Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer.

In a previous study (J Clin Oncol 7:1407-1417, 1989), we identified two dosage administration schedules of fluorouracil (5FU) combined with leucovorin that were superior to single-agent 5FU for the treatment of advanced colorectal cancer. In this same study, a regimen of 5FU plus high-dose methotrexate (MTX) demonstrated a suggestive advantage over 5FU alone. To permit a more definitive comparison, we have extended our evaluation of these three regimens to involve an additional 259 patients. In all, 457 patients with advanced colorectal cancer were randomly assigned to one of the following regimens: 5FU plus low-dose leucovorin, 5FU plus high-dose leucovorin, or 5FU plus high-dose MTX with leucovorin rescue. We have found that each of the 5FU/leucovorin regimens demonstrates a significant (P less than or equal to .01) advantage over 5FU plus high-dose MTX for objective tumor response and interval to tumor progression. Moreover, 5FU plus low-dose leucovorin confers a significant survival benefit (P less than or equal to .01) compared with 5FU plus high-dose MTX. The 5FU plus high-dose leucovorin regimen shows a survival benefit only in unadjusted analyses (P = .04), but this difference is not significant when adjusted for imbalances in prognostic variables (P = .44). Evaluation of the two 5FU/leucovorin regimens rules out a 10% decrease in death rate for the high-dose leucovorin regimen compared with the low-dose leucovorin regimen (P less than .05). The regimen of 5FU plus low-dose leucovorin has now been shown to offer a statistically significant survival advantage versus 5FU alone and versus 5FU plus high-dose MTX, a regimen that had shown promise in earlier trials. These data confirm the efficacy of leucovorin combined with 5FU in patients with advanced colorectal cancer and establish that it is not necessary to use high doses of leucovorin to achieve these results.

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Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.1989.7.10.1407 ◽

1989 ◽

Vol 7 (10) ◽

pp. 1407-1418 ◽

Cited By ~ 575

Author(s):

M A Poon ◽

M J O'Connell ◽

C G Moertel ◽

H S Wieand ◽

S A Cullinan ◽

...

Keyword(s):

Quality Of Life ◽

Colorectal Cancer ◽

Median Survival ◽

Low Dose ◽

Advanced Colorectal Cancer ◽

Performance Status ◽

Single Agent ◽

Biochemical Modulation ◽

High Dose

The purpose of this study was to evaluate the effectiveness of several new approaches designed to enhance the activity of fluorouracil (5-FU) in the management of advanced colorectal cancer. A total of 429 patients were randomized to one of the following regimens: single-agent 5-FU, given by standard 5-day, intensive-course intravenous bolus technique; 5-FU plus high-dose folinic acid (leucovorin) or 5-FU plus low-dose leucovorin; 5-FU plus high-dose methotrexate (MTX) with oral leucovorin rescue; 5-FU plus low-dose MTX; and 5-FU plus cisplatin (CDDP). The median survival for patients receiving 5-FU alone was 7.7 months. The high- and low-dose leucovorin plus 5-FU regimens had median survivals of 12.2 and 12.0 months, respectively, and offered a significant survival advantage over 5-FU alone with one-sided P values of .037 and .050, respectively (P = .051 for each treatment after correction for prognostic variables). The only other regimen possibly associated with improved survival was high-dose MTX plus 5-FU, with a median survival of 10.5 months (P = .21, P = .076 corrected). In addition, both high- and low-dose leucovorin plus 5-FU regimens were associated with significantly improved tumor response rates (P = .04 and .001) and significantly improved interval-to-tumor-progression rates (P = .015 and .007) when compared with 5-FU alone. Only the low-dose leucovorin plus 5-FU regimen was associated with significant (P less than .05) superiority in each of the following parameters of quality of life: performance status, weight gain, and symptomatic relief. The overall most therapeutically favorable regimen in this trial was 5-FU given with low-dose leucovorin; fortuitously, this regimen is associated with very low drug cost. Whereas this is the first study to demonstrate both improved palliation and survival for any regimen compared with 5-FU given by rapid intravenous (IV) injection for 5 consecutive days at a dose of 500 mg/m2/d in patients with advanced colorectal cancer, the magnitude of the gain is still relatively small. Our low-dose leucovorin plus 5-FU regimen is currently being studied in a national trial with the hope that this increased advanced disease activity may produce more substantive gains in the surgical adjuvant setting.

