cancers

Commentary
Neoadjuvant Chemotherapy for Colon Cancer
Marc T. Roth * and Cathy Eng
Division of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center,
Nashville, TN 37232, USA; cathy.eng@vumc.org
* Correspondence: marc.roth@vumc.org




Received: 30 August 2020; Accepted: 23 September 2020; Published: 26 September 2020


Simple Summary: Neoadjuvant chemotherapy is commonly used in several solid tumor malignancies,
but remains understudied in the setting of locally advanced colon cancer. Advantages of this strategy
extrapolated from other disease sites include early treatment of micro-metastatic disease, the ability to
decrease local disease burden potentially leading to more effective resections and improved treatment
tolerability. Approaches for accurate staging and safe administration of systemic treatment are being
investigated in large, randomized clinical trials, but available data are either not mature enough
or have not demonstrated a convincing argument for adoption into standard practice warranting
further investigation.

Abstract: Early stage colon cancer is typically managed with surgical resection, although not all
patients experience a durable remission. Adjuvant chemotherapy with a fluoropyrimidine, with or
without oxaliplatin, is commonly utilized to increase the chance of cure, but its efficacy in the
neoadjuvant setting is not well established. Preoperative chemotherapy has demonstrated safety and
efficacy in other gastrointestinal malignancies, but there is a paucity of data from large, prospective
randomized trials, although multiple are ongoing. In this review, we will discuss the theoretical risks
and benefits, logistical difficulties, and available safety and efficacy data pertaining to the use of
chemotherapy in locally advanced colon cancer.

Keywords: colon cancer; neoadjuvant; chemotherapy; immunotherapy; microsatellite instability;

MSI-H

1. Introduction
Colon cancer accounted for nearly 1.1 million new cancer cases and was responsible for over
550,000 deaths globally in 2018 [1]. Furthermore, colorectal cancers are the third leading cause of
cancer-related deaths worldwide. Over 70% of patients will present with localized or regional disease,
which represents the best opportunity for cure via mesocolic excision [2]. After surgery, a surveillance
plan is generally set forth to detect early recurrence, including a scheduled history and physical labs
including tumor markers, imaging and endoscopic examinations. Per the National Comprehensive
Cancer Network (NCCN) guidelines, adjuvant chemotherapy can be considered for stage II disease,
with stronger evidence to support its use as staging increases due to depth of invasion and lymph
node involvement as in stage III disease [3]. Typically, a fluoropyrimidine, with or without oxaliplatin
(depending on stage and presence of high-risk features), is provided to reduce the risk of disease
recurrence. Even with adjuvant chemotherapy, the risk of recurrence at five years for colorectal cancer
can be over 25% [4].
Recently, there has been increasing interest in the utilization of neoadjuvant chemotherapy (NAC)
in colon cancer. Although few prospective randomized clinical trials have been conducted to inform the
subject, retrospective studies and small institutional trials have postulated there may be some benefit.
NAC is already widely used in other gastrointestinal malignancies, including esophageal, gastric and

Cancers 2020, 12, 2368; doi:10.3390/cancers12092368 www.mdpi.com/journal/cancers

Cancers 2020, 12, 2368 2 of 10

rectal cancers [5,6]. Multiple theories exist regarding the potential advantages in locally-advanced
colon cancer (LACC). First, NAC may aid in the earlier eradication of micro-metastatic disease and
decrease the size/stage of the primary tumor. This, in turn, could lead to increased R0 (margin
negative) resection rates. Animal models have demonstrated that surgical trauma leads to locoregional
metastasis [7]; however, through cytotoxic debulking with NAC, tumor cell shedding could decrease
during surgery. In addition, multiple observational studies have shown that chemotherapy is better
tolerated preoperatively, leading to fewer delays [8,9].
Neoadjuvant chemotherapy is not without its risks, however. Peripheral neuropathy from
oxaliplatin is a major morbidity incurred from adjuvant chemotherapy for colorectal cancer, so much
so that large clinical trials have investigated the efficacy of shortening durations of treatment [10].
Moving treatment into the pre-surgical space could lead to the overtreatment of low-risk patients if
they have incorrect radiographic staging [11,12]. Although NAC allows observation of disease biology
and assessment of chemo-responsiveness, delaying surgery in nonresponsive tumors could lead to
tumor growth, predisposing patients to obstruction and/or perforation, requiring an emergent surgery
associated with high morbidity and mortality.
This article will discuss the evidence for and against the use of neoadjuvant chemotherapy in
locally advanced colon cancer, with a special focus on recent randomized clinical trials and implications
of molecular subclasses. A comprehensive search of the literature was conducted for all clinical trial
phases involving neoadjuvant chemotherapy use in non-metastatic colon cancer. This search included
PubMed, clinicaltrials.gov and a review of all major conference abstracts. Of note, rectal cancer and
chemoradiation is excluded from this chapter and will be discussed elsewhere in this issue.

