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ACS CLINICAL RESEARCH PROGRAM
by Jason Zell, DO, MPH; Robert Krouse, MD, FACS;
Judy C. Boughey, MD, FACS; and Y. Nancy You, MD, FACS
Preventing colorectal adenomas
in cancer survivors:
An update on the PACES/S0820 trial
Preventing Adenomas of the Colon with Eflornithine and Sulindac (PACES)/
S0820 is an important phase
III National Clinical Trials
Network (NCTN)-based
colorectal cancer prevention
clinical trial, and to ensure
the success of PACES/S0820,
major changes were instituted
in April 2017. These changes
affected the study design, the
translational aims, as well as the
leadership across the NCTN.
PACES launched in March
2013 as a tertiary prevention
clinical trial for colorectal
cancer survivors (from stage
0-III disease). Its goal was to
test whether the rate of high-
risk adenomas or second
primary colorectal cancers
can be reduced by agents
called polyamine inhibitors,
such as eflornithine and
sulindac. Patients in the trial
take these agents for three
years (postoperative years
one to four). Polyamines are
molecules that are essential
for normal physiology but,
when in excess, can act as
carcinogens within epithelial
tissues (particularly within the
colon, breast, and prostate).
PACES investigators are testing
two polyamine inhibitors
for their anti-carcinogenic
effects: first, eflornithine
(difluoromethylornithine or
DFMO) is a suicide inhibitor of
ornithine decarboxylase, the
rate-limiting step of polyamine
synthesis; and second, sulindac
(a cyclooxygenase nonspecific nonsteroidal anti-inflammatory drug) is known
to promote polyamine export
from epithelial tissues.
The PACES launch came
on the heels of another phase
III clinical trial to prevent
colorectal adenomas, involving
three years of treatment with a
combination of eflornithine and
sulindac versus combination
placebos. 1 When compared
with placebo, these agents led
to a 70 percent decrease in total
adenomas and, importantly, a
more than 92 percent decrease
in high-risk adenomas (large
adenomas >1cm, adenomas
with high-grade dysplasia and
multiple adenomas) and second
primary colorectal cancers. The
regimen was well-tolerated, with
no significant side effects when
compared with the placebo
group. Due to concerns about
eflornithine-associated hearing
loss observed in older trials that
used up to 40-fold higher doses of
eflornithine, detailed audiometry
studies were done on patients in
the adenoma study. 2 No clinical
hearing loss was observed,
and the observed 8 percent
non-significant reduction in
audiogram thresholds at end-
of-study essentially resolved
three to six months after the
discontinuation of eflornithine.
Given the favorable efficacy
versus safety profile, PACES
was launched to investigate
these polyamine-inhibitor
agents in colorectal cancer
survivors who remain at risk
for high-risk adenomas and
secondary colorectal cancers
in the surveillance period.
Changes to PACES to
enhance accrual
Accrual to PACES was
significantly slower than
anticipated. Therefore,
to enhance accrual and
ensure feasibility of this
cancer prevention trial, in