Fluorouracil (Monograph)
Brand name: Adrucil
Drug class: Antineoplastic Agents
Introduction
Pyrimidine antagonist; antimetabolite; antineoplastic agent.205
Uses for Fluorouracil
Cancers
Treatment of adenocarcinoma of the colon, rectum, breast, stomach, and pancreas.205
Adjunct to surgery for the treatment of various solid tumors (e.g., adenocarcinoma of the colon,226 227 228 229 230 231 232 233 252 253 256 261 280 rectal carcinoma).230 234 235 236 237 238 239 240 242 243 280
Colorectal Cancer
Drug of choice (combined with leucovorin or levoleucovorin and other drugs [e.g., irinotecan, oxaliplatin]) for advanced colorectal cancer in the adjuvant or metastatic setting.289 386 387 388 397 410 411 412 413 414 415 446 447
Doublet regimens (i.e., fluorouracil, oxaliplatin, and leucovorin or levoleucovorin [FOLFOX]; fluorouracil, irinotecan, and leucovorin or levoleucovorin [FOLFIRI]; capecitabine and oxaliplatin [CapeOx; CapOx]) are the current standard of care for the adjuvant or palliative treatment of advanced colorectal cancer.411 412 415 416 417 419 420 446 10008
Fluorouracil combined with leucovorin or levoleucovorin is an acceptable treatment option in limited-resource settings or in patients unable to tolerate a doublet regimen.419
Weekly schedule of fluorouracil/leucovorin (high-dose leucovorin or Roswell Park regimen) has equal efficacy as monthly schedule (low-dose or Mayo Clinic schedule), but the weekly schedule is a preferred regimen for adjuvant therapy because of ease of use and less toxicity.386 388 (See Colorectal Cancer under Dosage and Administration.)
Bimonthly, continuous IV infusion schedule of fluorouracil/leucovorin (LV5FU2 or deGramont regimen) also evaluated as adjuvant therapy390 and shown to be safer than direct IV injection regimen of these drugs.388 390 Simplified version of this regimen also evaluated.391 (See Colorectal Cancer under Dosage and Administration.)
Role of regional adjuvant therapy (e.g., portal vein or hepatic artery infusion† [off-label]) for liver metastases requires further elucidation.230 253 256 257 258 259 260 264 275 280
Leucovorin and levoleucovorin enhance cytotoxicity,221 286 291 303 305 306 307 308 309 310 395 397 potentiate fluorouracil antineoplastic activity, and improve response for advanced colorectal carcinoma treatment.200 201 211 215 216 218 219 220 266 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 311 313 314 315 317 395
Leucovorin and levoleucovorin may potentiate risk of fluorouracil GI toxicity (e.g., diarrhea, nausea, stomatitis, vomiting) and myelosuppression.214 215 217 218 266 286 289 292 293 294 295 296 311 395
Breast Cancer
Combined with other drugs (e.g., cyclophosphamide, doxorubicin, methotrexate) as an adjunct to surgery and for metastatic breast cancer.244 249 251 279 319 320 322 323 324 325 326 328
Decision regarding use of adjuvant endocrine therapy with or without sequential combination chemotherapy may be guided by prognostic tools, such as recurrence score based on 21-gene assay results, to predict absolute benefit of combination chemotherapy in addition to adjuvant endocrine therapy.433
Adjunct to surgery, may improve outcome.244 245 246 247 248 249 250 251 254 270 271 272
Esophageal Cancer
Has been used alone330 334 336 and in combination therapy (e.g., with cisplatin)249 329 330 331 334 336 for the treatment of localized or advanced esophageal cancer† [off-label].
Head and Neck Cancer
Has been used in combination chemotherapy for metastatic or recurrent squamous cell carcinoma of the head and neck† [off-label].349
Has been used in combination chemotherapy with radiation therapy for palliative treatment of unresectable locally advanced head and neck cancer,337 and for larynx preservation in locally advanced laryngeal or hypopharyngeal cancer.354 355 356 357
Used in combination with docetaxel and cisplatin as induction therapy prior to radiotherapy or chemoradiotherapy in the treatment of locally advanced squamous cell carcinoma of the head and neck.393 394
Cervical Cancer
Has been used in combination with cisplatin concurrently with radiation therapy for invasive cervical cancer† [off-label].249 359 360 361 362 364
Metastatic or recurrent cervical cancer† [off-label].249 365 366 367 369 370 371
Renal Cell Carcinoma
Has been used alone374 or in combination regimens375 376 377 378 379 380 381 382 383 384 for the treatment of metastatic renal cell carcinoma†.
Carcinoid Tumors
Has been used for the treatment of carcinoid tumors†.249
Other Uses
Has been used as second-line therapy in the treatment of ovarian epithelial cancer†, including platinum-refractory disease.241 Also, cancers of the liver† (e.g., hepatoblastoma†).249
Fluorouracil Dosage and Administration
Administration
Administer IV.205
Has been administered by regional infusion into the venous or arterial blood supply of a tumor† (e.g., portal vein or hepatic artery infusions for liver metastases).230 253 256 258 259 264 275 280
IV Administration
For solution and drug compatibility information, see Compatibility under Stability.
2.5- or 5-g pharmacy bulk package is intended for individual dose preparation, not for direct IV infusion.205
Use an established IV line to administer fluorouracil by direct IV injection.205
For IV infusion regimens, administer fluorouracil via a central venous catheter using a controlled infusion device (e.g., pump).205
Avoid extravasation.205
Dilution
No dilution necessary for usual injection formulation.205
Rate of Administration
Administer by direct IV injection or continuous IV infusion.205
Dosage
Base dosage on actual weight.205
May calculate dosage based on body surface area.215 218 220 266 275 286 289 292 293 294 295 296 298 300 304 305 317 320 321 322 323 328
Individualize dosage and dosage schedule based on tumor type, specific regimen, clinical response, and concomitant comorbidities.205
Consult published protocols for the dosage and method and sequence of administration of fluorouracil with other chemotherapeutic agents.
Adults
Colorectal Cancer
Various fluorouracil/leucovorin combination dosage regimens have been used.215 220 266 289 296 298 304 305 317
IV
Direct IV injection: 500 mg/m2 by direct IV injection in combination with leucovorin or levoleucovorin on days 1, 8, 15, 22, 29, and 36 in each 8-week cycle.205
IV infusion: 400 mg/m2 by direct IV injection on day 1 followed by 2400–3000 mg/m2 as a continuous IV infusion over 46 hours every 14 days in combination with leucovorin or levoleucovorin with or without oxaliplatin or irinotecan.205
Combination Regimen: Fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX)
IVDay 1: Oxaliplatin 85 mg/m2 and leucovorin 200 mg/m2 concurrently (in separate containers using a Y-type administration set) by IV infusion over 2 hours, followed by fluorouracil 400 mg/m2 by direct IV injection, and then fluorouracil 600 mg/m2 by IV infusion over 22 hours.411 446
Day 2: Leucovorin 200 mg/m2 by IV infusion over 2 hours, followed by fluorouracil 400 mg/m2 by direct IV injection, and then fluorouracil 600 mg/m2 by IV infusion over 22 hours.411 446
Following schedule also used: Oxaliplatin 85–100 mg/m2 and leucovorin 400 mg/m2 by IV infusion over 2 hours, followed by fluorouracil 400 mg/m2 by direct IV injection, and then fluorouracil 2400–3000 mg/m2 by IV infusion over 46 hours.446
Repeat cycles every 2 weeks.411 446
Combination Regimen: Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI)
IVIrinotecan 180 mg/m2 and leucovorin 400 mg/m2 administered concurrently by IV infusion over 2 hours, followed by fluorouracil 400 mg/m2 by direct IV injection, and then fluorouracil 2400–3000 mg/m2 by IV infusion over 46 hours; repeat cycles every 2 weeks.418 446
Combination Regimen: Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan (FOLFOXIRI)
IVIrinotecan 165 mg/m2 by IV infusion over 1 hour, followed by leucovorin 200 mg/m2 and oxaliplatin 85 mg/m2 administered concurrently by IV infusion over 2 hours, and then fluorouracil 3200 mg/m2 by IV infusion over 48 hours; repeat cycles every 2 weeks.441 446
Monthly Schedule (Mayo Clinic Regimen)
Direct IV InjectionLeucovorin 20 mg/m2 IV or levoleucovorin 10 mg/m2 IV followed by fluorouracil 425 mg/m2 IV; administer fluorouracil and either leucovorin or levoleucovorin daily for 5 consecutive days and repeat regimen at 4-week intervals for 2 additional courses; thereafter, may repeat the regimen at intervals of 4–5 weeks provided toxicity from the previous course has resolved completely.286 289 386 388 395 Frequently administered for a total of 6 cycles in the adjuvant setting.386 388
Alternatively, leucovorin 200 mg/m2 IV or levoleucovorin 100 mg/m2 IV over ≥3 minutes followed by fluorouracil 370 mg/m2 IV; administer fluorouracil and either leucovorin or levoleucovorin daily for 5 consecutive days and repeat regimen at 4-week intervals for 2 additional courses; thereafter, may repeat the regimen at intervals of 4–5 weeks provided toxicity from the previous course has resolved completely.286 395 397
Adjust fluorouracil dosage in subsequent courses according to tolerance;286 395 reduce daily fluorouracil dosage by 20% for moderate hematologic or GI toxicity in prior course and by 30% for severe toxicity266 286 289 395 (leucovorin or levoleucovorin dosage is not adjusted286 395 ).
May increase fluorouracil dosage by 10% if no toxicity occurred in the prior course.286 395
Weekly Schedule (Roswell Park Regimen)
IV InfusionLeucovorin 500 mg/m2 as a 2-hour IV infusion followed by fluorouracil 500 mg/m2 as a slow IV injection administered 1 hour after the start of the leucovorin infusion.386 388 Administer both drugs weekly for 6 consecutive weeks followed by a 2-week rest; repeat cycles every 8 weeks for a total of 4 courses in the adjuvant setting.386 388
Adjust fluorouracil dosage in subsequent courses according to tolerance;286 reduce daily fluorouracil dosage by 20% for moderate hematologic or GI toxicity in prior course and by 30% for severe toxicity266 286 289 (leucovorin dosage is not adjusted286 ).
