Research Article

Dig Surg Received: June 25, 2019

Accepted: September 15, 2019
DOI: 10.1159/000503446 Published online: October 29, 2019

Neoadjuvant Chemotherapy for Locally Advanced

T4 Colon Cancer: A Nationwide Propensity-Score
Matched Cohort Analysis
Jan-Marie de Gooyer a Marlies G. Verstegen a Jorine ’t Lam-Boer a
Sandra A. Radema b Rob H.A. Verhoeven a, c Cornelis Verhoef d
Jennifer M.J. Schreinemakers a, e Johannes H.W. de Wilt a
a Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlands; b Department of Medical

Oncology, Radboud University Medical Center, Nijmegen, The Netherlands; c Department of Research and Development,
The Netherlands Comprehensive Cancer Organisation, Utrecht, The Netherlands; d Department of Surgery, Erasmus MC
Cancer Institute, Rotterdam, The Netherlands; e Department of Surgery, Amphia Hospital, Breda, The Netherlands

Keywords After neoadjuvant CT, a significant response was observed

Locally advanced colon cancer · Neoadjuvant in 13 (9%) patients with 5 (4%) patients showing a complete
chemotherapy · Systemic treatment · Preoperative response. Complete resection margins (R0) were achieved in
treatment 77% in the neoadjuvant group versus 86% in the adjuvant
treated group (p = 0.037). Significantly less tumor positive
lymph nodes were found in the neoadjuvant group (median
Abstract 0 vs. 2, p < 0.001). Major complication rates and 5-year over-
Introduction: Neoadjuvant chemotherapy (CT) for locally all survival did not differ between both groups (67–65%, p =
advanced colon cancer (LACC) could potentially lead to tu- 0.87). Conclusion: Neoadjuvant CT seems safe and feasible
mor shrinkage, eradication of micrometastases, and preven- with similar long-term survival compared to patients who
tion of tumor cell shedding during surgery. This retrospec- are treated with adjuvant CT. © 2019 The Author(s)
tive study investigates the surgical and oncological out- Published by S. Karger AG, Basel

comes of preoperative CT for LACC. Methods: Using the

Netherlands Cancer Registry, data of patients with stage II or
III colon cancer, diagnosed between 2008 and 2016 was col-
lected. A propensity score matching (PSM; 1: 2) was per- Introduction
formed and compared patients with clinical tumor (cT) 4 co-
lon cancer who were treated with neoadjuvant CT to pa- Colorectal cancer is the third most common type of
tients with cT4 colon cancer treated with adjuvant CT (Fig. 1). cancer worldwide [1]. With >14,000 novel cases annually
Results: A total of 192 patients treated with neoadjuvant CT in the Netherlands, colorectal cancer can be held account-
were compared to 1,954 patients that received adjuvant CT. able for approximately 5,000 cancer deaths a year. About
After PSM, 149 patients in the neoadjuvant group were com-
pared to 298 patients in the control group. No significant
differences were found in baseline characteristics after PSM. J.-M.G. and M.G.V. contributed equally to this publication.

