Fluorouracil plus racemic leucovorin versus fluorouracil combined with the pure l-isomer of leucovorin for the treatment of advanced colorectal cancer: a randomized phase III study.

Scheithauer, Werner; Kornek, Gabriela; Marczell, A; Salem, G.; Karner, J.; Kovats, E.; Burger, Doris; Greiner, R; Pidlich, Johann; Schneeweiß, Bruno; Raderer, Markus; Rosén, Harald; Depisch, D.

doi:10.1200/jco.1997.15.3.908

Cited by 31 publications

(11 citation statements)

References 23 publications

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“…Regarding the l-LV dose in the present regimen, we selected a fixed dose of 25 mg/body rather than 20 mg/m 2 , not only because the optimal concentration of LV to effectively modulate 5-FU varies substantially depending on the experimental system but also because l-LV has been shown to be clinically equivalent to either the same or a double dose of d,l-LV in its antitumor activity against colon cancer. 23,24 A recent randomized phase II study revealed that oxaliplatin, a 1,2-diaminocyclohexane platinum compound, in combination with CPT-11, has equivalent clinical activity to other 5-FU-based combinations, with manageable toxicity. 25 Moreover, oxaliplatin, in combination with 5-FU/LV (FOLFOX4), has demonstrated superiority over oxaliplatin/CPT-11 (IROX) or CPT-11/5-FU/LV (Saltz) in terms of the toxicity profile.…”

Section: Discussionmentioning

confidence: 99%

Phase I study of CPT-11 and bolus 5-FU/ l -leucovorin in patients with metastatic colorectal cancer

Fujishima

Kikuchi

Miyanaga

et al. 2004

International Journal of Clinical Oncology

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This CPT-11/5-FU/ l-LV regimen administered weekly for 3 weeks every 28 days has substantial antitumor activity, with manageable toxicities. A multicenter phase II study is currently underway. Irinotecan (CPT-11) and bolus 5-fluorouracil (5-FU)/leucovorin (LV) administered weekly for 4 weeks every 42 days (Saltz regimen) is active but substantially toxic in patients with metastatic colorectal cancer (CRC). The efficacy and toxicity of this regimen, however, have not been determined in Japanese patients with metastatic CRC.

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Section: Discussionmentioning

confidence: 99%

Phase I study of CPT-11 and bolus 5-FU/ l -leucovorin in patients with metastatic colorectal cancer

Fujishima

Kikuchi

Miyanaga

et al. 2004

International Journal of Clinical Oncology

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“…Although intermittent rather than 'essentially uninterrupted use of chemotherapy until progression or death' seems more likely to achieve this goal of palliative tumour therapy, the latter therapeutic strategy is commonly used, at least in the large majority of reported clinical trials in solid tumours, including advanced colorectal cancer. Although in several recently published (European) trials, the duration of treatment has generally been limited to six courses/months, with or without the option to continue treatment when clinical benefit was perceived (Kohne-Womper et al, 1990, British Journal of Cancer (1998) 78(6), [760][761][762][763][764] Reinduction therapy in colorectal cancer 763 1992; Scheithauer et al, 1994Scheithauer et al, , 1997Stoffregen et al, 1996;Zalcberg et al, 1996;Rougier et al, 1997), or to 4 or 12 weeks in patients achieving CR or CR/PR/SD (Labianca et al, 1991;Jager et al, 1996), and occasionally was to be restarted for tumour progression (Kohne-Womper et al, 1990;Scheithauer et al, 1994;Stoffregen et al, 1996;Jager et al, 1996), the therapeutic outcome in patients receiving reinduction has not been reported. As there is virtually no information on the optimal duration of chemotherapy in advanced colorectal cancer in the medical literature, the present study was undertaken.…”

