Tumor microsatellite instability (MSI) and the benefit of 5-FU based chemotherapy in stage II & stage III colon cancer: a pooled molecular reanalysis of randomized chemotherapy trials

Reviewer: Ryan Smith, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 18, 2002

Presenter: C.M. Ribic
Presenter's Affiliation: Lunenfeld Research Institute
Type of Session: Scientific

Background

Adding adjuvant chemoradiation therapy to resected T3-4 and N+ colon cancer increases survival, based on several large randomized studies. However, since these trials were completed, new information on the carcinogenesis of colon cancer has emerged. There appears to be two separate pathways in the development of colon cancer: chromosomal instability and microsatellite instability (MSI). Patients with MSI have been shown to have better survival than those with microsatellite stable (MSS) tumors. This study was done to determine if there is a difference in these two groups with respect to response to chemotherapy.

Materials and Methods

MSI analyses were done on tumor specimens in patients enrolled in multi-institutional studies done to study the adjuvant treatment of colon cancer.
MSI was deemed as those patients >2 of 5 or >4 of 10 sites
results based on 570 patients

Results

95 patients (17%) had MSI
Those patients not recieving chemotherapy: pts. with MSI had much better survival (approx 90% vs. approx 50% in pts with MSS)
Those patients receiving chemotherapy: no difference between MSI and MSS groups (survival of both around 65%)
MSS patients: survival with chemotherapy better (approx 65%) than without chemotherapy (approx 53%)
MSI patients: survival with chemotherapy worse (approx 65%) with chemotherapy than without chemotherapy (approx 90%)

Author's Conclusions

Chemotherapy is not warranted in those patients with stage II and stage III colon cancer with MSI
Additional studies are needed to determine why survival in MSI patients treated with chemotherapy is worse.

Clinical/Scientific Implications

Adjuvant chemotherapy has been proven to be benefitial in patients with stage II and stage III colon cancer. However, the studies that proved this were done combining stage II and stage III patients. The efficacy of adjuvant therapy in some of these patients (especially T3N0-Stage II) has been called into question. Other prognostic factors have been hypothesized to account for this. As per this study, one of these important factors could be MSI. Although further, prospective randomized studies are obviously needed for proof of this, perhaps adjuvant chemotherapy can be avoided in stage II patients with MSI. Although in this retrospective study patients with MSI did worse with chemotherapy, this does not prove chemotherapy should be held in this group of patients in the face of multiple large prospective studies that have shown the benefit of chemotherapy.

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