Research

JAMA Oncology | Original Investigation

Incidence of Recurrence and Time to Recurrence in Stage I to III Colorectal

Cancer
A Nationwide Danish Cohort Study
Jesper Nors, MD; Lene Hjerrild Iversen, MD, DMSc; Rune Erichsen, MD, PhD;
Kåre Andersson Gotschalck, MD, PhD; Claus Lindbjerg Andersen, PhD

Editorial
IMPORTANCE Management of colorectal cancer (CRC) has been updated continuously over Supplemental content
the past 2 decades. While the combination of these initiatives has had implications for
improved survival, the implications for rates of recurrence remain unexplored.

OBJECTIVE To ascertain the rates of recurrence and describe time to recurrence within 5 years
of surgery with curative intent for stages I to III CRC.

DESIGN, SETTING, AND PARTICIPANTS This cohort study used the Danish Colorectal Cancer
Group Database to identify patients with Union for International Cancer Control (UICC) stages
I to III CRC who underwent primary surgery between January 1, 2004, and December 31,
2019. They were followed up until recurrence (event), death (competing event), diagnosis of
a second cancer (competing event), emigration (censoring event), 5 years postoperatively
(censoring event), or January 1, 2023 (censoring event), whichever came first. Recurrence
status was ascertained through individual-level linked data from the Danish Cancer Registry,
Danish National Patient Registry, and Danish Pathology Registry using a validated algorithm.
Data were analyzed from January 1 to August 8, 2023.

EXPOSURE Primary surgery performed during 3 calendar periods (2004-2008, 2009-2013,

and 2014-2019) stratified by tumor site (colon or rectum) and UICC stage (I, II, and III).

MAIN OUTCOMES AND MEASURES Stage-specific 5-year recurrence reported as the cumulative
incidence function (CIF) of recurrence, the association between calendar period of primary
surgery and recurrence risk reported as subdistribution hazard ratios (sHRs), and the time
from surgery to recurrence.

RESULTS Of the 34 166 patients with UICC stages I to III CRC (median [IQR] age, 70 [62-77]
years); 18 552 males [54.3%]) included in the study, 7027 developed recurrence within 5
years after the primary surgery. For colon cancer, the 5-year CIF of recurrence decreased over
the 3 calendar periods from 16.3% to 6.8% for UICC stage I, from 21.9% to 11.6% for UICC
stage II, and from 35.3% to 24.6% for UICC stage III colon cancer. For rectal cancer, the 5-year
CIF decreased over the 3 periods from 19.9% to 9.5% for stage I, from 25.8% to 18.4% for
stage II, and from 38.7% to 28.8% for stage III disease. Patients with stage III disease had a
Author Affiliations: Department of
shorter time from surgery to recurrence compared with those with stage I disease (time ratio Molecular Medicine, Aarhus
stage III vs stage I = 0.30; 95% CI, 0.28-0.32). Cancers detected through screening were University Hospital, Aarhus, Denmark
associated with lower stage-adjusted risks of recurrence (sHR, 0.81; 95% CI, 0.73-0.91) (Nors, Andersen); Department of
Clinical Medicine, Aarhus University,
compared with cancers not detected through screening.
Aarhus, Denmark (Nors, Iversen,
CONCLUSIONS AND RELEVANCE In this cohort of patients with CRC, the risk of recurrence Erichsen, Gotschalck, Andersen);
Department of Surgery, Aarhus
decreased in patients with stages I to III disease during the study period. Cancer detection by University Hospital, Aarhus, Denmark
screening was associated with an even lower risk of recurrence. Time to recurrence differed (Iversen); Department of Clinical
according to UICC stage. Because the risk of recurrence was so low in selected patient groups, Epidemiology, Aarhus University
Hospital, Aarhus, Denmark
future research is warranted to explore risk-stratified surveillance protocols in patients with
(Erichsen); Department of Surgery,
CRC. Randers Regional Hospital, Randers,
Denmark (Erichsen); Department of
Surgery, Horsens Regional Hospital,
Horsens, Denmark (Gotschalck).
Corresponding Author: Claus
Lindbjerg Andersen, PhD,
Department of Molecular Medicine,
Aarhus University Hospital, Palle
JAMA Oncol. doi:10.1001/jamaoncol.2023.5098 Juul-Jensens Blvd 99, DK-8200
Published online November 16, 2023. Aarhus N, Denmark (cla@clin.au.dk).

