Time From Colorectal Cancer Surgery to Adjuvant Chemotherapy

Post Hoc Analysis of the SCOT Randomized Clinical Trial

Mikail Gögenur, MD; Andreas Weinberger Rosen, MD; Timothy Iveson, MD; Rachel S. Kerr, MBChB, PhD;

Mark P. Saunders, MD, PhD; Jim Cassidy, MD; Josep Tabernero, MD, PhD; Andrew Haydon, MD, PhD;

Bengt Glimelius, MD, PhD; Andrea Harkin, BA; Karen Allan, BA; Sarah Pearson, BA; Kathleen A. Boyd, MSc, PhD;

Andrew H. Briggs, MD, PhD; Ashita Waterston, MD, PhD; Louise Medley, MD, PhD; Richard Ellis, MD, PhD;

Amandeep S. Dhadda, MD, PhD; Mark Harrison, MD, PhD; Stephen Falk, MD; Charlotte Rees, MBBS;

Rene K. Olesen, MD; David Propper, MD; John Bridgewater, MD, PhD; Ashraf Azzabi, MD; David Cunningham, MD;

Tamas Hickish, MD, MBBS, DNB; Simon Gollins, MD, DPhil; Harpreet S. Wasan, MD; Caroline Kelly, PhD;

Ismail Gögenur, MD, DMSc; Niels Henrik Holländer, MD

IMPORTANCE The timing of adjuvant chemotherapy after surgery for colorectal cancer and its

association with long-term outcomes have been investigated in national cohort studies,

with no consensus on the optimal time from surgery to adjuvant chemotherapy.

OBJECTIVE To analyze the association between the timing of adjuvant chemotherapy

after surgery for colorectal cancer and disease-free survival.

DESIGN, SETTING, AND PARTICIPANTS This is a post hoc analysis of the phase 3 SCOT

randomized clinical trial, from 244 centers in 6 countries, investigating the noninferiority

of 3 vs 6 months of adjuvant chemotherapy. Patients with high-risk stage II or stage III

nonmetastatic colorectal cancer who underwent curative-intended surgery were randomized

to either 3 or 6 months of adjuvant chemotherapy consisting of fluoropyrimidine and

oxaliplatin regimens. Those with complete information on the date of surgery, treatment

type, and long-term follow-up were investigated for the primary and secondary end points.

Data were analyzed from May 2022 to February 2024.

INTERVENTION In the post hoc analysis, patients were grouped according to the start of

adjuvant chemotherapy being less than 6 weeks vs greater than 6 weeks after surgery.

MAIN OUTCOMES AND MEASURES The primary end point was disease-free survival.

The secondary end points were adverse events in the total treatment period or the first cycle

of adjuvant chemotherapy.

RESULTS A total of 5719 patients (2251 [39.4%] female; mean [SD] age, 63.4 [9.3] years) were

included in the primary analysis after data curation; among them, 914 were in the early-start

group and 4805 were in the late-start group. Median (IQR) follow-up was 72.0 (47.3-88.1)

months, with a median (IQR) of 56 (41-66) days from surgery to chemotherapy. Five-year

disease-free survival was 78.0% (95% CI, 75.3%-80.8%) in the early-start group and 73.2%

(95% CI, 72.0%-74.5%) in the late-start group. In an adjusted Cox regression analysis,

the start of adjuvant chemotherapy greater than 6 weeks after surgery was associated with

worse disease-free survival (hazard ratio, 1.24; 95% CI, 1.06-1.46; P = .01). In adjusted logistic

regression models, there was no association with adverse events in the total treatment

period (odds ratio, 0.82; 95% CI, 0.65-1.04; P = .09) or adverse events in the first cycle

of treatment (odds ratio, 0.77; 95% CI, 0.56-1.09; P = .13).

CONCLUSIONS AND RELEVANCE In this international population of patients with high-risk stage

II and stage III colorectal cancer, starting adjuvant chemotherapy more than 6 weeks after

surgery was associated with worse disease-free survival, with no difference in adverse events

between the groups.

TRIAL REGISTRATION isrctn.org Identifier: ISRCTN59757862

JAMA Surg. doi:10.1001/jamasurg.2024.1555

Published online June 12, 2024.

Supplemental content

Author Affiliations: Author

affiliations are listed at the end of this

article.

Corresponding Author: Mikail

Gögenur, MD, Center for Surgical

Science, Department of Surgery,

Zealand University Hospital,

Lykkebækvej 1, 4600 Køge, Denmark

(mgog@regionsjaelland.dk).