May increase fluorouracil dosage by 10% if no toxicity occurred in the prior course.286
Bimonthly Schedule (Modified deGramont Regimen)
IV InfusionLeucovorin 400 mg/m2 as a 2-hour IV infusion on day 1 followed by fluorouracil 400 mg/m2 as an IV injection on day 1; then fluorouracil 1500 mg/m2 as a continuous IV infusion over 23 hours on days 1 and 2 (i.e., total 3000 mg/m2 by continuous IV infusion over 46 hours);391 repeat cycles every 2 weeks.
Breast Cancer
Various combination regimens have been used; consult published protocols for dosages and method and sequence of administration.246 269 271 272 320 321 322 323 324 325 326 328
Avoid arbitrary dose reductions of adjuvant combination chemotherapy; dose intensity appears to be an important factor influencing clinical outcome in early node-positive breast cancer (increasing response with increasing intensity).244 322
IV
500 or 600 mg/m2 IV on days 1 and 8 of each 28-day cycle for a total of 6 cycles in combination with a cyclophosphamide-based regimen.205
Combination Regimen: Cyclophosphamide, Methotrexate, and Fluorouracil
IVRegimen containing IV fluorouracil in combination with oral cyclophosphamide and IV methotrexate is described in the table.320 321
|
Drug |
Dose |
Administration Days per Cycle |
|---|---|---|
|
Fluorouracil |
||
|
Cyclophosphamide |
||
|
Methotrexate |
Repeat monthly (i.e., allow a 2-week rest period between cycles).320 321
Total of 6–12 cycles (i.e., 6–12 months of therapy); clinical superiority between 6- versus 12-month regimens not demonstrated.244 319 320 321
Initial fluorouracil and methotrexate dosages have been reduced in patients >60 years of age.321 (See Geriatric Patients under Special Populations.)
Also, dosage was reduced if myelosuppression developed.320 321
Sequential Regimen: Cyclophosphamide, Methotrexate, and Fluorouracil Plus Doxorubicin
In early breast cancer and >3 positive axillary lymph nodes, doxorubicin addition may improve outcome, and sequential regimens (i.e., several courses of doxorubicin first) may be more effective than alternating regimens; no additional benefit when fewer positive nodes are present.323 326
IVInitially, doxorubicin hydrochloride 75 mg/m2 IV at 3-week intervals for 4 doses.323 328
Subsequently, fluorouracil 600 mg/m2 IV, methotrexate 40 mg/m2 IV, and cyclophosphamide 600 mg/m2 IV at 3-week intervals for 8 cycles.323 328
Total of about 9 months of therapy.323 328
Generally, myelosuppression has delayed cycle rather than reducing dosage.323 328
Gastric Cancer
IV
200–1000 mg/m2 as a continuous IV infusion over 24 hours in combination with a platinum-based regimen.205 Consult published protocols for frequency of dosing and duration of each cycle for the specific regimen.205
Pancreatic Cancer
IV
400 mg/m2 by direct IV injection on day 1 followed by 2400 mg/m2 as a continuous IV infusion over 46 hours every 14 days in combination with leucovorin or as part of a multi-drug regimen containing leucovorin.205
Dosage Modification for Toxicity
For grade 3 or 4 diarrhea or mucositis, grade 4 myelosuppression, or grade 2 or 3 palmar-plantar erythrodysesthesia (hand-foot syndrome), withhold therapy; resume therapy at a reduced dosage when the toxicity has resolved or improved to grade 1.205
Temporarily withhold therapy if cardiotoxicity (i.e., angina, myocardial infarction or ischemia, arrhythmia, heart failure) develops in patients with no history of coronary artery disease or cardiac dysfunction; also withhold therapy if hyperammonemic encephalopathy or neurologic effects (i.e., acute cerebellar syndrome, confusion, disorientation, ataxia, visual disturbance) occur.205 Manufacturer makes no dosage recommendations for resumption of fluorouracil therapy following development of cardiotoxicity, hyperammonemic encephalopathy, or neurologic effects.205
Special Populations
Geriatric Patients
Breast Cancer
In patients >60 years of age receiving oral cyclophosphamide, IV methotrexate, and IV fluorouracil combination therapy, reduce initial methotrexate dosage to 30 mg/m2 and fluorouracil dosage to 400 mg/m2.321
Cautions for Fluorouracil
Contraindications
-
Manufacturer states none known.205
Warnings/Precautions
Dipyrimidine Dehydrogenase (DPD) Activity Deficiency
Acute early-onset or unusually severe toxicity may indicate near-complete or total absence of DPD activity; withhold or permanently discontinue fluorouracil in such patients.205
Certain homozygous or compound heterozygous mutations in the DPD gene result in complete or near-complete absence of DPD activity.205 Patients with such mutations are at increased risk for acute early-onset and severe, life-threatening, or fatal toxicity (e.g., mucositis, diarrhea, neutropenia, neurotoxicity).205 Patients with partial DPD activity also may have increased risk of severe, life-threatening, or fatal toxicity.205
Safety not established in patients with complete absence of DPD activity.205
Data insufficient to support dosage recommendations for those with partial DPD activity.205
Cardiac Effects
Myocardial ischemia/infarction,205 207 208 heart failure,205 arrhythmias,205 and angina205 207 208 209 (including Prinzmetal variant angina)209 reported.
Administration of drug by continuous IV infusion and presence of coronary artery disease may increase risk of cardiotoxicity.205
Safety of resuming fluorouracil after resolution of cardiotoxicity not established.205
Nervous System Effects
Disorientation, confusion, ataxia, visual disturbances, and acute cerebellar syndrome reported.205 Insufficient data on risks of resuming fluorouracil after resolution of neurologic adverse effects.205
Hyperammonemic encephalopathy, in the absence of liver disease or other identifiable cause, reported.205 Altered mental status, confusion, disorientation, ataxia, or coma in presence of elevated serum ammonia concentrations, may occur ≤72 hours following initiation of fluorouracil infusion.205
If hyperammonemic encephalopathy or neurologic effects occur, temporarily interrupt therapy.205
GI Toxicity
Mucositis, stomatitis, and esophagopharyngitis and subsequent mucosal sloughing or ulceration reported more frequently following administration of the drug by direct IV injection compared with administration by continuous IV infusion.205 Diarrhea occurs frequently and may be severe.205
Temporarily withhold fluorouracil if grade 3 or 4 diarrhea or mucositis occurs; resume drug at a reduced dosage when the toxicity resolves or improves to grade 1.205 Potential for diarrhea to result in rapid clinical deterioration and death in patients receiving reduced folates (leucovorin, levoleucovorin) concomitantly; close monitoring is required.214 286 315 395
Initiate fluid and electrolyte replacement or antidiarrheal therapy as clinically necessary.205
Hand-foot Syndrome
Palmar-plantar erythrodysesthesia (hand-foot syndrome) reported.201 206
Erythematous, desquamative rash that involves the hands and feet,201 205 206 may be accompanied by tingling sensation, pain, swelling, and erythema with tenderness.205
If grade 2 or 3 hand-foot syndrome occurs, temporarily interrupt therapy until the toxicity resolves or improves to grade 1.205
May be treated with oral pyridoxine therapy or topical emollients (e.g., hand creams, udder balm).406 407
Hematologic Toxicity
Myelosuppression (e.g., neutropenia, thrombocytopenia, anemia), sometimes severe or fatal, reported.205 Nadir neutrophil count usually occurs 9–14 days following initiation of therapy.205
Obtain complete blood cell counts (CBCs) prior to each treatment cycle, weekly (if administered on a weekly or similar schedule), and as clinically indicated.205
If grade 4 myelosuppression occurs, temporarily interrupt therapy until the toxicity resolves or improves to grade 1.205
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm.205
Advise women of childbearing potential and men with such female partners to use effective contraceptive methods during fluorouracil therapy and for up to 3 months after the last dose of the drug.205
If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.205
Impairment of Fertility
Results of animal studies suggest that fluorouracil may impair male and female fertility.205
Specific Populations
Pregnancy
Category D.205 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Lactation
Not known whether fluorouracil or its metabolites are distributed into human milk.205 Discontinue nursing or the drug.205
Pediatric Use
Safety and efficacy in children not established.205
Common Adverse Effects
Stomatitis, esophagopharyngitis, anorexia, nausea, vomiting, diarrhea, leukopenia (principally granulocytopenia), thrombocytopenia, anemia, alopecia, dermatitis (principally pruritic maculopapular rash).205
Drug Interactions
Drugs Metabolized by Hepatic Microsomal Enzymes
Substrates of CYP2C9: Fluorouracil or its metabolites may inhibit CYP isoenzyme 2C9.205
Specific Drugs
|
Drug |
Interaction |
Comments |
|---|---|---|
|
Coumarin anticoagulants (e.g., warfarin) |
Clinically significant elevations in coagulation parameters (e.g., increased prothrombin time [PT], increased INR)205 |
Closely monitor INR or PT; adjust anticoagulant dosage as necessary205 |
|
Leucovorin |
Leucovorin potentiates cytotoxicity of fluorouracil in certain GI cancers215 216 218 219 220 221 222 223 224 225 230 253 262 263 265 266 267 |
Used to therapeutic advantage in GI cancers200 201 202 203 204 212 215 216 218 219 220 230 253 Use concomitantly with extreme caution in geriatric or debilitated patients; more likely to develop serious toxicity214 286 |
|
Levoleucovorin |
Levoleucovorin enhances therapeutic effects of fluorouracil in colorectal cancer395 Levoleucovorin enhances fluorouracil toxicity395 |
Used to therapeutic advantage in colorectal cancer395 397 Use concomitantly with extreme caution in geriatric or debilitated patients; more likely to develop serious toxicity214 286 315 395 |