2. Radiographic Staging
An integral component of the appropriate use of NAC in the preoperative setting in colon cancer
is the ability to accurately stage patients via imaging. Traditionally, adjuvant therapy is indicated
based on pathologic staging—the gold standard. However, pathologic staging becomes less useful in
dictating the need for adjuvant treatment after exposure to cytotoxic chemotherapy due to expected
tumor regression. Early studies utilizing computed tomography (CT) to stage LACC found that T
and N staging was correctly predicted by radiologists in 60% and 62%, respectively [11]. A pilot
study for the FOxTROT clinical trial (discussed below) also assessed radiologist’s staging accuracy
within their protocol, finding that sensitivity and specificity for identifying T3/T4 vs. T1/T2 through
tumor infiltration beyond the muscularis propria were 95% and 50%, respectively [12]. One large
retrospective analysis of the National Cancer Database (NCDB) evaluated 105,569 patients with clinical
and pathologic staging, finding that the correlation for the T stage was 80%, and 83% for N stage.
Agreement increased with high T and N stages, suggesting that early stage disease is more difficult
to accurately assess [13]. Other modalities have been evaluated for use, such as MRI [14,15] and
CT colonography [16–18], but they have not yet replaced CT as standards within this space, in part
due to cost and invasiveness. Understanding the contribution of each radiographic staging modality
and when to use them may improve diagnostic accuracy further, to ensure that patients receive the
appropriate treatment for their disease.

3. Retrospective Studies
One of the earliest groups to report the potential benefit of neoadjuvant therapy in LACC was
from Arredondo et al. in 2013 [19]. Their analysis included 22 patients with stage III colon cancer who
received preoperative CAPOX (capecitabine 1000 mg/m2 twice daily on days 1–7, oxaliplatin 85 mg/m2
on day 1 every other week) ×4 between 2009 and 2010. After resection, they went on to receive four
additional cycles of adjuvant CAPOX. All patients experienced a radiographic response with a median
of 69.5% tumor volume reduction. No progressive disease occurred during preoperative chemotherapy.
At 14.4 months post-op, the actuarial overall survival (OS) was 100% and progression-free survival
(PFS) was 90%. Forty-three additional patients were evaluated on the same protocol between 2009
Cancers 2020, 12, 2368 3 of 10

and 2014 (infusional 5-FU was used in some cases [20]). Out of 65 total patients, the majority (93.8%)
completed planned treatment and no surgeries were delayed, with a median start time of 71 days
from chemotherapy to surgery. Tumor volume reduction assessed via CT was reported at 62.5%.
Pathologic complete response (pCR) was seen in 4.6% of patients. Adjuvant chemotherapy was only
given to 60% of patients, but five-year actuarial OS was over 95%. These findings formed the basis
of ELECLA (NCT04188158); the larger, randomized phase II study of neoadjuvant CAPOX in LACC,
which is ongoing.
Many of the retrospective data regarding neoadjuvant chemotherapy are derived from its use in
patients with T4b disease, defined as a tumor that directly invades or adheres to adjacent organs [3].
In 2016, the option for NAC in T4b disease was added to NCCN guidelines, after which two large
retrospective reviews of national databases were reported. In 2017, Dehal et al. published a retrospective
analysis of 921 patients in the NCDB, who received neoadjuvant chemotherapy between 2006 and
2014 [21]. Propensity score matching was used to compare this cohort to a standard of care group
treated with upfront surgery and adjuvant chemotherapy. Of note, patients treated with NAC were
younger, with higher-grade histology and advanced clinical T stage, but less advanced N stage than the
adjuvant group. At a median follow up of 3.6 years, 3-year OS was improved in the T4b neoadjuvant
cohort at 74%, compared to 66% after adjuvant chemotherapy (Hazard ratio (HR) 0.7, 95% CI 0.56–0.87;
p = 0.0002). This comparison remained statistically significant after propensity score matching. No
survival difference was noted in the T3 or T4a cohorts.
A similar study was reported in 2019, using data from the Netherlands Cancer Registry [22].
Propensity score matching was used to evaluate 149 patients with clinical T4 LACC treated with
neoadjuvant chemotherapy. In contrast to the NCDB study, R0 resection was achieved in only 77% of
those treated with NAC, vs. 86% of those after adjuvant chemotherapy (p = 0.037). Five-year OS did
not vary between the two groups (67% vs. 65%, p = 0.87). Still, no difference in surgical complications
was found between the two groups.

