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Adjuvant Chemo Controversy in Microsatellite Unstable Colon Cancer

Adjuvant Chemo Controversy in Microsatellite Unstable Colon Cancer

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.

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