Fluorouracil Pharmacokinetics
Distribution
Extent
Distributed into intestinal mucosa, bone marrow, liver, CSF, and brain tissue.205
Usually higher concentration of fluorouracil or metabolites in tumor than in surrounding tissue or in corresponding normal tissue, and persists longer in some tumors than in the normal host tissues, perhaps due to impaired uracil catabolism; suggests some tumor specificity.a
Not known whether fluorouracil or its metabolites are distributed into human milk.205
Elimination
Metabolism
A small portion is anabolized in tissues to 5-fluoro-2′-deoxyuridine, then to active metabolite (5-fluoro-2′-deoxyuridine-5′-monophosphate).a
The major portion is degraded in the liver, to inactive metabolites (e.g., CO2, urea, α-fluoro-β-alanine, α-fluoro-β-guanidopropionic acid, and α-fluoro-β-ureidopropionic acid).a
Elimination Route
5–20% is excreted unchanged in urine within 6 hours.205
Metabolites (e.g., urea, α-fluoro-β-alanine) are excreted in urine over 3–4 hours.205
Half-life
8–20 minutes following direct IV injection; increases with dose.205
Stability
Storage
Parenteral
Injection
Discard unused portion of 2.5 or 5 g pharmacy bulk package 4 hours after the vial has been entered.205
20–25°C; do not freeze, protect from light.205
Fluorouracil precipitation occurs commonly, particularly following exposure to low temperatures.274
Ease of dissolution may depend on the crystal size and location (e.g., those lodged between the stopper and glass container).274 Attempts to dissolve precipitate with heat and agitation may be unsuccessful.274
Store in adequately heated areas during cold weather to minimize frequency of precipitation.274
Undiluted solutions stored in syringe: 25°C for up to 4 hours.205
Diluted solutions: 25°C for up to 4 hours.205
Compatibility
Parenteral
Solution Compatibilityb
|
Compatible |
|---|
|
Amino acids 4.25%, dextrose 25% |
|
Dextrose 5% in Ringer’s injection, lactated |
|
Dextrose 5% in water |
|
Sodium chloride 0.9% |
Drug Compatibility
|
Compatible |
|---|
|
Bleomycin sulfate |
|
Cyclophosphamide |
|
Cyclophosphamide with methotrexate sodium |
|
Etoposide |
|
Floxuridine |
|
Hydromorphone HCl |
|
Ifosfamide |
|
Methotrexate sodium |
|
Mitoxantrone HCl |
|
Vincristine sulfate |
|
Incompatible |
|
Carboplatin |
|
Ciprofloxacin |
|
Cisplatin |
|
Cytarabine |
|
Diazepam |
|
Doxorubicin HCl |
|
Epirubicin HCl |
|
Fentanyl citrate |
|
Leucovorin calcium |
|
Levoleucovorin calcium |
|
Metoclopramide HCl |
|
Morphine sulfate |
|
Compatible |
|---|
|
Allopurinol sodium |
|
Amifostine |
|
Anidulafungin |
|
Aztreonam |
|
Bleomycin sulfate |
|
Cisplatin |
|
Cyclophosphamide |
|
Doripenem |
|
Doxorubicin HCl |
|
Doxorubicin HCl liposome injection |
|
Etoposide phosphate |
|
Fludarabine phosphate |
|
Furosemide |
|
Gemcitabine HCl |
|
Granisetron HCl |
|
Heparin sodium |
|
Hydrocortisone sodium succinate |
|
Leucovorin calcium |
|
Linezolid |
|
Mannitol |
|
Melphalan HCl |
|
Methotrexate sodium |
|
Metoclopramide HCl |
|
Mitomycin |
|
Paclitaxel |
|
Palonosetron HCl |
|
Pemetrexed disodium |
|
Piperacillin sodium–tazobactam sodium |
|
Potassium chloride |
|
Propofol |
|
Sargramostim |
|
Teniposide |
|
Thiotepa |
|
Vinblastine sulfate |
|
Vincristine sulfate |
|
Incompatible |
|
Aldesleukin |
|
Droperidol |
|
Filgrastim |
|
Gallium nitrate |
|
Topotecan HCl |
|
Vinorelbine tartrate |
|
Variable |
|
Ondansetron HCl |
Actions
-
Precise mechanisms of action of fluorouracil have not been fully elucidated.a
-
May interfere with DNA synthesis, RNA processing, and protein synthesis.358
-
Main mechanism may be the binding of the deoxyribonucleotide of the drug (FdUMP) and the folate cofactor, N5–10-methylenetetrahydrofolate, to thymidylate synthase (TS) to form a covalently bound ternary complex, which inhibits the formation of thymidylate from uracil, interfering with DNA synthesis.358
-
In addition, FUTP can be incorporated into RNA in place of uridine triphosphate (UTP), producing a fraudulent RNA and interfering with RNA processing and protein synthesis.358
Advice to Patients
-
Importance of informing clinician of any known deficiency in DPD activity.205
-
Risk of cardiotoxicity.205 Importance of immediately informing clinician or seeking emergency care if new-onset chest pain, shortness of breath, dizziness, or lightheadedness occurs.205
-
Risk of CNS effects.205 Importance of immediately informing clinician or seeking emergency care if new-onset mental status changes (e.g., disorientation, confusion), visual disturbances, or difficulty with balance or coordination occurs.205
-
Importance of informing clinician if severe diarrhea or mucositis that prevents normal oral intake of food or fluids occurs.205
-
Importance of informing clinician if tingling, burning, redness, flaking, swelling, blisters, or sores on hands or feet occur.205
-
Risk of myelosuppression.205 Importance of monitoring CBCs during therapy.205 Importance of immediately contacting clinician if fever or other signs of infection occur.205
-
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., warfarin) and OTC drugs as well as any concomitant illnesses.205
-
Risk of fetal harm.205 Necessity of advising women of childbearing potential and men who are partners of such women to avoid pregnancy and to use an effective method of contraception during and for up to 3 months after discontinuance of therapy.205 Importance of women informing their clinician if pregnancy occurs during therapy or up to 3 months after discontinuance of the drug.205
-
Importance of advising women to avoid breast-feeding during fluorouracil therapy.205
-
Risk of impaired female or male fertility.205
-
Importance of informing patients of other important precautionary information. 205 (See Cautions.)
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
|
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
|---|---|---|---|---|
|
Parenteral |
Injection, for IV use |
50 mg/mL* |
Fluorouracil Injection |
|
|
50 mg/mL (2.5 or 5 g) pharmacy bulk package* |
Adrucil |
Teva |
||
|
Fluorouracil Injection |
AHFS DI Essentials™. © Copyright 2025, Selected Revisions July 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.
References
Only references cited for selected revisions after 1984 are available electronically.
200. Machover D, Schwarzenberg L, Goldschmidt E et al. Treatment of advanced colorectal and gastric adenocarcinomas with 5-FU combined with high-dose folinic acid: a pilot study. Cancer Treat Rep. 1982; 66:1803-7. https://pubmed.ncbi.nlm.nih.gov/6982099
201. Budd GT, Fleming TR, Bukowski RM et al. 5-Fluorouracil and folinic acid in the treatment of metastatic colorectal cancer: a randomized comparison. A Southwest Oncology Group study. J Clin Oncol. 1987; 5:272-7. https://pubmed.ncbi.nlm.nih.gov/3543246
202. Panasci L, Ford J, Margolese R. A phase II study of sequential methotrexate and fluorouracil in advanced colorectal cancer. Cancer Chemother Pharmacol. 1985; 15:164-6. https://pubmed.ncbi.nlm.nih.gov/4017165
203. Glimelius B, Ginman C, Graffman S et al. Sequential methotrexate-5-FU-leucovorin (MFL) in advanced colorectal cancer. Eur J Cancer Clin Oncol. 1986; 22:295-300. https://pubmed.ncbi.nlm.nih.gov/3486768
204. Hansen RM, Ritch PS, Anderson T. Sequential methotrexate, 5-fluorouracil, and calcium leucovorin in colorectal carcinoma. Am J Clin Oncol. 1986; 9:352-4. https://pubmed.ncbi.nlm.nih.gov/3489407
205. Teva Parenteral Medicines Inc. Adrucil (fluorouracil) injection prescribing information. North Wales, PA; 2017 Feb.
206. Feldman LD, Ajani JA. Fluorouracil-associated dermatitis of the hands and feet. JAMA. 1985; 254:3479. https://pubmed.ncbi.nlm.nih.gov/2933539
207. Monk MR, Sanchez JD, Phelps CD et al. Myocardial ischemia with fluorouracil and floxuridine therapy. Clin Pharm. 1987; 6:659-61. https://pubmed.ncbi.nlm.nih.gov/2961503
208. Burger AJ, Mannino S. 5-Fluorouracil-induced coronary vasospasm. Am Heart J. 1987; 114:433-6. https://pubmed.ncbi.nlm.nih.gov/3604903
209. Kleiman NS, Lehane DE, Geyer CE Jr et al. Prinzmetal’s angina during 5-fluorouracil chemotherapy. Am J Med. 1987; 82:566-8. https://pubmed.ncbi.nlm.nih.gov/3826112
210. Santos AM, Medina FS. Anaphylactic reaction following IV administration of 5-fluorouracil. Cancer Treat Rep. 1986; 70:1346. https://pubmed.ncbi.nlm.nih.gov/3768880
211. Machover D, Goldschmidt E, Chollet P et al. Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high-dose folinic acid. J Clin Oncol. 1986; 4:685-96. https://pubmed.ncbi.nlm.nih.gov/3517242
212. Leone BA, Romero A, Rabinovich MG et al. Sequential therapy with methotrexate and 5-fluorouracil in the treatment of advanced colorectal carcinoma. J Clin Oncol. 1986; 4:23-7. https://pubmed.ncbi.nlm.nih.gov/3941331
213. Burroughs Wellcome. Wellcovorin (leucovorin calcium) prescribing information. In: Barnhart ER, publisher. Physicians’ desk reference. 43rd ed. Oradell, NJ: Medical Economics Company Inc; 1989(Suppl B):B8.
214. Grem JL, Shoemaker DD, Petrelli NJ et al. Severe and fatal toxic effects observed in treatment with high- and low-dose leucovorin plus 5-fluorouracil for colorectal carcinoma. Cancer Treat Rep. 1987; 71:1122. https://pubmed.ncbi.nlm.nih.gov/3499982
215. Petrelli N, Douglass HO Jr, Herrera L et al. The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. J Clin Oncol. 1989; 7:1419-26. https://pubmed.ncbi.nlm.nih.gov/2674331
216. Petrelli NJ, Madajewicz S, Herrera L et al. Biologic modulation of 5-fluorouracil with high-dose leucovorin and combination chemotherapy of 5-fluorouracil and cisplatin in metastatic colorectal adenocarcinoma. In: Development of folates and folic acid antagonists in cancer chemotherapy. NCI monographs 1987 No. 5. NIH Publication No. 87-2901 Number 5 1987. Bethesda, MD: National Cancer Institute; 1987:189-92.
