Intravenous fluorouracil has shown similar benefit when administered by bolus or infusion,89
although continuous infusion has been associated with lower incidence of severe toxicity.90 The
efficacy of the oral fluoropyrimidine capecitabine
has been shown to be equivalent to that of fluorouracil.91
Fluorouracil-based treatment remained the
standard of care until the introduction of oxaliplatin in the mid-1990s. After encouraging results in the metastatic setting,92,93 the agent was
moved to the adjuvant setting. The MOSAIC
trial (Table 3) randomly assigned patients with
stage II and III colon cancer to fluorouracil with
leucovorin (FULV) versus FOLFOX given once
every 2 weeks for 12 cycles. Analysis with respect
to stage III patients showed a clear survival benefit, with a 10-year OS of 67.1% with FOLFOX
chemotherapy versus 59% with fluorouracil and
leucovorin.94,95 The NSABP C-07 (Table 3) trial
used a similar trial design but employed bolus
fluorouracil. More than 2400 patients with stage
II and III colon cancer were randomly assigned
to bolus FULV or bolus fluorouracil, leucovorin,
and oxaliplatin (FLOX). The addition of oxaliplatin significantly improved outcomes, with
4-year DFS of 67% versus 71.8% for FULV and
FLOX, respectively, and a HR of death of 0.80
with FLOX.59,96 The multicenter N016968 trial
(Table 3) randomly assigned 1886 patients with
stage III colon cancer to adjuvant capecitabine
plus oxaliplatin (XELOX) or bolus fluorouracil
plus leucovorin (FU/FA). The 3-year DFS was
70.9% versus 66.5% with XELOX and FU/FA,
respectively, and 5-year OS was 77.6% versus
74.2%, respectively.97,98
In the metastatic setting, additional agents
have shown efficacy, including irinotecan,99,100
bevacizumab,101,102 cetuximab,103,104 and rego-
rafenib.105 This observation led to testing of
these agents in earlier stage disease. The CALGB
89803 trial compared fluorouracil, leucovorin,
and irinotecan to fluorouracil with leucovorin
alone. No benefit in 5-year DFS or OS was
seen.106 Similarly, infusional fluorouracil, leucov-
orin, and irinotecan (FOLFIRI) was not found
to improve 5-year DFS as compared to fluoro-
uracil with leucovorin alone in the PETACC- 3
trial.107 The NSABP C-08 trial considered the
addition of bevacizumab to FOLFOX. When
compared to FOLFOX alone, the combina-
tion of bevacizumab to FOLFOX had similar
3-year DFS (77.9% versus 75.1%) and 5-year OS
(82.5% versus 80.7%).108 This finding was con-
firmed in the Avant trial.109 The addition of ce-
tuximab to FOLFOX was equally disappointing,
as shown in the N0147 trial110 and PETACC- 8
trial.111 Data on regorafenib in the adjuvant
setting for stage III colon cancer is lacking;
however, 2 ongoing clinical trials, NCT02425683
and NCT02664077, are each studying the use of
regorafenib following completion of FOLFOX
for patients with stage III disease.
Thus, after multiple trials comparing various regimens and despite attempts to improve
outcomes by the addition of a third agent, the
standard of care per National Comprehensive Cancer Network (NCCN) guidelines for
management of stage III colon cancer remains
12 cycles of FOLFOX chemotherapy. Therapy
should be initiated within 8 weeks of surgery.
Data are emerging to support a short duration
of therapy for patients with low-risk stage III
tumors, as shown in an abstract presented at
the 2017 American Society of Clinical Oncology
annual meeting. The IDEA trial was a pooled
analysis of 6 randomized clinical trials across
multiple countries, all of which evaluated 3 versus 6 months of FOLFOX or capecitabine and
oxaliplatin in the treatment of stage III colon
cancer. The analysis was designed to test noninferiority of 3 months of therapy as compared to
6 months. The analysis included 6088 patients
across 244 centers in 6 countries. The overall
analysis failed to establish noninferiority. The
3-year DFS rate was 74.6% for 3 months and
75.5% for 6 months, with a DFS HR of 1.07
and a confidence interval that did not meet
the prespecified endpoint. Subgroup analysis
suggested noninferiority for lower stage disease
