Irinotecan plus raltitrexed as first-line treatment in advanced colorectal cancer: a phase II study

Feliú, Jaime; Salud, Antonieta; Escudero, P.; López-Gómez, Luis; Pericay, Carles; Castañón, Carmen Luisa Pérez; Tejada, M.; Rodríguez-García, Julián; Martinez, Mathilde; Martín, Miguel; Sánchez, José Javier; Barón, Manuel González

doi:10.1038/sj.bjc.6601713

Cited by 21 publications

(13 citation statements)

References 26 publications

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“…However, we should note the frequency of toxic deaths observed in the study, one in the raltitrexedoxaliplatin arm (2%) and three (6.5%) in the raltitrexedirinotecan arm, which represents an overall rate of toxic deaths of 4.1% in the study. These results contrast with our previous experience with the raltitrexed -irinotecan scheme in a phase II trial including 91 patients in which we did not observe any toxic death (Feliu et al, 2004). On the other hand, the toxic death rate with the bimonthly continuous-infusion regimens of 5FU -LV with either oxaliplatin or irinotecan is usually o3% (Douillard et al, 2000;Giacchetti et al, 2000;de Gramont et al, 2000;Goldberg et al, 2004;Tournigand et al, 2004).…”

Section: Discussioncontrasting

confidence: 99%

“…The response rates achieved are similar to those reported by other authors, both with schemes combining raltitrexed with oxaliplatin (39 -54% response rate) (Cascinu et al, 2002;Seitz et al, 2002;Santini et al, 2004;Grávalos et al, 2005) and those combining raltitrexed with irinotecan (34 -46%) (Carnaghi et al, 2002;Feliu et al, 2004). Similarly, these results are comparable to those obtained with combinations of 5FU -LV with oxaliplatin or irinotecan (Douillard et al, 2000;Giacchetti et al, 2000;de Gramont et al, 2000;Saltz et al, 2000;Grothey et al, 2002;Tournigand et al, 2004).…”

Section: Discussionsupporting

confidence: 88%

“…Several phase II studies with the raltitrexed -CPT-11 combination have shown response rates of 34 -46% (Carnaghi et al, 2002;Feliu et al, 2004) and median survivals of 12 -15.6 months. On the other hand, with the raltitrexed -oxaliplatin combination, response rates of 41 -54% and median survivals of 14.6 -14.8 months have been reported (Cascinu et al, 2002;Seitz et al, 2002;Santini et al, 2004).…”

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confidence: 99%

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Phase II randomised trial of raltitrexed–oxaliplatin vs raltitrexed–irinotecan as first-line treatment in advanced colorectal cancer

et al. 2005

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The purpose of this phase II randomised trial was to determine which of two schemes, raltitrexed-irinotecan or raltitrexed-oxaliplatin, offered better activity and less toxicity in patients with advanced colorectal cancer (CRC). A total of 94 patients with previously untreated metastatic CRC were included and randomised to receive raltitrexed 3 mg m À2 followed by oxaliplatin 130 mg m À2 on day 1 (arm A), or CPT-11 350 mg m À2 followed by raltitrexed 3 mg m À2 (arm B). In both arms treatment was repeated every 3 weeks. Intent-to-treat (ITT) analysis showed an overall response rate of 46% (95% CI, 29.5 -57.7%) for arm A, and 34% (95% CI, 19.8 -48.4%) for arm B. Median time to progression was 8.2 months for arm A and 8.8 months for arm B. After a median follow-up of 14 months, 69% of patients included in arm A were still alive, compared to 59% of those included in arm B. Overall, 31 patients (65%) experienced some episode of toxicity in arm A and 32 patients (70%) in arm B, usually grade 1 -2. The most common toxicity was hepatic, with 29 patients (60%) in arm A and 24 patients (62%) in arm B, and was grade 3 -4 in four (8%) and four (9%) patients, respectively. In all, 14 patients (29%) from arm A and 24 patients (52%) from arm B had some grade of diarrhoea (Po0.03). Neurologic toxicity was observed in 31 patients (64%) in arm A, and was grade 3 -4 in five patients (10%), while a cholinergic syndrome was detected in nine patients (19%) in arm B. There were no differences in haematologic toxicity. One toxic death (2%) occurred in arm A and three (6.5%) in arm B. In conclusion, both schemes have high efficacy as first-line treatment in metastatic CRC and their total toxicity levels are similar. Regimens with raltitrexed seem a reasonable alternative to fluoropyrimidines.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 88%

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Phase II randomised trial of raltitrexed–oxaliplatin vs raltitrexed–irinotecan as first-line treatment in advanced colorectal cancer

et al. 2005

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“…The observed pattern of toxicity resembles that described in previous phase I–II trials of the same combination [9,10,11,12,13,14]. Hematological toxicity and mucositis seem to be lower than with combinations of 5-FU and CPT-11, whereas diarrhea, emesis, and asthenia are somewhat higher.…”