217. Bruckner HW, Petrelli NJ, Stablein D et al. Comparison of unique leucovorin and 5-fluorouracil “escalating” and “maximum” dosage strategies. In: Development of folates and folic acid antagonists in cancer chemotherapy. NCI monographs 1987 No. 5. NIH Publication No. 87-2901 Number 5 1987. Bethesda, MD; National Cancer Institute; 1987:179-84.
218. Erlichman C, Fine S, Wong A et al. A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma. J Clin Oncol. 1988; 6:469-75. https://pubmed.ncbi.nlm.nih.gov/3280741
219. Doroshow JH, Bertrand M, Newman E et al. Preliminary analysis of a randomized comparison of 5-fluorouracil versus 5-fluorouracil and high-dose continuous-infusion folinic acid in disseminated colorectal cancer. In: Development of folates and folic acid antagonists in cancer chemotherapy. NCI Monograph 1987 No. 5. NIH Publication No. 87-2901, Number 5, 1987. Bethesda, MD; National Cancer Institute; 1987: 171-4.
220. Petrelli N, Herrera L, Rustum Y et al. A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol. 1987; 5:1559-65. https://pubmed.ncbi.nlm.nih.gov/2443619
221. Evans RM, Laskin JD, Hakala MT. Effect of excess folates and deoxyinosine on the activity and site of action of 5-fluorouracil. Cancer Res. 1981; 41:3288-95. https://pubmed.ncbi.nlm.nih.gov/6973389
222. Lockshin A, Danenberg PV. Biochemical factors affecting the tightness of 5-fluorodeoxyuridylate binding to human thymidylate synthetase. Biochem Pharmacol. 1981; 30:247-57. https://pubmed.ncbi.nlm.nih.gov/6939434
223. Ullman B, Lee M, Martin DW Jr et al. Cytotoxicity of 5-fluoro-2-rdeoxyuridine: requirement for reduced folate cofactors and antagonism by methotrexate. Proc Natl Acad Sci USA. 1978; 75:980-3. https://pubmed.ncbi.nlm.nih.gov/147465
224. Waxman S, Bruckner H, Wagle A et al. Potentiation of 5-fluorouracil (5-FU) antimetabolic effect by leucovorin (LV). Proc Annu Meet Am Assoc Cancer Res Proc Annu Meet Am Soc Clin Oncol. 1978; 19:149.
225. Berger SH, Hakala MT. Relationship of dUMP and free FdUMP pools to inhibition of thymidylate synthase by 5-fluorouracil. Mol Pharmacol. 1984; 25:303-9. https://pubmed.ncbi.nlm.nih.gov/6608049
226. Janssen Pharmaceutica. Ergamisol (levamisole hydrochloride) tablets prescribing information. Piscataway, NJ; 1990 Jun.
227. Moertel CG, Fleming TR, MacDonald JS et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. New Engl J Med. 1990; 322:352-8. https://pubmed.ncbi.nlm.nih.gov/2300087
228. Mayer RJ. Does adjuvant therapy work in colon cancer? New Engl J Med. 1990; 322:399-401. Editorial.
229. Windle R, Bell PRF, Shaw D. Five year results of a randomized trial of adjuvant 5-fluorouracil and levamisole in colorectal cancer. Br J Surg. 1987; 74:569-72. https://pubmed.ncbi.nlm.nih.gov/3304518
230. National Institutes of Health Office of Medical Applications of Research. Consensus conference: adjuvant therapy for patients with colon and rectal cancer. JAMA. 1990; 264:1444-50. https://pubmed.ncbi.nlm.nih.gov/2202842
231. Anon. Consensus panel considers adjuvant therapy for colon and rectal cancer, identifies levamisole-fluorouracil as standard in colon cancer. Clin Pharm. 1990; 9:493, 501-2.
232. Anon. Levamisole with fluorouracil for colon cancer. Med Lett Drugs Ther. 1989; 31:29-30.
233. Brandman JF. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. New Engl J Med. 1990; 323:197-8. https://pubmed.ncbi.nlm.nih.gov/2362611
234. Krook JE, Moertel CG, Gunderson LL et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med. 1991; 324:709-15. https://pubmed.ncbi.nlm.nih.gov/1997835
235. Clinical Announcement: Adjuvant Therapy of Rectal Cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 1991 Oct 8.
236. Moertel CG, Krook JE, Wieand HS. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med. 1991; 325:519-20. https://pubmed.ncbi.nlm.nih.gov/1852188
237. Rectal cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 1991 Oct 8.
238. Krook JE, Moertel CG, Gunderson LL et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med. 1991; 324:709-15. https://pubmed.ncbi.nlm.nih.gov/1997835
239. O’Connell M, Wieand H et al. Lack of value for methyl-CCNU (MeCCNU) as a component of effective rectal cancer surgical adjuvant therapy: interim analysis of intergroup protocol 86-47-51. Paper presented at the Proceedings of the American Society for Clinical Oncology, 1991 May.
240. Reynolds T. Combined treatment substantially improves outlook for rectal cancer. J Natl Cancer Inst. 1991; 83:386-7. https://pubmed.ncbi.nlm.nih.gov/1999843
241. Ovarian epithelial cancer. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Jul.
242. Gastrointestinal Tumor Study Group. Prolongation of the disease-free interval in surgically treated rectal carcinoma. N Engl J Med. 1985; 312:1465-72. https://pubmed.ncbi.nlm.nih.gov/2859523
243. Gastrointestinal Tumor Study Group. Survival after postoperative combination treatment of rectal cancer. N Engl J Med. 1986; 315:1294-5. https://pubmed.ncbi.nlm.nih.gov/3773947
244. Breast cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 1995 Dec 12.
245. Fisher B, Redmond C, Dimitrov NV et al. A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med. 1989; 320:473-8. https://pubmed.ncbi.nlm.nih.gov/2644531
246. McGuire WL. Adjuvant therapy of node-positive breast cancer. N Engl J Med. 1989; 320:525-7. https://pubmed.ncbi.nlm.nih.gov/2915655
247. De Vita VT Jr. Breast cancer therapy: exercising all our options. N Engl J Med. 1989; 320:527-9. https://pubmed.ncbi.nlm.nih.gov/2915656
248. Fisher B, Redmond C, Wickerham LD et al. Systemic therapy in patients with node-negative breast cancer: a commentary based on two National Surgical Adjuvant Breast and Bowel project (NSABP) clinical trials. Ann Intern Med. 1989; 111:703-12. https://pubmed.ncbi.nlm.nih.gov/2679288
249. Anon. Drugs of choice for cancer chemotherapy. Med Lett Drugs Ther. 2000; 42:83-92. https://pubmed.ncbi.nlm.nih.gov/10994034
250. Anon. Adjuvant chemotherapy of early breast cancer. Med Lett Drugs Ther. 1990; 32:49-50. https://pubmed.ncbi.nlm.nih.gov/2333039
251. National Institutes of Health Office of Medical Applications of Research. Consensus conference: treatment of early-stage breast cancer. JAMA. 1991; 265:391-5. https://pubmed.ncbi.nlm.nih.gov/1984541
252. Laurie JA, Moertel CG, Fleming TR et al. Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. J Clin Oncol. 1989; 7:1447-56. https://pubmed.ncbi.nlm.nih.gov/2778478
253. Colon cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 1991 Oct 8.
254. Gelber RD, Goldhirsch A, Cavalli F. Quality-of-life adjusted evaluation of adjuvant therapies for operable breast cancer. Ann Intern Med. 1991; 114:621-8. https://pubmed.ncbi.nlm.nih.gov/2003707
255. Chrisp P, McTavish D. Levamisole/fluorouracil: a review of their pharmacology and adjuvant therapeutic use in colorectal cancer. Drugs & Aging. 1991; 1:317-37.