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Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1994.12.1.14 ◽

1994 ◽

Vol 12 (1) ◽

pp. 14-20 ◽

Cited By ~ 204

Author(s):

T R Buroker ◽

M J O'Connell ◽

H S Wieand ◽

J E Krook ◽

J B Gerstner ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Low Dose ◽

Performance Status ◽

Single Agent ◽

High Dose ◽

Financial Cost ◽

Intensive Course ◽

Dosage Administration ◽

Administration Schedules

PURPOSE To compare two commonly used schedules of fluorouracil (5FU) and leucovorin in the treatment of patients with advanced metastatic colorectal cancer. Each of these dosage administration schedules has been demonstrated to be superior to single-agent bolus 5FU in previous controlled trials. PATIENTS AND METHODS Three hundred seventy-two ambulatory patients with metastatic colorectal cancer were stratified according to performance status, and presence and location of any measurable indicator lesion(s). They were then randomized to receive chemotherapy with one of the following regimens: (1) intensive-course 5FU plus low-dose leucovorin (5FU 425 mg/m2 plus leucovorin 20 mg/m2 intravenous [IV] push daily for 5 days with courses repeated at 4- to 5-week intervals); (2) weekly 5FU plus high-dose leucovorin (5FU 600 mg/m2 IV push plus leucovorin 500 mg/m2 as a 2-hour infusion weekly for 6 weeks with courses repeated every 8 weeks). RESULTS Three hundred sixty-two of 372 patients randomized (97.3%) were eligible and included in the analysis. Three hundred forty-six patients (95.6%) have died. There were no significant differences in therapeutic efficacy between the two 5FU/leucovorin regimens tested with respect to the following parameters: objective tumor response (35% v 31%), survival (median, 9.3 v 10.7 months), and palliative effects (as assessed by relief of symptoms, improved performance status, and weight gain). There were significant (P < .05) differences in toxicity, with more leukopenia and stomatitis seen with the intensive-course regimen, and more diarrhea and requirement for hospitalization to manage toxicity with the weekly regimen. Financial cost was also higher with the weekly regimen. CONCLUSION Intensive-course 5FU plus low-dose leucovorin appears to have a superior therapeutic index compared with weekly 5FU plus high-dose leucovorin using the dosage administration schedules applied in this study based on similar therapeutic effectiveness, but lower financial cost, and less need for hospitalization to manage chemotherapy toxicity.

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735 L-Leucovorin (LLV) as a modulator of 5-days 5-fluorouracil (5FU) in advanced colorectal cancer (ACC): High dose (HD) versus low dose (LD)

European Journal of Cancer ◽

10.1016/0959-8049(95)95984-e ◽

1995 ◽

Vol 31 ◽

pp. S153-S154

Author(s):

R. Labianca ◽

S. Cascinu ◽

S. Barni ◽

G. Fiorentini ◽

L. Frontini ◽

...

Keyword(s):

Colorectal Cancer ◽

Low Dose ◽

Advanced Colorectal Cancer ◽

High Dose

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Double biochemical modulation of 5-fluorouracil by leucovorin and cyclic low dose interferon alpha 2b in advanced colorectal cancer patients

Annals of Oncology ◽

10.1093/oxfordjournals.annonc.a058244 ◽

1992 ◽

Vol 3 (6) ◽

pp. 489-491 ◽

Cited By ~ 13

Author(s):

S. Cascinu ◽

A. Fedeli ◽

S. Luzi Fedeli ◽

G. Catalano

Keyword(s):

Colorectal Cancer ◽

Cancer Patients ◽

Interferon Alpha ◽

Low Dose ◽

Advanced Colorectal Cancer ◽

Biochemical Modulation ◽

Interferon Alpha 2B ◽

Colorectal Cancer Patients

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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.

Journal of Clinical Oncology ◽

10.1200/jco.1997.15.2.808 ◽

1997 ◽

Vol 15 (2) ◽

pp. 808-815 ◽

Cited By ~ 662

Author(s):

A de Gramont ◽

J F Bosset ◽

C Milan ◽

P Rougier ◽

O Bouché ◽

...