© 2019 The Author(s) Jan-Marie de Gooyer, MD

Published by S. Karger AG, Basel Department of Surgery
Radboud University Medical Center
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Usage and distribution for commercial purposes as well as any dis-
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two-thirds of these patients present with colon cancer and awaited and until now there is limited experience with
approximately 15% of these patients present with locally this neo-adjuvant treatment strategy.
advanced disease (i.e., T3 with ≥5 mm invasion beyond The purpose of this population-based propensity-
the muscularis propria or T4) without signs of distant score matched cohort study was to investigate the surgical
metastases [2]. Current European guidelines recommend and oncological outcomes of neoadjuvant CT for patients
surgical resection of the primary tumor, followed by post- with locally advanced colon cancer (LACC). Surgical
operative chemotherapy (CT) in case of high-risk stage II complications and pathological response to CT expressed
or III tumors [3]. This recommendation has been dem- as downstaging, mortality, and overall survival was com-
onstrated to be effective in adenocarcinoma, but similar pared to patients with similar disease stage who received
improved survival has recently been demonstrated in surgery followed by adjuvant CT.
both mucinous and signet ring cell tumors [4, 5].
For locally advanced tumors located in the rectum,
neoadjuvant chemoradiation is already well and widely Methods
established as the standard treatment protocol. Neoadju-
vant CT is thought to enhance tumor regression and Data Acquisition
downsizing of the tumor, which improves tumor resect- Nationwide population-based data were acquired from the
ability and promotes higher rates of local control hence, Netherlands Cancer Registry (NCR). This database contains every
cancer diagnosis in the Netherlands since 1989 and has an esti-
achieve more R0 resections [6–9]. These benefits of neo- mated completeness of at least 95%. The database is based on no-
adjuvant chemo (radio) therapy have also been proven tification by the nationwide automated pathology registry and the
for locally advanced breast cancer [10], gastric cancer National Registry of Hospital Discharge Diagnosis. Trained data
[11], and esophageal cancer [12]. Another possible ad- managers of the Netherlands Comprehensive Cancer Organiza-
vantage of neoadjuvant therapy is the early eradication tion obtain all data directly from patient medical files. Classifica-
tion of tumor characteristics was done according to the TNM Clas-
of systemic micrometastases, approximately 12 weeks sification of Malignant Tumors [24] and International Classifica-
earlier compared to CT administered postoperatively tion of Diseases for Oncology (ICD-O) [25]. To retrieve follow-up
[13]. This could possibly prevent the occurrence of dis- on vital status, the NCR is linked to the Municipal Personal Re-
tant relapse and thus increase survival, particularly be- cords database annually. At the time of data extraction, follow-up
cause resection of the primary tumor has shown to in- had been completed up to February 1, 2019.
duce growth factor activity, which enhances growth of Patient Selection
micrometastases [14–18]. Moreover, in case of neoadju- The database contained all patients who presented with either
vant treatment, patients do not run the risk of suffering clinical or pathological stage II or III colon cancer (C18–C19) and
from postoperative complications which could lead to who were treated with CT between 2008 and 2016. Follow-up data
postponing or even omitting adjuvant CT. On the con- were available from the time of diagnosis until February 1, 2019.
All patients with clinically CT-staged T4 colon cancer were select-
trary, neoadjuvant CT does not always result in a re- ed. Patients who received radiotherapy were excluded since these
sponse, and disease progression could occur during were mainly rectosigmoid tumors treated with neoadjuvant
treatment. Progression could lead to obstruction and the chemoradiation according to rectal cancer treatment protocols.
need for emergency surgery, which is associated with Patients with tumor location coded as rectosigmoid were also ex-
worse oncological outcomes with higher morbidity and cluded because it is not possible to determine if they were treated
as rectal or sigmoid cancer based on the available information.
mortality [19]. In a worst case scenario, patients cannot ­Patients who were not treated with surgical resection of the pri-
be treated with a resection of the primary tumor because mary tumor were also excluded. LACC is defined as T4 or T3 with
of treatment-related toxicity or disease progression and ≥5 mm invasion beyond the muscularis propria but since the latter
inoperability. is not accurately distinguishable on CT, only patients with clini-
There have been small series describing the feasibility cally diagnosed clinical tumor (cT) 4 colon cancer were selected to
represent locally advanced disease. Patients treated with neoadju-
of neoadjuvant CT or chemoradiation in colon cancer. vant CT followed by surgery (with or without adjuvant CT) were
These studies demonstrated safety, high percentages of selected and compared to patients who underwent surgery fol-
R0 resections, and excellent local control rates [20–23]. lowed by adjuvant CT without any form of preoperative treatment
The most striking evidence so far has been published by (Fig. 1).
the foxtrot collaboration group. They published results
Data Selection
from a pilot phase randomized clinical study comparing The extracted data included the following variables: age, sex,
neo-adjuvant to adjuvant CT [21]. The preliminary out- localization of the tumor, differentiation grade, morphology, clin-
comes are promising but long-term outcomes are to be ical and pathological T and N stage, type of surgery, resection mar-

2 Dig Surg de Gooyer et al.

DOI: 10.1159/000503446
 The Netherlands cancer registry 2008–2016 16,177 patients with stage II or III
– Nationwide database colon cancer who were treated with
– Retrospective cohort a form of systemic CT

2,647 patient with clinically

stage T4 tumor

108 patients
211 patients 182 patients
with 2,146 T4 colon cancer patients
treated with not treated
rectosigmoid matching inclusion criteria
radiotherapy with surgery
cancer