256. Wolmark N, Fisher B, Rockette H et al. Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP protocol C-01. J Natl Cancer Inst. 1988; 80:30-6. https://pubmed.ncbi.nlm.nih.gov/3276901
257. Taylor I, Machin D, Mullee M et al. A randomized controlled trial of adjuvant portal vein cytotoxic perfusion in colorectal cancer. Br J Surg. 1985; 72:359-63. https://pubmed.ncbi.nlm.nih.gov/3888335
258. Wolmark N, Rockette H, Wickerham DL et al. Adjuvant therapy of Dukes’ A, B, and C adenocarcinoma of the colon with portal-vein fluorouracil hepatic infusion: preliminary results of the National Surgical Adjuvant Breast and Bowel Project Protocol C-02. J Clin Oncol. 1990; 8:1466-75. https://pubmed.ncbi.nlm.nih.gov/2202789
259. Beart RW Jr, Moertel CG, Wieand HS et al. Adjuvant therapy for resectable colorectal carcinoma with fluorouracil administered by portal vein infusion: a study of the Mayo Clinic and the North Central Cancer Treatment Group. Arch Surg. 1990; 125:897-901. https://pubmed.ncbi.nlm.nih.gov/2369315
260. Stagg RJ, Venook AP, Chase JL et al. Alternating hepatic intra-arterial floxuridine and fluorouracil: a less toxic regimen for treatment of liver metastases from colorectal cancer. J Natl Cancer Inst. 1991; 83:423-8. https://pubmed.ncbi.nlm.nih.gov/1825674
261. Mayer RJ, O’Connell MJ, Tepper JE et al. Status of adjuvant therapy for colorectal cancer. J Natl Cancer Inst. 1989; 81:1359-64. https://pubmed.ncbi.nlm.nih.gov/2674456
262. Petrelli N, Douglass HO Jr, Herrera L et al. The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. J Clin Oncol. 1989; 7:1419-26. https://pubmed.ncbi.nlm.nih.gov/2674331
263. Fisher B, Wolmark N, Rockette H et al. Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01. J Natl Cancer Inst. 1988; 80:21-9. https://pubmed.ncbi.nlm.nih.gov/3276900
264. Gerard A, Buyse M, Pector JC et al. Hepatic artery ligation with and without portal infusion of 5-FU: a randomized study in patients with unresectable liver metastases from colorectal carcinoma. Eur J Surg Oncol. 1991; 17:289-94. https://pubmed.ncbi.nlm.nih.gov/2044783
265. Machiavelli M, Leone BA, Romero A et al. Advanced colorectal carcinoma: a prospective randomized trial of sequential methotrexate, 5-fluorouracil, and leucovorin versus 5-fluorouracil alone. Am J Clin Oncol. 1991; 14:211-7. https://pubmed.ncbi.nlm.nih.gov/2031508
266. Doroshow JH, Multhauf P, Leong L et al. Prospective randomized comparison of fluorouracil versus fluorouracil and high-dose continuous infusion leucovorin calcium for the treatment of advanced measurable colorectal cancer in patients previously unexposed to chemotherapy. J Clin Oncol. 1990; 8:491-501. https://pubmed.ncbi.nlm.nih.gov/2407810
267. Scheithauer W, Rosen H, Scheissel R et al. Treatment of patients with colorectal cancer with cisplatin, 5-fluorouracil, and leucovorin. Cancer. 1991; 67:1294-8. https://pubmed.ncbi.nlm.nih.gov/1991292
268. Rosen PP, Groshen S, Kinne DW. Prognosis in T2NOMO stage I breast carcinoma: a 20-year follow-up study. J Clin Oncol. 1991; 9:1650-61. https://pubmed.ncbi.nlm.nih.gov/1875222
269. Rosen PP, Groshen S, Saigo PE et al. Pathological prognostic factors in stage I (T1NOMO) and stage II (T1N1MO) breast carcinoma: a study of 644 patients with median follow-up of 18 years. J Clin Oncol. 1989; 7:1239-51. https://pubmed.ncbi.nlm.nih.gov/2549203
270. Early Breast Cancer Trialists’ Collaborative Group. Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer: an overview of 61 randomized trials among 28,896 women. N Engl J Med. 1988; 319:1681-92. https://pubmed.ncbi.nlm.nih.gov/3205265
271. The Ludwig Breast Cancer Study Group. Prolonged disease-free survival after one course of perioperative adjuvant chemotherapy for node-negative breast cancer. N Engl J Med. 1989; 320:491-6. https://pubmed.ncbi.nlm.nih.gov/2644533
272. Mansour EG, Gray R, Shatila AH et al. Efficacy of adjuvant chemotherapy in high-risk node-negative breast cancer: an intergroup study. N Engl J Med. 1989; 320:485-90. https://pubmed.ncbi.nlm.nih.gov/2915651
273. Rubens RD. Breast cancer. In: Pinedo HM, ed. Cancer chemotherapy. Annual 1. New York: Elsevier North Holland, Inc; 1979:376-411.
274. Agitated by fluorouracil. USP Drug Product Quality Review. 1991; (Apr)17.
275. Reviewers’ comments (personal observations).
276. Muss HB, Case LD, Richards F II et al. Interrupted versus continuous chemotherapy in patients with metastatic breast cancer. N Engl J Med. 1991; 325:1342-8. https://pubmed.ncbi.nlm.nih.gov/1922236
277. Norton L. Metastatic breast cancer: length and quality of life. N Engl J Med. 1991; 325:1370-1. https://pubmed.ncbi.nlm.nih.gov/1922240
278. Coates A, Gebski V, Bishop JF et al. Improving the quality of life during chemotherapy for advanced breast cancer: a comparison of intermittent and continuous treatment strategies. N Engl J Med. 1987; 317:1490-5. https://pubmed.ncbi.nlm.nih.gov/3683485
279. Tannock IF. Treating the patient, not just the cancer. N Engl J Med. 1987; 1534-5. Editorial.
280. Slevin ML, Gray R. Adjuvant therapy for cancer of the colon: an important step forward. BMJ. 1991; 302:1100-1. https://pubmed.ncbi.nlm.nih.gov/2043778
281. O’Connell M, Poon M, Wieand C et al. Biochemical modulation of 5-fluorouracil (5FU) with leucovorin (LV): confirmatory evidence of improved therapeutic efficacy in the treatment of advanced colorectal cancer. Proc ASCO. 1990; 9:106.
282. Jones SE, Moon TE, Bonadonna G et al. Comparison of different trials of adjuvant chemotherapy in stage II breast cancer using a natural history database. Am J Clin Oncol. 1987; 10:387-95. https://pubmed.ncbi.nlm.nih.gov/3310603
283. Buzdar AU, Kau SW, Smith TL et al. Ten-year results of FAC adjuvant chemotherapy trial in breast cancer. Am J Clin Oncol. 1989; 12:123-8. https://pubmed.ncbi.nlm.nih.gov/2705401
284. Bonadonna G, Brusamolino E, Valagussa P et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med. 1976; 294:405-10. https://pubmed.ncbi.nlm.nih.gov/1246307
285. Smith DC, Ross DJ, Russell AR et al. Adjuvant chemotherapy in early breast cancer. Br J Cancer. 1979; 40:310.
286. Bedford Laboratories. Leucovorin calcium powder for injection and solution for injection prescribing information. Bedford, OH; 2008 Sep.
287. Rectal cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Library of Medicine; 1992 June 8.
288. Colon cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Library of Medicine; 1992 June 8.
289. Lederle. Combination chemotherapy with leucovorin calcium and 5-fluorouracil. Pearl River, NY; 1992 Mar.
290. DeLap RJ. The effect of leucovorin on the therapeutic index of fluorouracil in cancer patients. Yale J Biol Med. 1988; 61:23-34. https://pubmed.ncbi.nlm.nih.gov/3284210
291. Saltz L. Drug treatment of colorectal cancer: current status. Drugs. 1991; 42:616-27. https://pubmed.ncbi.nlm.nih.gov/1723364
292. Erlichman C. Fluorouracil and leucovorin for metastatic colorectal cancer. J Chemother. 1990; 2(Suppl 1):38-40. https://pubmed.ncbi.nlm.nih.gov/2195136
293. O’Connell MJ. A phase III trial of 5-fluorouracil and leucovorin in the treatment of advanced colorectal cancer: a Mayo Clinic/North Central Cancer Treatment Group study. Cancer. 1989; 63:1026-30. https://pubmed.ncbi.nlm.nih.gov/2465076
294. Poon MA, O’Connell MJ, Moertel CG et al. Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol. 1989; 7:1407-18. https://pubmed.ncbi.nlm.nih.gov/2476530
295. Poon MA, O’Connell MJ, Wieand HS et al. Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal carcinoma. J Clin Oncol. 1991; 9:1967-72. https://pubmed.ncbi.nlm.nih.gov/1941055
296. Valone FH, Friedman MA, Wittinger PS et al. Treatment of patients with advanced colorectal carcinomas with fluorouracil alone, high-dose leucovorin plus fluorouracil, or sequential methotrexate, fluorouracil, and leucovorin: a randomized trial of the Northern California Oncology Group. J Clin Oncol. 1989; 7:1427-36. https://pubmed.ncbi.nlm.nih.gov/2789272
297. Erlichman C. Fluorouracil/leucovorin study update. J Clin Oncol. 1991; 9:2076. https://pubmed.ncbi.nlm.nih.gov/1941066
298. Nobile MT, Canobbio L, Sobrero A et al. A randomized trial of 5-fluorouracil alone versus 5-fluorouracil and high-dose leucovorin in untreated advanced colorectal cancer patients. Adv Exp Med Biol. 1988; 244:213-8. https://pubmed.ncbi.nlm.nih.gov/3073656
299. Loffler TM, Weber FW, Hausamen TU. Protracted continuous-infusion 5-fluorouracil with intermittent high-dose leucovorin in advanced and metastatic colorectal cancer: a pilot study. In: Pinedo HM, Rustum YM, eds. Leucovorin modulation of fluoropyrimidines: a new frontier in cancer chemotherapy. New York: Royal Society of Medicine Services; 1989:65-8.
300. Labianca R, Pancera G, Aitini E et al. Folinic acid + 5-fluorouracil (5-FU) versus equidose 5-FU in advanced colorectal cancer. Phase III study of “GISCAD” (Italian Group for the Study of Digestive Tract Cancer). Ann Oncol. 1991; 2:673-9. https://pubmed.ncbi.nlm.nih.gov/1742223
301. Hines JD, Adelstein DJ, Speiss JL et al. Efficacy of high-dose oral leucovorin and 5-fluorouracil in advanced colorectal carcinoma. Cancer. 1989; 63(Suppl):1022-5. https://pubmed.ncbi.nlm.nih.gov/2783879
302. Laufman LR, Brenckman WD Jr, Stydnicki KA et al. Clinical experience with leucovorin and 5-fluorouracil. Cancer. 1989; 63(Suppl):1031-5. https://pubmed.ncbi.nlm.nih.gov/2783880
303. Rustum YM. Biochemical rationale for the 5-fluorouracil leucovorin combination and update of clinical experience. J Chemother. 1990; 2(Suppl 1):5-11. https://pubmed.ncbi.nlm.nih.gov/2195138
304. Gerstner J, O’Connell MJ, Wieand HS et al. A prospectively randomized clinical trial comparing 5-FU combined with either high- or low-dose leucovorin for the treatment of advanced colorectal cancer. Proc Annu Meet Am Soc Clin Oncol. 1991; 10:A404.
305. Advanced colorectal cancer meta-analysis project. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. J Clin Oncol. 1992; 10:896-903. https://pubmed.ncbi.nlm.nih.gov/1534121
306. Mini E, Trave F, Rustum YM et al. Enhancement of the antitumor effects of 5-fluorouracil by folinic acid. Pharmacol Ther. 1990; 47:1-19. https://pubmed.ncbi.nlm.nih.gov/2195551
307. Romanini A, Lin JT, Niedzwiecki D et al. Role of folylpolyglutamates in biochemical modulation of fluoropyrimidines by leucovorin. Cancer Res. 1991; 51:789-93. https://pubmed.ncbi.nlm.nih.gov/1988119
308. Machover D. Potentiation of the antitumour activity of the fluoropyrimidines by leucovorin: rationale and clinical data. In: Pinedo HM, Rustum YM, eds. Leucovorin modulation of fluoropyrimidines: a new frontier in cancer chemotherapy. New York: Royal Society of Medicine Services; 1989:1-9.
