Generic Name: Fluorouracil
Class: Antineoplastic Agents
VA Class: AN300
Chemical Name: 5-fluoro-2,4(1H,3H)-Pyrimidinedione
Molecular Formula: C4H3FN2O2
CAS Number: 51-21-8
Only for administration by, or under the supervision of, a clinician experienced in cancer chemotherapy and the use of antimetabolites.a
Severe toxic reactions are possible; hospitalize patients, at least during initial course of therapy.205
Introduction
Pyrimidine antagonist; antimetabolite; antineoplastic agent.a
Uses for Adrucil
Cancers
Principally for GI, breast, and head and neck cancers.a b
Palliative treatment of carcinoma of the colon, rectum, anus, stomach, biliary tract, esophagus, and pancreas that is not amenable to surgery or irradiation.a b 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
Cytotoxicity may be potentiated by leucovorin; combination of fluorouracil and leucovorin, alone or with methotrexate or cisplatin, is being evaluated for treatment of advanced colorectal or advanced gastric adenocarcinomas, but additional studies are needed to determine potential advantages of combinations.200 201 202 203 204 211 212 215 216 218 219 220 230 253 262 263 265 266
Colorectal Cancer
Drug of choice (combined with leucovorin) as an adjunct to surgery for colorectal cancer.b
Drug of choice (combined with leucovorin and other drugs [e.g., irinotecan, oxaliplatin]) for metastatic colorectal cancer.b
Apparently improves prognosis (compared with resection alone) when used with levamisole (currently not commercially available in the US) as adjunct to surgery for the treatment of TNM stage III (Dukes’ stage C or modified Astler-Coller stage C1-C3) adenocarcinoma of the colon.226 227 228 229 230 231 232 233 252 253 255 256 261 280
In less advanced disease (e.g., stage II [Dukes’ stage B]), not known whether adjuvant therapy provides substantial benefit compared with surgery alone, but generally good survival rates without adjuvant therapy in node-negative disease.227 230 252 253 275 280
Efficacy is improved by adding leucovorin to adjuvant fluorouracil-containing regimens.253 261 280 281
Role of regional adjuvant therapy (e.g., portal vein or hepatic artery infusion†) for liver metastases requires further elucidation.230 253 256 257 258 259 260 264 275 280
Leucovorin calcium enhances cytotoxicity,221 286 291 303 305 306 307 308 309 310 potentiates fluorouracil antineoplastic activity, improves response for palliative 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 designated an orphan drug by FDA for use with leucovorin for metastatic colorectal adenocarcinoma.335
Leucovorin 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
Esophageal Cancer
Drug of choice for treatment of esophageal cancer†.b
Has been used alone330 334 336 and in combination therapy (e.g., with cisplatin)b 249 329 330 331 334 336 for the treatment of localized or advanced esophageal cancer†.
Gastric Cancer
Drug of choice (with or without leucovorin and/or other drugs [e.g., cisplatin, epirubicin]) for treatment of gastric cancer.b
Anal Cancer
Drug of choice (e.g., combined with mitomycin or cisplatin) for treatment of anal cancer.b
Pancreatic Cancer
Drug of choice as adjunct to surgery and for localized unresectable pancreatic cancer.b
Biliary Tract Cancer
Drug of choice (with or without leucovorin) for treatment of biliary tract cancer.b
Breast Cancer
Drug of choice combined with other drugs (e.g., cyclosphosphamide and doxorubicin or methotrexate) as an adjunct to surgery and for metastatic breast cancer.b 244 249 251 279 319 320 322 323 324 325 326 328
Palliative treatment of carcinoma of the breast not amenable to surgery or irradiation.a
Adjunct to surgery, may improve outcome.244 245 246 247 248 249 250 251 254 270 271 272
Has been used most extensively with cyclophosphamide and methotrexate, and is considered a regimen of choice.244 249 251 279 319 320 321 322 323 324 325 326 328
Head and Neck Cancer
Drug of choice combined with cisplatin for head and neck cancer†.b
In combination chemotherapy for metastatic or recurrent squamous cell carcinoma of the head and neck†.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
Cervical Cancer
Drug of choice combined with other drugs (e.g., cisplatin) for treatment of locally advanced cervical cancer†.b
In combination with cisplatin concurrently with radiation therapy for invasive cervical cancer†.249 359 360 361 362 364