(Reprinted) E1

Downloaded from jamanetwork.com by Francisco Abarca on 11/17/2023

 Research Original Investigation
C
olorectal cancer (CRC) represents a considerable health
burden worldwide.1 The standard of care for patients
with nonmetastatic CRC (Union for International Can-
cer Control [UICC] TNM stages I-III) is surgery, with clinical stag-
ing informing the use of neoadjuvant therapy and histopatho-
logical staging informing the use of adjuvant chemotherapy.2,3
Although surgery is intended to be curative treatment, ap-
proximately 20% of patients experience recurrence of dis-
ease. Therefore, all patients with stages I to III CRC are of-
fered postoperative surveillance.
Over the past 2 decades, several initiatives aimed at re-
ducing the risk of recurrence and improving survival of pa-
tients with CRC have been implemented in most countries, in-
cluding Denmark4 (eFigure 1 in Supplement 1). Initiatives
include increased focus on improving primary treatment with
regularly updated national recommendations,5 a multidisci-
plinary team approach,6,7 enhanced recovery after surgery
protocols,8 and implementation of new surgical procedures;
the latter include central vascular ligation and dissection along
the embryological fascia as the underlying principle of com-
plete mesocolic excision9 and total mesorectal excision,10 with
increased lymph node yield. In addition, the treatment of CRC
has been centralized to specialized centers,11 and the patho-
logical examinations of surgical specimens12,13 and postop-
erative surveillance have been standardized.14-17 Lastly, popu-
lation-based screening programs have been implemented in
several countries,18 identifying patients with asymptomatic
CRC.19 While most of the initiatives have been associated with
better outcomes individually, nationwide population-based
studies are needed to investigate the implications of these ini-
tiatives for the risk of recurrence.
The aim of this study was to determine colon and rectal
cancer stage-specific rates of recurrence and, for those with
recurrence, the time from surgery to recurrence (TSTR) in a na-
tionwide cohort of patients who underwent surgery with cu-
rative intent for nonmetastatic CRC from 2004 to 2019 by com-
paring 3 calendar periods of surgery with curative intent: 2004
to 2008, 2009 to 2013, and 2014 to 2019. A secondary aim was
to describe the risk of recurrence in colon and rectal cancers
detected through screening.
Methods
Design and Study Population
This nationwide registry-based cohort study included all pa-
tients who underwent surgery with curative intent for UICC
TNM stages I to III CRC between January 1, 2004, and Decem-
ber 31, 2019. The study was approved by the Danish Colorec-
tal Cancer Group (DCCG) and the Danish Data Protection
Agency (Central Denmark Region) and adhered to the Euro-
pean Union General Data Protection Regulations.20 The study
was based on anonymized registry data and therefore was ex-
empt from review and informed consent in accordance with
the General Data Protection Regulations. The study was re-
ported according to the Strengthening the Reporting of Ob-
servational Studies in Epidemiology (STROBE) reporting
guideline.21
E2 JAMA Oncology Published online November 16, 2023 (Reprinted)
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Incidence of Recurrence and Time to Recurrence in Stage I to III Colorectal Cancer
Key Points
Question What are the colorectal cancer (CRC) stage-specific
rates of recurrence and time from surgery to recurrence in patients
undergoing surgery with curative intent?
Findings In this cohort study of 34 166 patients with CRC who
underwent surgery from 2004 to 2019, the risk of recurrence
decreased over time, and higher disease stage was associated with
shorter times from surgery to recurrence. Screening-detected CRC
was associated with a lower risk of recurrence.
Meaning Findings of this study suggest that the risk of CRC
recurrence and the time from surgery to recurrence differ
between patient groups, highlighting the importance of further
research on risk-stratified surveillance.
Patients were identified through the DCCG Database, which
is a prospective national clinical quality database with infor-
mation on all patients treated for first-time CRC in Denmark.22
A timeline and description of the management of nonmeta-
static CRC in Denmark from 2004 to 2019 are provided in eFig-
ure 1 and the eMethods in Supplement 1.
Patients with a diagnosis of cancer other than CRC or non-
melanoma skin cancer (NMSC) prior to curative CRC surgery
were excluded. Patients were also excluded if they emi-
grated, died, or were diagnosed with a new primary cancer
other than CRC or NMSC or metastasis of unspecified origin
within 180 days of the index CRC surgery.
Patients were followed up from 180 days after surgery un-
til the following event (whichever came first): recurrence
(event), second primary cancer (competing event), death (com-
peting event), emigration (censoring event), 5 years postop-
eratively (censoring event), or January 1, 2023 (censoring
event), when prospectively collected data from the national
health care registries were retrieved (eTable 1 in Supple-
ment 1). Hence, patients undergoing curative surgery from
2004 to 2017 had 5 years of follow-up, those undergoing cu-
rative surgery in 2018 had 4 years of follow-up, and those un-
dergoing curative surgery in 2019 had 3 years of follow-up.
Data Sources and Identification of Recurrence
Individual-level data were obtained from Danish health care
registries,23 including the Danish Cancer Register (DCR),24 the
Danish National Patient Registry (DNPR),25 and the Danish Pa-
thology Registry (DPR).26 Data records were linked using the
unique 10-digit civil registration number issued to each Dan-
ish resident by the Danish Civil Registration System.27
The DCCG Database provided information on the date of
CRC diagnosis, date of surgery, and patient characteristics, in-
cluding participation in the National Danish Colorectal Can-
cer Screening Program, which started in 2014 (linked from the
Danish Colorectal Cancer Screening Database28). The DNPR
contains administrative and clinical data and provides infor-
mation on chemotherapeutic treatment and diagnosis of me-
tastases. The DCR contains data on the incidence of malig-
nant neoplasms. The DPR provides electronically recorded data
