Adjuvant Chemo Controversy in Microsatellite Unstable Colon Cancer

August 1, 2002

ORLANDO-Adjuvant fluorouracil (5-FU)-based chemotherapy for stage II-III colon cancer has been associated with a trend toward decreased survival for patients whose tumors show high-frequency microsatellite instability (MSI-H). This

ORLANDO—Adjuvant fluorouracil (5-FU)-based chemotherapy for stage II-III colon cancer has been associated with a trend toward decreased survival for patients whose tumors show high-frequency microsatellite instability (MSI-H). This finding, from a pooled molecular reanalysis of data from randomized 5-FU trials, adds fuel to the controversy over the role of adjuvant chemotherapy for MSI-H tumors.

In the current analysis, presented at the 38th Annual Meeting of the American Society of Clinical Oncology (abstract 509), investigators culled 570 tissue specimens from five trials. They found that for the 16.7% of cases that exhibited MSI-H (defined as at least 2 of 5 microsatellite loci tested showing instability), 5-year survival was significantly better among those who did not receive adjuvant chemotherapy.

"Patients with MSI-H seem to have a natural survival advantage in the absence of chemotherapy," said University of Toronto medical student Christine M. Ribic, of the Samuel Lunenfeld Research Institute, Toronto. In contrast, there was no significant difference in survival between patients with MSI-H receiving or not receiving adjuvant chemotherapy. "In fact," she said, "there seems to be a trend toward worse survival" in the treated patients, compared with MSI-H patients who did not receive adjuvant chemotherapy (P = .07). Patients with microsatellite stable tumors had a significant benefit from chemotherapy (P = .02).

Conflicting Data

The results stand in direct contrast to findings of an Australian group that investigated DNA mismatch repair in 891 patients with stage III colorectal cancer. Patients with microsatellite stable or unstable cancers both derived benefit from adjuvant chemotherapy, with the greatest benefit accruing to the microsatellite unstable group (Elsaleh H et al: Clin Cancer Res 7:1343-1349, 2001).

These divergent results represent "a critically important distinction that demands resolution," said discussant Carmen Joseph Allegra, MD, formerly of the National Cancer Institute. "We may be either harming or at least not helping individuals with microsatellite instability by treating them with adjuvant chemotherapy, or we may be greatly helping by treating the same patient population with adjuvant chemotherapy, depending on which study represents reality."

The microsatellite instability pathway is one of two distinct molecular pathways leading to carcinogenesis in the colon, Ms. Ribic explained. The other is known as the chromosomal instability pathway. Tumors that develop via the microsatellite instability pathway are characterized by mutations and instability of short tandem repeats (also known as microsatellites) in areas throughout the genome.

Patients with the MSI phenotype have significantly better survival, compared with patients who have either microsatellite stable cancers or cancers that develop via the chromosomal instability pathway, studies show.

To resolve the controversy, additional large, retrospective studies are needed to determine the predictive value of MSI status, Dr. Allegra said. A prospective study could assess whether therapy selected based on MSI status actually improves clinical outcome. "Such a study should be undertaken only if additional retrospective studies convincingly demonstrate a predictive role," he said. "I don’t think we are there yet."

For now, the most important finding of this analysis may be that MSI status is potentially important in providing a more tailored, rational approach to the use of adjuvant chemotherapy. "The study verifies that colon cancer appears to be at least two separate diseases, from a molecular perspective," Ms. Ribic commented.