editorials
FOxTROT: Are We Ready to Dance?
ASSOCIATED
CONTENT
See accompanying
article on page 1541
Author affiliations
and support
information (if
applicable) appear
at the end of this
article.
Accepted on
October 3, 2022
and published at
ascopubs.org/journal/
jco on January 19,
2023: DOI https://doi.
org/10.1200/JCO.22.
02108
© 2023 by American
Society of Clinical
Oncology
1514 Volume 41, Issue 8
Julien Taieb, MD, PhD1 and Mehdi Karoui, MD, PhD2
Colon cancer (CC) outcomes have improved signifi-
cantly over the past two decades because of advances
in the nonmetastatic setting. Since 2004 and the
MOSAIC1 trial, infusional fluorouracil, leucovorin, and
oxaliplatin (FOLFOX; fluorouracil-leucovorin-oxaliplatin)
for 6 months has been the standard adjuvant treatment
for resected stage III patients and more controversially
for high-risk stage II. More recently, capecitabine and
oxaliplatin (CAPOX) has been shown to be associated
with very similar outcomes and is considered as a sec-
ond, albeit slightly more toxic standard.2
As all trials testing new agents, such as antivascular
endothelial growth factor3,4 and anti–epidermal growth
factor receptor5,6 drugs, have failed to improve onco-
logical outcome in the adjuvant setting during the past 20
years, academic groups have used this long period to
modify the schedule, timing and duration of adjuvant
treatment in attempts to improve disease-free survival
(DFS), or treatment tolerability.
Four years ago, the IDEA consortium showed that, as
compared with 6 months, 3 months of FOLFOX/
CAPOX significantly decreases treatment-related ad-
verse events and specifically long-lasting oxaliplatin-
related sensory neuropathy, without compromising DFS
and overall survival (OS) in patients with a T1-3/N1 stage III
disease.7
In the FOxTROT trial (Fig 1), reported in the article8
that accompanies this editorial, patients with operable,
nonobstructed, radiologically staged T3 or T4 (N0-2)
CC, without metastases, were randomly assigned 2:1
to receive 6 weeks of neoadjuvant chemotherapy
(NAC) with FOLFOX, followed by surgery and then
another 18 weeks of FOLFOX, whereas the control
group underwent surgery and then received postop-
erative FOLFOX for 24 weeks. Patients with wild-type
RAS tumors assigned to the NAC group had the option
to be randomly assigned 1:1 to receive panitumumab
during 6 weeks of NAC treatment. The protocol
allowed for two other options: a total chemotherapy
duration of 12 weeks instead of 24 weeks or treatment
with CAPOX instead of FOLFOX for patients who were
not in the panitumumab substudy.
Neoadjuvant treatment has been successful in many
other GI cancers (rectal, esophageal, and gastric) and has
the theoretical advantages of (1) improving treatment
feasibility by starting systemic treatment early and in a
larger proportion of patients, as this avoids the risk of delay
or precludes administration in the case of postoperative
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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.
complications; (2) testing tumor chemosensitivity and
potentially adapting postoperative treatment in the
event of poor radiological and/or pathological response;
and (3) improving patient outcome by treating micro-
metastatic disease upfront, inducing tumor downsizing
and thus improving the rate of complete (R0) onco-
logical surgery and potentially decreasing postoperative
complications.
NAC is currently recommended in guidelines in non-
metastatic T4b CC patients with a T4b tumor not suitable
for immediate surgery and remains an option for those
with obstruction after a defunctioning stoma.9,10
The FOxTROT trial in 1,052 patients recruited over
8.5 years, mainly in the United Kingdom, and selected
using standard computed tomography (CT) scan, shows
that NAC is safe, allows more R0 surgery (94.5 v 88.6%),
and does not increase perioperative morbidity. In ad-
dition, NAC not only induces substantial tumor down-
staging, with a 10% decrease in the rate of T4 and N2
tumors as compared with the control group, but also
more frequent mild-to-moderate pathological tumor
regression (55 v 20%). Finally, the primary end point of
the study was reached, with a recurrence rate that is
significantly lower at 2 years in the NAC group than with
the same chemotherapy given entirely postoperatively
(17 v 23%, risk ratio, 0.72; P 5 .037).
The question for the GI oncology community is thus
now: Is NAC going to be a new standard for patients
with locally advanced CC?
The answer is, in our opinion, not a standard but an
option, for the following reasons:
First, the results of FOxTROT were initially reported as
negative at ASCO 2019 and 2020 annual meetings
and have since become positive because of new
statistical analyses incorporating new events mainly
because of integration of data generated with CT scans
done a bit later than 2 years. In addition, the 2-year
recurrence rate primary end point is not standard for
adjuvant trials. Indeed, DFS defined as the time
elapsed between surgery and local or distant recur-
rences, second primary CC, or death, whichever oc-
curs first, has been accepted for 20 years as the most
relevant end point for adjuvant CC trials.11 DFS allows
analysis not only of the efficacy of a treatment in
controlling cancer but also of mortality from any cause
in a specific patient population and thus satisfies
oncologists, health authorities, and payers. DFS has
also been shown to be a good surrogate for long-term
 Editorial

