Survival of Patients With Advanced Colorectal Cancer Improves With the Availability of Fluorouracil-Leucovorin, Irinotecan, and Oxaliplatin in the Course of Treatment

Grothey, Axel; Sargent, Daniel J.; Goldberg, Richard M.; Schmoll, Hans Joachim

doi:10.1200/jco.2004.11.037

Cited by 985 publications

(533 citation statements)

References 19 publications

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“…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). Although it is too soon to analyse the effects on survival, there will probably not be any significant differences, since, as pointed out by several authors, what is important is to use standard drugs throughout the disease, regardless of the order in which they are used (Grothey et al, 2004;Tournigand et al, 2004), and, in our study, 64% of the patients in the raltitrexed -oxaliplatin arm and 68% of those in the raltitrexed -irinotecan arm received a second-line treatment.…”

Section: Discussionsupporting

confidence: 74%

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: Discussionsupporting

confidence: 74%

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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“…Oxaliplatin or irinotecan in combination with infusional 5FU has been shown to be effective in achieving an improved response and TTP compared with 5FU/LV in colorectal cancer (Grothey et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

A combination of gefitinib and FOLFOX-4 as first-line treatment in advanced colorectal cancer patients. A GISCAD multicentre phase II study including a biological analysis of EGFR overexpression, amplification and NF-kB activation

Cascinu

Berardi

Salvagni³

et al. 2007

Br J Cancer

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Interesting activity has been reported by combining chemotherapy with cetuximab. An alternative approach for blocking EGFR function has been the development of small-molecule inhibitors of tyrosine kinase domain such as gefitinib. We designed a multicentre phase II study in advanced colorectal cancer combining gefitinib þ FOLFOX in order to determine the activity and to relate EGFR expression and gene amplification and NF-kB activation to therapeutic results. Patients received FOLFOX-4 regimen plus gefitinib as first-line treatment. Tumour samples were analysed for EGFR protein expression by immunohistochemical analysis and for EGFR gene amplification by fluorescence in situ hybridisation (FISH), chromogenic in situ hybridisation (CISH) and NF-kB activation. Forty-three patients were enrolled into this study; 15 patients experienced a partial response (response rate ¼ 34.9%), whereas other 12 (27.9%) had a stable disease. Median progression-free survival (PFS) was 7.8 months and median overall survival (OS) was 13.9 months. We did not find any relationship with EGFR overexpression, gene amplification, while NF-kB activation was associated with a resistance to therapy. Gefitinib does not seem to increase the activity of FOLFOX in advanced colorectal cancer even in patients overexpressing EGFR or with EGFR amplification. Furthermore, while NF-kB activation seems to predict resistance to chemotherapy as demonstrated 'in vitro' models, gefitinib does not overcome this mechanism of resistance, as reported for cetuximab.

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“…These trials also reported interesting response rates and optimal toxicity profiles, but raised questions about the feasibility of chronomodulated chemotherapy (Garufi et al, 2003). However, the analysis of seven phase III trials in advanced CRC suggested that exposure to all three drugs, regardless of their sequence, is a key element able to extend the overall survival of patients to 18 -21 months (Grothey et al, 2004). Such a prospect strongly reinforces the need to optimise doses and schedules of doublet chemotherapy, in order to deliver the three drugs sequentially and obtain maximal cytotoxic activity and minimal toxicity.…”

Section: Discussionmentioning

confidence: 99%

Schedule-dependent activity of 5-fluorouracil and irinotecan combination in the treatment of human colorectal cancer: in vitro evidence and a phase I dose-escalating clinical trial

et al. 2006

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Several schedules of 5-fluorouracil (FU) and irinotecan (IRI) have been shown to improve overall survival in advanced colorectal cancer (CRC). Preclinical evidence suggests that the sequential administration of IRI and FU produces synergistic activity, although their clinical use has not been fully optimised. We investigated the interaction between short-term exposure to SN-38, the active metabolite of IRI, and prolonged exposure to FU in human CRC HT-29 cells and observed that the synergism of action between the two agents can be increased by extending the time of cell exposure to FU and reducing the interval between administration of the two agents. Based on these findings, we performed a phase I trial in 25 advanced CRC patients using a modified IRI/FU regimen as first-line therapy and evaluated three dose levels of IRI (150 -300 mg/m 2 ) and two of continuous infusion of FU (800 -1000 mg/m 2 ) in a 3-weekly schedule. The most severe grade III -IV toxicities were neutropoenia in four cycles and diarrhoea in three. One patient achieved complete response (4%), 12 a partial response (48%), the overall response rate was 52% (720, 95% CI); seven of 25 patients had stable disease (28%), the overall disease control was 80% (716, 95% CI). This modified IRI/FU schedule is feasible and exhibits potentially interesting clinical activity.

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Survival of Patients With Advanced Colorectal Cancer Improves With the Availability of Fluorouracil-Leucovorin, Irinotecan, and Oxaliplatin in the Course of Treatment

Cited by 985 publications

References 19 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

A combination of gefitinib and FOLFOX-4 as first-line treatment in advanced colorectal cancer patients. A GISCAD multicentre phase II study including a biological analysis of EGFR overexpression, amplification and NF-kB activation

Schedule-dependent activity of 5-fluorouracil and irinotecan combination in the treatment of human colorectal cancer: in vitro evidence and a phase I dose-escalating clinical trial

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