Fluorouracil is used for the treatment of adenocarcinoma of the colon, rectum, breast, stomach, and pancreas.205 The drug also is used as an 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 breast cancer).244,245,246,247,248,249,250
GI Cancers 
Combination Therapies for Colorectal Cancer
Leucovorin calcium and levoleucovorin calcium are used to potentiate the antineoplastic activity of, and thus improve response to, fluorouracil in the treatment of colorectal carcinoma.200,201,211,215,216,218,219,220,266,286,287,288,289,290,291,292,293,294,295,296,297,298,299,300,301,302,303,304,305,306,311,313,314,315,317,395,445 Fluorouracil is used in combination with leucovorin or levoleucovorin in an attempt to prolong survival relative to fluorouracil alone in patients with advanced disease.201,211,215,218,220,286,287,288,289,290,291,292,294,302,306,313,314,315 In vitro studies221,222,223,224,225,306 and clinical evidence215,216,218,219,220,266,286,289,292,293,294,295,296,395,397 have shown that the cytotoxicity of fluorouracil may be enhanced by reduced folates (e.g., leucovorin, levoleucovorin); it appears that elevated intracellular concentrations of reduced folates may stabilize the covalent ternary complex formed by fluorodeoxyuridylic acid, 5,10-methylenetetrahydrofolate, and thymidylate synthase, enhancing inhibition of this enzyme and thereby increasing the efficacy of fluorouracil.221,286,291,303,305,306,307,308,309,310,395 Leucovorin and levoleucovorin also may potentiate the risk of fluorouracil-induced toxicity (especially GI toxicity, including diarrhea, nausea, stomatitis, and vomiting, and, to a lesser degree, myelosuppression).214,215,217,218,266,286,289,292,293,294,295,296,311,395 (See Cautions: GI Effects.)
Combined therapy with fluorouracil and leucovorin or levoleucovorin with or without additional antineoplastic agents (e.g., oxaliplatin, irinotecan hydrochloride) has been evaluated in patients with advanced colorectal cancer in the adjuvant and metastatic settings.289,386,387,388,397,410,411,412,413,414,415,446,447
Approximately monthly combination regimens of fluorouracil and leucovorin studied in the North Central Cancer Treatment Group (Mayo/NCCTG) adjuvant study included 5-day courses of IV fluorouracil 370 mg/m2 plus IV leucovorin 200 mg/m2 daily or fluorouracil 425 mg/m2 plus leucovorin 20 mg/m2 daily; both regimens were repeated at 4- to 5-week intervals.286,289 A commonly used regimen that is administered on a weekly schedule (often referred to as the high-dose leucovorin or Roswell Park regimen), consists of fluorouracil 500 mg/m2 and leucovorin 500 mg/m2 both given IV once weekly for 6 consecutive weeks.386,388 Results from the Intergroup 0089 study have demonstrated equal efficacy between the low-dose (monthly or Mayo Clinic schedule) and the high-dose (weekly or Roswell Park schedule) leucovorin regimens; however, because of ease of use and less toxicity, the high-dose regimen is considered a preferred regimen in the adjuvant setting.386,388
A combination regimen of fluorouracil and leucovorin also has been evaluated as adjuvant treatment of colorectal cancer as a bimonthly continuous IV infusion (i.e., the LV5FU2 or deGramont regimen).390 The use of this regimen has been shown to be safer compared with the use of a direct IV injection (“bolus”) regimen of fluorouracil and leucovorin.388,390 A simplified version of the LV5FU2 regimen also has been evaluated. 391
Although combined therapy with fluorouracil and leucovorin or levoleucovorin has historically been considered the standard of care in the adjuvant or metastatic setting,289,386,387,388,397,418 use of a doublet regimen (i.e., fluorouracil, oxaliplatin, and leucovorin or levoleucovorin [FOLFOX]; fluorouracil, irinotecan, and leucovorin or levoleucovorin [FOLFIRI]; capecitabine and oxaliplatin [CapeOx; CapOx]) is the current standard of care for the adjuvant or palliative treatment of advanced colorectal cancer based on data from randomized controlled trials demonstrating improved response and prolonged survival in such patients.411,412,415,416,417,419,420,446,10008
Use of fluorouracil in combination with oxaliplatin and leucovorin as adjuvant therapy for stage III colon cancer is based principally on evidence of improved disease-free and overall survival from a multicenter, open-label, randomized study (Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer [MOSAIC]) in 2246 patients with stage II or III colon cancer who had undergone complete resection of the primary tumor.411,412,421 Eligible patients were randomized to receive a 2-day combination regimen of oxaliplatin, fluorouracil, and leucovorin (leucovorin 200 mg/m2 administered by IV infusion over 2 hours, followed by fluorouracil 400 mg/m2 administered by IV injection and fluorouracil 600 mg/m2 administered by IV infusion over 22 hours, administered for 2 consecutive days; oxaliplatin 85 mg/m2 was administered by IV infusion over 2 hours concurrently with leucovorin on the first day only) or a 2-day combination regimen of fluorouracil and leucovorin (leucovorin 200 mg/m2 administered by IV infusion over 2 hours, followed by fluorouracil 400 mg/m2 administered by IV injection and fluorouracil 600 mg/m2 administered by IV infusion over 22 hours).411 Treatment with both regimens was repeated at intervals of 2 weeks for a total of 12 cycles.411 Among patients with stage III colon cancer, treatment with the oxaliplatin/fluorouracil/leucovorin regimen was associated with higher rates of disease-free survival at 5 years and overall survival at 6 years (66 and 73%, respectively) compared with the fluorouracil/leucovorin regimen (59 and 69%, respectively).412 At a median follow-up of 9.5 years, the disease-free and overall survival benefit of oxaliplatin/fluorouracil/leucovorin in patients with stage III colon cancer was maintained (10-year disease-free and overall survival rates of 62 and 67%, respectively, with oxaliplatin/fluorouracil/leucovorin compared with 54 and 59%, respectively, with fluorouracil/leucovorin).421 Among patients with stage II disease, the oxaliplatin/fluorouracil/leucovorin regimen was associated with similar 5-year disease-free survival and 6-year overall survival as compared with the fluorouracil/leucovorin regimen.412 Disease-free and overall survival rates at 10 years also failed to show a benefit for oxaliplatin/fluorouracil/leucovorin compared with fluorouracil/leucovorin in patients with stage II disease.421 Grade 3 and 4 hematologic toxicity (neutropenia, thrombocytopenia, anemia) occurred more commonly with oxaliplatin/fluorouracil/leucovorin than with fluorouracil/leucovorin, although the incidence of febrile neutropenia was low with both regimens.411 Grade 3 and 4 GI toxicity (nausea, vomiting, diarrhea) also occurred more commonly with oxaliplatin/fluorouracil/leucovorin.411 Peripheral sensory neuropathy was reported in 92% of patients receiving oxaliplatin/fluorouracil/leucovorin compared with 16% of those receiving fluorouracil/leucovorin.411