309. Rustum YM. Rationale for the combination of 5-fluorouracil/leucovorin: role of dose, schedule and route of administration. In: Pinedo HM, Rustum YM, eds. Leucovorin modulation of fluoropyrimidines: a new frontier in cancer chemotherapy. New York: Royal Society of Medicine Services; 1989:11-19.
310. Peters GJ, van der Wilt CL, van Groeningen CJ et al. Development of leucovorin/5-fluorouracil combinations. In: Pinedo HM, Rustum YM, eds. Leucovorin modulation of fluoropyrimidines: a new frontier in cancer chemotherapy. New York: Royal Society of Medicine Services; 1989:21-35.
311. Creaven PJ, Petrelli NJ, Rustum YM. Leucovorin/5-fluorouracil: response and toxicity in relation to quality of life. In: Pinedo HM, Rustum YM, eds. Leucovorin modulation of fluoropyrimidines: a new frontier in cancer chemotherapy. New York: Royal Society of Medicine Services; 1989:57-64.
312. Wilke H, Preusser P, Stahl M et al. Leucovorin/5-fluorouracil alone or in combination with other cytostatic drugs in the treatment of advanced gastric carcinoma. In: Pinedo HM, Rustum YM, eds. Leucovorin modulation of fluoropyrimidines: a new frontier in cancer chemotherapy. New York: Royal Society of Medicine Services; 1989:87-95.
313. Schöber CH, Köhne-Wömpner CH, Schmoll HJ et al. A 3-day schedule of 5-fluorouracil and folinic acid in metastatic progressive colorectal cancer and its impact in terms of palliation. Semin Oncol. 1992; 19(Suppl 3):136-40. https://pubmed.ncbi.nlm.nih.gov/1557639
314. Schöber CH, Bokemeyer C, Stahl M et al. The role of schedule dependency of 5-fluorouracil/leucovorin combinations in advanced colorectal cancer. Semin Oncol. 1992; 19(Suppl 3):131-5. https://pubmed.ncbi.nlm.nih.gov/1557638
315. Steinke B, Günther E, Hirschmann WD et al. Fluorouracil versus folinic acid/fluorouracil in advanced colorectal cancer—preliminary results of a randomized trial. Semin Oncol. 1992; 19(Suppl 3):141-7. https://pubmed.ncbi.nlm.nih.gov/1557640
316. Lederle, Pearl River, NY: personal communication.
317. Nobile MT, Vidili MG, Sobrero A et al. 5-Fluorouracil (FU) alone or combined with high dose folinic acid (FA) in advanced colorectal cancer patients: a randomized trial. Proc Annu Meet Am Soc Clin Oncol. 1988; 7:A371.
318. O’Connell MJ, Martenson JA, Wieand HS et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med. 1994; 331:502-7. https://pubmed.ncbi.nlm.nih.gov/8041415
319. Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomized trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet. 1992; 339:1-15,71-85. https://pubmed.ncbi.nlm.nih.gov/1345950
320. Bonadonna G, Brusamolino E, Valagussa P et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med. 1976; 294:405-10. https://pubmed.ncbi.nlm.nih.gov/1246307
321. Bonadonna G, Valagussa P, Moliterni A et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med. 1995; 332:901-6. https://pubmed.ncbi.nlm.nih.gov/7877646
322. Wood WC, Budman DR, Korzun AH et al. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med. 1994; 330:1253-9. https://pubmed.ncbi.nlm.nih.gov/8080512
323. Bonadonna G, Zambetti M, Valagussa P. Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes: ten-year results. JAMA. 1995; 273:542-7. https://pubmed.ncbi.nlm.nih.gov/7837388
324. Fisher B, Constantino J, Redmond C et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med. 1989; 320:479-84. https://pubmed.ncbi.nlm.nih.gov/2644532
325. Fisher B, Brown AM, Dimitrov NV et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol. 1990; 8:1483-96. https://pubmed.ncbi.nlm.nih.gov/2202791
326. Moliterni A, Bonadonna G, Valagussa P et al. Cyclophosphamide, methotrexate, and fluorouracil with and without doxorubicin in the adjuvant treatment of resectable breast cancer with one to three positive nodes. J Clin Oncol. 1991; 9:1124-30. https://pubmed.ncbi.nlm.nih.gov/2045854
327. Fisher B, Redmond C, Wickerman DL et al. Doxorubicin-containing regimens for the treatment of stage II breast cancer: the National Surgical Adjuvant Breast and Bowel Project experience. J Clin Oncol. 1989; 7:572-82. https://pubmed.ncbi.nlm.nih.gov/2651576
328. Buzzoni R, Bonadonna G, Valagussa P et al. Adjuvant chemotherapy with doxorubicin plus cyclophosphamide, methotrexate, and fluorouracil in the treatment of resectable breast cancer with more than three positive axillary nodes. J Clin Oncol. 1991; 9:2134-40. https://pubmed.ncbi.nlm.nih.gov/1960555
329. Esophageal cancer. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Jul.
330. Kelsen DP, Ilson DH. Chemotherapy and combined-modality therapy for esophageal cancer. Chest. 1995; 107:S224-32. https://pubmed.ncbi.nlm.nih.gov/7781398
331. Herskovic A, Martz K, Al-Sarraf M et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med. 1992; 326:1593-8. https://pubmed.ncbi.nlm.nih.gov/1584260
332. Haller DG. Treatments for esophageal cancer. N Engl J Med. 1992; 326:1629-31. https://pubmed.ncbi.nlm.nih.gov/1584267
333. Cooper JS, Guo MD, Herskovic A et al. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. JAMA. 1999; 281:1623-7. https://pubmed.ncbi.nlm.nih.gov/10235156
334. DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 5th ed. Philadelphia, PA: Lippincott-Raven Publishers; 1997.
336. Ajani JA. Contributions of chemotherapy in the treatment of carcinoma of the esophagus: results and commentary. Semin Oncol. 1994; 21:474-82. https://pubmed.ncbi.nlm.nih.gov/8042045
337. Oropharyngeal cancer. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Jun.
338. Reviewers’ comments (personal observations) on cisplatin 10:00.
339. Clark PI, Slevin ML, Reznek RH et al. Two randomised phase II trials of intermittent intravenous versus subcutaneous alpha-2 interferon alone (trial 1) and in combination with 5-fluorouracil (trial 2) in advanced colorectal cancer. Int J Color Dis. 1987; 2:26-9.
340. Wadler S, Schwartz EL, Goldman M et al. Fluorouracil and recombinant alfa-2A-interferon: an active regimen against advanced colorectal carcinoma. J Clin Oncol. 1989; 7:1769-75. https://pubmed.ncbi.nlm.nih.gov/2585018
341. Kemeny N, Younes A, Seiter K et al. Interferon alpha-2a and 5-fluorouracil for advanced colorectal carcinoma. Assessment of activity and toxicity. Cancer. 1990; 66:2470-5. https://pubmed.ncbi.nlm.nih.gov/2249187
342. Huberman M, Bering H, Tessitore J et al. 5-fluorouracil (5FU) plus recombinant alpha interferon (Roferon A(R)) in advanced colorectal cancer. Proc Am Soc Clin Oncol. 1990; 9:116.
343. Pazdur R, Abbruzzese J, Faintuch J et al. Phase II study of recombinant interferon alpha (rIFN) and 5-fluorouracil (5-FU) in patients (PTS) with advanced colorectal cancer. Proc Am Soc Clin Oncol. 1990; 9:117.
344. Yalavarthi P, Murthy S, Budd GT et al. Phase I/II trial of FU, leucovorin (LV) and rHuIFNalpha2a in metastatic colorectal cancer: possible decrease in myelosuppression. Proc Am Soc Clin Oncol. 1990; 9:125.
345. Wadler S, Lyver A, Goldman M et al. Therapy with 5-fluorouracil (5FU) and recombinant alpha-2A-interferon (IFN) in refractory GI malignancies. Proc Am Soc Clin Oncol. 1989; 8:A384.
346. Wadler S, Goldman M, Lyver A et al. Phase I trial of 5-fluorouracil and recombinant alpha2a-interferon in patients with advanced colorectal carcinoma. Cancer Res. 1990; 50:2056-9. https://pubmed.ncbi.nlm.nih.gov/2317795
347. Wadler S, Wiernik PH. Clinical update on the role of fluorouracil and recombinant interferon alfa-2A in the treatment of colorectal carcinoma. Semin Oncol. 1990; 17(1 Suppl 1):16-21. https://pubmed.ncbi.nlm.nih.gov/2405491
349. Catimel G. Head and neck cancer: guidelines for chemotherapy. Drugs. 1996; 51:73-88. https://pubmed.ncbi.nlm.nih.gov/8741233
350. Jacobs C, Lyman G, Velez-Garcia E et al. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol. 1992; 10:257-63. https://pubmed.ncbi.nlm.nih.gov/1732427
351. Forastiere AA, Metch B, Schuller DE et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol. 1992; 10:1245-51. https://pubmed.ncbi.nlm.nih.gov/1634913
352. Merlano M, Vitale V, Rosso R et al. Treatment of advanced squamous-cell carcinoma of the head and neck with alternating chemotherapy and radiotherapy. N Engl J Med. 1992; 327:1115-21. https://pubmed.ncbi.nlm.nih.gov/1302472
353. Merlano M, Benasso M, Corvo R et al. Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst. 1996; 88:583-9. https://pubmed.ncbi.nlm.nih.gov/8609658
354. Vokes EE, Weichselbaum RR, Lippman SM et al. Head and neck cancer. N Engl J Med. 1993; 328:184-94. https://pubmed.ncbi.nlm.nih.gov/8417385
355. The Department of Veterans Affairs Laryngeal Cancer Study Group. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med. 1991; 324:1685-90. https://pubmed.ncbi.nlm.nih.gov/2034244
356. Spaulding MB, Fischer SG, Wolf GT. Tumor response, toxicity, and survival after neoadjuvant organ-preserving chemotherapy for advanced laryngeal carcinoma. The Department of Veterans Affairs Cooperative Laryngeal Cancer Study Group. J Clin Oncol. 1994; 12:1592-9. https://pubmed.ncbi.nlm.nih.gov/8040671
357. Lefebvre JL, Chevalier D, Luboinski B et al. Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst. 1996; 88:890-9. https://pubmed.ncbi.nlm.nih.gov/8656441
358. Pinedo HM, Peters GFJ. Fluorouracil: biochemistry and pharmacology. J Clin Oncol. 1988; 6:1653-64. https://pubmed.ncbi.nlm.nih.gov/3049954
359. Morris M, Eifel PJ, Lu J et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med. 1999; 340:1137-43. https://pubmed.ncbi.nlm.nih.gov/10202164
360. Peters WA III, Liu PY, Barrett R et al. Cisplatin, 5-fluorouracil plus radiation therapy are superior to radiation therapy as adjunctive therapy in high-risk, early-stage carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: report of a phase III Inter-Group Study. In: Abstracts of the 30th Annual Meeting of the Society of Gynecologic Oncologists, San Francisco, CA, 1999 Mar 20–24. Abstract.