Metastatic or recurrent cervical cancer†.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
Drug of choice for treatment of carcinoid tumors†.b
Other Uses
Second-line therapy in the treatment of ovarian epithelial cancer†, including platinum-refractory disease.b 241 Also, cancers of the liver† (e.g., hepatoblastoma†).b 249
Adrucil Dosage and Administration
Administration
Administer IV.a
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).a
IV Administration
2.5- or 5-g pharmacy bulk package is intended for individual dose preparation, not for direct IV infusion.a
Avoid extravasation.a
Dilution
No dilution necessary for usual injection formulation.a
Rate of Administration
Administer through a 25-gauge needle at any convenient rate.a
Dosage
Base dosage on actual weight.a
Base dosage on ideal weight if patient is obeseor has fluid retention.a
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
Base dosage on clinical and hematologic response and patient tolerance to obtain optimum results with minimum adverse effects.a
Consult published protocols for the dosage and method and sequence of administration of fluorouracil with other chemotherapeutic agents.a
Adults
Usual Dosage
IV
Initially, manufacturers recommend a course of 12 mg/kg once daily for 4 consecutive days, up to 800 mg daily; then (if toxicity does not preclude) administer 6 mg/kg on the 6th, 8th, 10th and 12th days (unless toxicity occurs before then).a
Poor risk and inadequate nutrition: initially, manufacturers suggest a course of 6 mg/kg daily for 3 days, up to 400 mg daily; then (if toxicity does not preclude) may administer 3 mg/kg on the 5th, 7th, and 9th days (unless toxicity occurs before then).a
Repeat courses: adjust schedule according to reaction to the previous course.a
Repeat course at 30-day intervals if toxicity has not been a problem.a
Alternatively, when toxicity of initial course has subsided, may administer 10–15 mg/kg (up to 1 g) once weekly for maintenance.a
Colorectal Cancer
IV
Optimum dosage for fluorouracil potentiation has not been clearly established.218 266 286 289 292 293 294 295 296 305
May administer leucovorin 20 mg/m2 IV followed by fluorouracil 425 mg/m2 daily for 5 days.286 289 293 294 295 305
Alternatively, may administer leucovorin 200 mg/m2 by slow IV injection (over a minimum of 3 minutes) followed by fluorouracil 370 mg/m2 daily for 5 days,218 275 286 289 293 294 295 305 but currently there is no evidence of superiority.294
May repeat either regimen at 4-week intervals for 2 additional courses, then at 4- to 5-week intervals provided toxicity from the previous course has subsided.286 289
Adjust fluorouracil dosage in subsequent courses according to tolerance; reduce daily fluorouracil dosage by 20% with moderate hematologic or GI toxicity in prior course and by 30% for severe toxicity (generally, leucovorin dosage is not adjusted).266 286 289
May increase fluorouracil dosage by 10% if no toxicity occurred in the prior course.286
Other combination dosage regimens also have been used.215 220 266 289 296 298 304 305 317
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
Combination Regimen: Cyclophosphamide, Methotrexate, and Fluorouracil
IV
Regimen 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 | 600 mg/m2 IV (≤60 yrs of age)320 321 | Days 1 and 8320 321 |
Cyclophosphamide | 100 mg/m2 orally320 321 | Days 1 through 14 320 321 |
Methotrexate | 40 mg/m2 IV (≤60 yrs of age)320 321 | Days 1 and 8 320 321 |
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
IV
Initially, 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
Prescribing Limits
Adults
General Dosage
IV
Initially (first 4 days), manufacturers recommend maximum of 800 mg daily.a
Poor risk and inadequate nutrition: manufacturers recommend initially (first 3 days) maximum of 400 mg daily.a
Alternative dosage for maintenance once toxicity of initial course has subsided: manufacturers recommend maximum of 1 g once weekly.a
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 Adrucil
Contraindications
Poor nutritional state.a
Depressed bone marrow function (generally a leukocyte count of ≤5000/mm3 and/or a platelet count of ≤100,000/mm3).a
Potentially serious infections.a
History of major surgery within the previous month.a
Known hypersensitivity to fluorouracil or any ingredient in the formulation.205
Warnings/Precautions
Warnings
Maximum Dosage.
