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generated. Did the authors conduct a reasonable and
justifiable analysis? Are their conclusions reasonable?: Patient Characteristics and Follow-up
A total of 459 patients were enrolled from 23
Australian centers between August 10, 2015,
and August 2, 2019, of whom 455 underwent
randomization. Of the 302 patients assigned to
ctDNA-guided management, 8 (3%) were ex-
cluded from the intention-to-treat population,
and of the 153 patients assigned to standard
management, 6 (4%) were excluded (Fig. S1). A
successful ctDNA analysis was performed for
291 of 294 patients (99%) in the ctDNA-guided
group. Of these patients, only 2 did not receive
ctDNA-guided management of their disease. Of
the 45 ctDNA-positive patients in the ctDNA-
guided group, 1 did not receive adjuvant chemo-
therapy, and 1 ctDNA-negative patient received
chemotherapy. The median follow-up from ran-
domization to database lock for analysis (Oc-
tober 15, 2021) was 37 months (37 months in
the ctDNA-guided group and 38 months in the
standard-management group).
The baseline characteristics of the patients in
the main analysis population were generally bal-
anced between the two groups, with the excep-
tion of a higher percentage of patients in the
ctDNA-guided group than in the standard-man-
agement group having tumors on the right side
(Tables 1 and S3). The median age of the pa-
tients was 64 years, and the majority of patients
(99%) had an ECOG performance-status score of
0 or 1. T4 disease was present in 15% of the
patients, and 5% had a lymph node yield of less
than 12. Clinical high-risk disease, defined as
one or more clinicopathological risk features
(T4, poor tumor differentiation, lymph node
yield <12, lymphovascular invasion, tumor per-
foration, or bowel obstruction) in association
with a proficient mismatch-repair tumor, was
present in 176 patients (40%). The baseline char-
acteristics of the patients in the per-protocol
population are shown in Table S2.
Treatment Delivered
A summary of the treatment delivered and adher-
ence in both trial groups is provided in Table 2.
A lower percentage of patients in the ctDNA-guided group than in the standard-management
group received adjuvant chemotherapy (15% vs.
28%; relative risk, 1.82; 95% confidence interval
[CI], 1.25 to 2.65). This difference was observed
across almost all patient subgroups, with the
exception of patients with a lymph node yield of
less than 12 and patients older than 70 years of
age (Fig. 1); the most notable difference was
seen among patients with T4 or poorly differen-
tiated tumors (relative risk, 2.57 and 5.06, re-
spectively). For patients with high-risk clinico-
pathological features, the likelihood of receiving adjuvant chemotherapy was 2.14 times as high in
the standard-management group as in the ctDNA-
guided group.
Among those who received adjuvant chemo-
therapy, an oxaliplatin-based doublet was ad-
ministered to a higher percentage of patients in
the ctDNA-guided group than in the standard-
management group (62% vs. 10%). In total, 8 of
86 patients (9%) with deficient mismatch-repair
tumors received adjuvant chemotherapy, 6 (75%)
of whom (including 4 patients in the ctDNA-
guided group) were treated with oxaliplatin-
based combination chemotherapy. The median
time to the start of treatment after surgery was
longer in the ctDNA-guided group than in the
standard-management group (83 days vs. 53
days); this difference was driven by the wait time
for the ctDNA result. No patient had disease
recurrence during this waiting period.
Efficacy According to Treatment Group
At the time of database lock, 43 events of disease
recurrence or death had occurred. Noninferiority
of ctDNA-guided management to standard man-
agement was confirmed in the intention-to-treat
population for both 2-year recurrence-free sur-
vival (absolute difference, 1.1 percentage points;
95% CI, −4.1 to 6.2) and the percentage of pa-
tients with recurrence within 2 years in the
time-to-event analysis (absolute difference, 0.7
percentage points; 95% CI, −4.3 to 5.7) (Figs.
2A, S2, S3, and S4). The percentages of patients
surviving without disease recurrence at 2 years
and at 3 years were similar in the ctDNA-guided
group and the standard-management group
(2-year recurrence-free survival, 93.5% and 92.4%,
respectively; 3-year recurrence-free survival, 91.7%
and 92.4%, respectively; hazard ratio, 0.96; 95%
CI, 0.51 to 1.82) (Fig. 2B). The analysis involving
the per-protocol population provided similar re-
sults (Figs. S6 and S7). Results were also gener-
ally similar in prespecified subgroup analyses
(Fig. S5).
Outcomes According to ctDNA Status in the
ctDNA-Guided Group
In the ctDNA-guided group, recurrence or death
occurred in 15 of 246 ctDNA-negative patients
(6%) and 8 of 45 ctDNA-positive patients (18%).
The estimated 3-year recurrence-free survival
was 92.5% among ctDNA-negative patients and
86.4% among ctDNA-positive patients (hazard ratio, 1.83; 95% CI, 0.79 to 4.27) (Fig. 3), and the
percentage of patients who had had a recurrence
at 3 years was 7% among ctDNA-negative pa-
tients, as compared with 14% among ctDNA-
positive patients (hazard ratio, 2.45; 95% CI,
1.00 to 5.99) (Fig. S8). Among the ctDNA-posi-
tive patients treated with adjuvant chemotherapy,
3-year recurrence-free survival was 92.6% among
those who received oxaliplatin-based chemo-
therapy and 76.0% among those who received
single-agent fluoropyrimidine chemotherapy.
In accordance with current guidelines, clini-
cians routinely base treatment recommendations
on clinical risk, with a T4 tumor being the strongest risk factor.6-8 In a post hoc exploratory
analysis, we examined the effect of ctDNA-neg-
ative status on recurrence-free survival among
patients with low-risk or high-risk disease and
T3 or T4 tumors. Among ctDNA-negative pa-
tients, 3-year recurrence-free survival was higher
among patients with clinical low-risk cancers
than among those with high-risk cancers (96.7% vs. 85.1%; hazard ratio, 3.04; 95% CI, 1.26 to
7.34) (Fig. S9). Similarly, 3-year recurrence-free
survival was higher among patients with T3 tu-
mors than among those with T4 tumors (94.2%
vs. 81.3%; hazard ratio, 2.60; 95% CI, 1.01 to
6.71) (Fig. S10). We did not investigate the effect
of ctDNA-positive status according to clinical risk
because of the small total number of patients
with a ctDNA-positive result