361. Rose PG, Bundy BN, Watkins EB et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med. 1999; 340:1144-53. https://pubmed.ncbi.nlm.nih.gov/10202165
362. Whitney CW, Sause W, Bundy BN et al. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol. 1999; 17:1339-48. https://pubmed.ncbi.nlm.nih.gov/10334517
363. Thomas GM. Improved treatment for cervical cancer—concurrent chemotherapy and radiotherapy. N Engl J Med. 1999; 340:1198-1200. https://pubmed.ncbi.nlm.nih.gov/10202172
364. Cervical cancer. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Jun.
365. Omura GA. Chemotherapy for stage IVB or recurrent cancer of the uterine cervix. J Natl Cancer Inst Monogr. 1996; (21):123-6. https://pubmed.ncbi.nlm.nih.gov/9023841
366. Fanning J, Ladd C, Hilgers RD. Cisplatin, 5-fluorouracil, and ifosfamide in the treatment of recurrent or advanced cervical cancer. Gynecol Oncol. 1995; 56:235-8. https://pubmed.ncbi.nlm.nih.gov/7896191
367. Look KY, Blessing JA, Valea FA et al. Phase II trial of 5-fluorouracil and high-dose leucovorin in recurrent adenocarcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 1997; 67:255-8. https://pubmed.ncbi.nlm.nih.gov/9441772
368. Reviewers’ comments (personal observations) on cervical cancer.
369. Look KY, Blessing JA, Gallup DG et al. A phase II trial of 5-fluorouracil and high-dose leucovorin in patients with recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Am J Clin Oncol. 1996; 19:439-41. https://pubmed.ncbi.nlm.nih.gov/8823469
370. Bonomi P, Blessing J, Ball H et al. A phase II evaluation of cisplatin and 5-fluorouracil in patients with advanced squamous cell carcinoma of the cervix: a Gynecologic Oncology Group Study. Gynecol Oncol. 1989; 34:357-9. https://pubmed.ncbi.nlm.nih.gov/2767528
371. Kaern J, Trope C, Sundfoer K et al. Cisplatin/5-fluorouracil treatment of recurrent cervical carcinoma: a phase II study with long-term follow-up. Gynecol Oncol. 1996; 60:387-92. https://pubmed.ncbi.nlm.nih.gov/8774643
372. Thomas GM, Dembo AJ, Black B et al. Concurrent radiation and chemotherapy for carcinoma of the cervix recurrent after radical surgery. Gynecol Oncol. 1987; 27:254-63. https://pubmed.ncbi.nlm.nih.gov/3114057
373. Eifel PJ. Concurrent chemotherapy and radiation: a major advance for women with cervical cancer. J Clin Oncol. 1999; 17:1334-5. https://pubmed.ncbi.nlm.nih.gov/10334515
374. Kish JA, Wolf M, Crawford ED et al. Evaluation of low dose continuous infusion 5-fluorouracil in patients with advanced and recurrent renal cell carcinoma. A Southwest Oncology Group Study. Cancer. 1994; 74:916-9. https://pubmed.ncbi.nlm.nih.gov/8039119
375. Atzpodien J, Kirchner H, Lopez Hanninen E et al. Alpha-interferon, interleukin-2 and 5-fluorouracil as a promising biochemotherapy regimen for the management of advanced renal cell carcinoma. Proc Annu Meet Am Soc Clin Oncol. 1993; 12:A708.
376. Sella A, Zukiwski A, Robinson E et al. Interleukin-2 (IL-2) with interferon-alfa (IFN-alpha) and 5-fluorouracil (5-FU) in patients (pts) with metastatic renal cell cancer (RCC). Proc Annu Meet Am Soc Clin Oncol. 1994; 13:A733.
377. Lopez Hanninen E, Kirchner H, Atzpodien J. Interleukin-2 based home therapy of metastatic renal cell carcinoma: risks and benefits in 215 consecutive single institution patients. J Urol. 1996; 155:19-25. https://pubmed.ncbi.nlm.nih.gov/7490829
378. Ellerhorst JA, Sella A, Amato RJ et al. Phase II trial of 5-fluorouracil, interferon-alpha and continuous infusion interleukin-2 for patients with metastatic renal cell carcinoma. Cancer. 1997; 80:2128-32. https://pubmed.ncbi.nlm.nih.gov/9392335
379. Ravaud A, Audhuy B, Gomez F et al. Subcutaneous interleukin-2, interferon alfa-2a, and continuous infusion of fluorouracil in metastatic renal cell carcinoma: a multicenter phase II trial. Groupe Francais d’Immunotherapie. J Clin Oncol. 1998; 16:2728-32. https://pubmed.ncbi.nlm.nih.gov/9704724
380. Tourani JM, Pfister C, Berdah JF et al. Outpatient treatment with subcutaneous interleukin-2 and interferon alfa administration in combination with fluorouracil in patients with metastatic renal cell carcinoma: results of a sequential nonrandomized phase II study. Subcutaneous Administration Propeukin Program Cooperative Group. J Clin Oncol. 1998; 16:2505-13. https://pubmed.ncbi.nlm.nih.gov/9667271
381. Dutcher JP, Atkins M, Fisher R et al. Interleukin-2-based therapy for metastatic renal cell cancer: the Cytokine Working Group experience, 1989-1997. Cancer J Sci Am. 1997; 3(Suppl 1):S73-8.
382. Igarashi T, Marumo K, Onishi T et al. Interferon-alpha and 5-fluorouracil therapy in patients with metastatic renal cell cancer: an open multicenter trial. The Japanese Study Group Against Renal Cancer. Urology. 1999; 53:53-9. https://pubmed.ncbi.nlm.nih.gov/9886588
383. Elias L, Blumenstein BA, Kish J et al. A phase II trial of interferon-alpha and 5-fluorouracil in patients with advanced renal cell carcinoma. A Southwest Oncology Group study. Cancer. 1996; 78:1085-8. https://pubmed.ncbi.nlm.nih.gov/8780547
384. Haarstad H, Jacobsen AB, Schjolseth SA et al. Interferon-alpha, 5-FU and prednisone in metastatic renal cell carcinoma: a phase II study. Ann Oncol. 1994; 5:245-8. https://pubmed.ncbi.nlm.nih.gov/8186172
385. Bukowski RM. Natural history and therapy of metastatic renal cell carcinoma: the role of interleukin-2. Cancer. 1997; 80:1198-220. https://pubmed.ncbi.nlm.nih.gov/9317170
386. Haller DG, Catalano PJ, Macdonald JS et al. Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol. 2005; 23:8671-8. https://pubmed.ncbi.nlm.nih.gov/16314627
387. Thirion P, Michiels S, Pignon JP et al. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: an updated meta-analysis. J Clin Oncol. 2004; 22:3766-75. https://pubmed.ncbi.nlm.nih.gov/15365073
388. Stage III colon cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2008 Oct 23.
389. Stage IV and recurrent colon cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2008 Oct 23.
390. de Gramont A, Bosset JF, Milan C et al. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol. 1997; 15:808-15. https://pubmed.ncbi.nlm.nih.gov/9053508
391. Tournigand C, Cervantes A, Figer A et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-Go fashion in advanced colorectal cancer--a GERCOR study. J Clin Oncol. 2006; 24:394-400. https://pubmed.ncbi.nlm.nih.gov/16421419
392. Leichman CG, Fleming TR, Muggia FM et al. Phase II study of fluorouracil and its modulation in advanced colorectal cancer: a Southwest Oncology Group study. J Clin Oncol. 1995; 13:1303-11. https://pubmed.ncbi.nlm.nih.gov/7751875
393. Sanofi-Aventis. Taxotere (docetaxel) injection concentrate prescribing information. Bridgewater, NJ; 2011 Sept.
394. Accord Healthcare, Inc. Docetaxel injection prescribing information. Durham, NC; 2011 Jun.
395. Spectrum Pharmaceuticals, Inc. Fusilev (levoleucovorin calcium) powder for injection and solution for injection prescribing information. Irvine, CA; 2011 Apr.
397. Goldberg RM, Hatfield AK, Kahn M et al. Prospectively randomized North Central Cancer Treatment Group trial of intensive-course fluorouracil combined with the l-isomer of intravenous leucovorin, oral leucovorin, or intravenous leucovorin for the treatment of advanced colorectal cancer. J Clin Oncol. 1997; 15:3320-9. https://pubmed.ncbi.nlm.nih.gov/9363861
399. Ison G, Beaver JA, McGuinn WD et al. FDA Approval: Uridine Triacetate for the Treatment of Patients Following Fluorouracil or Capecitabine Overdose or Exhibiting Early-Onset Severe Toxicities Following Administration of These Drugs. Clin Cancer Res. 2016; 22:4545-9. https://pubmed.ncbi.nlm.nih.gov/27401247
400. Bamat MK, Tremmel R, von Borstel R et al. Clinical experience with uridine triacetate for 5-FU overexposure: an update. J Clin Oncol. 2013; 31: Abstract e20592 (presented at the 2013 ASCO annual meeting).
401. Saif MW, Diasio RB. Benefit of uridine triacetate (Vistogard) in rescuing severe 5-fluorouracil toxicity in patients with dihydropyrimidine dehydrogenase (DPYD) deficiency. Cancer Chemother Pharmacol. 2016; 78:151-6. https://pubmed.ncbi.nlm.nih.gov/27278667
402. Andreica IW, Pfeifer E, Rozov M et al. Fluorouracil overdose: clinical manifestations and comprehensive management during and after hospitalization. J Hematol Oncol Pharm. 2015; 5:43-7.
