the prescriber for the regimen and the person. As a label position dated 2026, the US injection label's recommended infusional dose for colon and rectal cancer is 400 mg/m2 by intravenous bolus on Day 1 followed by 2,400 mg/m2 to 3,000 mg/m2 as a continuous infusion over 46 hours every two weeks. (Source 24)
• Upper limit: No single maximum dose is set. As a label position dated 2026, the US label instead says that no fluorouracil dose has been proven safe for people with complete DPD deficiency, and that in partial DPD deficiency the dose should be individualised and modified based on tolerability and the intent of treatment. (Source 25)
• Studied: QUASAR gave intravenous fluorouracil 370 mg/m2 with high-dose (175 mg) or low-dose (25 mg) L-folinic acid, either as six 5-day courses every 4 weeks or as 30 once-weekly courses. (Source 12)
• Studied: For actinic keratosis the topical label describes applying cream or solution twice daily, continued until the inflammatory response reaches the erosion stage, for a usual duration of 2 to 4 weeks. (Source 14)

A common belief, and what the research shows

The belief: A cream cannot be real chemotherapy, so fluorouracil cream must be harmless.

What the research shows: Fluorouracil cream is the same cytotoxic drug, and enough of it is absorbed to matter in susceptible people. The topical label records that "One case of life-threatening systemic toxicity has been reported with the topical use of EFUDEX in a patient with DPD enzyme deficiency." Even in people with normal DPD the local reaction is the point of treatment, not a side issue: in the randomised superficial basal cell carcinoma trial, "Patients treated with creams more often reported moderate to severe local swelling, erosion, crust formation, and itching of the skin than patients treated with MAL-PDT." (sources: efudex-label-dpdtox-2025, arits-2013-sbcc)

Questions and answers

What is it?

Fluorouracil is a laboratory-made chemical that looks enough like uracil, an RNA building block, to be taken up by cells and then jam their machinery. The label calls it a nucleoside metabolic inhibitor. It is converted inside the body into three main active metabolites. It exists both as an intravenous cancer drug and as a skin cream or solution. (Source 1)

What does it do in the body?

It stops cells making DNA, and to a lesser extent RNA. One metabolite blocks the enzyme thymidylate synthase, which cells need to make a DNA building block; the other two get built into RNA and DNA in place of the correct bases. Fast-dividing cells are affected most, which is why it damages tumours and also the mouth and gut lining, the bone marrow and treated skin. (Source 1)

Is it good or bad for you?

Both, and which one depends entirely on the setting. Used as a field cream for actinic keratosis or superficial basal cell carcinoma it clears most lesions; given intravenously after bowel cancer surgery it produces a small absolute survival gain. Used intravenously it also damages the heart, with a pooled incidence of 5.04% for all grades, 1.5% for grade 3 or higher and 0.29% of patients dying of severe cardiotoxicities in a meta-analysis of 211 studies and 63,186 patients. (Source 16)

How do you get more of it?

You do not get more of it from food or shops. It is a prescription-only cytotoxic medicine, given either intravenously in a cancer clinic or as a cream or solution prescribed for sun-damaged skin, and the dose is set by the prescriber for the regimen. The label's recommended infusional dose for colon and rectal cancer is given per square metre of body surface, not as a fixed amount. (Source 24)

If it is harmful, what reduces it?

When fluorouracil is doing harm, the main levers are stopping it and lowering the dose. The clearest evidence is for dose reduction guided by DPYD genotype: in a prospective study of 1103 patients, variant carriers given reduced starting doses had a relative risk of severe toxicity of 1·31 (95% CI 0·63-2·73) for DPYD*2A, against 2·87 (2·14-3·86) in a historical cohort given full doses. There is no antidote described in the sources we read. (Source 18)

Why might someone be low in it or missing it?

Fluorouracil is not something the body makes, so nobody is low in it. The equivalent question is who cannot safely have it, and that turns on the DPD enzyme that clears more than 80% of a dose. About 3-5% of white populations have partial DPD deficiency and 0.2% complete deficiency; the label says DPD deficiency is thought to be more common in Black or African American populations, and that there is not enough information to estimate it in other populations. (Source 26)

Which whole foods contain it or feed it?

No whole food contains fluorouracil and no food supplies it. It is a synthetic drug given by injection or applied to the skin, not a nutrient. We searched Europe PMC for food sources and found none; the closest source we read simply describes it as a nucleoside metabolic inhibitor given as a medicine. (Source 1)

We searched: Europe PMC REST searches for fluorouracil combined with diet, food and dietary sources; the US prescribing information for fluorouracil injection and for EFUDEX cream and solution

What happens if you do not have it?

Nothing happens from lacking the drug itself. What the trials show is what happens to people who have the condition and do not get it: in QUASAR there were 370 deaths and 359 recurrences in the observation group, against 311 deaths and 293 recurrences in the group given fluorouracil and folinic acid, over a median follow-up of 5.5 years. (Source 5)

How can you test for it?