Because the duration and severity of peripheral neuropathy appear to increase with increasing cumulative dosage of oxaliplatin,10009 the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration pooled data from 6 similarly designed prospective, randomized, controlled phase 3 studies (Cancer and Leukemia Group B/Southwest Oncology Group [CALGB/SWOG] study 80702, Short Course Oncology Treatment [SCOT], Adjuvant Chemotherapy for Colon Cancer with High Evidence [ACHIEVE], Three or Six Colon Adjuvant [TOSCA], Hellenic Oncology Research Group [HORG], IDEA France)10010,10011,10012,10013,10014,10015 to evaluate noninferiority of a shortened duration (i.e., 3 months) of adjuvant fluoropyrimidine-oxaliplatin doublet therapy compared to the standard duration of 6 months in patients with stage II or III colon cancer.10008 In this pooled analysis, 12,834 patients with stage III colon cancer received fluoropyrimidine-oxaliplatin doublet therapy with FOLFOX (i.e., FOLFOX4, modified FOLFOX6) or capecitabine in combination with oxaliplatin for 3 or 6 months.10008,10016 At the time of the initial analysis (median follow-up of 41.8 months), 3 months of fluoropyrimidine-oxaliplatin doublet therapy did not meet the noninferiority criterion for 3-year disease-free survival when compared to a duration of 6 months (74.6 versus 75.5%, respectively; hazard ratio of 1.07).10008 In a preplanned subgroup analysis based on treatment regimen, FOLFOX for a duration of 6 months was superior to a treatment duration of 3 months with an absolute difference in 3-year disease-free survival of 2.4% for patients with stage III disease.10008 Subgroup analysis based on risk of recurrence suggested that a duration of 3 months of fluoropyrimidine-oxaliplatin doublet therapy was at least equivalent to a duration of 6 months of therapy in patients with low-risk disease (stage T1-T3 and N1)10009 (hazard ratio of 1.01, which corresponded to an absolute difference in disease-free survival of 0.2% at 3 years); however, a duration of 6 months of therapy was superior to a duration of 3 months in patients with high-risk disease (stage T4 disease and/or N2)10009 (hazard ratio of 1.12, which corresponded to an absolute difference in disease-free survival of 1.7% at 3 years).10008 In patients with low-risk disease receiving FOLFOX, a duration of 3 months did not meet the noninferiority criterion for 3-year disease-free survival when compared to a duration of 6 months; however, in patients with high-risk disease, a duration of 6 months of therapy appeared to be superior to a duration of 3 months (hazard ratio of 1.2).10008 At the time of the final analysis, fluoropyrimidine-oxaliplatin doublet therapy for a duration of 3 months did not meet noninferiority criteria for 5-year disease-free survival (hazard ratio of 1.08) or overall survival (hazard ratio of 1.02) when compared to a duration of 6 months; however, in patients receiving FOLFOX, a duration of 6 months of therapy demonstrated superiority for 5-year disease-free survival (hazard ratio of 1.16), but not for overall survival (hazard ratio of 1.07), compared to a duration of 3 months of therapy.10017 The incidence of grade 3 or 4 neurosensory toxicity was substantially lower in patients receiving 3 months of fluoropyrimidine-oxaliplatin doublet therapy compared with those receiving 6 months of therapy (2.5-2.6 versus 8.9-15.9%, respectively).10008 Although the standard duration of adjuvant fluoropyrimidine-oxaliplatin doublet therapy has been 6 months, a shorter duration of therapy may be considered in certain patients based on these data.10008,10009,10017 Some clinicians state that factors that should be considered when selecting the duration of adjuvant fluoropyrimidine-oxaliplatin doublet therapy include tolerability, patient preference, patient characteristics, preexisting conditions, and other factors.10009
In a randomized phase 3 study (Gruppo Oncologico Dell'Italia Meridionale) comparing irinotecan, fluorouracil, and leucovorin combination therapy (FOLFIRI) and oxaliplatin, fluorouracil, and leucovorin combination therapy (FOLFOX4) in patients with previously untreated locally advanced or metastatic colorectal cancer, no substantial difference in overall response rate, time to progression, or overall survival was observed between the treatment groups.439 Efficacy also was similar in another phase 3 study (Groupe Coopérateur Multidisciplinaire en Oncologie [GERCOR]) comparing FOLFIRI followed by FOLFOX6 or the reverse sequence in patients with previously untreated metastatic colorectal cancer.418 In these studies, mucositis, nausea/vomiting, and alopecia occurred more frequently in patients receiving FOLFIRI, whereas thrombocytopenia and neurosensory toxicity occurred more frequently in patients receiving FOLFOX.418,439
Combined therapy with fluorouracil with leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) also has been used in patients with metastatic colorectal cancer.441,442 In a randomized clinical study (Gastrointestinal Committee of the Hellenic Oncology Research Group [HORG] study) comparing FOLFOXIRI and FOLFIRI, no substantial difference in overall response rate, time to progression, or overall survival was observed between the treatment groups;442 however, in another randomized clinical study (Gruppo Oncologico Nord Ovest [GONO]), progression-free survival and overall survival were substantially prolonged in patients receiving FOLFOXIRI compared with those receiving FOLFIRI.441 In these studies, alopecia, diarrhea, neurosensory toxicity, and neutropenia occurred more frequently in patients receiving FOLFOXIRI.441,442
Fluorouracil also has been used in combination with IV levoleucovorin given at one-half the usual dosage of leucovorin.395,397 Results from a comparative study demonstrated no substantial differences in response or tolerability between levoleucovorin and leucovorin when used in conjunction with fluorouracil for the palliative treatment of advanced colorectal cancer.395,397
IV fluorouracil also has been used in combination with orally administered leucovorin in a limited number of patients with advanced colorectal cancer.289,397
Monotherapy of Colorectal Cancer
Fluorouracil has been administered as monotherapy of advanced colorectal cancer in various disease regimens.218,266,286,292,294,295,296,300,304,305,446 However, these regimens have been replaced by the use of fluorouracil and leucovorin combination regimens in the adjuvant setting for patients with stage III disease.388,446
Hepatic Metastases
Fluorouracil also has been studied as a form of regional adjuvant therapy (e.g., portal vein or hepatic artery infusion) of liver metastases associated with colon cancer†; however, the potential role of this drug in this setting remains to be more fully elucidated.230,253,256,258,259,264,275,280,446
Breast Cancer