Research

JAMA Surgery | Original Investigation

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C olorectal cancer (CRC) incidence is increasing worldwide, and efforts to reduce recurrence andmortality are

needed.1

In 2030, it is estimated that 10% of colon cancer cases and 25% of rectal cancer cases will be among patients younger than 50 years.2 Surgery is the only curative modality for patients who present with nonmetastatic CRC, but

up to a third of patients experience a relapse, assumed to be

caused by micrometastatic disease at the time of diagnosis.3

Patients with either high-risk stage II disease or stage III condition are offered adjuvant chemotherapy treatment to lower

recurrence rates and improve disease-free and overall survival.4

The recommended adjuvant treatment for high-risk stage II and

stage III CRC is single-agent fluoropyrimidine or a fluoropyrimidine in combination with oxaliplatin. The International

Duration Evaluation of Adjuvant Therapy consortium trial

failed to show noninferiority for 3 months of treatment with

fluoropyrimidine and oxaliplatin (CAPOX [capecitabine and oxaliplatin] or FOLFOX [fluorouracil, leucovorin, and oxaliplatin]) compared with 6 months of treatment in relation to

disease-free survival,5 with an absolute risk difference of 0.4%

between the groups. Considering the known cumulative toxic

effects related to oxaliplatin treatment, this small difference

was not considered clinically significant.

Studies have also shown that the time from surgery to

adjuvant chemotherapy is essential for key oncological

outcomes.6 A recent meta-analysis showed across 7 cancer

types that a delay of 4 weeks or longer to adjuvant chemotherapy was associated with worse overall survival,7 while

European Society forMedical Oncology (ESMO) guidelines suggest that adjuvant chemotherapy be started within 8 weeks after surgery.8 However, the time from surgery to adjuvant chemotherapy has not been investigated in a large, international,

prospective, well-controlled trial. In the SCOT trial, an international randomized clinical trial, patients were randomly assigned to 3 or 6 months of adjuvant chemotherapy (CAPOX or

FOLFOX).9Three months of adjuvant chemotherapy was noninferior to 6 months of adjuvant chemotherapy across highrisk stage II and stage III CRC, with reduced adverse events in

patients randomized to 3months of therapy. In the study population, information about adjuvant chemotherapy, including

the time to start adjuvant chemotherapy, was recorded prospectively. We have investigated whether patients starting

adjuvant chemotherapy sooner after surgery had a better outcome regarding disease-free survival and whether their adverse events were different from those starting treatment later.

Methods

Study Design

Participants in the SCOT trial, a phase III randomized clinical

trial, were randomly assigned to receive either 3 or 6 months

of oxaliplatin-based adjuvant therapy, with the choice of either

FOLFOX or CAPOX. The SCOT trial was designed as a noninferiority trial, seeking to demonstrate that a reduction in adjuvant treatment duration would not result in a 2.5% decrease in

3-year disease-free survival. Further information on the SCOT

trial, including the intervention, randomization,methods, and

outcomes, can be found elsewhere.9 The trial protocol for the

original SCOT trial is available inSupplement 1, and the post hoc

analysis protocol is available in Supplement 2. The study was

done in accordancewith the Declaration ofHelsinki, and all parts

of the study received ethical approval from the National Research Ethics service or its equivalence in the participating

nations. All individuals provided written informed consent before enrollment. This study was reported according to the

Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines. Data were analyzed

from May 2022 to February 2024.

Setting

The SCOT trial enrolled 6088 patients from 244 centers in 6

countries (UK, Denmark, Spain, Sweden, Australia, and New

Zealand). Patients were followed up for a minimum of 3 years

and a maximum of 8 years after randomization.

Population

Eligible patients, aged 18 years or older, had undergone curative resection for stage III or high-risk stage II colon or rectal

adenocarcinoma. High-risk criteria included T4 disease, preoperative tumor obstruction, fewer than 10 harvested lymph

nodes, poorly differentiated histology, perineural invasion, or

extramural vascular invasion. Enrollment occurred within 11

weeks of surgery, with treatment beginning within 2 weeks

of randomization. Inclusion requirements were World Health

Organization (WHO) performance status 0 or 1, adequate organ

function, and life expectancy exceeding 5 yearswithout cancerrelated factors. Patients with rectal cancer required a total mesorectal excisionwith negative resectionmargins (>1-mm clearance). Exclusion criteria were recent chemotherapy;moderate

to severe kidney impairment; low hemoglobin, neutrophil, or

platelet counts; elevated liver enzyme concentrations; significant cardiovascular disease; pregnancy or lactation; previous

malignant neoplasms; and suspected dihydropyrimidine dehydrogenase deficiency.