4. Prospective Single-Arm Studies

Multiple prospective, single-arm studies have been conducted to verify feasibility of the NAC
approach in LACC. Jakobsen et al. enrolled 77 patients with high risk T3/T4 colon cancer and assigned
them to receive three cycles of CAPOX (capecitabine 2000 mg/m2 daily on days 1–14 and oxaliplatin
130 mg/m2 on day 1 every 3 weeks) if they harbored a KRAS, BRAF or PIK3CA mutation, or if
their mutational status was unknown [23]. Wildtype patients received CAPOX plus panitumumab.
Based on pathologic response, if patients normally would have received adjuvant chemotherapy,
they continued to receive CAPOX ×5 cycles without panitumumab. If they were converted to a lower
stage, not meeting adjuvant chemotherapy criteria, they were observed. The primary endpoint was the
rate of conversion from a higher clinical stage to a lower pathologic stage no longer requiring adjuvant
chemotherapy. Conversion rate in the wildtype group was 42% compared to 51% in patients with
a mutation, with three patients experiencing a complete response. The 3-year DFS was 94% in the
converted group, versus 63% who did not convert (p = 0.0005).
Shortly thereafter, a similar design was employed by Liu et al. in a single-arm phase II trial
evaluating neoadjuvant CAPOX for patients with LACC [24]. Forty-seven patients were enrolled,
with 42 of them completing two to four cycles of NAC (depending on response) prior to resection,
followed by adjuvant chemotherapy to include eight cycles in total. The total clinical response rate was
70.7%, including one pCR and a partial response (PR) rate of 68.3%. Of note, emergent operations were
observed in three patients who experienced perforation or obstruction, but perioperative morbidity
and mortality were low.
After the efficacy of triplet therapy with a fluoropyrimidine, irinotecan and oxaliplatin was
established in metastatic colorectal cancer and a feasibility study was conducted in localized disease in
the neoadjuvant setting [25]. Twenty-three patients with stage IIIB colon cancer received four cycles of
FOLFOXIRI, followed by resection and an additional six cycles of either FOLFOXIRI or CAPOX. Tumor
Cancers 2020, 12, 2368 4 of 10

volume reduction occurred in 91.3% of patients (including one pCR), with 56.6% experiencing grade
3–4 toxicities, although no severe complications from surgery were observed. Of note, one patient
experienced a delay in surgery due to sustained bone marrow suppression and two progressed during
neoadjuvant treatment. Only 52.2% of patients completed all four cycles of neoadjuvant chemotherapy,
most commonly due to toxicity. At a median follow up time of 28 months, the 2-year OS rate was
95.7%, with a 2-year recurrence rate of 26.1%.

5. Prospective Randomized Trials

Very few prospective randomized trials utilizing neoadjuvant chemotherapy in LACC have been
conducted. In 2015, a group from France published their phase II trial protocol for NAC [26]. High risk
T3, T4 and/or N2 LACC patients were randomized to receive either immediate resection followed by
adjuvant FOLFOX (oxaliplatin 85 mg/m2 , folinic acid 400 mg/m2 , 5-FU 400 mg/m2 bolus followed by
2400 mg/m2 continuous infusion over 46 h), versus four cycles of neoadjuvant FOLFOX (plus cetuximab
if RAS wildtype), followed by resection and eight additional cycles of FOLFOX to complete adjuvant
treatment. The primary endpoint was histological tumor regression grade (TRG), which considers the
presence of viable tumor cells and fibrosis. The accrual goal was 165 patients. After the interim analysis,
the data monitoring committee recommended stopping the cetuximab arm due to lack of prespecified
efficacy by TRG and a severe postoperative morbidity rate of 15% in this arm. Enrollment continued
into the two other arms and the results of the trial were published earlier this year [27]. Ultimately,
104 patients were included in the primary endpoint analysis. Significant pathologic regression was seen
in 44% of those receiving preoperative chemotherapy versus 8% in the control arm, yet the primary
endpoint in TRG was not met. In the control arm, nearly 33% of patients who were radiographically
staged as high risk T3, T4 or N2 LACC were found to have low-risk stage II colon cancer and could
have been overtreated (based on the current standard of care) due to clinical overstaging.
The FOxTROT phase III clinical trial is the largest reported randomized trial to date, investigating
neoadjuvant chemotherapy in LACC. The primary outcome was the relapse or persistent disease rate
after two years following resection. The trial was divided into a phase II lead-in to evaluate feasibility
and safety [28], followed by a larger phase III period. Secondary outcomes included complete resection
rate, perioperative safety, downstaging and tumor regression. The pilot study was also utilized to verify
the accuracy of CT staging of high-risk colon cancers [12]. Radiologists involved in the study attended
workshops in order to standardize the interpretation of good, intermediate and poor prognosis tumors.
Criteria defined as poor prognoses were T3 and tumor extension ≥ 5 mm beyond the muscularis
propria or T4 disease (these criteria were largely used by the trials previously mentioned). Preoperative
staging was then compared to surgical pathology, identifying only 7% of patients who were definitively
overstaged and would have received chemotherapy unnecessarily.
Patients with radiologically-staged, high-risk T3–T4, N0–2 colon cancer were randomized to either
(A) three cycles of FOLFOX, followed by surgery and then nine additional cycles after surgical resection,
or (B) surgical resection, followed by twelve cycles of adjuvant FOLFOX. Randomization occurred in
a 2:1 fashion (A:B) and 1053 patients were ultimately enrolled [29]. If patients were KRAS wildtype
(n = 279), they were further randomized to receive panitumumab, which was to take place within
six weeks of starting NAC. Two dealer’s choices were included, allowing investigators to limit total
chemotherapy duration to twelve weeks (instead of 24 weeks) in older or intermediate-risk patients
(T3 or < 5mm extramural extension), or utilize capecitabine instead of infusional 5-FU (excluding
those receiving panitumumab). The study was conducted across 85 centers in the United Kingdom,
Denmark and Sweden between 2008 and 2016.
In the initial update at ASCO 2019, the intervention was reported to be safe and well-tolerated [29].
A 4% (n = 25) pCR rate was reported after NAC, and perioperative morbidity was not significantly
increased. The primary endpoint of 2-year failure rate was not statistically significant between the
NAC and adjuvant chemotherapy arms (14% vs. 18%, HR = 0.77; p = 0.11). A planned interim report
was provided at ASCO 2020 [30]. Neoadjuvant chemotherapy was delivered on schedule in 85% of
Cancers 2020, 12, 2368 5 of 10

