Elsevier

European Journal of Cancer

Volume 45, Issue 3, February 2009, Pages 365-373
European Journal of Cancer

The efficacy of adjuvant chemotherapy with 5-fluorouracil in colorectal cancer depends on the mismatch repair status

https://doi.org/10.1016/j.ejca.2008.07.016Get rights and content

Abstract

Aims

The aim of this study is to evaluate if mismatch repair (MMR) defective colorectal cancer has a different response to adjuvant 5-fluorouracil (5-FU) chemotherapy in a cohort of patients prospectively followed during 5 years.

Methods

The cohort included 754 surgically treated patients with colorectal cancer. MMR status was diagnosed by MLH1 and MSH2 immunohistochemistry and microsatellite instability analysis. Median follow-up was 49.2 months (range 1–73). At inclusion, 505 patients were diagnosed as TNM II or III stage, analysis of the efficacy of adjuvant chemotherapy was made on this population. Adjuvant chemotherapy was applied to 248 patients (98.2% 5-FU based).

Results

MMR deficiency was found in 76 patients (10.1%). No differences were found in overall survival (log-rank p = 0.3) or disease-free survival (log-rank p = 0.3) regarding MMR status. Adjuvant chemotherapy improves survival in patients in the II or III stage, but this improvement is only evident in patients with MMR-competent tumours (log-rank p = 0.00001). Survival of patients with MMR-defective tumours does not improve with adjuvant chemotherapy (log-rank p = 0.7). A multivariate analysis showed an independent effect of the interaction between MMR status and adjuvant chemotherapy (Hazard ratio 2.04; 95% confidence interval: 1.42–2.93).

Conclusion

In a cohort of colorectal cancer patients, those with MMR-deficient tumours seem not to benefit from 5-FU-based chemotherapy.

Section snippets

Background

In the last 15–20 years, adjuvant chemotherapy for colorectal cancer has demonstrated efficacy and it is commonly used.1 To date, the appropriateness of chemotherapy is decided according to the TNM stage. Since the early 1990s, 5-fluorouracil (5-FU) is the mainstay drug in adjuvant chemotherapy in colorectal cancer, but in the last years, new drugs, such as oxaliplatin and irinotecan, as well as target drugs acting in key points in the tumourigenic cascade, such as cetuximab or bevacizumab have

Patients and methods

Between November 2000 and October 2001, all newly diagnosed colorectal cancer patients in 25 hospitals were included in the EPICOLON study, a clinical epidemiology survey aimed at establishing the incidence of hereditary non-polyposis colorectal cancer in Spain.12, 13 Ten of these 25 centres agreed to participate in a nested prospective follow-up investigation. Exclusion criteria were familial adenomatous polyposis, personal history of inflammatory bowel disease and patient’s refusal to

Relation between mismatch repair status and colorectal cancer prognosis

The cohort included 754 patients. Median follow-up was 49.2 months (range 1–73). Sixteen patients (2.1%) were not operated on due to advanced disease. The rest were surgically treated. Seventy-six (10.1%) tumours were MMR-deficient and 678 (89.9%) were MMR-proficient. Seven patients had germline mutations in MLH1 (n = 5) or MSH2 (n = 2) gene. Characteristics of patients at diagnosis, according to mismatch repair status can be seen in Table 1. We found no significant differences between patients

Discussion

The main finding of this study is that the efficacy of adjuvant 5-FU chemotherapy, in terms of mortality or tumour recurrence, is significantly different depending on the mismatch repair status of colorectal cancer. Patients in stage II or III disease, which tumours show a competent mismatch repair status, obtained an important benefit from 5-FU chemotherapy, improving their overall survival and disease-free survival to almost a 20%. However, patients having MMR-deficient tumours seem not to

Conflict of interest statement

All the authors disclose any financial or personal relationships with other people or organisations that could inappropriately influence (bias) our work in this manuscript.

Acknowledgements

This work was supported by grants from the Fondo de Investigación Sanitaria (FIS 01/0104) and from the Instituto de Salud Carlos III (RC03/02 and RC03/10).

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