THE TAKEAWAY
In the article8 that accompanies this editorial, the FOxTROT collaborative group shows that in patients with locally advanced
colon cancer (CC) on computed tomography scan, neoadjuvant chemotherapy with 6 weeks of infusional fluorouracil,
leucovorin, and oxaliplatin followed by 18 weeks of infusional fluorouracil, leucovorin, and oxaliplatin postoperatively is
safe and well tolerated and leads to improvement in 2-year recurrence rates as compared with the same treatment given
entirely postoperatively. This introduces neoadjuvant chemotherapy as a new treatment option for selected patients with
locally advanced CC but needs confirmation with more accurate radiological staging criteria and by integrating shorter
treatment duration and specific treatment options for different CC molecular subgroups.

OS, thus yielding conclusive trial results 2-3 years earlier abdomen and pelvic CT scan) at 2 years after random
than OS. Unfortunately, DFS was not chosen as the primary assignment was mandatory.
end point in the FOxTROT trial and although the authors
Second, FOxTROT does not integrate the results of the
report that 2- and 3-year DFS is also better for the NAC
IDEA Consortium and the robust result that 3 months of
group, classical DFS and OS curves with global Kaplan-
adjuvant therapy is enough, at least for the 60% of stage III
Meier curves, hazard ratio, and log-rank tests and numbers
patients with a T1-3/N1 CC.7 Although the authors have
of patients at risk over time are not shown in their paper. In
amended their protocol, , 6% of the study population was
addition, recurrence rate such as DFS is influenced by the
treated with a 12-week regimen, and in the forest plot
quality and planning of disease recurrence monitoring.
(appendix page 12), NAC is not favored at all in these
Although for adjuvant trials in CC minimal monitoring with
patients.
thorax abdomen and pelvic CT scan, twice yearly, together
with carcinoembryonic antigen assessment is recom- Third, CC staging preoperatively with a CT scan is currently
mended, in the FOxTROT trial only a full clinical assess- associated with 24%-33% of patients being overtreated (ie,
ment (including carcinoembryonic antigen and a thorax stage I or low-risk stage II disease).8,12 This is a clear argument

S
FOLFOX u FOLFOX
A x 6 weeks r x 18 weeks
g
e
B FOLFOX plus r Only for patients
FOLFOX
panitumumab y with RAS wild-type
x 18 weeks
x 6 weeks tumors
Operable
colon cancer
cT4 or high-risk cT3 R†
Fit for surgery S
(N ≈ 1,050) u
2:1
r
FOLFOX
C g
x 24 weeks
e
r
y

FOLFOX regimen is recommended. CAPOX should not be given to patients in the

panitumumab random assignment; otherwise, either FOLFOX or CAPOX may be used.

Although a 24-week total treatment duration was recommended initially, 12 weeks

were allowed after the IDEA results communication.

FIG 1. FOxTROT study design. CAPOX, capecitabine and oxaliplatin; FOLFOX, infusional fluorouracil, leuco-
vorin, and oxaliplatin.