Data Collection

Available information on the study population included country of inclusion, age, sex, tumor localization, WHO performance status, randomization group, choice of treatment, and

T and N stages. Tumors were staged using the fifth edition of

the TNM classification.10 Complete data on the date of surgery, treatment type, and long-term follow-up were required

for inclusion in the analyses.

Key Points

Question What is the optimal time from colorectal cancer surgery

to adjuvant chemotherapy?

Findings In this post hoc analysis of 5719 patients in the

international SCOT randomized clinical trial, starting adjuvant

chemotherapy more than 6 to 8 weeks after surgery was

associated with worse disease-free survival.

Meaning Starting adjuvant chemotherapy more than 6 to 8 weeks

after surgery was associated with worse disease-free survival.

Research Original Investigation Time From Colorectal Cancer Surgery to Adjuvant Chemotherapy

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Outcomes

The primary end point was disease-free survival, defined as

time to either death or recurrence within 5 years after randomization. Secondary end points were chemotherapyrelated adverse events. We investigated the time to recurrence and the completion of intended therapy as exploratory

end points.

Statistical Analysis

The overall and stratified characteristics were described using

descriptive statistics, including medians with IQRs for continuous variables and frequencies and proportions for categorical variables.

Unadjusted and adjusted Cox regression models were

used in the primary end point analysis. The variables

included were the start of adjuvant chemotherapy before or

after 6 weeks following surgery, country of inclusion (as a

fixed effect), age (continuous), sex, tumor localization, WHO

performance status, randomization group, treatment group,

and T and N stages. The proportional hazards assumption

was evaluated by testing a time-dependent effect of time on

adjuvant chemotherapy, including the previously mentioned covariates, and visual inspection of the proportional

hazards assumption through Schoenfeld residuals. Results

were presented as hazard ratios (HRs) with 95% CIs. Unadjusted and adjusted logistic regression models were used for

the secondary end point analysis. Country of inclusion was

not included in the logistic regression models in the subgroup analyses due to a low number of events in certain

countries. Results were presented as odds ratios (ORs) with

95% CIs. A 2-tailed P value less than .05 was considered statistically significant.

On analysis of the data, it was decided to group the

population into patients receiving adjuvant chemotherapy

within 6 weeks after surgery and more than 6 weeks after

surgery, as the number of patients receiving adjuvant chemotherapy within 4 weeks was very low (n = 113). Results

were also investigated for 8 weeks as a time point and using

the time to adjuvant chemotherapy as an ordinal variable,

with the levels of 6 weeks or less (<42 days), 6 to 8 weeks

(43-56 days), 8 to 10 weeks (57-70 days), and longer than 10

weeks (>70 days).

Several subgroup analyses were performed. We investigated the primary and secondary end points in patients with

high-risk stage II and stage III CRC, patients randomized to 3

or 6 months of therapy, patients receiving either CAPOX or

FOLFOX, and patients with a WHO performance status of

either 0 or 1. We likewise investigated the primary and

secondary end points in patients with either primary rectal

or colon cancer or patients 70 years or younger vs older than

70 years. In sensitivity analyses, we investigated the primary and secondary end points in the study population who

completed either 3 or 6 months of therapy (per-protocol

study population) and whether 8 or 10 weeks of delay before

oncological therapy was associated with disease-free

survival.

The statistical analysiswas performed usingR version 4.0.3

(R Foundation) and RStudio version 1.1.453 (Posit) software.

Results

A total of 5719 patients (2251 [3.9.4%] female; mean [SD] age,

63.4 [9.3] years) remained after data curation (flow diagram

available in eFigure 1 in Supplement 3), with 914 and 4805

patients receiving chemotherapy within 6 weeks or greater

than 6 weeks after surgery, respectively. Available baseline

characteristics are presented in Table 1. The median (IQR)

follow-up period was 72.0 (47.3-88.1) months for the entire

cohort, with a median (IQR) of 56 (41-66) days from surgery

to chemotherapy.