Outcome may be improved when fluorouracil is used as an adjunct to surgery in certain women with breast cancer.244,245,246,247,248,249,250,251,254,270,271,272 Combination chemotherapy (e.g., cyclophosphamide, methotrexate, and fluorouracil [CMF]) used as an adjunct to surgery has been shown to increase both disease-free (i.e., decreased recurrence) and overall survival in premenopausal and postmenopausal women with node-negative or -positive early (TNM stage I or II) breast cancer.244,246,247,249,251,269,270,271,272,279,319,320,321,322,323,324,325,326,327,328 Adjuvant therapy with such combination chemotherapy in both premenopausal and postmenopausal women has been associated with prolongation of disease-free survival and reduction of local, regional, and distant metastases, with tolerable adverse effects.244,245,246,247,248,249,250,251,254,270,271,272,275
In patients with hormone receptor-positive early-stage breast cancer, the American Society of Clinical Oncology (ASCO) and other experts state that the decision regarding use of adjuvant endocrine therapy with or without sequential combination chemotherapy may be guided by prognostic tools, such as the recurrence score based on 21-gene assay results, to predict the absolute benefits of combination chemotherapy in addition to adjuvant endocrine therapy.433 In patients with node-negative disease, use of adjuvant endocrine therapy with or without sequential combination chemotherapy should be individualized based on consideration of the risk of recurrent disease without such adjuvant therapy, the expected reduction in risk of recurrence and improvement in quality of life with such adjuvant therapy, and the potential adverse effects of such therapy.244,246,251,272,275,433,321 Some experts state that adjuvant endocrine therapy with sequential chemotherapy may be considered in patients with early-stage, hormone receptor-positive, human epidermal growth factor receptor type 2 (HER2)-negative, node-negative breast cancer whose tumors have recurrence scores greater than 30 based on 21-gene assay results and in those who are 50 years of age or younger with recurrence scores of 16-25.435 Patients with hormone receptor-positive, HER2-negative, node-negative breast cancer and poor prognosis may be suitable candidates for adjuvant chemotherapy.433 Although patients with early-stage hormone receptor-positive breast cancer whose tumors have low recurrence scores and limited to no nodal involvement have a favorable prognosis with or without chemotherapy,434 pooled analysis of a large number of randomized studies319 and other evidence244,251 have shown that effective adjuvant combination chemotherapy can increase both disease-free and overall survival in patients with node-negative disease, albeit less markedly than in those with node-positive disease.244,319
In patients with node-positive early breast cancer, an effective regimen of adjuvant combination chemotherapy (e.g., CMF; cyclophosphamide, doxorubicin, and fluorouracil; cyclophosphamide and doxorubicin with or without tamoxifen) is used to reduce the rate of recurrence and improve survival in both premenopausal and postmenopausal patients once treatment to control local disease (surgery, with or without radiation therapy) has been undertaken.244,319,320,321,322,323,324,325,326 These combinations have demonstrated superiority compared to single-agent therapy with conventional agents.244,319,320,321,322,323,324,325 Although long-term (e.g., 6 months or longer) chemotherapy with adjuvant regimens is clinically superior to short-term (e.g., preoperative and perioperative) adjuvant regimens, clinical superiority between 6- versus 12-month regimens has not been demonstrated.244,319 The dose intensity of adjuvant combination chemotherapy also appears to be an important factor influencing clinical outcome in patients with early node-positive breast cancer, with response increasing with increasing dose intensity; therefore, arbitrary reductions in dose intensity should be avoided.244,322 In a pooled analysis of 14 randomized controlled trials involving 5600 women with early-stage breast cancer and a high risk of recurrence (involvement of multiple local lymph nodes) receiving high-dose chemotherapy followed by autologous transplantation (bone marrow or stem cell) or conventional chemotherapy without autologous transplantation, high-dose chemotherapy followed by autologous transplantation was associated with an increased risk of treatment-related mortality and little or no increase in survival.437
Fluorouracil also is used in the treatment of more advanced forms of breast cancer, including inoperable cancer.244 In stage III (locally advanced) breast cancer, combination chemotherapy (with or without hormonal therapy) is used sequentially following surgery and radiation therapy for operable disease and following biopsy and radiation therapy for inoperable disease; commonly employed effective regimens include cyclophosphamide, methotrexate, and fluorouracil; cyclophosphamide, doxorubicin, and fluorouracil; and cyclophosphamide, methotrexate, fluorouracil, and prednisone.244 These and other regimens also have been used in the treatment or more advanced (stage IV) and recurrent disease.244
Fluorouracil alone has been reported to cause temporary objective remissions in patients with metastatic breast cancer; approximately 10-35% of patients respond. Response is improved in patients with metastatic disease when fluorouracil is used in combination with other antineoplastic agents. While continuous maintenance combination chemotherapy that included fluorouracil has been shown to delay disease progression after initial response or stabilization with induction therapy in women with metastatic disease and may improve quality of life, continuous maintenance therapy has not been shown to prolong overall survival compared with intermittent reinduction therapy that is initiated at the time of progression.276,277,278,279
Esophageal Cancer
Fluorouracil has been used alone330,334,336 and in combination therapy249,329,330,331,334,336 for the treatment of localized or advanced esophageal cancer†.
For the treatment of localized esophageal cancer, combined modality treatment consisting of combination chemotherapy with fluorouracil and cisplatin and concurrent radiation therapy may be used prior to surgery (as neoadjuvant therapy) or as an alternative to surgery (i.e., in patients who are not considered suitable surgical candidates or in an attempt to avoid perioperative mortality [less than 10%] and to relieve dysphagia).329,330,331,332,333 Combined modality therapy consisting of combination chemotherapy with fluorouracil and cisplatin and concurrent radiation therapy is more effective than radiation therapy alone in patients with localized esophageal carcinoma.330,331,333 Although the comparative benefit of combined chemotherapy and radiation versus surgery has not been established, some experts recommend combined modality treatment with combination chemotherapy (e.g., fluorouracil and cisplatin) and concurrent radiation therapy with or without surgery as primary treatment for localized, resectable esophageal cancer.275,329,333,338 (See Uses: Esophageal Cancer, in Cisplatin 10:00.)
