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Chemo of no benefit to some colon cancer patients

Updated Fri. May. 16 2008 1:55 PM ET

CTV.ca News Staff

Some colon cancer patients should not undergo chemotherapy because it
offers no benefit, and may in fact reduce survival times, new research
says.

The study says that 15 per cent of patients with so-called deficient DNA
mismatch repair (dMMR) tumours do not respond to treatment with the
chemotherapy 5-fluorouracil (5-FU), which is commonly used to treat colon
cancer.

Patients with dMMR tumours make up about 15 per cent of colon cancer
cases. These tumours are unable to repair DNA damage via the mechanism
known as DNA mismatch repair, a common system in the body for recognizing
and fixing DNA mutations.

The other 85 per cent of colon cancers are characterized by a cellular
problem known as chromosomal instability, a common characteristic of most
cancers that leads to an imbalance of chromosomes in the body's cells.

For their study, the researchers analyzed data from more than 1,000 men,
16 per cent of whom had dMMR tumours.

They found that the patients who had the chromosomal instability type of
tumour and who were treated with chemotherapy had a five-year survival
rate of 74 per cent. Those who did not receive chemotherapy had a
five-year survival rate of 66 per cent.

However, among those with dMMR tumours, the five-year survival rate with
chemotherapy was 75 per cent compared to a 93 per cent survival rate among
those that did not receive chemotherapy.

"We think it is very important for patients and their doctors to have this
information before considering treatment in a patient with stage II colon
cancer," Daniel Sargent, a Mayo Clinic biostatistician, said in a
statement.

"It could save patients the toxicity, inconvenience and expense of
treatment from which they will receive no benefit."

The study says that before diagnosing a treatment regimen, doctors should
test stage II colon cancer patients to determine which tumour subtype they
have. In stage II cancer, the disease has not yet spread to the lymph
nodes.

The research from the Mayo Clinic, conducted along with American and
Canadian scientists, was released Thursday in advance of the meeting of
the American Society of Clinical Oncology in Chicago at the end of the
month.

In 2003, the same team of researchers published a study in the New England
Journal of Medicine that recommended that patients with dMMR tumours
should not undergo chemotherapy. With this research, the scientists have
confirmed their earlier findings.

Because many laboratories are already familiar with the dMMR test, the
researchers said that it should be an easy transition to make it standard
procedure when treating patients with colon cancer.

Scientists still need to study why chemotherapy does not help patients
with dMMR tumours. The researchers speculated that chemotherapy causes
these cancer cells to mutate and become more aggressive because they
cannot repair damage caused by the treatment.

It could also be that chemotherapy compromises the innate healing
responses of dMMR cancers (as evidenced by the stronger survival rate
among those who did not receive chemotherapy).

Abstract:

Confirmation of deficient mismatch repair (dMMR) as a predictive marker
for lack of benefit from 5-FU based chemotherapy in stage II and III colon
cancer (CC): a pooled molecular reanalysis of randomized chemotherapy
trials.

Author Block: D. J. Sargent, S. Marsoni, S. N. Thibodeau, R. Labianca, S.
R. Hamilton, V. Torri, G. Monges, C. Ribic, A. Grothey, S. Gallinger; Mayo
Clinic, Rochester, MN; SENDO Foundation, Milano, Italy; Mayo Clinic,
Rochester, MN; Ospedali Riuniti, Bergamo, Italy; MD Anderson, Houston, TX;
Mario Negri Institute, Milano, Italy; Institut Paoli Calmettes, Marseille,
France; University of Toronto, Toronto, ON, Canada; Mayo Clinic,
Rochester, MN; Mount Sinai Hospital, Toronto, ON, Canada

Background: Patients (pts) with CC demonstrating high-frequency MSI
(MSI-H) have a stage-independent improved survival compared to pts with
microsatellite- stable (MSS) tumors. We have previously published that MSI
status is a predictive marker for lack of response to 5-FU-based
chemotherapy (rx) (Ribic, NEJM 2003). dMMR by immunohistochemistry for MMR
proteins is an almost perfect predictor for MSI status. We sought to
confirm the value of dMMR as a predictor of survival benefit from adjuvant
rx in stage II & III CC pts in an independent dataset drawn from
randomized clinical trials.

Methods: MSI or IHC analyses were performed on tumors from pts enrolled in
trials conducted by the NCCTG (N=135), GIVIO (N=183), and ECOG (N=23) that
have not been used in previous MSI or dMMR analyses. All trials randomized
pts with stage II and III CC to either 5-FU based rx (either 5-FU +
Levamisole or 5-FU + Leucovorin, N=166)) or no post-surgical rx (N=175).
XX microsatellite loci from the National Cancer Institute panel were used
to amplify genomic DNA and determine MSI status (GIVIO); IHC testing for
hMLHI and hMSH2 was used for the NCCTG and ECOG trials. Patients with
MSI-H tumors or negative IHC staining were classified as dMMR; the
remainder were considered to have proficient MMR (pMMR). Median follow-up
on living pts was 6.4 years with a primary outcome of overall survival
(OS).

Results: 341 tissue specimens were examined, of which 47 (13.8%, 20
treated, 27 untreated) exhibited dMMR. Adjuvant rx had a significant
beneficial effect on OS (HR = 0.69, p= 0.047) and DFS (HR = 0.59, p =
0.004 in pts with pMMR tumors. However, pts with dMMR tumors receiving
5-FU rx had no trend toward improved OS (HR = 1.26, p = 0.68) or DFS
(HR=1.41, p = 0.53) compared to those randomized to no rx. Results were
maintained in multivariate models adjusted for stage and age.

Conclusions: Stratification of pts according to MMR status provides a more
tailored approach to the use of adjuvant rx in CC. Our data suggest that
in a patient being considered for 5-FU alone rx (i.e. a stage II pt), MMR
status should be assessed and considered in rx decision making.