Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials

Cutsem, Éric Van; Hoff, Paulo M.; Harper, Peter; Bukowski, Ronald M.; Cunningham, David; Dufour, P.; Graeven, Ullrich; Lokich, J; Madajewicz, Stefan; Maroun, J.; Marshall, John L.; Mitchell, Edith P.; Perez-Manga, G.; Rougier, Philippe; Schmiegel, Wolff; Schöelmerich, Juergen; Sobrero, Alberto; Schilsky, Richard L.

doi:10.1038/sj.bjc.6601676

Cited by 359 publications

(158 citation statements)

References 34 publications

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“…Capecitabine is preferentially activated in neoplastic tissue by a process that exploits the high thymidine phosphorylase enzyme activity in tumours, thereby providing continuous targeted fluoropyrimidine exposure without the inconvenience for the patient of infusional delivery (Rich et al, 2004). Phase III trials in advanced CRC have shown an improved safety profile over bolus 5-FU/FA (Mayo Clinic regimen) (Van Cutsem et al, 2004a) and a recent randomised crossover trial has confirmed a high level of patient preference for oral over i.v. fluoropyrimidine therapy (Twelves et al, 2006).…”

Section: Oral Fluoropyrimidine Therapymentioning

confidence: 99%

Management of advanced colorectal cancer: state of the art

Saunders

Iveson

2006

Br J Cancer

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Colorectal cancer (CRC) caused over 500 000 deaths worldwide in 2002. Recent advances in the treatment of advanced disease include the incorporation of two new cytotoxic agents, irinotecan and oxaliplatin, into first-line regimens. The concept of planned sequential therapy involving three active agents during the course of a patient's treatment is evolving. Coupled with the integrated use of targeted monoclonal antibodies, we can now expect overall survival rates for advanced disease to exceed 20 months. This review considers current treatments and suggests where future progress may occur.

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Section: Oral Fluoropyrimidine Therapymentioning

confidence: 99%

Management of advanced colorectal cancer: state of the art

Saunders

Iveson

2006

Br J Cancer

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“…Two large randomised phase III trials have compared capecitabine against low-dose LV and 5FU (Mayo regimen) in patients with metastatic colorectal cancer with no difference in time to progression or overall survival (Van Cutsem et al, 2004). In addition, two randomised, controlled trials have shown at least equivalent disease-free survival with the use of an oral fluropyrimidine when compared with low-dose LV and 5FU as postoperative adjuvant therapy for stages II and III colon cancer (Wolmark et al, 2004;Twelves et al, 2005).…”

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confidence: 99%

Preoperative radiotherapy combined with 5 days per week capecitabine chemotherapy in locally advanced rectal cancer

