ACS Bulletin - October 2017

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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.