Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial

Douillard, Jean-Yves; Cunningham, David; Roth, Arnaud; Navarro, Matilde; James, Roger D; Karásek, Petr; Jandı́k, P; Iveson, T.; Carmichael, James; Alakl, May; Gruia, G.; Awad, Lucile; Rougier, P

doi:10.1016/s0140-6736(00)02034-1

Cited by 2,976 publications

(1,752 citation statements)

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“…The most promising of these agents are oxaliplatin and irinotecan. We added irinotecan to 5-fluorouracil in our study for two reasons: Owing to its high activity in advanced colorectal cancer (Douillard et al, 2000;Saltz et al, 2000) irinotecan appears particularly suited for intensified induction therapy; in addition, several studies have documented the radiosensitising properties of irinotecan (Boothmann et al, 1987;Boscia et al, 1993;Omura et al, 1997;Chen et al, 1999) that were observed even under hypoxic conditions (Boscia et al, 1993). As hypoxia may have an adverse effect on the radiosensitivity of cells (Kumar, 2000;Fyles et al, 2000), irinotecan may be particularly useful as a constituent of chemoradiotherapy programmes in patients with bulky pelvic tumours and poor blood supply that often contain hypoxic regions.…”

Section: Discussionmentioning

confidence: 99%

Intensified concurrent chemoradiotherapy with 5-fluorouracil and irinotecan as neoadjuvant treatment in patients with locally advanced rectal cancer

Klautke¹,

Feyerherd

Ludwig

et al. 2005

Br J Cancer

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This study aimed to evaluate the feasibility and efficacy of neoadjuvant chemoradiotherapy intensified with irinotecan in patients with locally advanced rectal cancer. Eligible patients had nonmetastatic disease at a locally advanced stage that made R0 resection and sphincter preservation uncertain. They received preoperative radiation over 6 weeks to 45 Gy and boost of 5.4 Gy and concurrent continuous infusion 5-fluorouracil 250 mg m À2 day À1 and weekly irinotecan 40 mg m À2 . In all, 37 patients entered the study. T stage at baseline as determined by ultrasound was T2/T3/T4 in 2/19/16 patients; 31 patients had lymph node involvement. The predominant toxicity was diarrhoea (grade 3/4 in 10/2 patients). Haematologic toxicity and surgical complications were moderate. Among 36 patients undergoing surgery, 32 (89%) had R0 resection and 23 (64%) sphincter preservation. Pathologic complete response (pCR) was achieved in eight (22%) of 36 patients, and 10 patients (28%) had only microscopic residual disease. At 4 years, overall survival was 66%, disease-free survival 73%, local relapse rate 7%, and distant failure rate 24%. Extent of resection and postoperative nodal status were significant predictors of overall and disease-free survival. Intensified neoadjuvant chemoradiotherapy with irinotecan can be safely administered and results in a high pCR rate.

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Section: Discussionmentioning

confidence: 99%

Intensified concurrent chemoradiotherapy with 5-fluorouracil and irinotecan as neoadjuvant treatment in patients with locally advanced rectal cancer

Klautke¹,

Feyerherd

Ludwig

et al. 2005

Br J Cancer

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“…The optimum fluoropyrimidine therapy may continue to be debated, but de Gramont's LV5FU2 regimen (dG) is a strong contender, with a good track record of efficacy and low toxicity in large phase III randomised trials (de Gramont et al, 1997;Douillard et al, 2000;Maughan et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…In the first trial, 210 patients received oxaliplatin+dG, grade 53 toxicities were frequent but manageable and one toxic death (51%) was reported . In the second, 145 patients received irinotecan+dG, again with significant but manageable grade 53 toxicity, and with one (51%) toxic death (Douillard et al, 2000). Both regimens are now being assessed as adjuvant therapy, and whilst full data are awaited, interim toxicity reports are reassuring (Rothenberg et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

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A ‘modified de Gramont’ regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer

