What assumptions did they need for the tests or
confidence intervals the authors used to run as expected?
What was it about the nature of the data and the nature of
the parameter investigated that justifies them using these
techniques?  The overall sample size was chosen to ensure a
minimum of 30 patients with a ctDNA-positive
result in the ctDNA-guided group and an accept-
able noninferiority margin of 8.5 percentage
points for the analysis of 2-year recurrence-free
survival, to exclude the largest absolute benefit
that could be derived from adjuvant oxaliplatin-
based chemotherapy for patients with stage II
disease.3,23 We calculated that a total sample of 450 patients would provide 80% power with a
type I error of 5% to show noninferiority of
ctDNA-guided management to standard manage-
ment, under the assumption of a 2-year recur-
rence-free survival of 84% with standard man-
agement and of 85% with ctDNA-guided
management and allowing for a 10% dropout
rate. The trial was powered to detect a nonin-
feriority margin of 5 percentage points for the
percentage of patients with recurrence within
2 years in a time-to-event analysis, as well as
a 20-percentage-point difference between the
standard-management group and the ctDNA-
guided group in the percentage of patients
treated with adjuvant chemotherapy, under the
assumption that 30% of the patients in the
standard-management group and 10% of those in
the ctDNA-guided group would receive treatment.
The primary efficacy end point was assessed
in the intention-to-treat population, which in-
cluded all eligible patients who underwent ran-
domization and had both week 4 and week 7
postsurgical blood specimens. A sensitivity analy-
sis was performed in the per-protocol popula-
tion, which included patients who had under-
gone 24-month surveillance imaging (unless
recurrence or death had already occurred) and,
for ctDNA-guided management, ctDNA-positive
patients who received at least 12 weeks of che-
motherapy or ctDNA-negative patients who re-
ceived no more than 4 weeks of chemotherapy.
Noninferiority of ctDNA-guided management to
standard management was to be accepted if the
lower bound of the 95% confidence interval
around the estimated difference in the 2-year
recurrence-free survival was above −8.5 percent-
age points. In addition, recurrence-free survival
and percentages of patients with recurrence
within 1, 2, and 3 years in a time-to-event
analysis were computed from the Kaplan–Meier
survival curves along with the associated 95%
confidence intervals. Hazard ratios and associ-
ated 95% confidence intervals were also report-
ed after evaluation of the proportional hazards
assumption with the use of the Schoenfeld re-
siduals test. The between-group difference in the
use of adjuvant chemotherapy was assessed as
percentages of patients in each group and as rela-
tive risk. No prespecified plan to control for
multiplicity of testing was made, and therefore
the 95% confidence intervals cannot be used to
infer effects. This analysis was conducted when
the last patient reached a minimum follow-up of 2 years. Statistical analyses were performed with
R software, version 3.6.1 (R Project for Statisti-
cal Computing), and SAS software, version 9.4
(SAS Institute).