192 patients 1,954 patients

vs.
Propensity score matching 1:2 neoadjuvant adjuvant
– Age, gender, year of diagnosis
– Tumor location, morfology, differentiation
– cN and cT stage
149 patients 298 patients
vs.
neoadjuvant adjuvant
Fig. 1. Flowchart of patient selection. CT,
chemotherapy; cT, clinical tumor.

gins, postoperative complications, length of follow-up, and vital for neoadjuvant treatment, χ2 was performed. A propensity score
status. Location of the tumor was coded according to the ICD-O matching (PSM) analysis including all baseline characteristics that
(C18.0-C19.9) [8]. Morphology was divided into 3 subtypes: mu- were significantly associated with neoadjuvant CT treatment and
cinous (ICD-O 8480, 8481), signet ring cell (8490) and non-muci- all unbalanced baseline covariables was performed to adjust for
nous, non-signet ring cell adenocarcinoma (8000, 8010, 8020, confounding. Variables used in matching were: age, gender, year
8021, 8140, 8141, 8143, 8144, 8210, 8211, 8220, 8221, 8260, 8261, of diagnosis, tumor location, morphology, differentiation grade,
8262, 8263). Date of diagnosis was defined as the date of first his- clinical T-stage, and clinical N-stage. Patients were matched in a
tological confirmation of malignancy, most often the day of endo- ratio of 1:2 between the neoadjuvant and the control groups since
scopic biopsy. After resection the pathologist performed final stag- this results in improved precision without an increase in bias [26].
ing. Pathological tumor (ypT) and nodal staging was compared to All patients without a matching counterpart were excluded from
clinical staging in both groups to assess downstaging effects of neo- the analyses. After PSM, baseline characteristics were compared to
adjuvant CT and to highlight differences between clinical and ypT assure that no major differences persisted between the groups. Af-
staging in the control group. R0 resections were achieved if the ter PSM, OS curves were rendered according to the Kaplan-Meier
resection margins were microscopically free of tumor. In case of method. The equality of the distribution between both groups was
irradical resections, the resection was either labeled R1 (micro- compared using the log-rank test. A landmark analysis was per-
scopic involvement of the resection margins) or R2 (macroscopic formed to correct for immortal time bias. The landmark was set at
involvement). Major postoperative complications were recorded the time point where 90% of both groups had started treatment.
(abscesses and/or anastomotic leakage). Thirty-day postoperative This cutoff point was determined to be 96 days. All patients with a
mortality was calculated for patients whose date of resection was follow-up of 95 days or less were excluded from the analysis. R0
known in the neoadjuvant group. Thirty-day mortality was not resection rates, postoperative complications, pT and pN stages
calculated in the adjuvant group because the control group only were compared using χ2 tests. The number of harvested and posi-
contains patients that were treated with adjuvant CT. tive lymph nodes was compared with independent sample t tests.
Clinical and ypT and nodal staging were compared to evaluate the
Data Analysis downstaging effects of neoadjuvant CT. Significant tumor down-
First, patient and tumor characteristics were compared using staging was defined as downstaging from cT4 to ypT2–0 and sig-
the χ2 test. The Fisher’s exact test was used in case one or more if nificant nodal downstaging as cN+ to ypN0. In the control group,
the expected outcomes were < 5. Continuous variables were de- clinical and pathological nodal stagings were compared to assess
picted as mean + 95% CI or median + range and compared using under- and overstaging. For all statistical analyses, IBM SPSS Sta-
independent sample t tests. p values < 0.05 were considered sig- tistics software, version 25.0 (IBM Corporation, Armonk, NY,
nificant. To assess the possibility of bias by baseline characteristics USA) was used.

