A phase III randomized trial of LV5FU2+CPT-11 vs. LV5FU2 alone in adjuvant high risk colon cancer (FNCLCC Accord02/FFCD9802)

Ychou, Marc; Raoul, Jean-Luc; Douillard, Jean-Yves; Bugat, R.; Mineur, Laurent; Viret, F.; Bécouarn, Y.; Bouché, Olivier; Jacob, Jacques-Henri; Gourgou-Bourgade, Sophie

doi:10.1200/jco.2005.23.16_suppl.3502

Cited by 67 publications

(29 citation statements)

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“…Second, the retrospective nature of this analysis along with the restriction to only one-third of the patients included in the clinical study may either be generating an uncontrolled bias or limiting the power to detect differences. Finally, adjuvant CPT-11-based chemotherapy has globally failed to demonstrate a significant improvement in terms of progressionfree survival in stage III CRC in three different studies (van Cutsem et al, 2005;Ychou et al, 2005;Saltz et al, 2007), which suggests that factors other than MSI status play an important role as prognostic factors in the adjuvant setting.…”

Section: Discussionmentioning

confidence: 99%

Microsatellite instability due to hMLH1 deficiency is associated with increased cytotoxicity to irinotecan in human colorectal cancer cell lines

et al. 2008

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Around 15% of colorectal cancers (CRCs) show microsatellite instability (MSI) due to dysfunction of the mismatch repair system (MMR). As a consequence of this, MSI tumours tend to accumulate errors in mononucleotide repeats as those in genes implicated in repairing double-strand breaks (DSBs). Previous studies have shown that irinotecan (CPT-11), a chemotherapy agent inducing DSB, is more active in MSI than in microsatellite stable (MSS) CRC. The purpose of this study was to compare the sensitivity to CPT-11 in a series of CRC cell lines with either proficient or deficient MMR and to assess the mutational status of two DSB repair genes, MRE11 and RAD50, in these cell lines. hMLH1-deficient cell lines due to either epigenetic silencing or mutation showed very similar IC 50 and were four-to nine-fold more sensitive to CPT-11 than the MSS line. Cell lines harbouring mutations in both MRE11 and RAD50 were most sensitive to CPT-11. We conclude that MSI cell lines display higher sensitivity to CPT-11 than MSS cells. Mutation of MRE11 and RAD50 could account for this difference in response to CPT-11. Future clinical trials tailoring chemotherapy regimens based on microsatellite status are warranted.

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Section: Discussionmentioning

confidence: 99%

Microsatellite instability due to hMLH1 deficiency is associated with increased cytotoxicity to irinotecan in human colorectal cancer cell lines

et al. 2008

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“…Three randomized trials of adjuvant irinotecan with either bolus or infusional fluorouracil and leucovorin have examined this premise [122][123][124] . Surprisingly, each of these studies demonstrated increased toxicity without a meaningful improvement in outcome among patients receiving irinotecan.…”

Section: Irinotecanmentioning

confidence: 99%

Systemic Treatment of Colorectal Cancer

2008

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Colorectal cancer is the fourth most common non-cutaneous malignancy in the United States and the second most frequent cause of cancer-related death. Over the past 12 years, significant progress has been made in the systemic treatment of this malignant condition. Six new chemotherapeutic agents have been introduced, increasing median overall survival for patients with metastatic colorectal cancer from less than 9 months with no treatment to approximately 24 months. For patients with stage III (lymph node positive) colon cancer, an overall survival benefit for fluorouracil-based chemotherapy has been firmly established, and recent data have shown further efficacy for the inclusion of oxaliplatin in such adjuvant treatment programs. For patients with stage II colon cancer, the use of adjuvant chemotherapy remains controversial, but may be appropriate in a subset of individuals at higher risk for disease recurrence. Ongoing randomized clinical trials are evaluating how best to combine currently available therapies, while smaller studies are evaluating new agents, with the goal of continued progress in prolonging life among patients with metastatic colorectal cancer and increasing cure rates among those with resectable disease.

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“…The use of the therapies within this appraisal needs to be considered alongside possible future NICE recommendations, although the initial results of irinotecan-based trials suggest that it is not an effective treatment in the adjuvant setting. [182][183][184] Any new recommendations regarding therapies for metastatic colorectal cancer should also be borne in mind, as these may impact upon the assumptions made within this appraisal regarding standard treatment for advanced disease.…”

Section: Availability Of Alternative Therapiesmentioning

confidence: 99%

The clinical and cost-effectiveness of oxaliplatin and capecitabine for the adjuvant treatment of colon cancer: systematic review and economic evaluation

Pandor¹,

Eggington²,

Paisley³

et al. 2006

Health Technol Assess

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A phase III randomized trial of LV5FU2+CPT-11 vs. LV5FU2 alone in adjuvant high risk colon cancer (FNCLCC Accord02/FFCD9802)

Cited by 67 publications

References 0 publications

Microsatellite instability due to hMLH1 deficiency is associated with increased cytotoxicity to irinotecan in human colorectal cancer cell lines

Microsatellite instability due to hMLH1 deficiency is associated with increased cytotoxicity to irinotecan in human colorectal cancer cell lines

Systemic Treatment of Colorectal Cancer

The clinical and cost-effectiveness of oxaliplatin and capecitabine for the adjuvant treatment of colon cancer: systematic review and economic evaluation

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