For the palliative treatment of metastatic (local or distant) disease or recurrent or locally advanced esophageal disease that is not amenable to surgery or radiation therapy, fluorouracil is used in combination chemotherapy with cisplatin,249,329,331,334,336 and such combined therapy is considered a regimen of choice.249,329,336
Head and Neck Cancer
Fluorouracil has been used in combination chemotherapy for the treatment of metastatic or recurrent squamous cell carcinoma of the head and neck†.349 Fluorouracil alone produces poor response rates (13-15%) in patients with advanced head or neck cancer;349,350 however, fluorouracil has a synergistic antitumor effect when used in combination with cisplatin.349 Combination chemotherapy with fluorouracil and cisplatin is commonly used for the palliative treatment of recurrent or metastatic head and neck cancer.249,350,351 (See Uses: Head and Neck Cancer in Cisplatin 10:00.)
Chemotherapy also has been administered in combination with radiation therapy for the palliative treatment of head and neck cancer in patients with locally advanced disease that is unresectable.337 Combination chemotherapy with fluorouracil and cisplatin administered in rapidly alternating sequence with radiation therapy has been shown to prevent local recurrence of tumor and prolong survival compared with radiation therapy alone in patients with unresectable locally advanced head and neck cancer.352,353 The use of chemotherapy combined with radiation therapy also is being investigated for larynx preservation; in 2 large randomized trials, patients receiving induction chemotherapy with fluorouracil and cisplatin followed by radiation therapy had similar survival rates as patients receiving laryngectomy and radiation therapy for locally advanced laryngeal or hypopharyngeal cancer.354,355,356,357 Induction chemotherapy with fluorouracil, cisplatin, and docetaxel also has been used prior to radiotherapy or chemoradiotherapy for the treatment of locally advanced squamous cell carcinoma of the head and neck.393,394 (See Uses: Head and Neck Cancer, in Docetaxel 10:00.)
Cervical Cancer
Fluorouracil in combination with cisplatin has been used concurrently with radiation therapy for the treatment of invasive cervical cancer†.249,359,360,361,362,364 Fluorouracil also has been used in the treatment of metastatic or recurrent cervical cancer†.249,365,366,367,369,370,371 (See Uses: Cervical Cancer in Cisplatin 10:00 for an overview of therapy for cervical cancer.)
Concurrent Chemotherapy and Radiation Therapy for Invasive Cervical Cancer
Fluorouracil is used in combination with cisplatin for concurrent chemotherapy and radiation therapy in patients with invasive cervical cancer (FIGO stages IB2 through IVA cervical cancer or FIGO stage IA2, IB, or IIA cervical cancer with poor prognostic factors, such as metastatic disease in pelvic lymph nodes, parametrial disease, or positive surgical margins, identified at the time of primary surgery),359,360,361,362,364 but randomized controlled studies are needed to determine if this combination regimen is superior to cisplatin alone.359,363,368,373 Results from one randomized trial suggest that cisplatin alone is as effective but less toxic than cisplatin-containing combination regimens for concomitant use with radiation therapy for the treatment of locally advanced cervical cancer.361,363
Chemotherapy for Metastatic or Recurrent Cervical Cancer
Response rates of about 10-20% have been reported with the use of fluorouracil alone or with leucovorin in advanced cervical cancer†.365,369 An overall response rate of 14% was observed in a small uncontrolled phase II study of patients receiving fluorouracil and leucovorin for recurrent adenocarcinoma of the cervix.367 The benefit of combination therapy with fluorouracil and cisplatin compared with cisplatin alone for metastatic or recurrent cervical cancer has not been established.370,371 Fluorouracil also has been used concurrently with radiation therapy for the treatment of recurrent pelvic disease following radical surgery for invasive cervical cancer.364,372 Further study is needed to define the role of fluorouracil in the treatment of advanced cervical cancer.365,366,367,368
Renal Cell Carcinoma
Fluorouracil 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†. Fluorouracil alone has minimal activity in the treatment of metastatic renal cell carcinoma with response rates of about 5-7% in phase II studies.374 Fluorouracil also has been used in combination with aldesleukin and/or interferon alfa for the treatment of metastatic renal cell carcinoma.375,376,377,378,379,380,381,382,383,384 Because of variable efficacy and/or greater toxicity reported with such regimens,378,379,380,382,383,384 further study is required to establish the role of fluorouracil in combination therapy for the treatment of metastatic renal cell carcinoma.385 (See discussion of fluorouracil in combination regimens in Uses: Renal Cell Carcinoma in Aldesleukin 10:00 and Interferon Alfa 10:00.)
Other Uses
Fluorouracil has been used as second-line therapy in the treatment of ovarian epithelial cancer†, including platinum-refractory disease.241 Fluorouracil also is used in the treatment of carcinoid tumors† and cancers of the liver† and biliary tract†.249 The optimal effectiveness and sequence of combination therapy of fluorouracil with other antineoplastic agents or with irradiation requires further investigation, and it should be kept in mind that any form of therapy that adds to the stress of the patient, interferes with nutrition, or depresses bone marrow function will increase fluorouracil toxicity.
For the use of fluorouracil in the treatment of actinic keratosis, see 84:92.
Administration
Fluorouracil is administered IV.205 Care should be taken to avoid extravasation of the drug. The usual injection formulation need not be further diluted. The 2.5- or 5-g pharmacy bulk package of fluorouracil is intended for preparation of individual doses of the drug and is not for direct IV infusion; after the vial has been entered, any unused portion should be discarded within 4 hours.205 An established IV line should be used to administer fluorouracil by direct IV injection.205 For IV infusion regimens, the drug should be administered via a central venous catheter using a controlled-infusion device (e.g., pump).205 Fluorouracil also has been infused regionally 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 For topical administration of fluorouracil, see 84:92..
Dosage
General Dosage
Dosage of fluorouracil is based on the patient's actual weight unless the patient is obese or has fluid retention. In these latter instances, dosage is based on ideal weight. Dosage also can be calculated according to 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
Various dosage schedules for fluorouracil therapy have appeared in literature. Dosage and dosage schedules of fluorouracil should be individualized based on the tumor type, specific regimen, clinical response, and concomitant comorbidities.205 Clinicians should consult published protocols for the dosage of fluorouracil and other chemotherapeutic agents and the method and sequence of administration.