on all biological specimens according to national guidelines for
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 Incidence of Recurrence and Time to Recurrence in Stage I to III Colorectal Cancer
uniform registration using the Danish version of the System-
atized Nomenclature of Medicine (SNOMED) codes.29
Recurrence was detected using a previously described
algorithm,30 with a few optimizations31 (eFigure 2 in Supple-
ment 1). The algorithm defines recurrence when at least 1 of
the following 4 indicators occurs:
1. Metastasis code (International Statistical Classification of Dis-
eases and Related Health Problems, Tenth Revision [ICD-10]
DC76-80) present in the DNPR or the DCR without a new
primary cancer diagnosis other than CRC (ICD-10 code DC18
or DC20) or NMSC (ICD-10 code DC44) in the DNPR or the
DCR;
2. Cytostatic therapy codes (BWHA1-2, BOHJ17, or BOHJ19B1)
present in the DNPR 60 or more days after the last cyto-
static therapy code and registered by an oncological depart-
ment (eTable 2 in Supplement 1) without a new primary can-
cer diagnosis other than CRC or NMSC in the DNPR or the
DCR;
3. SNOMED combinations present in the DPR; or
4. DNPR codes specific to CRC local recurrence (DC189X,
DC209X, or DC991).
All 4 indicators require the code to be registered 180 or more
days after surgery.
Covariates
The dates of curative surgery were grouped into 3 calendar pe-
riods: 2004 to 2008, 2009 to 2013, and 2014 to 2019. The lat-
ter period coincides with the introduction of the National Dan-
ish Colorectal Cancer Screening Program in 2014.
Eligible patients were categorized by sex (male or fe-
male), age group at curative surgery (<55, 55-64, 65-74, 75-
84, or ≥85 years), pathological UICC stage (I, II, or III), Charl-
son Comorbidity Index score (0, 1-2, or ≥3; higher scores
indicated a higher number of comorbidities),32 site of CRC tu-
mor (colon or rectum), and surgical priority (elective or emer-
gency). Disease stages were categorized according to the fifth
edition33 of the UICC TNM classification from 2004 to 2016 and
the eighth edition34 from 2017 to 2019. Patients in the 2014 to
2019 period were categorized according to whether the can-
cer was detected by screening (screening detected) or not (non-
screening detected).
Statistical Analysis
Patient demographics and treatment characteristics are pre-
sented with continuous data as medians (IQRs) and with cat-
egorical variables as the total number and percentage. Multi-
variable analysis was performed to investigate the association
between calendar period of curative surgery and the risk of CRC
recurrence, adjusted for patient and treatment characteris-
tics. Risk of recurrence was calculated as 1-, 3-, and 5-year cu-
mulative incidence function (CIF) estimates, with second pri-
mary cancer and death treated as competing events.
Cumulative incidence function curves were constructed using
the Aalen-Johansen estimator for visualization, grouped by the
calendar period of curative surgery, and stratified by tumor site
and UICC TNM stage. The association between calendar pe-
riod of curative surgery and the risk of recurrence was esti-
mated using the Fine-Gray competing risks method, with sec-
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Original Investigation Research
ond primary cancer and death treated as competing events,
and was reported as subdistribution hazard ratios (sHRs) with
95% CIs.35 Tumor site– and stage-specific sHRs were ad-
justed for age, sex, and Charlson Comorbidity Index score.
For patients with CRC recurrence, the TSTR was calcu-
lated as the time between the date of curative CRC surgery and
the date on which at least 1 of the 4 indicators in the algo-
rithm defined recurrence. The difference in TSTR between
UICC stages was estimated as a time ratio (with 95% CIs) using
an accelerated failure time model including tumor site, age,
sex, and Charlson Comorbidity Index score and right-
censoring data for patients at the time of a second primary can-
cer, death, emigration, 5 years postoperatively, or January 1,
2023, whichever came first.
A subgroup analysis was performed to assess the associa-
tion between patients with screening-detected CRC and those
with nonscreening-detected CRC. The risk of recurrence was
calculated and 1-, 3-, and 5-year CIF estimates of recurrence
and sHRs adjusted for age, sex, and Charlson Comorbidity In-
dex score were reported.
Statistical analyses were carried out using RStudio, ver-
sion 2021.9.1.372 (Posit PBC). Data were analyzed from Janu-
ary 1 to August 8, 2023.
Results
We identified 45 274 patients who underwent curative sur-
gery for pathological UICC stages I to III CRC between 2004
and 2019 (eFigure 3 in Supplement 1). After applying exclu-
sion criteria (approximately 15% of patients excluded; eRe-
sults in Supplement 1), the final cohort consisted of 34 166 pa-
tients (median [IQR] age, 70 [62-77] years; 18 552 males [54.3%]
and 15 614 females [45.7%]), with 9135 patients who under-
went curative surgery between 2004 and 2008, 9780 be-
tween 2009 and 2013, and 15 251 between 2014 and 2019.
Demographic and clinical characteristics of patients with
colon or rectal cancer stratified by calendar period of surgery
are summarized in Table 1. From 2004 to 2019, the distribu-
tion of UICC stages shifted toward a higher proportion of stage
I CRC and a lower proportion of stage II CRC (eFigure 4 in
Supplement 1). The shift was most prominent from 2014 to
2019, consistent with implementation of a population-wide
CRC screening program in 2014.
Risk of Recurrence
Within 5 years after curative surgery, 7027 patients devel-
oped recurrence. The 5-year CIF of recurrence for CRC was
26.9% (95% CI, 26.0%-27.8%) in the 2004 to 2008 period,
22.2% (95% CI, 24.4%-23.0%) in the 2009 to 2013 period, and
15.8% (95% CI, 15.2%-16.4%) in the 2014 to 2019 period
(eTable 3 in Supplement 1). Compared with the 2004 to 2008
period, the adjusted sHR in the 2009 to 2013 period was 0.82
(95% CI, 0.78-0.87), and the adjusted sHR in the 2014 to 2019
period was 0.59 (95% CI, 0.56-0.62).
For colon cancer, the 5-year CIF of recurrence decreased
over time: from 25.5% (95% CI, 24.4%-26.6%) in the 2004 to
2008 period, to 20.8% (95% CI, 19.8%-21.8%) in the 2009 to
(Reprinted) JAMA Oncology Published online November 16, 2023 E3
 Research Original Investigation Incidence of Recurrence and Time to Recurrence in Stage I to III Colorectal Cancer