Section: Discussionmentioning

confidence: 99%

“…This study is a prospective evaluation including all patients from two treatment centres who had achieved complete response (CR), partial response (PR) or stable disease (SD) after 6 months of firstline chemotherapy with 5-fluorouracil plus racemic leucovorin (LV) or 5-FU plus the 1-isomer of leucovorin (LLV) in a randomized phase III study that has been reported previously (Scheithauer et al, 1997). As defined in the original study protocol, patients eligible for reinduction had to have histologically confirmed metastatic or recurrent colorectal cancer, bidimensionally measurable and progressive disease, a World Health Organization (WHO) performance status score of 0 to 3, an adequate bone marrow reserve (leucocyte count > 3500 tl ', platelet count > 100 000 gl-1) and adequate renal (serum creatinine concentration < 132 ltmol) and hepatic functions (serum bilirubin level < 34 gmol 1-' and serum transaminase level <100 IU 1-').…”

Section: Methodsmentioning

confidence: 99%

“…Toxicity data are not reported separately for patients treated with 5-FU/LV or 5-FU/LLV, as [apart from only a minor difference in haematotoxicity (Scheithauer et al, 1997)] all patients had received an identical drug regimen during the induction and reintroduction phase of the study. Overall, 32 (65%) of the patients receiving first-line chemotherapy reported at least one adverse reaction, and nine (18%) had at least one severe adverse reaction.…”

Section: Survivalmentioning

confidence: 99%

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Reinduction therapy with the same cytostatic regimen in patients with advanced colorectal cancer

Hejna

Kornek²,

Raderer³

et al. 1998

Br J Cancer

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Summary The aim of the study was to investigate the therapeutic value of reinduction therapy with the same cytostatic treatment that had been used for induction treatment in patients with metastatic colorectal cancer. A total of 71 patients, all of whom had responded or achieved stable disease lasting >12 weeks after six monthly courses of first-line treatment with 5-fluorouracil + racemic leucovorin (5-FU/LV; n = 35) or 5-FU plus the I-isomer of LV (LLV; n = 34) were entered in this study. At the time of relapse, the same treatment was used for initial therapy: racemic LV or LLV was administered at 100 mg m-2 day-' by i.v. bolus injection, immediately followed by 5-FU 400 mg m-2 day-1 given as a 2-h infusion. Chemotherapeutic drugs were given on 5 consecutive days at 4-week intervals x 6 or until there was evidence of tumour progression. Among 49 evaluable patients, reinduction therapy that was initiated after a median treatment-free interval of 5.4 months (range 3-14.5) resulted in nine partial response (PR) (18%) and 26 stable disease (SD) (53%), yielding an overall tumour control rate of 69% (95% confidence interval, 54.6-81.7%). The median time to treatment failure from reinduction was 6.4 months, and the median survival duration from reinduction was 8.9 months (20.1 months as judged from the beginning of induction therapy). The toxicity associated with retreatment was generally mild to moderate; compared with initial treatment, there was no significant difference in terms of the overall rate (P = 0.33) or severity (P = 0.19) of adverse reactions. Our data suggest that in patients with advanced colorectal cancer an interrupted treatment strategy, i.e. retreatment with the same regimen in case of relapse .3 months after discontinuation of 6 months of successful treatment with 5-FU/LV or 5-FU/LLV is an acceptable therapeutic concept.Keywords: advanced colorectal cancer; chemotherapy; reinduction; 5-fluorouracil; leucovorin Advanced colorectal cancer remains a therapeutic challenge to clinicians involved in the management of this common malignant disease, which continues to be the second leading cause of cancer death in the Western world (Chu et al, 1994). Despite intensive efforts to improve the poor prognosis of patients with advanced colorectal cancer, therapeutic progress has been hampered by its apparent chemotherapeutic refractoriness. Although randomized trials have established with reasonable certainty that fluorouracil/leucovorin-based chemotherapy results in substantive therapeutic gain compared with best supportive care (The Nordic Gastrointestinal Tumour Adjuvant Therapy Group, 1992;Scheithauer et al, 1993) or treatment with 5-FU alone (Poon et al, 1989; Advanced Colorectal Cancer Meta-Analysis Project, 1992), there is considerable room for further improvement in terms of the response rates and tolerance of treatment. Until now, it has not been possible to define the optimal regimen of biochemical modulation of fluoropyrimidines (Doroshow, 1996), and there is also sparse information in terms of the...