Colorectal Cancer
If fluorouracil is administered by direct IV injection in combination with leucovorin or levoleucovorin for the treatment of adenocarcinoma of the colon and rectum, the manufacturers of fluorouracil recommend a dosage of 500 mg/m2 on days 1, 8, 15, 22, 29, and 36 of each 8-week cycle.205
If fluorouracil is administered by IV infusion in combination with leucovorin or levoleucovorin (with or without oxaliplatin or irinotecan) for the treatment of adenocarcinoma of the colon and rectum, the manufacturers of fluorouracil recommend a dosage of 400 mg/m2 by direct IV injection on day 1 followed by 2400-3000 mg/m2 by continuous IV infusion over 46 hours every 14 days.205
Monthly Direct IV Injection (“Bolus”) Schedule (Mayo Clinic Regimen)
A monthly regimen administered by direct IV injection is leucovorin 20 mg/m2 IV or an equivalent dose of levoleucovorin (10 mg/m2 IV) followed by IV fluorouracil 425 mg/m2; fluorouracil and either leucovorin or levoleucovorin are administered daily for 5 consecutive days.286,289,386,388,395 The regimen is repeated at 4-week intervals for 2 additional courses; thereafter, the regimen may be repeated at intervals of 4-5 weeks provided toxicity from the previous course has resolved completely.286,289,386,388,395 This regimen is frequently administered for a total of 6 cycles in the adjuvant setting.386,388
Alternatively, leucovorin 200 mg/m2 or an equivalent dose of levoleucovorin (100 mg/m2) may be administered by slow IV injection (over a minimum of 3 minutes) and followed by IV fluorouracil 370 mg/m2; fluorouracil and either leucovorin or levoleucovorin are administered daily for 5 consecutive days.286,395,397 The regimen is repeated at 4-week intervals for 2 additional courses; thereafter, the regimen may be repeated at intervals of 4-5 weeks provided toxicity from the previous course has resolved completely.286,395,397
Weekly IV Infusion Schedule (Roswell Park Regimen)
A weekly regimen administered by IV infusion is leucovorin 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 Both drugs are administered weekly for 6 consecutive weeks followed by a 2-week rest; cycles are repeated every 8 weeks for a total of 4 courses in the adjuvant setting. 386,388
Combination Therapy with Oxaliplatin
Combined therapy with fluorouracil, oxaliplatin, and leucovorin is administered over 2 consecutive days.411,446 On day 1, oxaliplatin 85 mg/m2 and leucovorin 200 mg/m2 are administered concurrently (in separate containers using a Y-type administration set) by IV infusion over 2 hours.411,446 Fluorouracil 400 mg/m2 then is administered by direct IV injection followed by fluorouracil 600 mg/m2 administered as an IV infusion over 22 hours.411,446 On day 2, leucovorin 200 mg/m2 is administered by IV infusion over 2 hours, followed by fluorouracil 400 mg/m2 administered by direct IV injection and then fluorouracil 600 mg/m2 administered as an IV infusion over 22 hours.411,446 This regimen is repeated every 2 weeks.411
Combined therapy with fluorouracil, oxaliplatin, and leucovorin also has been administered as 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 of each 2-week cycle.446
Combination Therapy with Irinotecan
When fluorouracil is administered in combination with leucovorin and irinotecan for the treatment of colorectal cancer, irinotecan 180 mg/m2 and leucovorin 400 mg/m2 are 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 of each 2-week cycle.418,446
Combination Therapy with Oxaliplatin and Irinotecan
When fluorouracil is administered in combination with leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) for the treatment of colorectal cancer, irinotecan 165 mg/m2 is administered 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 of each 2-week cycle.441,446
Dosage Modification for Mayo Clinic and Roswell Park Regimens
Dosage of fluorouracil in subsequent courses of therapy should be adjusted according to patient tolerance of the prior treatment course;286,395 dosage of leucovorin or levoleucovorin in subsequent courses is not adjusted because of toxicity.286,395 Daily fluorouracil dosage generally is reduced by 20% in patients who experienced moderate hematologic or GI toxicity in the prior course and by 30% in those patients who experienced severe toxicity.266,286,289,395 For patients who experienced no toxicity in the prior course of therapy, the dosage of fluorouracil may be increased by 10%.286,395 Other combination dosage regimens also have been used.215,220,266,289,296,298,304,305,317 (See Uses: Combination Therapies for GI Cancers.)
Bimonthly Infusion Schedule (Modified deGramont Regimen)
A simplified version of the LV5FU2 regimen (deGramont regimen) consists of leucovorin 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., a total of 3000 mg/m2 by continuous IV infusion over 46 hours);391 cycles are repeated every 2 weeks.391
Breast Cancer
Various fluorouracil-containing combination chemotherapy regimens have been used in the treatment of breast cancer, and published protocols should be consulted for dosages and the method and sequence of administration.246,269,271,272,320,321,322,323,324,325,326,328 The dose intensity of adjuvant combination chemotherapy appears to be an important factor influencing clinical outcome in patients with early node-positive breast cancer, with response increasing with increasing dose intensity; therefore, arbitrary reductions in dose intensity should be avoided.244,322
When fluorouracil is combined with a cyclophosphamide-based regimen for the treatment of breast cancer, the manufacturers of fluorouracil recommend a dosage of 500 or 600 mg/m2 IV on days 1 and 8 of each 28-day cycle for a total of 6 cycles.205
One commonly employed regimen for the treatment of early breast cancer includes a fluorouracil dosage of 600 mg/m2 IV on days 1 and 8 of each cycle combined with cyclophosphamide 100 mg/m2 orally on days 1 through 14 of each cycle and methotrexate 40 mg/m2 IV on days 1 and 8 of each cycle.320,321 In patients older than 60 years of age, the initial fluorouracil dosage was reduced to 400 mg/m2 IV and the initial methotrexate dosage was reduced to 30 mg/m2 IV.321 Dosage also was reduced if myelosuppression developed.320,321 Cycles generally were repeated monthly (i.e., allowing a 2-week rest period between cycles) for a total of 6-12 cycles (i.e., 6-12 months of therapy).320,321 Clinical superiority between 6- versus 12-month regimens has not been demonstrated.244,319
There is some evidence that the addition of doxorubicin to a regimen of cyclophosphamide, methotrexate, and fluorouracil can improve outcome further in patients with early breast cancer and more than 3 positive axillary lymph nodes,323 and that sequential (i.e., administering several courses of doxorubicin first) regimens are more effective than alternating regimens in such patients;323 in patients with fewer positive nodes, no additional benefit from doxorubicin has been demonstrated.323,326 In the sequential regimen, 4 doses of doxorubicin hydrochloride 75 mg/m2 IV were administered initially at 3-week intervals followed by 8 cycles of fluorouracil 600 mg/m2 IV, cyclophosphamide 600 mg/m2 IV, and methotrexate 40 mg/m2 IV at 3-week intervals for a total of approximately 9 months of therapy.323,328 If myelosuppression developed with this sequential regimen, the subsequent cycle generally was delayed rather than reducing dosage.323,328