At the 5-year disease-free survival analysis, there were 203

events (22.2%) in the patients with early start to adjuvant chemotherapy and 1365 events (28.4%) in the patients with late

start. Five-year disease-free survivalwas 78.0% (95% CI, 75.3%-

80.8%) in the early-start group and 73.2% (95% CI, 72.0%-

74.5%) in the late-start group (Figure 1). Unadjusted analysis

of time to chemotherapy showed a significant association with

disease-free survival, with the start of chemotherapy beyond

6 weeks from surgery associated with worse disease-free

survival (HR, 1.25; 95% CI, 1.07-1.44) (Table 2).

In adjusting for sex, age, country of inclusion, WHO

performance status, randomization group, tumor localizaTable 1. Baseline Characteristics of the Study Population

Stratified by Time to Adjuvant Therapy

Group

Time from surgery to adjuvant therapy, No. (%)

≤6 wk (n = 914) >6 wk (n = 4805)

Age, median (IQR), y 63 (57-68) 65 (59-70)

Sex

Female 378 (41.4) 1873 (39.0)

Male 536 (58.6) 2932 (61.0)

Tumor localization

Colon 781 (85.4) 3910 (81.4)

Rectum 133 (14.6) 895 (18.6)

T stage

1 28 (3.1) 151 (3.1)

2 80 (8.8) 453 (9.4)

3 546 (59.7) 2729 (56.8)

4 260 (28.4) 1472 (30.6)

N stage

0 169 (18.5) 868 (18.0)

1 516 (56.5) 2749 (57.2)

2 229 (25.0) 1188 (24.7)

WHO performance status

0 712 (77.9) 3386 (70.4)

1 202 (22.1) 1419 (29.6)

Randomization group

3-mo therapy 471 (51.5) 2405 (50.1)

6-mo therapy 443 (48.5) 2400 (49.9)

Treatment

CAPOX 677 (74.1) 3192 (66.4)

FOLFOX 237 (25.9) 1613 (33.6)

Abbreviations: CAPOX, capecitabine and oxaliplatin; FOLFOX, fluorouracil,

leucovorin, and oxaliplatin; WHO, World Health Organization.

Time From Colorectal Cancer Surgery to Adjuvant Chemotherapy Original Investigation Research

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tion, chemotherapy (CAPOX or FOLFOX), and T and N stage,

a persistent association was found between time to chemotherapy and disease-free survival, with chemotherapy greater

than 6 weeks from surgery associated with worse diseasefree survival (HR, 1.24; 95% CI, 1.06-1.46; P = .01) (Table 2).

Tests of the proportional hazards assumption showed a violation of the assumption for age, sex, and disease site, while

visual inspection of Schoenfeld residual plots showed no violation (eFigure 2 in Supplement 3). Including a time interaction term for age, sex, and disease site did not change the association between time to chemotherapy and disease-free

survival (HR, 1.24; 95% CI, 1.05-1.46). In an adjusted Cox regression model, time to chemotherapy greater than 6 weeks

was associated with worse time to recurrence (HR, 1.26;

95% CI, 1.06-1.50; P = .009).

Subgroup analysis showed a persistent association

between start of chemotherapy greater than 6 weeks from

surgery and worse disease-free survival in patients with

stage III disease (HR, 1.22; 95% CI, 1.03-1.45; P = .02),

patients randomized to 6 months of treatment (HR, 1.29;

95% CI, 1.02-1.62; P = .03), and patients treated with CAPOX

(HR, 1.32; 95% CI, 1.09-1.61; P = .005). An association was

also evident in patients with rectal cancer (HR, 2.31; 95% CI,

1.30-4.10; P = .004), patients aged 70 years or younger (HR,

1.30; 95% CI, 1.08-1.57; P = .005), and patients with a WHO

performance status of 0 (HR, 1.22; 95% CI, 1.01-1.47; P = .04)

(Figure 2). In a sensitivity analysis, we found that receiving

adjuvant chemotherapy greater than 8 weeks (n = 2828)

compared with less than or equal to 8 weeks (n = 2891) was

also significantly associated with disease-free survival (HR,

1.14; 95% CI, 1.03-1.30; P = .01). In an adjusted Cox model

where time to adjuvant chemotherapy was modeled as an

ordinal category, with the levels of 6 weeks or less, 6 to 8

weeks, 8 to 10 weeks, and more than 10 weeks, we saw a

time-associated increase in the HR for disease-free survival

(eFigure 3 in Supplement 3), with no significant difference

between 6 weeks or less and 6 to 8 weeks (HR, 1.17; 95% CI,

0.98-1.39; P = .08) and a significant difference between 6

weeks or less and 8 to 10 weeks (HR, 1.30; 95% CI, 1.09-1.55;

P = .003) and more than 10 weeks (HR, 1.26; 95% CI, 1.04-

1.53; P = .02).