Table 1. Demographics and Treatment Characteristics of Patients With Stages I to III Colorectal Cancer Grouped by Tumor Site and Stratified by
Calendar Period of Primary Surgery

Patients with colon cancer, No. (%) Patients with rectal cancer, No. (%)
Overall No. (%) 2004-2008 2009-2013 2014-2019 2004-2008 2009-2013 2014-2019
Variable (N = 34 166) (n = 5805) (n = 6411) (n = 10 470) (n = 3330) (n = 3369) (n = 4781)
Sex
Female 15 614 (45.7) 2959 (51.0) 3231 (50.4) 4961 (47.4) 1319 (39.6) 1284 (38.1) 1860 (38.9)
Male 18 552 (54.3) 2846 (49.0) 3180 (49.6) 5509 (52.6) 2011 (60.4) 2085 (61.9) 2921 (61.1)
Age, median (IQR), y 70 (62-77) 71 (63-78) 71 (64-79) 71 (64-77) 67 (59-75) 68 (61-75) 68 (60-74)
Body mass index, median (IQR)a 25.5 (23.0-28.7) 25.0 25.2 25.9 25.3 25.4 25.7
(22.6-27.8) (22.6-28.4) (23.2-29.2) (22.9-27.9) (23.1-28.4) (23.3-28.7)
Charlson Comorbidity Index score
0 20 607 (60.3) 3635 (62.6) 3918 (61.1) 5710 (54.5) 2243 (67.4) 2306 (68.4) 2795 (58.5)
1-2 10 712 (31.4) 1734 (29.9) 1982 (30.9) 3622 (34.6) 901 (27.1) 879 (26.1) 1594 (33.3)
≥3 2847 (8.3) 436 (7.5) 511 (8.0) 1138 (10.9) 186 (5.6) 184 (5.5) 392 (8.2)
Place of residence
Region of Northern Denmark 3825 (11.2) 667 (11.5) 681 (10.6) 1194 (11.4) 368 (11.1) 388 (11.5) 527 (11.0)
Central Denmark Region 7321 (21.4) 1151 (19.8) 1326 (20.7) 2359 (22.5) 706 (21.2) 705 (20.9) 1074 (22.5)
Region of Southern Denmark 7947 (23.3) 1323 (22.8) 1533 (23.9) 2436 (23.2) 782 (23.5) 807 (24.0) 1066 (22.3)
Region Zealand 5602 (16.4) 937 (16.1) 1132 (17.7) 1701 (16.2) 525 (15.8) 547 (16.2) 760 (15.9)
Capital Region of Denmark 9471 (27.7) 1727 (29.8) 1739 (27.1) 2780 (26.6) 949 (28.5) 922 (27.4) 1354 (28.3)
UICC stage
I 8664 (25.4) 1004 (17.3) 1145 (17.9) 2885 (27.6) 799 (24.0) 939 (27.9) 1892 (39.6)
II 13 755 (40.3) 2823 (48.6) 3155 (49.2) 4080 (39.0) 1238 (37.2) 1165 (34.6) 1294 (27.1)
III 11 747 (34.4) 1978 (34.1) 2111 (31.9) 3505 (33.5) 1293 (38.8) 1265 (37.5) 1595 (33.4)
T categoryb
T1 3890 (12.6) 456 (7.9) 444 (7.1) 1679 (16.5) 237 (10.6) 240 (9.5) 834 (21.7)
T2 5137 (16.6) 607 (10.5) 691 (11.0) 1502 (14.8) 545 (24.4) 652 (25.8) 1140 (29.6)
T3 16 567 (53.7) 3630 (62.5) 3670 (58.4) 5188 (51.0) 1173 (52.6) 1294 (51.2) 1612 (41.9)
T4 3806 (12.3) 812 (14.0) 1001 (15.9) 1493 (14.7) 147 (6.6) 173 (6.8) 180 (4.7)
Tx 1456 (4.7) 300 (5.2) 477 (7.6) 303 (3.0) 129 (5.8) 167 (6.6) 80 (2.1)
N categoryc
N0 18 547 (60.3) 3430 (59.6) 3705 (59.1) 6346 (62.4) 1256 (56.7) 1428 (56.7) 2382 (62.0)
N1 6351 (20.6) 1226 (21.3) 1243 (19.8) 2169 (21.3) 431 (19.5) 482 (19.1) 800 (20.8)
N2 3533 (11.5) 708 (12.3) 730 (11.6) 1111 (10.9) 280 (12.6) 327 (13.0) 377 (9.8)
Nx 2338 (7.6) 390 (6.8) 596 (9.5) 538 (5.3) 248 (11.2) 282 (11.1) 284 (7.4)
Histological classification
Adenocarcinoma 31 150 (91.5) 5200 (90.0) 5703 (89.4) 9361 (89.7) 3161 (95.2) 3190 (94.8) 4535 (95.0)
Mucinous adenocarcinoma 2720 (8.0) 538 (9.3) 633 (9.9) 1015 (9.7) 146 (4.4) 161 (4.8) 227 (4.8)
Signet ring cell carcinoma 179 (0.5) 38 (0.7) 44 (0.7) 56 (0.5) 15 (0.5) 15 (0.4) 11 (0.2)
Adjuvant chemotherapy 8823 (25.8) 1392 (24.0) 2022 (31.5) 3076 (29.4) 337 (10.1) 869 (25.8) 1127 (23.6)
Neoadjuvant treatment 3310 (9.7) 0 (0) 128 (2.0) 305 (2.9) 1099 (33.0) 843 (25.0) 935 (19.6)
Priority of surgeryc
Elective 32 055 (94.0) 5107 (88.0) 5776 (90.1) 9796 (93.6) 3302 (99.2) 3348 (99.4) 4726 (99.7)
Emergency 2063 (6.0) 697 (12.0) 634 (9.9) 667 (6.4) 28 (0.8) 21 (0.6) 16 (0.3)
b
Abbreviation: UICC, Union for International Cancer Control. Not reported for patients treated with neoadjuvant oncological therapy.
a c
Body mass index calculated as weight in kilograms divided by height in meters If the patient underwent resection.
squared.