Neoadjuvant CT for Locally Advanced T4 Dig Surg 3

Colon Cancer DOI: 10.1159/000503446
 (with a match tolerance of 0.01). After matching there
Neoadjuvant Adjuvant
100 were no significant differences in baseline characteristics
between both groups (Table 1).
Distribution of treatments, % per year

80
Staging Accuracy in the Control Group
60
Comparison between clinical T stage and pathological
stage shows that 105 (35%) patients with a T3 tumor and
1 patient with a T2 tumor were overstaged as T4. Clinical
40
nodal staging with CT detected lymph node metastases in
119 (52%) of all 228 patients that were node-positive after
20
pathological analysis. Seventy seven (34%) of these 228
patients were understaged as cN0 and nodal status based
0 on imaging was lacking in 32 (14%) of these 228 patients.
2008 2009 2010 2011 2012 2013 2014 2015 2016
Overstaging based on clinical imaging occurred in 16
Year of incidence
(23%) of all 68 patients that showed no evidence of nodal
involvement after pathological assessment (Table 2b).
Fig. 2. Distribution of treatment regimen per year in percentage.
Downstaging
In patients treated with neoadjuvant CT, cT stage was
Results compared to the ypT stage to investigate the effect of neo-
adjuvant CT on tumor load.
Baseline Characteristics before Matching In all patients, cT stage was reported before start of
From 2008 until 2016, 16,177 patients were diagnosed neoadjuvant CT. A total of 13 patients suggested signifi-
with stage II or III colon cancer and treated with CT. Only cant downstaging of the primary tumor after systemic
2,146 of these patients were diagnosed with cT4 colon therapy (cT4 to pT0–2, 8.7%). Five of these patients
cancer and matched the inclusion criteria. The majority showed a complete pathological response (pT0; Table 3).
of these (1,954 patients [91%]) were treated with surgery In the control group, only 1 clinically T4 staged tumor
and adjuvant CT and 192 (9%) received neoadjuvant CT was overstaged as a pathological T2 stage (0.3%). This
followed by surgery. The use of neoadjuvant CT treat- downstaging effect was statistically significant (p < 0.001).
ment increased significantly over time (p < 0.001; Fig. 2). Nodal downstaging was suggested in 34 of 65 patients
In 2008, 4% of all patients diagnosed with a cT4 tumor who were clinically node-positive (52%; Table 2a). Nodal
were treated with neoadjuvant therapy compared to overstaging in the control group occurred only in 16
21.4% in 2016. Age was not significantly different be- (23%) patients that were diagnosed with cN+ even though
tween both groups, median age in the neoadjuvant group they had pN0 disease. There were significantly less patho-
was 64 (range 29–84) vs. 64 years (range 25–88) in the logically positive lymph nodes (median 0, range [0–23])
control group, p = 0.9 (Table 1). Patients in the neoadju- in the neoadjuvant group compared to the control group
vant group had significantly more tumors located in the median 2 (0–23), (p = 0.01) The number of sampled
sigmoid colon (42 vs. 34%, p = 0.007) and significantly lymph nodes was more than adequate in both groups,
more T4b tumors (74 vs. 57.5%, p = < 0.001). with a median of 17 (4–53) sampled nodes in the neoad-
juvant group and 20 (0–71) in the control group.
Propensity Score Matching
A propensity score was calculated to adjust for biases Surgical Outcomes
caused by differences in baseline characteristics between After matching the difference in incomplete resection,
the 2 groups. The propensity score was calculated based rates in favor of the adjuvant group remained significant.
on: age (categories 0–50, 51–55, 56–60, 61–65, 66–70, 71– In 77.2% of patients (n = 115) in the neoadjuvant group,
75, 76–80, 80–>80), gender, year of diagnosis, tumor lo- a complete resection (R0) was achieved. In 19 patients
cation, differentiation grade, morphology, clinical-T (12.8%), the resection margins were macroscopically free
stage, and clinical-N stage. The PSM excluded 43 patients of disease but microscopically positive for tumor invasion
in the neoadjuvant group and 1,656 patients in the con- (R1). In 6 patients (4%) it was not possible to achieve
trol group because no matching counterpart was found complete resection of the tumor and there was macro-

4 Dig Surg de Gooyer et al.

DOI: 10.1159/000503446
Table 1. Baseline and tumor characteristics of neoadjuvant CT, compared to the locally advanced control group, raw and matched data

Raw data Propensity matched data

neoadjuvant CT + surgery + adjuvant p value neoadjuvant CT + surgery + adjuvant p value
surgery (n = 192) CT (n = 1,954) surgery (n = 149) CT (n = 298)