Do not exceed 800 mg daily.205
Poor Risk Patients
Use extreme caution in patients with history of high-dose pelvic irradiation, previous use of alkylating agents, widespread bone marrow metastases, impaired hepatic or renal function.205
Dipyrimidine Dehydrogenase Activity Deficiency
Deficiency of dipyrimidine dehydrogenase activity may cause prolonged fluorouracil clearance and toxicity.205 348
Severe, unexpected toxic reactions (including stomatitis, diarrhea, neutropenia, and neurotoxicity) have been reported.205 348
Rechallenge with fluorouracil (at a reduced dosage) has caused recurrent, progressive toxicity and increased morbidity.205 348
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm.205
Advise women to avoid becoming pregnant.205 205
Inform women who become pregnant while taking fluorouracil that there is a potential hazard to the fetus.205
Use during pregnancy only if the potential benefit justifies the risk to the fetus.205
Combination Therapy
Any therapy that adds stress, interferes with nutrition, or depresses bone marrow function will increase fluorouracil toxicity.205
Leucovorin
Extreme caution when combined with leucovorin calcium in geriatric or debilitated patients, since they are more likely to develop serious fluorouracil toxicity.214 286 (See Interactions.)
Sensitivity Reactions
Hand-foot Syndrome
Palmar-plantar erythrodysesthesia (hand-foot syndrome); in some cases, with prolonged infusions of high dosages.201 206
Erythematous, desquamative rash that involves the hands and feet,201 206 may be accompanied by tingling or painful hands and feet, swollen palms and soles, and phalangeal tenderness.205
Effects may gradually disappear over 5–7 days after fluorouracil discontinuance.205 348
May be treated with oral pyridoxine therapy, but safety and efficacy of pyridoxine for this condition have not been fully established.205 348
General Precautions
Toxicity
Highly toxic, very low therapeutic index; therapeutic response is unlikely without some evidence of toxicity.a 205 (See Boxed Warning.)
May produce severe hematologic toxicity, GI hemorrhage, and even death.a
Severe toxicity most likely in poor risk patients, but fatality may occur even in those in relatively good condition.205
GI Toxicity
Discontinue promptly at first visible sign of stomatitis or esophagopharyngitis.205
Discontinue promptly for intractable vomiting.205
Discontinue promptly for diarrhea, frequent bowel movements, watery stools.205
Discontinue promptly for GI ulceration and bleeding.205
Hematologic Toxicity
Discontinue promptly for leukopenia (WBC < 3500/mm3) or rapidly falling WBC; place in protective isolation and take appropriate measures for prevention of infection if the leukocyte count drops to < 2000/mm3.a
Discontinue promptly for thrombocytopenia (platelets < 100,000/mm3).