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“…Two randomised trials have compared the standard racemic leucovorin (d,l-leucovorin with the levorotatory isomer l-leucovorin, and found them to yield similar response rates and survival when combined with uorouracil (134,135). Only l-leucovorin is transformed into active folate cofactors.…”

Section: Fluorouracil In Combination With Leuco×orinmentioning

confidence: 99%

A Systematic Overview of Chemotherapy Effects in Colorectal Cancer

Ragnhammar¹

2001

Acta Oncologica

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A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scienti c literature are described separately (Acta Oncol 2001; 40: 155 -65). This synthesis of the literature on adjuvant and palliative therapy with cytostatics for colorectal cancer is based on 208 scienti c articles, including eight meta-analyses and 162 randomised studies. These studies involve approximately 126 800 patients. The conclusions reached can be summarized into the following points:The bene t of postoperative adjuvant chemotherapy with uorouracil and levamisole in patients with colon cancer stage Dukes' C was demonstrated more than ten years ago in two phase III trials. There was a reduction of recurrence from 56% to 39% and reduction of death from 51% to 40% after more than ve years of follow-up. Although this combination has been widely accepted as standard adjuvant treatments for stage Dukes' C colon cancer, there is still debate on whether adjuvant treatment with uorouracil alone would be equally ef cacious. Several phase III trials with postoperative adjuvant chemotherapy with uorouracil and leucovorin in patients with colon cancer stage Dukes' C have demonstrated a similar statistically signi cant improvement in disease-free and overall survival in comparison with a control arm. Six months of treatment with uorouracil and leucovorin is as ef cient as twelve months of uorouracil and levamisole. This treatment is, thus, recommended for routine use. No convincing bene t from adjuvant chemotherapy is proven in colon cancer stage Dukes' B although some randomised trials have shown the same relative survival gain as seen in stage Dukes' C. There is less knowledge on survival bene ts from adjuvant chemotherapy for Dukes' stage B and C rectal cancer. In small randomised trials, postoperative radiochemotherapy has, however, improved survival to the same extent as chemotherapy in colon cancer Dukes' stage C. A meta-analysis of nine randomised trials revealed a small but statistically signi cant bene t in ve-year survival and a reduction in the risk of death for the patients receiving immediate postoperative portal vein infusion compared with controls. At present, however, the use of portal vein infusion or intraperitoneal therapy outside of a research trial cannot be recommended in the light of the limited effects. This conclusion is further supported by similarly limited effects in two recently reported very large European multicentre trials. In advanced colorectal cancer, chemotherapy may prolong survival, decrease tumour-related symptoms, improve general well-being or maintain it at a high level for a longer time period compared with best supportive care. These effects have been seen using systemic chemotherapy and using regional chemotherapy in patients with metastases limited to the liver. Subjective responses and quality of life improvements are seen more frequently than objective tumour remissions. Altho...

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Fluorouracil plus racemic leucovorin versus fluorouracil combined with the pure l-isomer of leucovorin for the treatment of advanced colorectal cancer: a randomized phase III study.

Abstract: The combination of FU/l-LV produced response rates, response durations, and survival times similar to those with FU/d,l-LV. Biochemical modulation of FU by either pure l-LV or racemic LV thus appears to result in equivalent clinical efficacy.

Cited by 31 publications

References 23 publications

Phase I study of CPT-11 and bolus 5-FU/ l -leucovorin in patients with metastatic colorectal cancer

Phase I study of CPT-11 and bolus 5-FU/ l -leucovorin in patients with metastatic colorectal cancer

Reinduction therapy with the same cytostatic regimen in patients with advanced colorectal cancer

A Systematic Overview of Chemotherapy Effects in Colorectal Cancer

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