Age, years, median (range) 64 (29–84) 64 (25–88) 0.905 66.0 66.0 0.662
Gender, n (%)
Male 101 (52.6) 993 (50.8) 0.651 74 (49.7) 155 (52.0) 0.640
Female 91 (47.4) 961 (49.2) 75 (50.3) 143 (48.0)
Localization, n (%)
Coecum 31 (16.1) 503 (25.7) 0.007 28 (18.8) 63 (21.1) 0.808
Colon 80 (41.7) 772 (39.5) 64 (43.3) 129 (43.3)
Sigmoid 81 (42.2) 679 (34.7) 57 (38.8) 106 (35.6)
Differentiation grade, n (%)
Well/moderate 72 (37.5) 1,231 (63.0) 0.432 71 (47.7) 141 (47.3) 0.945
Poorl/undifferentiated 26 (13.5) 540 (27.6) 26 (17.4) 49 (16.4)
Unknown 94 (49.0) 183 (9.4) 52 (34.9) 108 (36.2)
Morphology, n (%)
Adenocarcinoma 159 (82.8) 1,554 (79.5) 0.222 120 (80.5) 228 (76.5) 0.730
Mucinous carcinoma 31 (16.1) 332 (17.0) 27 (18.1) 66 (22.1)
Signet ring cell carcinoma 0 (0) 37 (1.9) 0 (0) 1 (0.3)
Other/unknown 2 (1.0) 31 (1.6) 2 (1.3) 3 (1.0)
Clinical T-stage, n (%)
T4 19 (9.9) 397 (20.3) <0.001 13 (8.7) 25 (8.4) 0.941
T4a 31 (16.1) 433 (22.2) 24 (16.1) 52 (17.4)
T4b 142 (74.0) 1,124 (57.5) 112 (75.2) 221 (74.2)
Clinical N-stage, n (%)
N0 81 (42.2) 721 (36.9) 0.061 65 (43.6) 120 (40.3) 0.483
N1 63 (32.8) 633 (32.4) 47 (31.5) 84 (28.2)
N2 23 (12.0) 193 (9.9) 18 (12.1) 51 (17.1)
Nx/unknown 25 (13.0) 407 (20.8) 19 (12.8) 43 (14.4)

Bold p values indicate statistical significance.

CT, chemotherapy; T-stage, tumor stage; N-stage, nodal stage.

scopically visible residual disease (R2). In the control able Cox regression was not calculated since the Kaplan-
group, an R0 resection rate of 86.2% (n = 225) was Meier curves crossed, and therefore the assumption of
achieved. There were 6% (n = 18) R1 resections and 1.7% proportional hazards is violated.
(n = 5) R2 resections. Data regarding complications was
available in 92% of the patients (n = 137) in the neoadju-
vant group and in 93% (n = 275) of the control group Discussion
(Table 3). There were no significant differences in surgi-
cal complications such as anastomotic leakage and ab- Neoadjuvant CT for LACC is infrequently used and cur-
scess formation between the 2 groups (p = 0.854). rent research is inconclusive regarding its potential benefit.
With only a few studies published, it not surprising that
Survival neoadjuvant CT for LACCs is not considered a common
The median follow-up was 44 (4–133) months in the practice in the Netherlands yet [21–23]. This nationwide
neoadjuvant group and 44 (0–133) months in the control database study illustrates that preoperative CT is safe, re-
group. The 5-year overall survival was 67% in the neoad- sults in significant tumor and nodal downstaging and yields
juvant group and 65% in the control group. However, this excellent long-term outcomes in a selected group of pa-
difference was not statistically significant (p = 0.867; tients with clinically locally advanced (cT4) colon cancer.
Fig. 3). Thirty day mortality after surgery was 0% in the Preoperative systemic therapy is shown to be non-in-
neoadjuvant group. This could not be compared to the ferior in terms of safety and does not increase surgical
control group because of immortal time bias. Multivari- morbidity or mortality when compared to standard sur-