2013 period, and to 14.6% (95% CI, 13.9%-15.3%) in the 2014
to 2019 period (Figure 1A). Although rectal cancer had a higher
risk of recurrence compared with colon cancer, a similar pat-
tern of decreasing 5-year CIF was observed across the 3 peri-
ods: from 29.4% (95% CI, 27.8%-30.9%) in the 2004 to 2008
period, to 24.9% (95% CI, 23.4%-26.3%) in the 2009 to 2013
period, and to 18.3% (95% CI, 17.2%-19.5%) in the 2014 to 2019
period (Figure 1B). A consistent pattern of decreasing 5-year
CIF of recurrence was also observed in stage-stratified analy-
ses (eFigure 5 in Supplement 1). Tumor site– and stage-
specific 1-, 3-, and 5-year CIFs of recurrence are presented in
Table 2.

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 Incidence of Recurrence and Time to Recurrence in Stage I to III Colorectal Cancer Original Investigation Research

Figure 1. Cumulative Incidence Function Curves for Colorectal Cancer Recurrence Stratified by Tumor Site and
Compared by Calendar Period of Curative Surgery

A Colon cancer B Rectal cancer

2004-2008: 1 [Reference] 2004-2008: 1 [Reference]

2009-2013: sHR, 0.80; 95% CI, 0.74-0.86 2009-2013: sHR, 0.84; 95% CI, 0.77-0.92
2014-2019: sHR, 0.55; 95% CI, 0.51-0.59 2014-2019: sHR, 0.63; 95% CI, 0.57-0.69

50 50
Cumulative incidence function

Cumulative incidence function

40 40
of recurrence, %

of recurrence, %
30 30

20 20

10 10
Curves were constructed using the
Aalen-Johansen estimator. Patients
0 0 were right-censored at emigration, 5
0 1 2 3 4 5 0 1 2 3 4 5
years of follow-up, or on January 1,
Time since surgery, y Time since surgery, y 2023, whichever came first. sHR
No. at risk No. at risk indicates subdistribution hazard ratio
2004-2008 5805 5199 4449 3993 3618 3300 2004-2008 3330 3015 2517 2235 2022 1835 calculated using Fine-Gray regression
2009-2013 6411 5862 5151 4692 4317 4012 2009-2013 3369 3079 2657 2435 2230 2095 adjusted for sex, age, comorbidities,
2014-2019 10 470 9901 8931 8356 6600 5105 2014-2019 4781 4492 4056 3797 3018 2372 and Union for International Cancer
Control stage.