et al. 2007

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There is increasing evidence supporting the use of preoperative chemoradiotherapy in patients with locally advanced rectal cancer in an attempt to facilitate complete surgical resection with clear margins. We describe our experience of using a 5-day per week regime of preoperative capecitabine chemoradiotherapy. Between November 2004 and September 2006, 70 patients with MRI-defined locally advanced rectal cancer were selected for treatment. Capecitabine was given at a dose of 900 mg m À2 for 5 days per week combined with 45 Gy of radiotherapy in 25 doses. This regime was well tolerated with 89% of our patients receiving the full dose of chemotherapy and 96% receiving the full dose of radiotherapy. Ninety-three per cent proceeded to macroscopically complete surgical resection. The pathological complete response rate was 9.2% with a node-negative rate of 66%. A negative circumferential margin was achieved by 79% of the patients who underwent resection. Compared to studies using a 7-day per week capecitabine schedule, our results show increased compliance and less dose reductions with comparable pathological outcome. There is clear evidence from two systematic reviews that adjuvant radiotherapy reduces the risk of local recurrence in patients with resectable rectal cancer (Camma et al, 2000; Colorectal Cancer Collaborative, 2001). The greatest benefit is seen when preoperative radiotherapy is used with a biologically equivalent dose of 430 Gy. Further clinical trials were required to assess the benefit of adding concurrent chemotherapy to preoperative radiotherapy.The recent publication of two phase III trials confirms that preoperative concurrent chemoradiation (CRT) is superior to long-course radiotherapy alone in patients with T3/4 or nodepositive resectable rectal cancer. The EORTC 22921 (Bosset et al, 2005) and FFCD 9203 (Gerard et al, 2006) trials compared intravenous 5-fluorouracil (5FU) and leucovorin (LV) given during the first and fifth weeks of radiotherapy with radiotherapy alone (dose of RT was 45 Gy in 25 fractions in both arms of the studies). Both trials demonstrated a reduction in the rates of local recurrence at 5 years from 17% with radiotherapy alone to 8 -9% with preoperative CRT, but neither trial showed any difference in overall survival. A further recent phase III trial has demonstrated that preoperative 5FU CRT is superior to post-operative CRT with a significant reduction in local recurrence from 12 to 6% as well as a significant reduction in both acute and long-term toxicity (Sauer et al, 2004). This evidence will clearly result in an increasing use of fluoropyrimidine-based CRT.Intravenous 5FU-based chemoradiation presents many logistical challenges. Continuous infusion of 5FU requires the insertion of a central venous line with its attendant risks of thrombosis and infection as well as the inconvenience of a portable infusion pump. The use of the bolus 5FU/LV regimen used in the EORTC and FFCD trials requires 10 daily visits to the chemotherapy day unit, with associated waiting time, t...

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“…The final step in its conversion to FU is catalysed by thymidine phosphorylase, an enzyme that is overexpressed in gastric cancers (Miwa et al, 1998), which could potentially offer a therapeutic index advantage for capecitabine over FU. The drug is widely used in colorectal cancer where it has proven at least equivalent efficacy but a favourable toxicity profile when compared to bolus intravenous FU/LV in randomised phase III studies (Van Cutsem et al, 2004;Twelves et al, 2005). It also appears active in gastroesophageal adenocarcinoma.…”

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confidence: 99%

A phase I and II study of 2-weekly irinotecan with capecitabine in advanced gastroesophageal adenocarcinoma

et al. 2006

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We investigated 2-weekly intravenous irinotecan combined with oral capecitabine in patients with advanced gastroesophageal adenocarcinoma. In phase I, doses were escalated in chemotherapy naïve or pretreated patients to establish maximum tolerated doses (MTD). In phase II, patients were treated at MTD as first-line therapy with the primary end point of RECIST response. Dose levels in phase I were as follows: Level 1: irinotecan 150 mg m À2 on day 1; capecitabine 850 mg m À2 12-hourly on days 1 -9. Level 2: as level 1 but capecitabine 1000 mg m À2 . Level 3: as level 2 but irinotecan 180 mg m À2 . Level 4: as level 3 but capecitabine 1250 mg m À2 . In phase I, 21 patients were entered. Maximum tolerated dose was level 3. Dose-limiting toxicities were lethargy, diarrhoea, vomiting and mucositis. In phase II, 31 patients were entered at level 3. During the first six cycles, 13 of these patients underwent dose reduction and three patients stopped treatment for toxicity. A further six patients stopped for progressive disease. The commonest grade 3 -4 toxicities were lethargy (20%), diarrhoea (17%), nausea (10%) and anorexia (10%). There were no treatment-related deaths. The response rate was 32% (95% CI 16 -52%). Median overall survival was 10 months. This regimen is active in gastroesophageal adenocarcinoma. However, using the MTD defined in phase I, fewer than 50% patients tolerated six cycles without modification in phase II; therefore, modification of these doses is recommended for further study.

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Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials

Cited by 359 publications

References 34 publications

Management of advanced colorectal cancer: state of the art

Management of advanced colorectal cancer: state of the art

Preoperative radiotherapy combined with 5 days per week capecitabine chemotherapy in locally advanced rectal cancer

A phase I and II study of 2-weekly irinotecan with capecitabine in advanced gastroesophageal adenocarcinoma

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