Neoadjuvant CT for Locally Advanced T4 Dig Surg 5

Colon Cancer DOI: 10.1159/000503446
Table 2. of the effect since a significant number of patients were
a Nodal downstaging in patients who received neoadjuvant CT understaged in the control group. Neoadjuvant treatment
has been proposed as a risk factor for inadequate lymph
Pathological N-score
node sampling in rectal cancer and more recently in colon
pN0 pN+ pNx Total cancer [27, 28]. This was not observed in the present
Clinical N-score
study as the median number of sampled lymph nodes was
cN0 47 17 1 65 significantly higher than the recommended minimum of
cN+ 34 31 0 65 12 in both groups.
cNx 11 8 0 19 Pathological and clinical staging were compared in the
Total 92 56 1 149 control group because there it is debated whether CT
staging is an accurate tool to distinguish high-risk tumors
b Comparison of clinical and pathological nodal staging in pa- suitable for neoadjuvant treatment. Significant tumor
tients treated with adjuvant CT downsizing was defined as a reduction from cT4 to ypT2–
0 because distinction between T3 and T4 is difficult on
Clinical N-score
cN0 42 77 1 120 CT, especially distinction between low-risk T1-T3ab and
cN+ 16 119 0 135 high-risk T3cd-T4 [29, 30]. This choice seems justified by
cNx 10 32 1 43 the data that shows 35% of all clinically diagnosed T4 tu-
Total 68 228 2 298 mors in the control group having a T3 tumor after patho-
logical assessment, suggesting significant overstaging.
CT, chemotherapy. Conversely, the comparison of clinical and pathological
nodal staging shows that the problem mostly lies in un-
derstaging with 35% of pN+ cases being diagnosed as
gery. The occurrence of major complications such as clinically node-negative disease. This is in line with the
anastomotic leakage and abscess formation was equal be- recent literature on nodal staging in colorectal cancer
tween both the groups. Patients in the neoadjuvant group [31]. This remains an important disadvantage of the neo-
were more likely to receive a stent or stoma prior to sur- adjuvant strategy because a significant number of pa-
gery (8.7 vs. 1.0%) but far less likely to undergo emergen- tients could potentially receive neoadjuvant CT without
cy surgery compared to the control group (2.6 vs. 10.4%). appropriate indication. However, these data were collect-
These are encouraging results because they do not show ed over a longer period of time (2008–2016) and advanc-
evidence of tumor progression, warranting emergency es have been made in radiological staging T of colon can-
resection during neoadjuvant treatment. This is in accor- cer [32].
dance with the preliminary results of the Foxtrot trial One of the hypothetical advantages of tumor downsiz-
where no differences in postoperative morbidity and ing and staging is a reduction of the amount of multivis-
mortality were observed between the 2 groups [21]. Re- ceral resections performed and a higher R0 resection rate.
grettably, this dataset only contains patients that were In this study this could not be demonstrated, since mul-
treated with neoadjuvant treatment and surgery. Data re- tivisceral resections were performed more often in the
garding patients that received CT with neoadjuvant in- neoadjuvant group (9.4 vs. 5.0%) even though this differ-
tent but who were deemed inoperable because of tumor ence was not significant. The rate and absolute number of
progression are lacking. On the contrary, in the Foxtrot patients who underwent a multivisceral resection is much
trial all patients who were treated with neo-adjuvant CT lower compared to 33% multivisceral resections reported
underwent surgery and no mortality or progression lead- by Govindarajan et al. [33] in patients with LACC based
ing to irresectable disease occurred in the pilot phase [21]. on data retrieved from the SEER registry. The significant-
Another potential benefit of preoperative CT that was ly lower rate of R0 resections in the neoadjuvant group is
shown is significant downsizing of the primary tumor a cause for concern since R0 resection strongly correlates
and downstaging of lymph nodes metastases. Evidence of with recurrence and survival in colorectal cancer [34, 35].
significant downstaging was demonstrated in 13% of the Nevertheless, this dataset contains no data regarding the
patients and a complete pathological response was ob- presumed indication for neoadjuvant CT, rendering it
served in 5 patients. Also, an 18% reduction of lymph highly difficult to determine if there is a causal relation-
node involvement after preoperative treatment was ob- ship between neoadjuvant treatment and the higher num-
served. These numbers might still be an underestimation ber of incomplete resections. There might be unknown

6 Dig Surg de Gooyer et al.

DOI: 10.1159/000503446
Table 3. Surgical outcomes in patients treated with neoadjuvant CT, compared to the locally advanced control group, raw and matched data

Raw data Propensity matched data

neoadjuvant CT adjuvant CT p value neoadjuvant CT adjuvant CT p value
(n = 192) (n = 1,954) (n = 149) (n = 298)