Table 2. Risk of Recurrence in Patients With Stages I to III Colorectal Cancer

Cumulative incidence function, % (95% CI)a

Characteristic 1y 3y 5y sHR (95% CI)b
Colon cancer
UICC stage I
2004-2008 3.4 (2.4-4.6) 11.5 (9.6-13.5) 16.3 (14.0-18.6) 1 [Reference]
2009-2013 4.1 (3.1-5.4) 9.5 (7.9-11.3) 12.5 (10.7-14.5) 0.75 (0.60-0.94)
2014-2019 1.5 (1.1-2.0) 4.4 (3.7-5.2) 6.8 (5.9-7.8) 0.37 (0.30-0.45)
UICC stage II
2004-2008 7.2 (6.3-8.2) 17.0 (15.6-18.4) 21.9 (20.4-23.4) 1 [Reference]
2009-2013 5.4 (4.6-6.2) 13.6 (12.4-14.8) 17.0 (15.7-18.3) 0.76 (0.68-0.85)
2014-2019 3.6 (3.0-4.2) 9.7 (8.8-10.6) 11.6 (10.6-12.6) 0.50 (0.44-0.56)
UICC stage III
2004-2008 12.2 (10.8-13.7) 29.8 (27.8-31.8) 35.3 (33.2-37.4) 1 [Reference]
2009-2013 11.6 (10.2-13.0) 26.9 (25.0-28.8) 31.1 (29.1-33.1) 0.85 (0.77-0.95)
2014-2019 9.8 (8.9-10.8) 21.8 (20.4-23.1) 24.6 (23.2-26.1) 0.65 (0.59-0.71)
Rectal cancer
UICC stage I
2004-2008 5.4 (4.0-7.1) 13.9 (11.6-16.4) 19.9 (17.2-22.8) 1 [Reference]
2009-2013 5.1 (3.8-6.7) 13.1 (11.0-15.3) 17.1 (14.8-19.6) 0.84 (0.68-1.05)
2014-2019 2.7 (2.0-3.5) 7.3 (6.2-8.5) 9.5 (8.2-10.9) 0.44 (0.36-0.55) Abbreviations: sHR, subdistribution
hazard ratio; UICC, Union for
UICC stage II International Cancer Control.
2004-2008 8.2 (6.8-9.9) 20.8 (18.5-23.1) 25.8 (23.4-28.2) 1 [Reference] a
Cumulative incidence function of
2009-2013 7.6 (6.1-9.2) 18.9 (16.7-21.2) 22.7 (20.4-25.2) 0.87 (0.74-1.02) colorectal cancer recurrence
treating death and second primary
2014-2019 5.1 (4.0-6.4) 14.8 (13.0-16.8) 18.4 (16.3-20.6) 0.66 (0.56-0.79)
cancer (other than colorectal cancer
UICC stage III or nonmelanoma skin cancer) as
2004-2008 12.4 (10.6-14.2) 32.3 (29.7-34.8) 38.7 (36.0-41.3) 1 [Reference] competing events.
b
2009-2013 11.9 (10.2-13.8) 28.1 (25.6-30.6) 32.6 (30.0-35.1) 0.83 (0.73-0.94) sHRs calculated by Fine-Gray
regression adjusted for age, sex, and
2014-2019 11.1 (9.6-12.7) 24.0 (21.9-26.1) 28.8 (26.6-31.1) 0.70 (0.62-0.80)
Charlson Comorbidity Index score.

Time From Surgery to Recurrence in Supplement 1). Over the 3 calendar periods, the proportion
The proportion of diagnosed recurrences was highest in the of recurrences diagnosed within the first 3 years after surgery
first 3 years after surgery in all 3 calendar periods (eFigure 6 increased (2004-2008, 80.0%; 2009-2013, 82.7%; and 2014-