Gastric Cancer
When fluorouracil is combined with a platinum-based regimen for the treatment of gastric adenocarcinoma, the manufacturers of fluorouracil recommend a dosage of 200-1000 mg/m2 as a continuous IV infusion over 24 hours.205 Clinicians should consult published protocols for the frequency of fluorouracil dosing and duration of each cycle for the specific regimen.205
Pancreatic Cancer
When fluorouracil is used in combination with leucovorin or as a component of a multidrug regimen that includes leucovorin for the treatment of pancreatic adenocarcinoma, the manufacturers of fluorouracil recommend a dosage of 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.205
Dosage Modification for Toxicity
If grade 3 or 4 diarrhea or mucositis, grade 4 myelosuppression, or grade 2 or 3 palmar-plantar erythrodysesthesia (hand-foot syndrome) occurs, fluorouracil should be withheld.205 When the toxicity has resolved or improved to grade 1, fluorouracil may be resumed at a reduced dosage.205
Fluorouracil should be temporarily withheld 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.205 Therapy with the drug also should be withheld if hyperammonemic encephalopathy or neurologic effects (i.e., acute cerebellar syndrome, confusion, disorientation, ataxia, visual disturbance) develop.205 The manufacturers state that there is no recommended dosage for resumption of fluorouracil therapy following development of cardiotoxicity, hyperammonemic encephalopathy, or neurologic effects.205
The major toxic effects of fluorouracil are on the normal, rapidly proliferating tissues particularly of the bone marrow and lining of the GI tract.
GI Effects
Anorexia and nausea are common adverse effects of fluorouracil, and vomiting occurs frequently. These reactions generally occur during the first week of therapy, can often be alleviated by antiemetics, and generally subside within 2 or 3 days following therapy. Mucositis, stomatitis, and esophagopharyngitis and subsequent mucosal sloughing or ulceration also may occur during fluorouracil therapy; these adverse effects have been reported more frequently in patients who received fluorouracil by direct IV injection than in those who received the drug by continuous IV infusion.205 Stomatitis is one of the most common and often the earliest sign of specific toxicity, appearing as early as the fourth day but more commonly on the fifth to eighth day of therapy. Diarrhea, which occurs frequently and may be severe, usually appears slightly later than stomatitis, but may occur concurrently or even in the absence of stomatitis. Esophagitis, proctitis, and GI ulceration and bleeding have been reported, and paralytic ileus occurred in two patients who received excessive dosage. Patients must be closely monitored for adverse GI effects. (See Cautions: Precautions and Contraindications.)
GI toxicities (particularly stomatitis and diarrhea) occur more frequently and may be more severe or prolonged in patients receiving leucovorin or levoleucovorin concomitantly with fluorouracil.214,215,216,217,286,395 A GI syndrome characterized by progression from mild GI symptoms to potentially fatal enterocolitis has been reported in several studies in patients with advanced colorectal carcinoma receiving combined therapy with the drugs; in these studies, adverse GI effects (e.g., severe diarrhea) were the dose-limiting toxicity.215,216,217 In one comparative study, severe (grade 3 or 4) diarrhea or stomatitis occurred in 18.9 or 8.6%, respectively, of patients receiving IV levoleucovorin (100 mg/m2), 15.7 and 11.2%, respectively, of those receiving oral leucovorin (500 mg/m2 in 4 divided doses), and 17.6 and 14.2%, respectively, of those receiving IV leucovorin (200 mg/m2) concomitantly with fluorouracil.397 In one study, severe or exacerbated diarrhea occurred in 25 or 13% of patients receiving fluorouracil combined with high- (500-mg/m2 doses) or low- (25-mg/m2 doses) dose leucovorin, respectively.214 In another study, diarrhea required dose reduction in 50% of patients receiving fluorouracil and high-dose leucovorin.214 Death occurred in several geriatric patients who developed severe diarrhea, with or without nausea and vomiting, and subsequent dehydration during combined therapy.213,214,215,217 Limited data suggest that once-weekly administration of fluorouracil plus leucovorin may be associated with a higher risk of developing serious adverse GI effects than 5-day regimens administered at approximately monthly intervals.214,215,286,289 Severe diarrhea appears to be the dose-limiting toxicity associated with once-weekly administration of the combination,215,275,289 while diarrhea and/or mucositis appear to be the dose-limiting toxicities associated with the 5-day regimens.275,289,294 GI bleeding also has been associated with such fatal toxicity in some patients,217 and neutropenia, fever, sepsis (possibly related to disruption of the GI mucosa), and acute renal failure also were present in some but not all of the patients who died.213,214,217 Autopsy findings in 2 patients revealed evidence of enterocolitis, including hemorrhagic enterocolitis in one, as well as erosions of the gastric mucosa.214 In a patient who developed hypotension and abdominal pain and tenderness during combined fluorouracil and leucovorin therapy, there was histologic evidence of ileitis, duodenitis, and esophageal ulceration; the patient responded to hydration, parenteral nutrition, transfusions, and anti-infective therapy.214,220
Combined therapy with fluorouracil and a reduced folate (leucovorin or levoleucovorin) should not be initiated or continued in patients with symptomatic GI toxicity until such symptoms have completely resolved.215,286,289,395 Fluorouracil dosage reduction may be necessary in patients who develop adverse GI effects,214,215,216,217 particularly in geriatric patients.217 Close monitoring is particularly important in patients who develop diarrhea with such combined therapy since rapid clinical deterioration and death can occur.214,286,315,395
Hematologic Effects
Myelosuppression (e.g., neutropenia, thrombocytopenia, anemia), sometimes severe or fatal, may occur during fluorouracil therapy.205 Leukopenia, predominantly of the granulocytopenic type, thrombocytopenia, and anemia occur commonly with fluorouracil therapy; leukopenia usually occurs after an adequate course of fluorouracil therapy. Pancytopenia and agranulocytosis also have occurred. (See Cautions: Precautions and Contraindications.) The patient's hematologic status must be carefully monitored. The nadir neutrophil count usually occurs from the ninth to the fourteenth day after therapy is initiated205 but may occur as late as the 25th day after the first dose of fluorouracil. Maximum thrombocytopenia has been reported to occur from the seventh to seventeenth day of therapy. Hematopoietic recovery is usually rapid and by the thirtieth day, blood cell counts have usually reached the normal range.