Number of harvested lymph

nodes, mean(95% CI) 20.2 (18.8–21.6) 19.9 (19.5–20.4) 0.523 19.6 (18.1–21.2) 22.5 (21.2–22.0) 0.01
Number of positive lymph
nodes, mean (95% CI) 1.3 (0.9–1.7) 3.1 (3.0–3.3) <0.001 1.3 (0.8–1.8) 3.6 (3.1–4.1) <0.001
Pathological T-stages, n (%)
T0 8 (4.2) 0 (0) <0.001 5 (3.4) 0 (0) <0.001
T1 2 (1.0) 0 (0) 2 (1.3) 0 (0)
T2 8 (4.2) 12 (0.6) 6 (4.0) 1 (0.3)
T3 70 (36.5) 734 (37.6) 52 (34.9) 105 (35.2)
T4 104 (54.2) 1,207 (61.8) 84 (56.4) 192 (64.4)
Tx 0 (0) 1 (0.1) 0 0
Pathological N-stages, n (%)
N0 117 (60.9) 532 (27.2) <0.001 92 (61.7) 68 (22.8) <0.001
N1 52 (27.1) 829 (42.4) 38 (25.5) 121 (40.6)
N2 22 (11.5) 588 (30.1) 18 (12.1) 107 (35.9)
Nx 1 (0.5) 5 (0.3) 1 (0.7) 2 (0.7)
Resection margins, n (%)
R0 150 (78.1) 1,681 (86.0) 0.001 115 (77.2) 225 (85.6) 0.037
R1 24 (12.5) 100 (5.1) 19 (12.8) 18 (6.0)
R2 7 (3.6) 55 (2.8) 6 (4.0) 5 (1.7)
Unknown 11 (5.7) 118 (6.0) 9 (6.0) 20 (6.7)
Type of surgery, n (%)
Colon 100 (52.1) 1,175 (60.1) 0.187 82 (55.0) 172 (57.7) 0.485
Sigmoid 66 (34.4) 592 (30.3) 47 (31.5) 95 (31.9)
(Sub)total colon 7 (3.6) 55 (2.8) 5 (3.4) 14 (4.7)
Multivisceral resection 18 (9.4) 120 (6.1) 14 (9.4) 15 (5.0)
Unknown 1 (0.5) 12 (0.6) 1 (0.7) 2 (0.7)
Type of surgery, n (%)
Elective 171 (89.1) 1,727 (88,4) <0.001 132 (88.6) 263 (88.3) <0.001
Emergency 5 (2.6) 203 (10.4) 2 (2.6) 31 (10.4)
Previous stoma/stent 16 (8.3) 17 (0.9) 13 (8.7) 3 (1.0)
Unknown 0 (0) 7 (0.4) 0 1 (0.3)
Complication, n (%)
No anastomotic leakage or
abscess 152 (79.2) 1,707 (87.4) 0.64 124 (83.2) 257 (86.2) 0.854
Anastomotic leakage 11 (5.7) 58 (3.0) 8 (5.4) 9 (3.0)
Abscess 9 (4.7) 36 (1.8) 4 (2.7) 7 (2.3)
Both 1 (0.5) 17 (0.9) 1 (0.7) 2 (0.7)
Unknown 19 (9.9) 136 (7.0) 12 (8.1) 23 (7.7)
Targeted therapy, n (%)
Yes 54 (28.1) 33 (1.7) <0.001 47 (31.5) 4 (1.3) <0.001
No 138 (71.9) 1,921 (98.3) 102 (68.5) 294 (98.7)

Bold p values indicate statistical significance.

CT, chemotherapy; T-stage, tumor stage; N-stage, nodal stage.

bias influencing the choice of neoadjuvant treatment. tumors. This is supported by the finding that 28% of pa-
Since national guidelines recommend surgery in case of tients in the neoadjuvant group were treated with target-
resectable tumors, presumably a significant percentage of ed therapy while treatment with the VEGF-A inhibitor
patients treated with neoadjuvant CT had tumors with Bevacizumab is normally reserved for palliative treat-
unfavorable characteristics and/or clinically unresectable ment and not recommended in resectable disease [36].