Discontinue promptly for hemorrhage from any site.205
Specific Populations
Pregnancy
Category D.205 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Lactation
Not known whether fluorouracil is distributed into milk.205 Discontinue nursing while receiving the drug; fluorouracil inhibits DNA, RNA, and protein synthesis.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).a 205
Interactions for Adrucil
Specific Drugs
Drug | Interaction | Comments |
|---|---|---|
Leucovorin calcium | 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 Leucovorin enhances fluorouracil toxicity214 286 | 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 |
Adrucil Pharmacokinetics
Distribution
Extent
Distributed into tumors, intestinal mucosa, bone marrow, liver, and other tissues.a
Readily crosses the blood-brain barrier (despite limited lipid solubility), and distributes into CSF and brain tissue.a
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
Crosses the placenta in rats.205 Not known whether fluorouracil is 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
7–20% is excreted unchanged in urine within 6 hours; >90% of this in the 1st hour.a 205
Inactive metabolites are excreted as respiratory CO2 and (in urine) as urea, α-fluoro-β-alanine, α-fluoro-β-guanidopropionic acid, and α-fluoro-β-ureidopropionic acid.a
Half-life
About 16 minutes (range: 8–20 minutes) and is dose dependent; no intact drug is detected in plasma after 3 hours.a
Stability
Storage
Parenteral
Injection
Discard unused portion of 2.5 or 5 g pharmacy bulk package 1 hour after the vial has been entered.a
25°C (may be exposed to 15–30°C);348 do not freeze, protect from light.a
Slight discoloration during storage does not adversely affect potency or safety.a
Fluorouracil precipitation occurs commonly, particularly following exposure to low temperatures.274 Dissolve precipitate by heating to 60°C and shaking vigorously; cool to body temperature before using.a
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
Compatibility
For information on systemic interactions resulting from concomitant use, see Interactions.
Parenteral
Solution CompatibilityHID
Compatible |
|---|
Amino acids 4.25%, dextrose 25% |
Dextrose 5% in Ringer’s injection, lactated |
Dextrose 3.3% in sodium chloride 0.3% |
Dextrose 5% in water |
Plasmalyte 3G5 |
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 |
Cisplatin |
Cytarabine |
Diazepam |
Doxorubicin HCl |
Epirubicin HCl |
Fentanyl citrate |
Leucovorin calcium |
Metoclopramide HCl |
Morphine sulfate |
Compatible |
|---|
Allopurinol sodium |
Amifostine |
Aztreonam |
Bleomycin sulfate |
Cefepime HCl |
Cisplatin |
Cyclophosphamide |
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 |
Pemetrexed disodium |
Piperacillin sodium–tazobactam sodium |
Potassium chloride |
Propofol |
Sargramostim |
Teniposide |
Thiotepa |
Vinblastine sulfate |
Vincristine sulfate |
Vitamin B complex with C |
Incompatible |
Aldesleukin |
Amphotericin B cholesteryl sulfate complex |
Droperidol |
Gallium nitrate |
Filgrastim |
Lansoprazole |
Topotecan HCl |
Vinorelbine tartrate |
Variable |
Ondansetron HCl |
ActionsActions
Precise mechanisms of action of fluorouracil have not been fully elucidated.a
May interfere with 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
Advise patients about expected toxic effects, especially oral manifestations.a
Advise patients that alopecia is possible, but usually transient.205
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.a
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.a
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
* 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* | Adrucil | Sicor |
Fluorouracil Injection | Abraxis, Valeant | |||
50 mg/mL (2.5 or 5 g) pharmacy bulk package* | Adrucil | Sicor | ||
Fluorouracil Injection | Abraxis |
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Fluorouracil 50MG/ML Solution (APP PHARMACEUTICAL): 50/$25.99 or 100/$39.97
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions August 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
† 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. [IDIS 160753] [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 3489407]
205. Baxter. Fluorouracil injection prescribing information. Deerfield, IL; 2000 Jun..
206. Feldman LD, Ajani JA. Fluorouracil-associated dermatitis of the hands and feet. JAMA. 1985; 254:3479. [PubMed 2933539]
207. Monk MR, Sanchez JD, Phelps CD et al. Myocardial ischemia with fluorouracil and floxuridine therapy. Clin Pharm. 1987; 6:659-61. [IDIS 232518] [PubMed 2961503]
208. Burger AJ, Mannino S. 5-Fluorouracil-induced coronary vasospasm. Am Heart J. 1987; 114:433-6. [PubMed 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. [IDIS 226744] [PubMed 3826112]
210. Santos AM, Medina FS. Anaphylactic reaction following IV administration of 5-fluorouracil. Cancer Treat Rep. 1986; 70:1346. [IDIS 228496] [PubMed 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. [PubMed 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. [PubMed 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. [IDIS 236651] [PubMed 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. [PubMed 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-fl
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