patients, with only one delay in surgery due to neutropenia. Otherwise, there were no significant
differences in post-operative morbidity or length of hospital stays between the two cohorts. Relapse or
persistent disease after two years showed a trend toward improvement at 15.6% for NAC vs. 19.5% for
adjuvant chemotherapy, but did not meet statistical significance (HR = 0.76, 95% confidence interval
(CI 0.56–1.02; p = 0.07). Patients in the experimental group had significantly down-staged tumors
(p < 0.001 for pT and pN) and fewer incomplete resections (5% vs. 10%, p = 0.001). In a subgroup
analysis, tumor characteristics which appeared to benefit from NAC included left-sided primary tumor
location (OR 0.58, 0.38–0.91) and T4 lesions (OR 0.59, 0.35–1.00). Furthermore, the addition of EGFR
inhibition did not seem to affect the primary outcome.
Additional analyses were conducted comparing mismatch repair (MMR) status assessed by
immunohistochemistry (IHC) in response to neoadjuvant chemotherapy. MMR status was obtained
in 86.8% of patients, with 20.2% being MMR-deficient (dMMR) and 79.8% being MMR-proficient
(pMMR), or unknown. As expected, based on the known behavior of dMMR tumors, a lower rate of
tumor regression with chemotherapy compared to pMMR was seen (OR = 0.37, 0.22–0.61, p < 0.0001).
Similarly, reductions in recurrence at two years were primarily seen in pMMR tumors (RR = 0.72,
0.52–1.00, p = 0.05), compared with dMMR tumors (RR = 0.94, 0.43–2.07, p = 0.9). These data, and those
from other clinical trials, suggest that dMMR tumors should be treated differently than pMMR in
nonmetastatic colon cancer. Studies are ongoing and discussed below.
The largest randomized phase III trial utilizing neoadjuvant CAPOX is currently recruiting in
China [31]. Goal accrual is 1370 patients with a primary outcome of 3-year DFS. Objective response
rate, R0 resection rate, OS and safety will be secondary endpoints. Of note, this trial will take into
account MMR/MSI status when screening. Other ongoing clinical trials are listed in Table 1.
Cancers 2020, 12, 2368 6 of 10

Table 1. Ongoing neoadjuvant therapy trials in localized colon cancer

Trial Number Intervention Population Status Phase Accrual Goal Location(s) Primary Endpoint
CAPOX ×4 → surgery → CAPOX ×4
NCT03125980 Vs. LACC Recruiting III 1370 China 3-year DFS
surgery → CAPOX ×8
neoadjuvant FOLFOX ×4 → surgery → adjuvant FOLFOX ×8
NCT03426904 vs. LACC Recruiting III 560 Korea RFS
surgery → adjuvant FOLFOX × 12
neoadjuvant CAPOX ×3 → surgery → adjuvant CAPOX (if
Denmark
indicated based on pathology)
NCT01918527 LACC Recruiting III 250 Sweden 2-year DFS
vs.
Norway
surgery → adjuvant CAPOX ×4–8
colonic stent → FOLFOX ×3 or CAPOX ×2 → surgery →
NCT02972541 FOLFOX ×5–9 or CAPOX ×4–6
LACC Recruiting 248 China DFS
(NACSOC) vs.
colonic stent → surgery → FOLFOX ×8–12 or CAPOX ×6–8
neoadjuvant CAPOX ×3 → surgery → adjuvant CAPOX ×5
NCT04188158
vs. LACC Recruiting II 238 Spain 2-year DFS
(ELECLA)
surgery → adjuvant CAPOX ×8
neoadjuvant FOLFOX ×4 ± cetuximab → surgery → adjuvant
NCT01675999 FOLFOX ×8 ± cetuximab Tumor response by
LACC Recruiting II 186 France
(ECKINOXE) vs. TRG
surgery → adjuvant FOLFOX ×12
NCT03026140 Stages I–III
ipilimumab + nivolumab ± celecoxib → surgery Recruiting II 60 Netherlands Safety
(NICHE) CC
pembrolizumab → surgery
Not yet
NCT04231526 vs. LACC II 46 USA Feasibility
recruiting
surgery
toripalimab (anti-PD1) + FOLFOX ×6 → surgery → same ×6 pCR rate
Not yet
NCT03985891 vs. LACC I/II 40 China rCR rate
recruiting
FOLFOX ×6 → surgery → FOLFOX ×6 ORR
Not yet Tumor
NCT03484195 FOLFOXIRI ×4 → surgery LACC II 30 China
recruiting downstaging
Abbreviations: CAPOX = capecitabine+oxaliplatin, LACC = locally advanced colon cancer, DFS = disease free survival, FOLFOX = 5-fluorouracil+folinic acid + oxaliplatin, RFS = relapse
free survival, TRG = tumor response grade, CC = colon cancer, pCR = pathologic complete response, rCR = radiographic complete response, ORR = objective response rate,
FOLFOXIRI = 5-FU + folinic acid + oxaliplatin + irinotecan.
Cancers 2020, 12, 2368 7 of 10