Adverse Events

Unadjusted analyses of time to chemotherapy showed no association of treatment within 6 weeks of surgery with any increased chemotherapy-related adverse events (OR, 0.91;

95% CI, 0.74-1.11; P = .30) or increased adverse events in the

first cycle of treatment (OR, 0.83; 95% CI, 0.62-1.13; P = .20)

(Table 3). After adjusting for country of inclusion, sex, age,

WHO performance status, randomization group, tumor localization, chemotherapy, and T and N stage, no significant associationwas found between treatment startingwithin 6weeks

of surgery and any increase in chemotherapy-related adverse

events (OR, 0.82; 95% CI, 0.65-1.04; P = .09) or increase in adverse events in the first cycle of treatment (OR, 0.77; 95% CI,

0.56-1.09; P = .13) (Table 3).

Subgroup analysis showed no association of chemotherapy start after 6 weeks with any chemotherapy-related adverse effect in the total treatment period or the first cycle in

any subgroups (eFigures 4 and 5 in Supplement 3).

Completion of Intended Therapy

Analysis in the total per-protocol study population showed no

association of time to chemotherapy with completion of

therapy (OR, 0.93; 95% CI, 0.77-1.11; P = .41), with similar results in patients randomized to 3 months of therapy (OR, 0.99;

95% CI, 0.72-1.34; P = .96) or 6 months of therapy (OR, 0.92;

95% CI, 0.74-1.14; P = .47).

Discussion

In this analysis of the SCOT trial, we found that starting adjuvant chemotherapy 6 weeks or more after surgery in patients

with high-risk stage II or stage III CRC was associated with

worse disease-free survival. There was no association between the early start of adjuvant chemotherapy and adverse

events in the treatment period or the first cycle of adjuvant

chemotherapy.

Time to adjuvant chemotherapy and delays in this period

have been investigated in several studies within several

cancers.11-14 In a recent meta-analysis, Hanna and colleagues7

showed that a 4-week increment of delay of adjuvant chemotherapy start was associated with a 13% decrease in overall survival in patients with CRC. Only US or Canadian retrospective

observational studies were included in the analysis, investigating patients with stage II or III colon or rectal cancer. There

were no defined criteria for rectal cancer surgery specimen

quality, while the definition of stage II disease differed in the

studies including these patients. Data on treatment completion was provided in one study,15 while adverse events were

not reported in any of the included studies. Our study confirms the findings of the meta-analysis with disease-free

survival as an outcome while being based on an international

cohort with prospective data collection of the adjuvant treatment, including the treatment period, whether treatment was

completed as intended, and detailed adverse event registration. The SCOT study used contemporary definitions of adjuvant chemotherapy regimens, stage II disease, and oncological rectal cancer surgery, defined as the total mesorectal

Figure 1. Unadjusted Disease-Free Survival by Study Group

0

No. at risk

0 2 3 4 5 6

100

80 Disease-free survival, %

Time after enrollment, y

60

40

20

1

Treatment start >6 wk

Treatment start ≤6 wk

Treatment start >6 wk

Treatment start ≤6 wk

914 838 752 614 482 433

4805 4309 3852 3508 3219 2944

Research Original Investigation Time From Colorectal Cancer Surgery to Adjuvant Chemotherapy

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excision approach with negative resection margins. Patients

undergoing neoadjuvant chemoradiation, besides short-course

radiotherapy, were excluded. Our study found that adjuvant

chemotherapy more than 6 weeks after surgery was associated with worse disease-free survival in the intent-to-treat

population, and an association was also shown in the timeto-recurrence analysis. Of note, we did see that the association persisted in the subgroups of patientswith stage III disease.

ESMO guidelines suggest a start of adjuvant chemotherapy

within 8 weeks after surgery, with no formal suggestion in

American Society of Clinical Oncology guidelines.8,16,17 We

found a significant association comparing patients waiting

more than 8 weeks and a time-associated increase in the HR

for disease-free survival when time to adjuvant chemotherapy wasmodeled as an ordinal variable.However, our data

suggest a higher benefit if the adjuvant chemotherapy is started

within 6 weeks after surgery.