Section: Discussionsupporting

confidence: 65%

“…Preclinical data suggest a synergistic activity between CPT-11 and raltitrexed and three recent phase I studies have shown that single-agent full doses of both drugs can be safely given thrice-weekly [9,10,11]. The reported efficacy ranged from 15.4% (in second-line) [12] to 34–46% (in first-line treatment) [13,14] in only two of three phase II studies published to date.…”

Section: Introductionmentioning

confidence: 99%

First-Line Treatment with Irinotecan and Raltitrexed in Metastatic Colorectal Cancer

Aparicio

Vicent²,

Maestu³

et al. 2005

Oncology

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Objectives: The combination of irinotecan and raltitrexed is safe and active in 5-fluorouracil-refractory, metastatic colorectal cancer (CRC), with the advantage of its convenient three-weekly schedule. The aim of this multicenter phase II study was to assess its efficacy and toxicity in first-line treatment. Methods: Between May 2000 and March 2001, 62 previously untreated patients received irinotecan (350 mg/m²) plus raltitrexed (3 mg/m²), with courses repeated every 21 days. Objective response was assessed every three courses, and treatment maintained until tumor progression or unacceptable toxicity. Results: A total of 331 cycles were administered, with a median of five cycles per patient (range, 1–16). Seventeen patients achieved a partial response and 2 a complete response, for an overall intention-to-treat response rate of 30% (95% confidence interval, 18–44%). The incidence of grade 3–4 toxicity per patient was diarrhea (27%), emesis (13%), anemia (12%), neutropenia (9%), and asthenia (7%). Three patients (5%) died from treatment-related adverse events (diarrhea plus neutropenia). The median potential follow-up is now 37 months. Median survival was 12.2 months, and median time to progression was 6.3 months. Conclusions: The combination of irinotecan plus raltitrexed is an easy comfortable schedule for patients with metastatic CRC, but both efficacy and toxicity results seem suboptimal for first-line treatment.

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Uridine diphosphate glucuronosyl transferase 1A1 promoter polymorphism predicts the risk of gastrointestinal toxicity and fatigue induced by irinotecan‐based chemotherapy

Massacesi

M.Sc.

Marcucci

et al. 2006

Cancer

105

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BACKGROUNDIn the current Phase II study, the authors evaluated the association between genomic polymorphic variants in uridine diphosphate glucuronosyl transferase (UGT1A1), methylenetetrahydrofolate reductase (MTHFR), and thymidylate synthase (TS) genes, and the incidence of the adverse effects of irinotecan and raltitrexed in previously heavily treated patients with metastatic colorectal carcinoma.METHODSFifty‐six patients received irinotecan (at a dose of 80 mg/m2 on Days 1, 8, 15, and 22 every 5 wks), combined with raltitrexed (at a dose of 3 mg/m2 every 3 wks). Genotyping for the MTHFR C677T polymorphism, the TATA box region in the UGT1A1 promoter, and tandem repeats in the TS promoter was performed on genomic DNA extracted from blood. Nineteen variables related to patient, disease, and treatment characteristics, together with genotypes, were analyzed using a binary logistic regression model with stepwise selection to evaluate their correlation with adverse reactions.RESULTSToxicities (determined according to the National Cancer Institute Common Toxicity Criteria) were evaluated in 169 cycles. Grade 3/4 neutropenia was reported to occur in 2% of cycles, Grade 2–4 nausea was reported to occur in 19% of cycles, Grade 2–4 emesis was reported to occur in 9% of cycles, Grade 2–4 diarrhea was reported to occur in 20% of cycles, Grade 2/3 fatigue was reported to occur in 11% of cycles, and Grade 3/4 hepatic toxicity was reported to occur in 7% of cycles. Homozygosis for six TA repeats in the promoter region of the UGT1A1 gene was found to be the main predictive factor for diarrhea (P < 0.00005), emesis (P = 0.0001), and fatigue (P = 0.007). Homozygosis for two tandem repeats in the TS promoter was found to be predictive of a reduced incidence of fatigue (P = 0.044). MTHFR C677T polymorphism was not found to be associated with any adverse reaction.CONCLUSIONSIn the current study, UGT1A1 promoter polymorphism was found to be predictive of the risk of diarrhea, emesis, and fatigue caused by chemotherapy with irinotecan and raltitrexed. Screening for UGT1A1 promoter polymorphism may be clinically useful for identifying patients at a higher risk of developing a severe or potentially life‐threatening toxicity after irinotecan‐based chemotherapy. Cancer 2006. © 2006 American Cancer Society.

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Irinotecan plus raltitrexed as first-line treatment in advanced colorectal cancer: a phase II study

Cited by 21 publications

References 26 publications

Phase II randomised trial of raltitrexed–oxaliplatin vs raltitrexed–irinotecan as first-line treatment in advanced colorectal cancer

Phase II randomised trial of raltitrexed–oxaliplatin vs raltitrexed–irinotecan as first-line treatment in advanced colorectal cancer

First-Line Treatment with Irinotecan and Raltitrexed in Metastatic Colorectal Cancer

Uridine diphosphate glucuronosyl transferase 1A1 promoter polymorphism predicts the risk of gastrointestinal toxicity and fatigue induced by irinotecan‐based chemotherapy

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