Dermatologic and Sensitivity Reactions
Hair loss occurs frequently with fluorouracil therapy, and cosmetically significant alopecia has occurred in a substantial number of patients. Regrowth of hair has been reported even in patients receiving repeated courses of the drug. Partial loss of nails has occurred rarely, and diffuse melanosis of the nails has been reported. The most common type of dermatologic toxicity is a pruritic maculopapular rash which usually appears on the extremities and less frequently on the trunk. This rash is generally reversible and usually responsive to symptomatic treatment.
Palmar-plantar erythrodysesthesia (commonly referred to as hand-foot syndrome), an erythematous, desquamative rash involving the hands and feet, has been reported in patients receiving fluorouracil.201,205,206 Hand-foot syndrome has been reported more frequently in patients who received fluorouracil by continuous IV infusion than in those who received the drug by direct IV injection.205 Hand-foot syndrome also has been reported more frequently in patients who have previously received chemotherapy.205 The rash may be accompanied by a tingling sensation, pain, swelling, desquamation, and erythema with tenderness.205 Hand-foot syndrome generally occurs within 8-9 weeks of initiation of fluorouracil.205 Hand-foot syndrome may be treated with oral pyridoxine therapy.406,407
Other dermatologic manifestations of fluorouracil toxicity have included dry skin and fissuring, diffuse erythema, and scaling. Exposure to strong sunlight may intensify skin reactions to the drug. Seborrheic dermatitis has been reported in a few patients, but could not always be definitely attributed to fluorouracil.
Photosensitivity manifested by erythema or increased pigmentation can occur with fluorouracil therapy. Anaphylaxis205,210 and generalized allergic reactions205 have occurred in patients receiving fluorouracil.
Nervous System Effects
Disorientation, confusion, ataxia, visual disturbances, and acute cerebellar syndrome have occurred in patients receiving fluorouracil.205 There are insufficient data on the risks of resuming fluorouracil after resolution of neurologic adverse effects.205
Hyperammonemic encephalopathy, in the absence of liver disease or other identifiable cause, also has occurred in patients receiving fluorouracil.205 Manifestations of hyperammonemic encephalopathy, including altered mental status, confusion, disorientation, ataxia, or coma in the presence of elevated serum ammonia concentrations, may begin within 72 hours following initiation of fluorouracil infusion.205
Ocular Effects
Lacrimation, dacryostenosis, visual changes, and photophobia have been reported in patients receiving fluorouracil.205
Cardiovascular Effects
Myocardial ischemia/infarction,205,207,208 heart failure,205 arrhythmias,205 and angina205,207,208,209 (including Prinzmetal variant angina)209 have occurred in patients receiving fluorouracil. The exact mechanism(s) is not known, but the drug may cause these effects by inducing coronary artery vasospasm.208,209 Administration of fluorouracil by continuous IV infusion and presence of coronary artery disease have been reported to increase the risk of cardiotoxicity.205 Safety of resuming fluorouracil after resolution of cardiotoxicity has not been established.205
Other Adverse Effects
Fever that occurred during the end of the second week following the first dose of fluorouracil, and which usually was not accompanied by demonstrable infection, has been reported. Epistaxis, thrombophlebitis, and vein pigmentation also have been reported.
Precautions and Contraindications
Fluorouracil is a highly toxic drug with a very low therapeutic index. The drug can produce severe hematologic toxicity, GI hemorrhage, and even death. Fluorouracil should be given only by, or under the supervision of, a clinician who is experienced in cancer chemotherapy and in the use of antimetabolites.
If intractable vomiting occurs, fluorouracil should be immediately discontinued. Patients should be questioned and the mouth examined daily for early evidence of stomatitis. Appearance of stomatitis, as evidenced by either oral mucosal erythema or ulceration at the inner margin of the lips, or of esophagopharyngitis as evidenced by a sore throat or dysphagia, necessitates cessation of therapy. Diarrhea necessitates immediate discontinuance of the drug. GI ulceration or bleeding, or hemorrhage at any site, also requires prompt cessation of treatment.
If angina, myocardial infarction or ischemia, arrhythmia, or heart failure develops in patients without a history of coronary artery disease or cardiac dysfunction, therapy with fluorouracil should be interrupted.205 Patients experiencing new-onset angina, shortness of breath, dizziness, or lightheadedness should promptly inform their clinician or seek emergency treatment.205
Since leucovorin calcium and levoleucovorin calcium enhance the toxicity of fluorouracil, combined therapy with fluorouracil and either leucovorin or levoleucovorin should be used with extreme caution in geriatric or debilitated patients since such patients are more likely to develop serious toxicity from fluorouracil.214,286,395 If grade 3 or 4 diarrhea or mucositis occurs, therapy with fluorouracil should be interrupted until diarrhea or mucositis resolves or decreases in intensity to grade 1.205 If diarrhea occurs, fluid and electrolyte replacement or an antidiarrheal agent should be initiated as clinically necessary.205
Complete blood cell counts (CBCs) should be performed prior to each treatment cycle, weekly (if administered on a weekly or similar schedule), and as clinically indicated.205 Leukocyte counts with differential should be made before each dose of fluorouracil is given and if the leukocyte count falls to below 3500/mm3 or decreases rapidly, or if there is a fall in the platelet count to below 100,000/mm3, the drug should be discontinued. If the leukocyte count drops to less than 2000/mm3, the patient should be placed in protective isolation and appropriate measures taken for the prevention of infection. If grade 4 myelosuppression occurs, administration of fluorouracil should be interrupted until the toxicity resolves or decreases in intensity to grade 1.205
If grade 2 or 3 hand-foot syndrome occurs, administration of fluorouracil should be interrupted until the toxicity resolves or decreases in intensity to grade 1.205 Topical emollients (e.g., hand creams, udder balm)406,407 or oral pyridoxine therapy406,407 may ameliorate the manifestations of hand-foot syndrome in patients receiving fluorouracil.205
If hyperammonemic encephalopathy or neurologic effects occur, therapy with fluorouracil should be interrupted.205 Patients experiencing new-onset confusion, disorientation, visual disturbances, or difficulty with balance or coordination should promptly inform their clinician or seek emergency treatment.205
Fluorouracil should be withheld or permanently discontinued in patients experiencing acute early-onset or unusually severe toxicity, which may indicate near-complete or total absence of dihydropyrimidine dehydrogenase (DPD) activity.205 Patients with certain homozygous or certain compound heterozygous mutations in the DPD gene resulting in complete or near complete absence of DPD activity are at increased risk for acute early-onset toxicity and severe, life-threatening, or fatal toxicity (e.g., mucositis, diarrhea, neutropenia, neurotoxicity); patients with partial DPD activity also may be at increased risk for severe, life-threatening, or fatal toxicity.205 The manufacturer states that safety of fluorouracil in patients with complete absence of DPD activity has not been established; there are insufficient data to support dosage recommendations for those with partial DPD activity.205 Patients should be advised to inform their clinician if they are known to have deficient DPD activity.205
Results of animal studies suggest that fluorouracil may impair female and male fertility.205
Pediatric Precautions
Safety and efficacy of fluorouracil in children have not been established.205
Mutagenicity and Carcinogenicity
Fluorouracil has been shown to be mutagenic in vitro in the bacterial reverse mutation (Ames) assay and induced chromosomal aberrations in hamster fibroblasts in vitro and in the micronucleus test on mouse bone marrow cells.205 Although the risk of mutagenesis in patients receiving fluorouracil has not been evaluated, the possibility must be considered.