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 Research Original Investigation
Figure 2. Time From Surgery to Colorectal Cancer Recurrence by Union
for International Cancer Control (UICC) Stage
0.06
UICC stage
0.05
0.04
Density
0.03
0.02
0.01
0 and 0.74 (95% CI, 0.65-0.86) for stage III screening-detected
0 1 2 3 4 5
Time from surgery to recurrence, y
Vertical dashed lines represent median time from curative surgery to
recurrence. Shaded areas represent time points of surveillance imaging at 12
and 36 months after surgery (as per Danish guidelines since 2009).
2019, 85.4%). From 2004 to 2008, the distribution of recur-
rences was dominated by a peak at 1 year postoperatively, while
the pattern shifted such that by the 2014 to 2019 period, there
were marked peaks at both year 1 and year 3 postoperatively
(eFigure 7 in Supplement 1).
Stage-specific TSTR revealed a shorter TSTR for patients
with stage III CRC than for patients with stage II and particu-
larly for those with stage I (Figure 2). The median (IQR) TSTR
was 22.6 (20.2-24.2) months in patients with stage I CRC, 18.2
(17.2-19.1) months in those with stage II (time ratio stage II vs
I, 0.58; 95% CI, 0.54-0.62), and 15.9 (15.4-16.5) months in those
with stage III (time ratio stage III vs stage I, 0.30; 95% CI, 0.28-
0.32). This difference was consistent through all 3 calendar pe-
riods (eFigure 8 in Supplement 1).
Recurrences Associated With Screening Status
In the 2014 to 2019 period, 43.6% of patients with stage I CRC,
20.5% of those with stage II CRC, and 22.5% of those with stage
III CRC were diagnosed through screening (eTable 4 in Supple-
ment 1). Patients with screening-detected CRC more often had
lower-stage disease and were more often male, were younger,
and had fewer comorbidities at curative surgery compared with
those with nonscreening-detected CRC.
Elaboration on the stage differences revealed that, within
each N category, patients with screening-detected CRC had
lower T categories than patients with nonscreening-detected
CRC (eFigure 9 in Supplement 1). The stage-stratified 5-year
CIF of recurrence was lower among patients with screening-
detected CRC than in those with nonscreening-detected CRC
(Figure 3; eTable 5 in Supplement 1). Screening-detected vs
nonscreening-detected stage III CRC had a 5-year CIF of re-
currence of 21.7% (95% CI, 19.3%-24.2%) vs 27.1% (95% CI,
25.7%-28.5%). The 5-year CIF of recurrence for screening-
detected vs nonscreening-detected stage II CRC was 10.1% (95%
CI, 8.3%-12.0%) vs 14.1% (95% CI, 13.0%-15.1%). The 5-year CIF
of recurrence of screening-detected vs nonscreening-
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Incidence of Recurrence and Time to Recurrence in Stage I to III Colorectal Cancer
detected stage I CRC was 6.5% (95% CI, 5.5%-7.7%) vs 8.9%
(95% CI, 7.8%-10.0%).
The risk of recurrence for screening-detected CRC was
lower when adjusted for age, sex, comorbidity, tumor site,
stage, and T category (sHR, 0.81; 95% CI, 0.73-0.91). For pa-
tients with nonscreening-detected CRC, the 5-year CIF of re-
I
II currence between 2014 and 2019 (eTable 5 in Supplement 1)
III
was lower than the rates of recurrence prior to national screen-
ing implemented in 2014 (Table 2). Stage-specific reductions
in recurrence were higher (by 0.8 to 5.6 percentage points) for
patients with screening-detected CRC compared with non-
screening-detected CRC (eTable 6 in Supplement 1). Com-
pared with nonscreening-detected CRC, the sHR was 0.76 (95%
CI, 0.61-0.96) for stage I, 0.65 (95% CI, 0.53-0.81) for stage II,
CRC.
Discussion
From 2004 to 2019, many initiatives were implemented at a
national level in Denmark to improve the treatment of pa-
tients with CRC (eFigure 1 in Supplement 1). This evolution of
CRC management is not unique to Denmark, as international
guidelines have changed multiple times over the past
decades.36-39 While the combined implications of these ini-
tiatives have been associated with improved survival,4,40 their
implications for risk of recurrence remain unexplored. The re-
sults of the present study show that the CRC recurrence rate
has decreased substantially and continuously from 2004 to
2019, even after stratifying results by tumor site and UICC stage.
In 2014, population-based CRC screening via fecal immu-
nochemical testing was implemented in Denmark and iden-
tified a group of younger patients with asymptomatic CRC. Con-
sistent with reports from other countries,19 we saw that the
screening prevalence round from 2014 to 2017 was associ-
ated with an increase in the number of patients with diag-
nosed CRC, with a shift toward lower UICC stages at diagnosis.41
Our comparison of screening-detected and nonscreening-
detected CRC revealed lower rates of not only overall recur-
rence but also stage-specific recurrence in cancers detected by
screening. Speculating whether screening was the main fac-
tor in the low stage-specific recurrence rates observed from
2014 to 2019, we explored the recurrence rate in patients whose
cancer was not detected through screening. Their recurrence
rate in the 2014 to 2019 period was still lower than recurrence
rates observed in the 2 earlier periods, suggesting that other
initiatives implemented in this period also had implications
for the risk of recurrence (eFigure 1 in Supplement 1).
Additionally, detection through screening was associ-
ated with lower T category within each UICC stage. This change
toward lower T category contributed to the lower stage-
specific recurrence rates observed for the patients with screen-
ing-detected CRC, as advanced T category is a known factor
associated with CRC recurrence.42 The T category–specific re-
currence rates were also lower in patients with screening-
detected vs nonscreening detected CRC. The persistent lower
recurrence rate in those with screening-detected CRC could be
jamaoncology.com
 Incidence of Recurrence and Time to Recurrence in Stage I to III Colorectal Cancer Original Investigation Research

Figure 3. Cumulative Incidence Function Curves for Colorectal Cancer Recurrence According to Cancer
Detection Method (Screening or Not Screening) Stratified by Union for International Cancer Control (UICC)
Stage

Stage and screening status Screening vs nonscreening

I, nonscreening Stage I: sHR, 0.76; 95% CI, 0.61-0.96
I, screening Stage II: sHR, 0.65; 95% CI, 0.53-0.81
II, nonscreening Stage III: sHR, 0.74; 95% CI, 0.65-0.86
30
II, screening
Cumulative incidence function of recurrence, %

III, nonscreening
III, screening
25

20

15

10

0 1 2 3 4 5
Curves were constructed using the
Time since surgery, y
Aalen-Johansen estimator. Patients
No. at risk
were right-censored at emigration, 5
Stage I, nonscreening 2694 2607 2453 2324 1876 1459
Stage II, nonscreening 4272 4068 3673 3422 2721 2141
years of follow-up, or on January 1,
Stage III, nonscreening 3953 3520 2945 2648 2015 1525 2023, whichever came first. sHR
Stage I, screening 2083 2046 1951 1888 1552 1229 indicates subdistribution hazard ratio
Stage II, screening 1102 1077 1002 960 759 588 calculated using Fine-Gray regression
Stage III, screening 1147 1075 963 911 695 535 adjusted for sex, age, comorbidities,
and UICC stage.