Journal of Clinical Oncology 1515

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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.
 Editorial

for more relevant radiologic criteria to identify high-risk stage II
and stage III CC patients who should receive current adjuvant
treatments. This may be achieved by updated CT scan cri-
teria defined by expert radiologist on large patient numbers or
by explorating new imaging methods such as magnetic res-
onance imaging already validated for rectal cancer.
Fourth, current clinical research in the field of adjuvant
treatment for CC focuses on biomarkers that not only may
allow intensification of treatment for patients that will recur
despite surgery and adjuvant chemotherapy but also may
allow adjuvant chemotherapy to be decreased or skipped in
those already cured by surgery. Indeed, it is estimated that
we may be treating 100 patients to save 20 lives with ad-
juvant treatments, exposing the whole population to che-
motherapy and its side effects. Circulating tumor DNA
(ctDNA) has become a highly explored tool to detect minimal
residual disease, after CC surgery, and to select patients for
escalation (in ctDNA1) or de-escalation (in ctDNA–) trials.13
ctDNA performed postoperatively may individualize a group
of patients who will not need any chemotherapy after sur-
gery. This does not tally with the idea of giving 6 weeks of
treatment preoperatively to all patients.
However, despite these limitations, FOxTROT remains an
important research effort. The results convince us that NAC is
feasible and safe and certainly not detrimental for patients.
This opens a new avenue for preoperative treatments in
patients with resectable CC. The FOxTROT results suggest
that NAC may be particularly effective in T4 tumors and in
patients older than 70 years (Data Supplement8). These
observations should be confirmed by new trials such as the
ongoing FOxTROT 2 trial testing NAC in frail and elderly
patients.
In addition, specific molecular subgroups such as
microsatellite-unstable (MSI), BRAFV600E-mutant, or RAS-
mutant CC are now treated differently in the metastatic
setting, and new treatment options are under development
for KRAS G12C, G12D, and G12 V mutants as for HER2-
amplified CC. The first neoadjuvant treatments with tar-
geted agents have been tested using immune checkpoint
inhibitors in MSI CC with impressive results, as in, for in-
stance, the NICHE 2 trial which was recently presented at
the ESMO 2022 annual meeting. One cycle of nivolumab
plus ipilimumab followed by one cycle of nivolumab alone
before surgery led to a pathological complete response in
67% of patients, with no evidence of residual cancer, and to
a major pathological response, with only some residual
cancer cells left in the tumor, in 95% of the 112 patients
with MSI CC enrolled in this trial.14 Although the magnitude
of efficacy seems more limited for other molecular treat-
ments in CC with specific molecular alterations, the neo-
adjuvant setting seems a promising way for therapeutic
optimization in the future and neoadjuvant pilot studies for
all these molecular subgroups are ongoing or will start in the
near future, with a view to increasing the potential for cure
in our patients with CC.

AFFILIATIONS AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF

1
Department of Hepato-Gastroenterology and GI Oncology, Georges INTEREST
Pompidou European Hospital, Université Paris Cité, SIRIC CARPEM, Disclosures provided by the authors are available with this article at DOI
Paris, France https://doi.org/10.1200/JCO.22.02108.
2
Department of GI and Oncologic Surgery, Georges Pompidou European
Hospital, Université Paris Cité, SIRIC CARPEM, Paris, France
AUTHOR CONTRIBUTIONS
Conception and design: All authors
CORRESPONDING AUTHOR Manuscript writing: All authors
Julien Taieb, MD, PhD, Department of Hepato-Gastroenterology and GI Final approval of manuscript: All authors
Oncology, Université Paris-Cité, Hôpital Européen Georges Pompidou, Accountable for all aspects of the work: All authors
Assistance Publique Hôpitaux de Paris (APHP), 20 rue Leblanc, 75015
Paris, France; e-mail: jtaieb75@gmail.com.

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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.
 Editorial

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n n n

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 Editorial

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

FOxTROT: Are We Ready to Dance?
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted.
Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript.
For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Julien Taieb
Consulting or Advisory Role: Roche, Merck KGaA, Amgen, Servier, MSD, Pierre
Fabre, Novartis, AstraZeneca, BMS
Speakers’ Bureau: Servier, Amgen, Merck, MSD, Pierre Fabre
No other potential conflicts of interest were reported.

© 2023 by American Society of Clinical Oncology Volume 41, Issue 8

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