In our cohort, we found no association between the time

to start of adjuvant chemotherapy and adverse events in the

total treatment period or the first cycle of treatment in the study

population or subgroup analyses, underscoring that early start

of adjuvant chemotherapy did not pose an additional risk for

Table 2. Analysis of Disease-Free Survival in the Study Population

Time from surgery to

adjuvant therapy Patients, No. Events, No.

IR, No./10 000

person-years

Unadjusted Adjusted

HR (95% CI) P value HR (95% CI) P value

≤6 wk 914 203 487 1 [Reference]

.004

1 [Reference]

.01

>6 wk 4805 1362 562 1.25 (1.07-1.44) 1.24 (1.06-1.46)

Abbreviations: HR, hazard ratio; IR, incidence rate.

Figure 2. Subgroup Analysis of the Association of Time to Adjuvant Chemotherapy Start and Disease-Free Survival

P value

0.5 5 1

HR (95% CI)

No. of

patients

No. of

events IRa

Variable by

treatment start

Stage 2 disease

HR

(95% CI)

≤6 wk 1 [Reference]

>6 wk

Stage 3 disease

≤6 wk 1 [Reference]

>6 wk

Arm 1 (3 mo)

≤6 wk 1 [Reference]

>6 wk

Arm 2 (6 mo)

≤6 wk 1 [Reference]

>6 wk

CAPOX treatment

≤6 wk 1 [Reference]

>6 wk

FOLFOX treatment

≤6 wk 1 [Reference]

>6 wk

Primary rectal cancer

≤6 wk 1 [Reference]

>6 wk

Primary colon cancer

≤6 wk 1 [Reference]

>6 wk

Age ≤70 y

≤6 wk 1 [Reference]

>6 wk

Age >70 y

≤6 wk 1 [Reference]

>6 wk

WHO PS 0

≤6 wk 1 [Reference]

>6 wk

WHO PS 1

≤6 wk 1 [Reference]

>6 wk

169

868

745

3937

471

2405

443

2400

677

3192

237

1613

133

895

781

3910

748

3678

166

1127

712

3386

202

1419

21

173

182

1189

105

674

98

688

151

932

52

430

17

229

186

1133

157

983

46

379

150

912

53

450

246

359

549

612

486

557

489

566

491

578

477

529

271

488

526

579

450

525

682

683

473

541

534

608

1.52 (0.91-2.53)

1.22 (1.03-1.45)

1.23 (0.98-1.55)

1.29 (1.02-1.62)

1.32 (1.09-1.61)

1.11 (0.82-1.50)

2.31 (1.30-4.10)

1.16 (0.98-1.38)

1.30 (1.08-1.57)

1.09 (0.78-1.53)

1.22 (1.01-1.47)

1.31 (0.95-1.80)

.11

.02

.08

.03

.005

.49

.004

.08

.005

.60

.04

.10

Arm 1 includes patients

randomized to 3 months of therapy;

arm 2, patients randomized to 6

months of therapy. CAPOX indicates

capecitabine and oxaliplatin;

FOLFOX, fluorouracil, leucovorin,

and oxaliplatin; HR, hazard ratio;

IR, incidence rate; WHO PS, World

Health Organization performance

status.

a

The IR is per 10 000 person-years.

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the patients. Delay of adjuvant chemotherapy and its association with adverse events of the treatment has, to our knowledge, not been reported before. We did not find that time to

adjuvant chemotherapy was associated with reduced completion of intended therapy in the whole population.

Based on others’ and our findings in this field, efforts

should be made to facilitate circumstances that allow patients to quickly recover from CRC surgery so adjuvant treatment can be initiated. Studies using a state-of-the-art enhanced

recovery after surgery (ERAS) program have shown that patients with colon cancer can recover fully within 2 weeks from

surgery.18This is interesting considering the preliminary data

of a randomized clinical trial that allocated patients to receive adjuvant chemotherapy within 2 weeks or more than 2

weeks after surgery.19There was no difference in adverse event

rates, while long-term follow-up data are still awaited.

Recent results from the FOxTROT trial20 have shown the

benefit of neoadjuvant and adjuvant chemotherapy in patients with nonmetastatic colon cancer. The authors showed

a significant effect of the treatment regimen on 2-year recurrence rates and noted that patients randomized to neoadjuvant therapy were more likely to continue adjuvant chemotherapy than the control group. Patients waited at least 8 weeks

from neoadjuvant chemotherapy until surgery and were

referred to adjuvant therapy within 11 weeks from surgery.