6. Individualized Therapy
Immune checkpoint inhibition (ICPI) has shown efficacy in metastatic colorectal cancer and
was recently approved in the first-line setting for microsatellite instability “high” (MSI-H) patients.
Naturally, interest in ICPI use in the neoadjuvant space in colon cancer has grown after successes in
other malignancies [32–34]. In the exploratory NICHE study, investigators proposed utilizing ICPI in
both dMMR and pMMR LACC [35]. They postulated that there may be greater efficacy in early stage
pMMR colon cancer over late stage due to the higher degree of T-cell infiltration in the former [36].
Within the pMMR group, celecoxib was also added, based on preclinical evidence that it may be
synergistic with ICPI and increase tumor-promoting inflammation [37]. Patients received dual ICPI
with ipilimumab (day 1) and nivolumab (days 1 and 15), followed by surgery to occur within six
weeks of study consent. The primary objective was safety and feasibility in this phase II study. Out of
21 dMMR patients and 20 pMMR patients enrolled, 20 with dMMR and 15 with pMMR were included
in the analysis. There were no delays in surgery and adverse events were in line with the reported
side effect profiles of the therapies. Within the dMMR cohort, 100% had a pathologic response (60%
had a pCR). Of the pMMR tumors, 27% experienced a pathologic response (13% pCR). Four patients
(1 dMMR, 3 pMMR) went on to receive adjuvant chemotherapy after resection. At a median follow up
of nine months, all dMMR patients were alive and without disease. One pMMR patient developed
metastatic disease treated with palliative chemotherapy, and one died due to unrelated circumstances.
This study continues patient accrual.
The PePiTA study (Preoperative chemosensitivity testing as Predictor of Treatment benefit in
Adjuvant stage III colon cancer) is evaluating adjuvant therapy but utilizes a component of neoadjuvant
chemotherapy in its design. In this prospective, single-arm study, LACC patients received one cycle of
FOLFOX, followed by surgery and standard of care adjuvant chemotherapy. PET/CT responses before
and after one cycle of preoperative chemotherapy were used to predict adjuvant outcomes measured
by 3-year DFS. Metabolic response on imaging was defined as a decrease in ≥ 15% in SUVmax after
one cycle of chemotherapy. In a preliminary analysis, metabolic response was reported in 204/240
patients [38]. In 218 patients who received NAC, a metabolic response was observed in 65.2% of
patients. Although evaluating neoadjuvant therapy was not the primary interest of this study, results
may shed light on which patients are likely to benefit from chemotherapy in this setting.

7. Conclusions
Neoadjuvant chemotherapy will likely find its niche in the treatment of locally advanced colon
cancer as data continue to unfold. Teasing out which populations are likely to benefit through molecular
characterization and radiographic response will be necessary. Likewise, avoiding operative delays in
those with a low likelihood of response to cytotoxic treatment will be imperative. The inclusion of novel
approaches with immunotherapy or other targeted agents outside of traditional chemotherapy could
provide significant survival advantages, including for a personalized approach. The generalizability
of any of these approaches must be kept in mind, especially with a burgeoning young adult cohort
that may be appropriate for treatment intensification, and an elderly patient population that is above
the median age reflected in the aforementioned trials. The momentum of the field is encouraging
and with continued ingenuity, neoadjuvant treatment of colon cancer has the potential to evolve into
a new standard of care with improved advances in diagnostic imaging, molecular characterization,
and clinical trial enrollment.