The test that matters is not for the drug but for the enzyme that clears it. The US label tells prescribers to test for DPYD gene variants before starting intravenous fluorouracil unless treatment cannot wait. Its own caveat about reliability is blunt: there is no FDA-authorized test for DPYD, and the tests in use may vary in accuracy and in which variants they look for. (Source 25)

References

1. DailyMed / Fresenius Kabi USA, LLC. FLUOROURACIL injection, solution — FDA prescribing information, section 12.1 Mechanism of Action. 2026. Read the source
2. DailyMed / Fresenius Kabi USA, LLC. FLUOROURACIL injection, solution — FDA prescribing information (boxed warning). 2026. Read the source
3. New England Journal of Medicine. Randomized Trial of Four Treatment Approaches for Actinic Keratosis. — abstract, Results. 2019. PMID 30855743, DOI 10.1056/nejmoa1811850. Read the source
4. The Lancet Oncology. Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial. — abstract, Findings. 2013. PMID 23683751, DOI 10.1016/s1470-2045(13)70143-8. Read the source
5. The Lancet. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. — abstract, Findings. 2007. PMID 18083404, DOI 10.1016/s0140-6736(07)61866-2. Read the source
6. DailyMed / Fresenius Kabi USA, LLC. FLUOROURACIL injection, solution — FDA prescribing information, Highlights: Indications and Usage. 2026. Read the source
7. JAMA Dermatology. Chemoprevention of Basal and Squamous Cell Carcinoma With a Single Course of Fluorouracil, 5%, Cream: A Randomized Clinical Trial.. 2018. PMID 29299592, DOI 10.1001/jamadermatol.2017.3631. Read the source
8. Cochrane Database of Systematic Reviews. 5-Fluorouracil for glaucoma surgery.. 2014. PMID 24554410, DOI 10.1002/14651858.cd001132.pub2. Read the source
9. Acta Dermato-Venereologica. Intralesional 5-fluorouracil in keloid treatment: a systematic review.. 2015. PMID 25805099, DOI 10.2340/00015555-2106. Read the source
10. JAMA Dermatology. Effect of Topical Fluorouracil Cream on Photodamage: Secondary Analysis of a Randomized Clinical Trial. — abstract, Results. 2017. PMID 28877312, DOI 10.1001/jamadermatol.2017.2578. Read the source
11. DailyMed / Fresenius Kabi USA, LLC. FLUOROURACIL injection, solution — FDA prescribing information, section 7.1 Anticoagulants and CYP 2C9 Substrates. 2026. Read the source
12. The Lancet. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. — abstract, Methods. 2007. PMID 18083404, DOI 10.1016/s0140-6736(07)61866-2. Read the source
13. New England Journal of Medicine. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer.. 2004. PMID 15175436, DOI 10.1056/nejmoa032709. Read the source
14. DailyMed / Bausch Health US, LLC. EFUDEX (fluorouracil) cream and topical solution — FDA prescribing information, DOSAGE AND ADMINISTRATION. 2025. Read the source
15. DailyMed / Bausch Health US, LLC. EFUDEX (fluorouracil) cream and topical solution — FDA prescribing information, WARNINGS. 2025. Read the source
16. Pharmaceuticals (Basel). Redefining the Incidence and Profile of Fluoropyrimidine-Associated Cardiotoxicity in Cancer Patients: A Systematic Review and Meta-Analysis.. 2023. PMID 37111268, DOI 10.3390/ph16040510. Read the source
17. The Lancet Oncology. Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data.. 2015. PMID 26603945, DOI 10.1016/s1470-2045(15)00286-7. Read the source
18. The Lancet Oncology. DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. — abstract, Findings. 2018. PMID 30348537, DOI 10.1016/s1470-2045(18)30686-7. Read the source
19. Pharmacotherapy. Comparison of the 5-fluorouracil-warfarin and capecitabine-warfarin drug interactions.. 2010. PMID 21128758, DOI 10.1592/phco.30.12.1259. Read the source
20. DailyMed / Bausch Health US, LLC. EFUDEX (fluorouracil) cream and topical solution — FDA prescribing information, ADVERSE REACTIONS. 2025. Read the source
21. DailyMed / Bausch Health US, LLC. EFUDEX (fluorouracil) cream and topical solution — FDA prescribing information, CONTRAINDICATIONS. 2025. Read the source
22. JAMA Dermatology. Long-term Efficacy of Topical Fluorouracil Cream, 5%, for Treating Actinic Keratosis: A Randomized Clinical Trial. — abstract, Results. 2015. PMID 25950503, DOI 10.1001/jamadermatol.2015.0502. Read the source
23. The Lancet. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. — abstract, Interpretation. 2007. PMID 18083404, DOI 10.1016/s0140-6736(07)61866-2. Read the source
24. DailyMed / Fresenius Kabi USA, LLC. FLUOROURACIL injection, solution — FDA prescribing information, section 2.3 Recommended Dosage for Adenocarcinoma of the Colon and Rectum. 2026. Read the source
25. DailyMed / Fresenius Kabi USA, LLC. FLUOROURACIL injection, solution — FDA prescribing information, section 2.1 Evaluation and Testing for DPD Deficiency Before Initiating Fluorouracil. 2026. Read the source
26. DailyMed / Fresenius Kabi USA, LLC. FLUOROURACIL injection, solution — FDA prescribing information, section 12.5 Pharmacogenomics. 2026. Read the source