Neoadjuvant CT for Locally Advanced T4 Dig Surg 7

Colon Cancer DOI: 10.1159/000503446
 patients would introduce a form of bias benefitting the
Overall survival
100 neoadjuvant group, since patients treated with neoadju-
vant intent but found to be not eligible for surgery are
80
also not included in this study. It is encouraging that
survival is still comparable between both groups, under-
Survival probability

60
lining the potential value of neoadjuvant treatment in
this select group of patients. Unfortunately, the NCR
does not contain data on disease recurrence and thus
40
disease-free survival cannot be calculated. The overall
survival percentages in both groups are comparable
20
Neoadjuvant since tumor recurrence is significantly associated with
Adjuvant overall survival [40]. Pathological data on tumor regres-
0 sion after neoadjuvant treatment are also absent and
0 1 2 3 4 5
5-years overall survival probability curves of neoadjuvant
could be of interest since this is known to correlate with
and adjuvant regimens, years recurrence-free survival in other gastrointestinal malig-
nancies [41, 42]. Finally, the NCR does not contain spe-
cific data on the type of CT and whether patients suf-
Fig. 3. Landmarked overall survival after propensity matching.
fered treatment-related toxicity. However, the standard
adjuvant treatment regimen for colon cancer in the
Netherlands consists of a fluoropyrimidine and oxali-
The difference in R0 resections is, therefore, more likely platin combination and it is highly likely that neoadju-
a result of persisting bias based on unfavorable tumor vant treatment also consists of this combination.
characteristics and primary irresectability and not of the In conclusion, this is the first nationwide population-
neoadjuvant treatment itself. This is supported by the based analysis which shows that neoadjuvant CT for lo-
preliminary data from the Foxtrot trial where in a ran- cally advanced cT4 colon cancer seems safe and yields
domized setting the percentage of margin involvement is similar overall survival compared to adjuvant CT. A low-
significantly lower in the neoadjuvant group (4 vs. 20%). er R0 resection rate was observed in the neoadjuvant
An encouraging finding of this study is that despite the group but there is no significant increase in postoperative
higher R0 resection rate, an excellent 5-year overall sur- complications or mortality. Moreover, it leads to signifi-
vival rate of 67% was demonstrated in the neoadjuvant cant downstaging of tumor and lymph node stage. The
group. This is similar to the survival in the control group long-term survival benefit of this treatment is to be estab-
(65%) and comparable to recent literature [37–39]. Most lished in a large randomized trial, but it already seems to
importantly, these results are in accordance with the first be a useful and safe modality in patients with locally ad-
results of the randomized phase FOxTROT trial that were vanced and possibly unresectable primary tumors.
presented at the ASCO annual meeting 2019. The authors
reported that there was no significant difference observed
in the 2-year failure rate between both groups. Five-year Statement of Ethics
overall survival results are required to confirm the long-
All research was conducted ethically in accordance with the
term benefits but the concordance with the results in this World Medical Association Declaration of Helsinki. The data re-
cohort is encouraging. quest and study protocol was approved by the Netherlands Com-
This study has some limitations; some degree of se- prehensive Cancer Organization.
lection bias is inevitable, owing to the observational na-
ture of the study. However, PSM was performed to bal-
ance the cohorts and differences in baseline characteris- Disclosure Statement
tics between the groups were no longer significant. The authors have no conflicts of interest to declare.
Moreover, selection bias could have occurred in the
control group since only patients who were able to un-
dergo adjuvant CT were included and as such patients Funding Sources
who died postoperatively or suffered from severe com-
plications were excluded. Nevertheless, including these There was no funding provided for this manuscript.

8 Dig Surg de Gooyer et al.

DOI: 10.1159/000503446
 Author Contributions control of data and algorithms. J.-M.G., M.G.V., J.L.-B., R.H.A.V.,
and J.M.J.S.: data analysis and interpretation. J.-M.G., M.G.V., J.L.-
S.A.R., C.V., J.M.J.S., and J.H.W.W.: study concepts. J.M.J.S. B., and R.H.A.V.: statistical analysis. J.-M.G., M.G.V., and J.L.-B.:
and J.H.W.W.: study design. J.-M.G., M.G.V., R.H.A.V., and J.L.- manuscript preparation. All authors: manuscript editing. All au-
B.: data acquisition. J.-M.G., M.G.V., J.L.-B., and J.M.J.S.: quality thors: manuscript review.

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10 Dig Surg de Gooyer et al.

DOI: 10.1159/000503446