Author Contributions: M.T.R., C.E.; writing—original draft preparation, reviewing and editing. All authors have
read and agreed to the published version of the manuscript
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
Cancers 2020, 12, 2368 8 of 10

References
1. Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018:
GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA A Cancer
J. Clin. 2018, 68, 394–424. [CrossRef] [PubMed]
2. SEER Cancer Stat Facts: Colorectal Cancer. National Cancer Institute. Available online: https://seer.cancer.
gov/statfacts/html/colorect.html (accessed on 15 August 2020).
3. National Comprehensive Cancer Network. Colon Cancer (Version 2.2020). Available online: https:
//www.nccn.org/professionals/physician_gls/pdf/colon.pdf (accessed on 14 April 2020).
4. André, T.; Boni, C.; Navarro, M.; Tabernero, J.; Hickish, T.; Topham, C.; Bonetti, A.; Clingan, P.; Bridgewater, J.;
Rivera, F.; et al. Improved Overall Survival with Oxaliplatin, Fluorouracil, and Leucovorin as Adjuvant
Treatment in Stage II or III Colon Cancer in the MOSAIC Trial. J. Clin. Oncol. 2009, 27, 3109–3116. [CrossRef]
[PubMed]
5. Al-Batran, S.-E.; Homann, N.; Pauligk, C.; O Goetze, T.; Meiler, J.; Kasper, S.; Kopp, H.-G.; Mayer, F.;
Haag, G.M.; Luley, K.; et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and
docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable
gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): A randomised, phase 2/3 trial. Lancet 2019,
393, 1948–1957. [CrossRef] [PubMed]
6. Hospers, G.; Bahadoer, R.R.; Dijkstra, E.A.; Van Etten, B.; Marijnen, C.; Putter, H.; Kranenbarg, E.M.-K.;
Roodvoets, A.G.; Nagtegaal, I.D.; Beets-Tan, R.G.; et al. Short-course radiotherapy followed by chemotherapy
before TME in locally advanced rectal cancer: The randomized RAPIDO trial. J. Clin. Oncol. 2020, 38, 4006.
[CrossRef]
7. Van Der Bij, G.J.; Oosterling, S.J.; Beelen, R.H.J.; Meijer, S.; Coffey, J.C.; Van Egmond, M. The Perioperative
Period is an Underutilized Window of Therapeutic Opportunity in Patients With Colorectal Cancer. Ann. Surg.
2009, 249, 727–734. [CrossRef]
8. Bayraktar, U.D.; Chen, E.; Bayraktar, S.; Sands, L.R.; Marchetti, F.; Montero, A.J.; Rocha-Lima, C.M.S.
Does delay of adjuvant chemotherapy impact survival in patients with resected stage II and III colon
adenocarcinoma? Cancer 2010, 117, 2364–2370. [CrossRef]
9. Biagi, J.J.; Raphael, M.J.; MacKillop, W.; Kong, W.; King, W.D.; Booth, C. Association Between Time to
Initiation of Adjuvant Chemotherapy and Survival in Colorectal Cancer. JAMA 2011, 305, 2335–2342.
[CrossRef]
10. André, T.; Vernerey, D.; Mineur, L.; Bennouna, J.; Desrame, J.; Faroux, R.; Fratte, S.; De Larauze, M.H.;
Paget-Bailly, S.; Chibaudel, B.; et al. Three Versus 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy
for Patients with Stage III Colon Cancer: Disease-Free Survival Results from a Randomized, Open-Label,
International Duration Evaluation of Adjuvant (IDEA) France, Phase III Trial. J. Clin. Oncol. 2018, 36,
1469–1477. [CrossRef]
11. Smith, N.J.; Bees, N.; Barbachano, Y.; Norman, A.R.; Swift, R.I.; Brown, G. Preoperative computed tomography
staging of nonmetastatic colon cancer predicts outcome: Implications for clinical trials. Br. J. Cancer 2007, 96,
1030–1036. [CrossRef]
12. Dighe, S.; Swift, I.; Magill, L.; Handley, K.; Gray, R.; Quirke, P.; Morton, D.; Seymour, M.; Warren, B.; Brown, G.
Accuracy of radiological staging in identifying high-risk colon cancer patients suitable for neoadjuvant
chemotherapy: A multicentre experience. Color. Dis. 2012, 14, 438–444. [CrossRef]
13. Dehal, A.N.; Graff-Baker, A.N.; Vuong, B.; Nelson, D.W.; Chang, S.-C.; Lee, D.Y.; Goldfarb, M.; Bilchik, A.J.
Correlation Between Clinical and Pathologic Staging in Colon Cancer: Implications for Neoadjuvant
Treatment. J. Gastrointest. Surg. 2018, 22, 1764–1771. [CrossRef] [PubMed]
14. Rollvén, E.; Lörinc, E.; Holm, T.; Glimelius, B.; Blomqvist, L. Potentials of high resolution magnetic resonance
imaging versus computed tomography for preoperative local staging of colon cancer. Acta Radiol. 2013, 54,
722–730. [CrossRef] [PubMed]
15. Nerad, E.; Lambregts, D.M.J.; Kersten, E.L.J.; Maas, M.; Bakers, F.C.H.; Bosch, H.C.M.V.D.; Grabsch, H.I.;
Beets-Tan, R.G.H.; Lahaye, M.J. MRI for Local Staging of Colon Cancer. Dis. Colon Rectum 2017, 60, 385–392.
[CrossRef] [PubMed]
Cancers 2020, 12, 2368 9 of 10