Future studies in this field should aim toward shortening the

time to adjuvant chemotherapy.

Limitations

Our study includes several limitations. Although the SCOT trial

was a randomized study, patients were not randomized according to adjuvantchemotherapystart.Patientswere enrolledwithin

11weekswithout information concerning surgical treatment, including the surgical approach, whether an ERAS approach

wasused, and postoperative complications.Themean age in our

cohort was 63.4 years, which implicates a younger population

than the general population of patients with CRC.

Conclusions

In the international SCOT trial study population, the start of

adjuvant chemotherapy more than 6 weeks after surgery was

associated with worse disease-free survival but not with worse

adverse events in the total treatment period or the first cycle.

The results suggest that efforts toward facilitating the early start

of adjuvant chemotherapy may improve long-term oncological outcomes.

ARTICLE INFORMATION

Accepted for Publication: March 22, 2024.

Published Online: June 12, 2024.

doi:10.1001/jamasurg.2024.1555

Author Affiliations: Center for Surgical Science,

Department of Surgery, Zealand University

Hospital, Køge, Denmark (M. Gögenur, Rosen,

I. Gögenur); Southampton University,

Southampton, United Kingdom (Iveson, Rees,

Propper); Department of Oncology, University of

Oxford, Oxford, United Kingdom (Kerr); The

Christie Hospital, Manchester, United Kingdom

(Saunders); Glasgow Oncology Clinical Trials Unit,

School of Cancer Sciences, University of Glasgow,

Glasgow, United Kingdom (Cassidy, Harkin, Allan,

Kelly); Vall d’Hebron University Hospital and

Institute of Oncology, Universitat Autònoma de

Barcelona, Centro de Investigación Biomédica en

Red de Cáncer, Barcelona, Spain (Tabernero);

Australasian Gastro-Intestinal Trials Group, Sydney,

Australia (Haydon); Department of Immunology,

Genetics and Pathology, University of Uppsala,

Uppsala, Sweden (Glimelius); Oncology Clinical

Trials Office, Department of Oncology, University of

Oxford, Oxford, United Kingdom (Pearson); School

of Health and Wellbeing, University of Glasgow,

Glasgow, United Kingdom (Boyd, Briggs); London

School of Hygiene and Tropical Medicine, London,

United Kingdom (Briggs); Beatson West of Scotland

Cancer Centre, Glasgow, United Kingdom

(Waterston); Royal United Hospital, Bath, United

Kingdom (Medley); Royal Cornwall Hospitals,

National Health Service Trust, Cornwall, United

Kingdom (Ellis); Castle Hill Hospital, Hull, United

Kingdom (Dhadda); Mount Vernon Cancer Centre,

Northwood, United Kingdom (Harrison); Bristol

Cancer Institute, Bristol, United Kingdom (Falk);

Department of Oncology, Aalborg University

Hospital, Aalborg, Denmark (Olesen); Barts Cancer

Institute, Queen Mary, University of London,

London, United Kingdom (Propper); University

College London, London, United Kingdom

(Bridgewater); Newcastle upon Tyne Hospitals,

National Health Service Foundation Trust,

Newcastle, United Kingdom (Azzabi); Brighton and

Sussex University Hospital Trust, Brighton, United

Kingdom (Cunningham); University Hospitals

Dorset, Bournemouth University, Bournemouth,

United Kingdom (Hickish); North Wales Cancer

Treatment Centre, Rhyl, United Kingdom (Gollins);

Hammersmith Hospital, Imperial College London,

London, United Kingdom (Wasan); Danish

Colorectal Cancer Group, Copenhagen, Denmark

(I. Gögenur); Department of Clinical Medicine,

University of Copenhagen, Copenhagen, Denmark

(I. Gögenur); Department of Clinical Oncology and

Palliative Care, Zealand University Hospital, Køge,

Denmark (Holländer).

Author Contributions: Dr M. Gögenur had full

access to all of the data in the study and takes

responsibility for the integrity of the data and the

accuracy of the data analysis. Drs I. Gögenur and

Holländer are co–senior authors.