et al. 2002

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The standard de Gramont (dG) regimen of fortnightly leucovorin, bolus fluorouracil and 22-h infusion of fluorouracil, d1+2, and the same regimen plus oxaliplatin, are effective but also cumbersome. We therefore present simplified 'Modified de Gramont' (MdG) regimens. Forty-six advanced gastrointestinal cancer patients entered a dose-exploring study of MdG, including an expanded cohort of colorectal cancer patients at optimum dose. Treatment (fortnightly) comprised: 2-h i.v.i. leucovorin (350 mg d,l-LV or 175 mg l-LV, not adjusted for patient surface area); bolus fluorouracil (400 mg m 72 ), then ambulatory 46-h fluorouracil infusion (2000 -3600 mg m 72 , cohort escalation). Subsequently, 62 colorectal patients (25 unpretreated; 37 fluorouracil-resistant) received MdG plus oxaliplatin (OxMdG) 85 mg m 72 . Fluorouracil pharmacokinetics during MdG were compared with dG. The optimum fluorouracil doses for MdG alone were determined as 400 mg m 72 bolus + 2800 mg m 72 46-h infusion. A lower dose of 400 mg m 72 bolus + 2400 mg m 72 infusion which, like dG produces minimal toxicity, was chosen for the OxMdG combination. Fluorouracil exposure (AUC 0 -48 h ) at this lower dose is equivalent to dG. With OxMdG, grade 3 -4 toxicity was rare (neutropenia 2.8% cycles; vomiting or diarrhoea 51% cycles), but despite this there were two infection-associated deaths. Oxaliplatin was omitted for cumulative neurotoxicity in 17 out of 62 patients. Objective responses in colorectal cancer patients were: 1st-line MdG (22 assessable): PR=36%, NC=32%, PD=32%. 1st-line OxMdG (24 assessable): CR/PR=72%; NC=20%; PD=8%; 2nd line OxMdG (34 assessable): PR=12%; NC=38%; PD=50%. 1988). It was compared with the Mayo Clinic 5-day bolus FU/LV regimen in a 448-patient randomised trial, and showed a better response rate (32.6% vs 14.4%; P=0.0004), and median progression-free survival (27.6 vs 22 weeks; P50.0012) with significantly reduced rates of diarrhoea, mucositis and neutropenia; however, overall survival was not significantly improved (de Gramont et al, 1997). Following this trial dG was adopted as a standard therapy option by many oncologists, especially in France and the UK.Its low toxicity profile makes dG a good basis for combination chemotherapy. Pivotal trials of the design 'dG+new agent' have been performed in first-line therapy of metastatic colorectal cancer using oxaliplatin or irinotecan (Douillard et al, 2000), in each case producing a high response rate and good safety profile. Similar trials are now ongoing in the adjuvant setting.Although dG can be administered on an ambulatory, out-patient basis, many units find it more convenient to admit patients. This, together with the high dose of LV, and a labour-intensive administration schedule, place high demands on healthcare resources (Ross et al, 1998). Furthermore, repeated hospital visits or admissions during dG may detract from the benefits of its low toxicity profile.Along with others (see Discussion), we reasoned that it would be possible to modify the dG regimen, reducing its ...

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“…On-going studies are currently addressing the interest of other types of interferon, such as α-2c IFN and β-IFN (Villar Grimalt et al, 1999). However, new agents, such as CPT-11 (irinotecan) (Douillard et al, 2000;Saltz et al, 2000) or oxaliplatin (de Gramont et al, 2000) have demonstrated clinical benefits in advanced colorectal cancer, and are therefore more plausible candidates for the adjuvant setting.…”

Section: Discussionmentioning

confidence: 99%

Alpha-interferon does not increase the efficacy of 5-fluorouracil in advanced colorectal cancer

2001

Br J Cancer

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Two meta-analyses were conducted to quantify the benefit of combining α-IFN to 5FU in advanced colorectal cancer in terms of tumour response and survival. Analyses were based on a total of 3254 individual patient data provided by principal investigators of each trial. The meta-analysis of 5FU ± LV vs. 5FU ± LV + α-IFN combined 12 trials and 1766 patients. The meta-analysis failed to show any statistically significant difference between the two treatment groups in terms of tumour response or survival. Overall tumour response rates were 25% for patients receiving no α-IFN vs. 24% for patients receiving α-IFN (relative risk, RR = 1.02), and median survivals were 11.4 months for patients receiving no α-IFN vs. 11.5 months for patients receiving α-IFN (hazard ratio, HR = 0.95). The meta-analysis of 5FU + LV vs. 5FU + α-IFN combined 7 trials, and 1488 patients. This meta-analysis showed an advantage for 5FU + LV over 5FU + α-IFN which was statistically significant in terms of tumour response (23% vs. 18%; RR = 1.26; P = 0.042), and of a borderline significance for overall survival (HR = 1.11; P = 0.066). Metastases confined to the liver and primary rectal tumours were independent favourable prognostic factors for tumour response, whereas good performance status, metastases confined to the liver or confined to the lung, and primary tumour in the rectum were independent favourable prognostic factors for survival. We conclude that α-IFN does not increase the efficacy of 5FU or of 5FU + LV, and that 5FU + α-IFN is significantly inferior to 5FU + LV, for patients with advanced colorectal cancer. © 2001 Cancer Research Campaign http://www.bjcancer.com

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Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial

Cited by 2,976 publications

References 14 publications

Intensified concurrent chemoradiotherapy with 5-fluorouracil and irinotecan as neoadjuvant treatment in patients with locally advanced rectal cancer

Intensified concurrent chemoradiotherapy with 5-fluorouracil and irinotecan as neoadjuvant treatment in patients with locally advanced rectal cancer

A ‘modified de Gramont’ regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer

Alpha-interferon does not increase the efficacy of 5-fluorouracil in advanced colorectal cancer

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