16. Horvat, N.; Raj, A.; Liu, S.; Matkowskyj, K.A.; Knezevic, A.; Capanu, M.; Shia, J.; Pickhardt, P.J.; Gollub, M.J.
CT Colonography in Preoperative Staging of Colon Cancer: Evaluation of FOxTROT Inclusion Criteria for
Neoadjuvant Therapy. Am. J. Roentgenol. 2019, 212, 94–102. [CrossRef] [PubMed]
17. Filippone, A.; Ambrosini, R.; Fuschi, M.; Marinelli, T.; Genovesi, D.; Bonomo, L. Preoperative T and N
Staging of Colorectal Cancer: Accuracy of Contrast-enhanced Multi–Detector Row CT Colonography—Initial
Experience. Radiology 2004, 231, 83–90. [CrossRef] [PubMed]
18. Flor, N.; Mezzanzanica, M.; Rigamonti, P.; Guerini-Rocco, E.; Bosari, S.; Ceretti, A.P.; Soldi, S.; Peri, M.;
Sardanelli, F.; Cornalba, G.P. Contrast-Enhanced Computed Tomography Colonography in Preoperative
Distinction between T1–T2 and T3–T4 Staging of Colon Cancer. Acad. Radiol. 2013, 20, 590–595. [CrossRef]
[PubMed]
19. Arredondo, J.; Pastor, C.; Baixauli, J.; Rodriguez, J.; González, I.; Vigil, C.; Chopitea, A.; Hernández-Lizoain, J.L.
Preliminary outcome of a treatment strategy based on perioperative chemotherapy and surgery in patients
with locally advanced colon cancer. Color. Dis. 2013, 15, 552–557. [CrossRef]
20. Arredondo, J.; Baixauli, J.; Pastor, C.; Chopitea, A.; Sola, J.J.; González, I.; Cienfuegos, J.A.; Martínez, P.;
Rodriguez, J.; Hernández-Lizoain, J.L. Mid-term oncologic outcome of a novel approach for locally advanced
colon cancer with neoadjuvant chemotherapy and surgery. Clin. Transl. Oncol. 2016, 19, 379–385. [CrossRef]
21. Dehal, A.; Graff-Baker, A.N.; Vuong, B.; Fischer, T.; Klempner, S.J.; Chang, S.C.; Grunkemeier, G.L.; Bilchik, A.J.;
Goldfarb, M. Neoadjuvant Chemotherapy Improves Survival in Patients with Clinical T4b Colon Cancer.
J. Gastrointest. Surg. 2018, 22, 242–249. [CrossRef]
22. De Gooyer, J.M.; Verstegen, M.G.; Lam-Boer, J.T.; Radema, S.A.; Verhoeven, R.H.; Verhoef, C.;
Schreinemakers, J.M.; De Wilt, J.H. Neoadjuvant Chemotherapy for Locally Advanced T4 Colon Cancer:
A Nationwide Propensity-Score Matched Cohort Analysis. Dig. Surg. 2019, 37, 1–10. [CrossRef]
23. Jakobsen, A.; Andersen, F.; Fischer, A.; Jensen, L.H.; Jørgensen, J.C.R.; Larsen, O.; Lindebjerg, J.; Pløen, J.;
Rafaelsen, S.R.; Vilandt, J. Neoadjuvant chemotherapy in locally advanced colon cancer.A phase II trial.
Acta Oncol. 2015, 54, 1747–1753. [CrossRef]
24. Liu, F.; Yang, L.; Wu, Y.; Li, C.; Zhao, J.; Keranmu, A.; Zheng, H.; Huang, D.; Wang, L.; Tong, T.; et al. CapOX
as neoadjuvant chemotherapy for locally advanced operable colon cancer patients: A prospective single-arm
phase II trial. Chin. J. Cancer Res. 2016, 28, 589–597. [CrossRef] [PubMed]
25. Zhou, H.; Department of Colorectal Surgery; Song, Y.; Jiang, J.; Niu, H.; Zhao, H.; Liang, J.; Su, H.; Wang, Z.;
Zhou, Z.; et al. A pilot phase II study of neoadjuvant triplet chemotherapy regimen in patients with locally
advanced resectable colon cancer. Chin. J. Cancer Res. 2016, 28, 598–605. [CrossRef] [PubMed]
26. Karoui, M.; Rullier, A.; Luciani, A.; Bonnetain, F.; Auriault, M.-L.; Sarran, A.; Monges, G.; Trillaud, H.;
Le Malicot, K.; Leroy, K.; et al. Neoadjuvant FOLFOX 4 versus FOLFOX 4 with Cetuximab versus immediate
surgery for high-risk stage II and III colon cancers: A multicentre randomised controlled phase II trial–the
PRODIGE 22–ECKINOXE trial. BMC Cancer 2015, 15, 511. [CrossRef] [PubMed]
27. Karoui, M.; Rullier, A.; Piessen, G.; Legoux, J.L.; Barbier, E.; De Chaisemartin, C.; Lecaille, C.; Bouche, O.;
Ammarguellat, H.; Brunetti, F.; et al. Perioperative FOLFOX 4 Versus FOLFOX 4 Plus Cetuximab Versus
Immediate Surgery for High-Risk Stage II and III Colon Cancers: A Phase II Multicenter Randomized
Controlled Trial (PRODIGE 22). Ann. Surg. 2020, 271, 637–645. [CrossRef]
28. FOxTROT Collaborative Group. Feasibility of preoperative chemotherapy for locally advanced, operable
colon cancer: The pilot phase of a randomised controlled trial. Lancet Oncol. 2012, 13, 1152–1160. [CrossRef]
29. Seymour, M.T.; Morton, D.; on behalf of the International FOxTROT Trial Investigators. FOxTROT:
An international randomised controlled trial in 1052 patients (pts) evaluating neoadjuvant chemotherapy
(NAC) for colon cancer. J. Clin. Oncol. 2019, 37, 3504. [CrossRef]
30. Seligmann, J.F.; FOxTROT Collaborative Group. FOxTROT: Neoadjuvant FOLFOX chemotherapy with or
without panitumumab (Pan) for patients (pts) with locally advanced colon cancer (CC). J. Clin. Oncol. 2020,
38, 4013. [CrossRef]
31. Liu, F.; Tong, T.; Huang, D.; Yuan, W.; Li, D.; Lin, J.; Cai, S.; Xu, Y.; Chen, W.; Sun, Y.; et al. CapeOX
perioperative chemotherapy versus postoperative chemotherapy for locally advanced resectable colon
cancer: Protocol for a two-period randomised controlled phase III trial. BMJ Open 2019, 9, e017637.
[CrossRef]
Cancers 2020, 12, 2368 10 of 10