Keyword(s):

Colorectal Cancer ◽

Continuous Infusion ◽

Low Dose ◽

Advanced Colorectal Cancer ◽

Progression Free Survival ◽

High Dose ◽

Survival Times ◽

Free Survival ◽

Therapeutic Ratio ◽

Grade 3

PURPOSE This multicenter study compared the therapeutic ratio of a monthly schedule of low-dose leucovorin (LV) and fluorouracil (5-FU) bolus with a bimonthly schedule of high-dose LV and 5-FU bolus plus continuous infusion in patients with advanced colorectal cancer. PATIENTS AND METHODS Of the 448 patients randomly assigned to treatment, 433 were assessable. Treatment A was a monthly regimen of intravenous (IV) LV 20 mg/m2 plus bolus 5-FU 425 mg/m2 for 5 days every 4 weeks. Treatment B was a bimonthly regimen of IV LV 200 mg/m2 as a 2-hour infusion followed by bolus 5-FU 400 mg/m2 and 22-hour infusion 5-FU 600 mg/m2 for 2 consecutive days every 2 weeks. Therapy was continued until disease progression. Second-line chemotherapy, which included 5-FU continuous infusion, was allowed in both arms. RESULTS The response rates in 348 patients with measurable lesions were 14.4% (monthly regimen) and 32.6% (bimonthly regimen) (P = .0004). The median progression-free survival times were 22 weeks (monthly regimen) and 27.6 weeks (bimonthly regimen) (P = .0012). The median survival times were 56.8 weeks (monthly regimen) and 62 weeks (bimonthly regimen) (P = .067). Grade 3-4 toxicities occurred in 23.9% of patients in the monthly arm compared with 11.1% of those in the bimonthly arm (P = .0004). Patients in arm A more frequently experienced severe granulocytopenia (7.3% v 1.9%), diarrhea (7.3% v 2.9%), and mucositis (7.3% v 1.9%) than patients in arm B. CONCLUSION The bimonthly regimen was more effective and less toxic than the monthly regimen and definitely increased the therapeutic ratio. However, there was no evidence of increased survival.

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Efficacy of Prophylactic Anticoagulation To Prevent Thalidomide-Related Deep Venous Thrombosis.

Blood ◽

10.1182/blood.v106.11.5132.5132 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5132-5132 ◽

Cited By ~ 1

Author(s):

Nadeem Ikhlaque

Keyword(s):

Venous Thrombosis ◽

Deep Venous Thrombosis ◽

Low Dose ◽

Single Agent ◽

Bleeding Complications ◽

High Dose ◽

Dose Warfarin ◽

High Doses ◽

Few Data ◽

Prophylactic Anticoagulation

Abstract Deep venous thrombosis (DVT) is a known complication of treatment with thalidomide, occurring in up to 25% of patients. Although prophylactic anticoagulation has been recommended by some authors, there are few data available to assess whether this is beneficial. We reviewed the records of 131 patients receiving thalidomide for a variety of indications. Ninety-three patients had multiple myeloma, 12 had MDS or myelofibrosis and 26 had solid tumors. The mean and median dose of thalidomide was 200 mg/day. Fifty-five patients were prescribed warfarin with the intent of preventing DVT. Thirty-seven patients received warfarin at a dose of 1–2 mg per day (low dose) and 18 received a dose intended to raise the INR to 2–3 (high dose). Of 25 patients on single-agent thalidomide; only 4 received warfarin. Twenty-one of the 131 patients developed venous thrombosis during thalidomide treatment. All patients who developed DVT were receiving thalidomide in combination with dexamethasone or some form of chemotherapy. Only one patient who developed DVT was receiving thalidomide at more than 200 mg/day. Eighteen of the 76 patients (23.7%) who were not prescribed prophylactic anticoagulation developed DVT compared to three of the 55 patients (5.5%) who were prescribed any dose of prophylactic warfarin (p=.010). Only one of the 37 patients who received low dose warfarin developed DVT (p=.011). Bleeding complications occurred in 4 patients who were all receiving high dose warfarin. Two previous unrandomized studies suggested that low dose warfarin was not protective of DVT but both used high doses of thalidomide (250–400 mg) in combination with other agents which is no longer recommended. Our study suggests that low dose warfarin prophylaxis may be sufficient and safe for patients receiving thalidomide at a dose of 200 mg/day in combination with other agents.

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