Carcinogenicity studies of fluorouracil have not been performed.205
Pregnancy, Fertility, and Lactation
Pregnancy
Fluorouracil may cause fetal harm when administered to pregnant women.205 The drug has been shown to be embryotoxic and teratogenic in animals at dosages lower than a human dose of 12 mg/kg.205 Fetal malformations included cleft palate, skeletal defects, and deformed appendages, paws, and tails.205 In monkeys, doses greater than an approximate human dose of 12 mg/kg resulted in abortion.205
There are no adequate and controlled studies using fluorouracil in pregnant women,205 and the drug should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective. Women of childbearing potential and males with female partners of childbearing potential should be advised to use effective contraceptive methods during fluorouracil therapy and for up to 3 months after the last dose of the drug.205 If the drug is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.205
Fertility
Following intraperitoneal administration of fluorouracil at doses greater than or equal to 1.7 times the human dose of 12 mg/kg in male rats, chromosomal aberrations in spermatogonia were induced; spermatogonial differentiation also was inhibited, resulting in transient infertility.205 Following intraperitoneal administration of fluorouracil at doses greater than or equal to 0.33 times the human dose of 12 mg/kg during the preovulatory phases of oogenesis in female rats, fetotoxicity, decreased fertile matings, and increased preimplantation loss were observed.205
Lactation
It is not known whether fluorouracil or its metabolites are distributed into milk.205 Because many drugs are distributed into human milk and because of the potential for serious adverse reactions to fluorouracil in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother.205
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. [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. 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. [PubMed 2933539]
207. Monk MR, Sanchez JD, Phelps CD et al. Myocardial ischemia with fluorouracil and floxuridine therapy. Clin Pharm . 1987; 6:659-61. [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. [PubMed 3826112]
210. Santos AM, Medina FS. Anaphylactic reaction following IV administration of 5-fluorouracil. Cancer Treat Rep . 1986; 70:1346. [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. [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-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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 2859523]
243. Gastrointestinal Tumor Study Group. Survival after postoperative combination treatment of rectal cancer. N Engl J Med . 1986; 315:1294-5. [PubMed 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. [PubMed 2644531]
246. McGuire WL. Adjuvant therapy of node-positive breast cancer. N Engl J Med . 1989; 320:525-7. [PubMed 2915655]
247. De Vita VT Jr. Breast cancer therapy: exercising all our options. N Engl J Med . 1989; 320:527-9. [PubMed 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. [PubMed 2679288]
249. Anon. Drugs of choice for cancer chemotherapy. Med Lett Drugs Ther . 2000; 42:83-92. [PubMed 10994034]
250. Anon. Adjuvant chemotherapy of early breast cancer. Med Lett Drugs Ther . 1990; 32:49-50. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 1922236]
277. Norton L. Metastatic breast cancer: length and quality of life. N Engl J Med . 1991; 325:1370-1. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 3284210]
291. Saltz L. Drug treatment of colorectal cancer: current status. Drugs . 1991; 42:616-27. [PubMed 1723364]
292. Erlichman C. Fluorouracil and leucovorin for metastatic colorectal cancer. J Chemother . 1990; 2(Suppl 1):38-40. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 2789272]
297. Erlichman C. Fluorouracil/leucovorin study update. J Clin Oncol . 1991; 9:2076. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 2783879]
302. Laufman LR, Brenckman WD Jr, Stydnicki KA et al. Clinical experience with leucovorin and 5-fluorouracil. Cancer . 1989; 63(Suppl):1031-5. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 1584260]
332. Haller DG. Treatments for esophageal cancer. N Engl J Med . 1992; 326:1629-31. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 2405491]
349. Catimel G. Head and neck cancer: guidelines for chemotherapy. Drugs . 1996; 51:73-88. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 8609658]
354. Vokes EE, Weichselbaum RR, Lippman SM et al. Head and neck cancer. N Engl J Med . 1993; 328:184-94. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 8656441]
358. Pinedo HM, Peters GFJ. Fluorouracil: biochemistry and pharmacology. J Clin Oncol . 1988; 6:1653-64. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 10334517]
363. Thomas GM. Improved treatment for cervical cancer—concurrent chemotherapy and radiotherapy. N Engl J Med . 1999; 340:1198-1200. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 3114057]
373. Eifel PJ. Concurrent chemotherapy and radiation: a major advance for women with cervical cancer. J Clin Oncol . 1999; 17:1334-5. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 8186172]
385. Bukowski RM. Natural history and therapy of metastatic renal cell carcinoma: the role of interleukin-2. Cancer . 1997; 80:1198-220. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [Web]
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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 22870097]
446. PDQ® Adult Treatment Editorial Board. PDQ Colon Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated 2020 Jul 31. Accessed 2020 Aug 26. [Web]
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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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; [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 33271092]