32. Blank, C.U.; A Rozeman, E.; Fanchi, L.; Sikorska, K.; Van De Wiel, B.; Kvistborg, P.; Krijgsman, O.;
Braber, M.V.D.; Philips, D.; Broeks, A.; et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in
macroscopic stage III melanoma. Nat. Med. 2018, 24, 1655–1661. [CrossRef]
33. Powles, T.; Kockx, M.; Rodriguez-Vida, A.; Duran, I.; Crabb, S.J.; Van Der Heijden, M.S.; Szabados, B.;
Pous, A.F.; Gravis, G.; Herranz, U.A.; et al. Clinical efficacy and biomarker analysis of neoadjuvant
atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat. Med. 2019, 25, 1706–1714.
[CrossRef] [PubMed]
34. Forde, P.M.; Chaft, J.E.; Smith, K.N.; Anagnostou, V.; Cottrell, T.R.; Hellmann, M.D.; Zahurak, M.; Yang, S.C.;
Jones, D.R.; Broderick, S.; et al. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N. Engl. J. Med.
2018, 378, 1976–1986. [CrossRef] [PubMed]
35. Chalabi, M.; Fanchi, L.F.; Dijkstra, K.K.; Berg, J.G.V.D.; Aalbers, A.G.; Sikorska, K.; Lopez-Yurda, M.;
Grootscholten, C.; Beets, G.L.; Snaebjornsson, P.; et al. Neoadjuvant immunotherapy leads to pathological
responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat. Med. 2020, 26, 566–576.
[CrossRef] [PubMed]
36. Mlecnik, B.; Bindea, G.; Angell, H.K.; Maby, P.; Angelova, M.; Tougeron, D.; Church, S.E.; Lafontaine, L.;
Fischer, M.; Fredriksen, T.; et al. Integrative Analyses of Colorectal Cancer Show Immunoscore Is a Stronger
Predictor of Patient Survival Than Microsatellite Instability. Immunity 2016, 44, 698–711. [CrossRef] [PubMed]
37. Zelenay, S.; Van Der Veen, A.G.; Böttcher, J.P.; Snelgrove, K.J.; Rogers, N.; Acton, S.E.; Chakravarty, P.;
Girotti, M.R.; Marais, R.; Quezada, S.A.; et al. Cyclooxygenase-Dependent Tumor Growth through Evasion
of Immunity. Cell 2015, 162, 1257–1270. [CrossRef]
38. Hendlisz, A.; Caparica, R.; Deleporte, A.; Van Laethem, J.-L.; Vergauwe, P.; Eynde, M.V.D.; DeBoever, G.;
Janssens, J.; Demolin, G.; Holbrechts, S.; et al. Preoperative chemosensitivity testing as predictor of treatment
benefit in adjuvant stage III colon cancer: Preliminary analysis of the PePiTA study. J. Clin. Oncol. 2019,
37, 3610. [CrossRef]

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