due to a further downstaging of tumor burden beyond T cat- late sequelae, and cost-effectiveness.47 Interventional, pref-
egory, such as tumor size, or to distinct differences in the bio- erably randomized studies are needed to explore shifting from
logical characteristics, such as growth rate. Further studies are one-size-fits-all surveillance toward a personalized surveil-
needed to address this finding. lance strategy.48
The main goal of follow-up protocols is to detect recur-
rence early to maximize the patient’s survival. The European Strengths and Limitations
Society for Medical Oncology recommends a combination of Strengths of the current study include the nationwide ap-
clinical assessments, regular measurements of carcinoembry- proach, reflecting standardized CRC management rather than
onic antigen levels, computed tomography (CT), and a colo- the performance of individual centers. Also, the large sample
noscopy with higher frequencies for the first 3 years after cu- size increased the statistical power and confidence of the re-
rative surgery and for a total duration of 5 years in patients with ported recurrence rates.
nonmetastatic CRC.14,43 However, substantial variation has Current knowledge about CRC recurrence is based primar-
been found between national surveillance guidelines,44 and ily on intensive follow-up of selected patient cohorts, such as
a Cochrane Review45 found no benefit of intensified surveil- those enrolled in clinical trials or cohorts from individual
lance on overall survival. Denmark participated in the inter- centers.49 Herein we used registry data to obtain recurrence
national multicenter randomized clinical trial COLOFOL,46 status, which is an efficient and inexpensive approach to ob-
which did not show improved 5-year overall survival or CRC- tain follow-up data compared with medical record review,
specific survival associated with more frequent CT scans and which is time and resource intensive. Furthermore, we re-
carcinoembryonic antigen measurements (5 times vs 2 times), cently validated the algorithm we used and found that it was
which is why Denmark follows a surveillance program with 2 highly accurate (sensitivity, 94%; specificity, 99%; positive pre-
CT scans. dictive value, 94%; and negative predictive value, 99%) when
We found that the 5-year CIF of recurrence is now below using contemporary registry data,31 which is in line with pre-
7% and 10% for TNM stage I colon and rectal cancers, respec- vious validations on historical cohorts.30 Also, the registry data
tively (Table 2), and is even lower for cancers detected by needed for the algorithm is available for the entire cohort, as
screening. Furthermore, TSTR was longer for patients with all Danish citizens have unrestricted access to a public tax-
stage I CRC than for patients with stage II and particularly stage supported health care system.50
III CRC. Due to this difference in the pattern of recurrence for It can be considered a limitation that we excluded approxi-
patients with stage I disease, less intensive surveillance, or even mately 15% of patients, particularly patients with previous can-
no surveillance, may be noninferior to current guidelines— cers, as the algorithm cannot discern whether recurrence oc-
especially when also considering health-related quality of life, curs due to one or the other cancer. Although this exclusion

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 Research Original Investigation Incidence of Recurrence and Time to Recurrence in Stage I to III Colorectal Cancer

may have introduced selection bias and affected the general-
izability of the study, we decided to exclude these patients to
improve the internal validity and accuracy of recurrence rates.
The algorithm does not diagnose recurrence within 180 days
after surgery. This quarantine was used to allow for comple-
tion of primary cancer treatment with up to 6 months of ad-
juvant chemotherapy and to avoid diagnosing synchronous
metastases as a recurrence.51 Also, patients who died within
180 days after surgery were excluded to ensure all patients ex-
perienced time at risk of recurrence after 180 days.
stages I to III CRC from 2004 to 2019. The risk reductions were
seen for all stages and for both colon and rectal cancers; re-
ductions were especially notable in patients with screening-
detected CRC but were also seen in patients whose CRC was
not diagnosed through screening. Time to recurrence dif-
fered according to UICC stage. We believe that the risk of CRC
recurrence has become so low in selected patient groups that
further research on personalized surveillance protocols is in-
dicated.

Conclusions
This register-based cohort study found substantial reduc-
tions in CRC recurrence risk for Danish patients with UICC

ARTICLE INFORMATION
Accepted for Publication: August 21, 2023.
Published Online: November 16, 2023.
doi:10.1001/jamaoncol.2023.5098
Open Access: This is an open access article
distributed under the terms of the CC-BY License.
© 2023 Nors J et al. JAMA Oncology.
Author Contributions: Dr Nors and Prof Andersen
had full access to all of the data in the study and
take responsibility for the integrity of the data and
the accuracy of the data analysis. Dr Gotschalck and
Prof Andersen shared senior authorship.
Concept and design: All authors.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Nors, Gotschalck.
Critical review of the manuscript for important
intellectual content: All authors.
Statistical analysis: Nors, Erichsen.
Obtained funding: Nors, Andersen.
Administrative, technical, or material support:
Andersen.
Supervision: Iversen, Erichsen, Gotschalck,
Andersen.
Conflict of Interest Disclosures: Prof Andersen
reported receiving grants from the Novo Nordisk
Foundation, Innovation Fund Denmark, and Danish
Cancer Society during the conduct of the study. No
other disclosures were reported.
Funding/Support: This study was funded by a
scholarship from the Institute of Clinical Medicine,
Aarhus University, Denmark (Dr Nors), Novo
Nordisk Foundation grant NNF17OC0025052 (Prof
Andersen), Innovation Fund Denmark grant
9068-00046B (Dr Andersen), and Danish Cancer
Society grants R231-A13845 and R257-A14700 (Prof
Andersen).
Role of the Funder/Sponsor: The funders had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Meeting Presentation: This work was presented in
part at the Annual Meeting of the American
Association for Cancer Research; April 18, 2023;
Orlando, Florida; and at the Aarhus University PhD
Day; January 20, 2023; Aarhus, Denmark.
Data Sharing Statement: See Supplement 2.
Additional Contributions: We extend our gratitude
to the Danish Colorectal Cancer Group for providing
data from their national database and to the Center
for Clinical and Genomic Data (CONNECT) at Aarhus
University Hospital for assistance in applying to
receive data from the Danish Health Data Authority.
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