403. Institute for Safe Medication Practices. Accidental overdoses involving fluorouracil infusions. ISMP Medication Safety Alert! Acute Care edition. Horsham, PA; 2015 Jun. From ISMP website. https://www.ismp.org/resources/accidental-overdoses-involving-fluorouracil-infusions
404. Daniele B, Perrone F, Gallo C et al. Oral glutamine in the prevention of fluorouracil induced intestinal toxicity: a double blind, placebo controlled, randomised trial. Gut. 2001; 48:28-33. https://pubmed.ncbi.nlm.nih.gov/11115819
405. Wellstat Therapeutics Corporation. Vistogard (uridine triacetate) oral granules prescribing information. Rockville, MD; 2017 Feb.
406. Berg D. Managing the side effects of chemotherapy for colorectal cancer. Semin Oncol. 1998; 25(Suppl 11):53-9. https://pubmed.ncbi.nlm.nih.gov/9786317
407. Van Cutsem E, Findlay M, Osterwalder B et al. Capecitabine, an oral fluoropyrimidine carbamate with substantial activity in advanced colorectal cancer: results of a randomized phase II study. J Clin Oncol. 2000; 18:1337-45. https://pubmed.ncbi.nlm.nih.gov/10715306
408. von Borstel R, O'Neil J, Bamat M. Vistonuridine: an orally administered, life-saving antidote for 5-fluorouracil (5FU) overdose. J Clin Oncol. 2009; 27: Abstract 9616 (presented at the 2009 ASCO annual meeting).
409. McEvilly M, Popelas C, Tremmel B. Use of uridine triacetate for the management of fluorouracil overdose. Am J Health Syst Pharm. 2011; 68:1806-9. https://pubmed.ncbi.nlm.nih.gov/21930638
410. Goldberg RM, Sargent DJ, Morton RF et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004; 22:23-30. https://pubmed.ncbi.nlm.nih.gov/14665611
411. André T, Boni C, Mounedji-Boudiaf L et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004; 350:2343-51. https://pubmed.ncbi.nlm.nih.gov/15175436
412. André T, Boni C, Navarro M et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009; 27:3109-16. https://pubmed.ncbi.nlm.nih.gov/19451431
413. André T, Louvet C, Maindrault-Goebel F et al. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. GERCOR. Eur J Cancer. 1999; 35:1343-7. https://pubmed.ncbi.nlm.nih.gov/10658525
414. Giacchetti S, Perpoint B, Zidani R et al. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2000; 18:136-47. https://pubmed.ncbi.nlm.nih.gov/10623704
415. de Gramont A, Figer A, Seymour M et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000; 18:2938-47. https://pubmed.ncbi.nlm.nih.gov/10944126
416. Douillard JY, Cunningham D, Roth AD et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000; 355:1041-7. https://pubmed.ncbi.nlm.nih.gov/10744089
417. Grothey A, Sargent D, Goldberg RM et al. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol. 2004; 22:1209-14. https://pubmed.ncbi.nlm.nih.gov/15051767
418. Tournigand C, André T, Achille E et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004; 22:229-37. https://pubmed.ncbi.nlm.nih.gov/14657227
419. Chiorean EG, Nandakumar G, Fadelu T et al. Treatment of Patients With Late-Stage Colorectal Cancer: ASCO Resource-Stratified Guideline. JCO Glob Oncol. 2020; 6:414-438. https://pubmed.ncbi.nlm.nih.gov/32150483
420. Van Cutsem E, Cervantes A, Nordlinger B et al. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014; 25 Suppl 3:iii1-9. https://pubmed.ncbi.nlm.nih.gov/25190710
421. André T, de Gramont A, Vernerey D et al. Adjuvant Fluorouracil, Leucovorin, and Oxaliplatin in Stage II to III Colon Cancer: Updated 10-Year Survival and Outcomes According to BRAF Mutation and Mismatch Repair Status of the MOSAIC Study. J Clin Oncol. 2015; 33:4176-87. https://pubmed.ncbi.nlm.nih.gov/26527776
433. Henry NL, Somerfield MR, Abramson VG et al. Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision Making for Early-Stage, Operable Breast Cancer: Update of the ASCO Endorsement of the Cancer Care Ontario Guideline. J Clin Oncol. 2019; 37:1965-1977. https://pubmed.ncbi.nlm.nih.gov/31206315
434. Curigliano G, Burstein HJ, Winer EP et al. De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017. Ann Oncol. 2017; 28:1700-1712. https://pubmed.ncbi.nlm.nih.gov/28838210
435. Andre F, Ismaila N, Henry NL et al. Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: ASCO Clinical Practice Guideline Update-Integration of Results From TAILORx. J Clin Oncol. 2019; 37:1956-1964. https://pubmed.ncbi.nlm.nih.gov/31150316
437. Farquhar C, Marjoribanks J, Lethaby A et al. High-dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with early poor prognosis breast cancer. Cochrane Database Syst Rev. 2016; :CD003139. https://pubmed.ncbi.nlm.nih.gov/27200512
439. Colucci G, Gebbia V, Paoletti G et al. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol. 2005; 23:4866-75. https://pubmed.ncbi.nlm.nih.gov/15939922
441. Falcone A, Ricci S, Brunetti I et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007; 25:1670-6. https://pubmed.ncbi.nlm.nih.gov/17470860
442. Souglakos J, Androulakis N, Syrigos K et al. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer. 2006; 94:798-805. https://pubmed.ncbi.nlm.nih.gov/16508637
445. Tsujimoto H, Tsukioka S, Ono S et al. Effect of leucovorin on the antitumor efficacy of the 5-FU prodrug, tegafur-uracil, in human colorectal cancer xenografts with various expression levels of thymidylate synthase. Oncol Lett. 2010; 1:973-980. https://pubmed.ncbi.nlm.nih.gov/22870097
446. PDQ Adult Treatment Editorial Board. PDQ Colon Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated 2020 Jul 31. Accessed 2020 Aug 26. https://www.cancer.gov/types/colorectal/hp/colon-treatment-pdq
447. André T, Bensmaine MA, Louvet C et al. Multicenter phase II study of bimonthly high-dose leucovorin, fluorouracil infusion, and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen. J Clin Oncol. 1999; 17:3560-8. https://pubmed.ncbi.nlm.nih.gov/10550155
10008. Grothey A, Sobrero AF, Shields AF et al. Duration of Adjuvant Chemotherapy for Stage III Colon Cancer. N Engl J Med. 2018; 378:1177-1188. https://pubmed.ncbi.nlm.nih.gov/29590544
10009. Lieu C, Kennedy EB, Bergsland E et al. Duration of Oxaliplatin-Containing Adjuvant Therapy for Stage III Colon Cancer: ASCO Clinical Practice Guideline. J Clin Oncol. 2019; 37:1436-1447. https://pubmed.ncbi.nlm.nih.gov/30986117
10010. Oxaliplatin, Leucovorin Calcium, and Fluorouracil With or Without Celecoxib in Treating Patients With Stage III Colon Cancer Previously Treated With Surgery. From ClinicalTrials.gov registry. Accessed 2020 Aug 4.
10011. André T, Vernerey D, Mineur L et al. Three Versus 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Patients With Stage III Colon Cancer: Disease-Free Survival Results From a Randomized, Open-Label, International Duration Evaluation of Adjuvant (IDEA) France, Phase III Trial. J Clin Oncol. 2018; 36:1469-1477. https://pubmed.ncbi.nlm.nih.gov/29620995
10012. Sobrero A, Lonardi S, Rosati G et al. FOLFOX or CAPOX in Stage II to III Colon Cancer: Efficacy Results of the Italian Three or Six Colon Adjuvant Trial. J Clin Oncol. 2018; 36:1478-1485. https://pubmed.ncbi.nlm.nih.gov/29620994
10013. Combination Chemotherapy After Surgery in Treating Patients With High-Risk Stage II or Stage III Colorectal Cancer. From ClinicalTrials.gov registry. Accessed 2020 Aug 4.
10014. Yoshino T, Yamanaka T, Oki E et al. Efficacy and Long-term Peripheral Sensory Neuropathy of 3 vs 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Colon Cancer: The ACHIEVE Phase 3 Randomized Clinical Trial. JAMA Oncol. 2019; https://pubmed.ncbi.nlm.nih.gov/31513248
10015. Souglakos J, Boukovinas I, Kakolyris S et al. Three- versus six-month adjuvant FOLFOX or CAPOX for high-risk stage II and stage III colon cancer patients: the efficacy results of Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) project. Ann Oncol. 2019; 30:1304-1310. https://pubmed.ncbi.nlm.nih.gov/31228203
10016. André T, Iveson T, Labianca R et al. The IDEA (International Duration Evaluation of Adjuvant Chemotherapy) Collaboration: Prospective Combined Analysis of Phase III Trials Investigating Duration of Adjuvant Therapy with the FOLFOX (FOLFOX4 or Modified FOLFOX6) or XELOX (3 versus 6 months) Regimen for Patients with Stage III Colon Cancer: Trial Design and Current Status. Curr Colorectal Cancer Rep. 2013; 9:261-269. https://pubmed.ncbi.nlm.nih.gov/24032000
10017. André T, Meyerhardt J, Iveson T et al. Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials. Lancet Oncol. 2020; 21:1620-1629. https://pubmed.ncbi.nlm.nih.gov/33271092
a. AHFS drug information 2004. McEvoy GK, ed. Fluorouracil. Bethesda, MD: American Society of Health-System Pharmacists; 2004:1000-5.
b. ASHP Injectable Drug Information. Oxaliplatin. American Society of Health-System Pharmacists; Updated 31 Jan 2020. Accessed 12 Nov 2020 https://injectables.ashp.org
Frequently asked questions
More about fluorouracil
- Check interactions
- Compare alternatives
- Pricing & coupons
- Reviews (4)
- Latest FDA alerts (4)
- Side effects
- Dosage information
- During pregnancy
- Support group
- Drug class: antimetabolites
- Breastfeeding
- En español