Concept and design: M. Gögenur, Iveson, Kerr,

Cassidy, Allan, Boyd, Briggs, Falk, Azzabi,

I. Gögenur, Holländer.

Acquisition, analysis, or interpretation of data:

M. Gögenur, Rosen, Iveson, Saunders, Cassidy,

Tabernero, Haydon, Glimelius, Harkin, Pearson,

Boyd, Waterston, Medley, Ellis, Dhadda, Harrison,

Rees, Olesen, Propper, Bridgewater, Cunningham,

Hickish, Gollins, Wasan, Kelly, Holländer.

Drafting of the manuscript: M. Gögenur, Saunders,

Table 3. Analysis of Association With Adverse Events in the Total Treatment Period or First Cycle of Treatment in the Study Population

Time from surgery to adjuvant therapy Patients, No. Events, No.

Unadjusted Adjusted

OR (95% CI) P value OR (95% CI) P value

Adverse events in total treatment period

≤6 wk 914 130 1 [Reference]

.30

1 [Reference]

.09

>6 wk 4805 626 0.91 (0.74-1.11) 0.82 (0.65-1.04)

Adverse events in first cycle of treatment

≤6 wk 914 56 1 [Reference]

.20

1 [Reference]

.13

>6 wk 4805 246 0.83 (0.62-1.13) 0.77 (0.56-1.09)

Abbreviation: OR, odds ratio.

Research Original Investigation Time From Colorectal Cancer Surgery to Adjuvant Chemotherapy

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Falk, Bridgewater, Wasan, I. Gögenur.

Critical review of the manuscript for important

intellectual content: M. Gögenur, Rosen, Iveson,

Kerr, Cassidy, Tabernero, Haydon, Glimelius, Harkin,

Allan, Pearson, Boyd, Briggs, Waterston, Medley,

Ellis, Dhadda, Harrison, Rees, Olesen, Propper,

Bridgewater, Azzabi, Cunningham, Hickish, Gollins,

Wasan, Kelly, I. Gögenur, Holländer.

Statistical analysis: M. Gögenur, Rosen, Boyd,

Olesen, I. Gögenur.

Obtained funding: Iveson, Kerr, Cassidy, Harkin,

Briggs, Holländer.

Administrative, technical, or material support:

M. Gögenur, Iveson, Cassidy, Tabernero, Glimelius,

Harkin, Allan, Pearson, Ellis, Dhadda, Harrison, Falk,

Gollins, Kelly, I. Gögenur.

Supervision: Cassidy, Tabernero, Dhadda, I. Gögenur.

Conflict of Interest Disclosures: Dr Saunders

reported receiving personal fees from Servier,

Bayer, Takeda, and MSD outside the submitted

work. Dr Tabernero reported receiving personal

fees from Alentis Therapeutics, AstraZeneca,

Boehringer Ingelheim, Cardiff Oncology, CARSgen

Therapeutics, Chugai, Daiichi Sankyo, F.

Hoffmann-La Roche Ltd, Genentech Inc, hC

Bioscience, Ikena Oncology, Immodulon

Therapeutics, Inspirna Inc, Lilly, Medscape

Education, Menarini, Merck Serono, Merus, Mirati,

MSD, Neophore, Novartis, Ona Therapeutics, Orion

Biotechnology, PeerView Institute for Medical

Education, Peptomyc, Pfizer, Physicians Education

Resource, Pierre Fabre, Samsung Bioepis, Sanofi,

Scandion Oncology, Scorpion Therapeutics, Seattle

Genetics, Servier, Sotio Biotech, Taiho, Takeda

Oncology, and Tolremo and holding stock in Oniria

Therapeutics, Alentis Therapeutics, Pangaea

Oncology, and 1TRIALSP outside the submitted

work. Dr Glimelius reported receiving grants from

the Swedish Cancer Society during the conduct of

the study. Dr Pearson reported receiving grants

from the National Institute for Health and Care

Research during the conduct of the study; and

receiving personal fees from Cancer Research UK

outside the submitted work. Dr Boyd reported

receiving grants from the National Institute for

Health Research during the conduct of the study;

and receiving grants from Cancer Research UK

outside the submitted work. Dr Briggs reported

receiving personal fees from Daiichi Sankyo,

AstraZeneca, Boehringer Ingelheim, Idorsia,

Rhythm, Gilead, GSK, Roche, Novartis, Eisai,

and Takeda outside the submitted work. Dr Ellis

reported receiving personal fees from Eisai and

Amgen outside the submitted work. Dr Hickish

reported receiving grants from the National

Institute for Health and Care Research during the

conduct of the study; and receiving grants from

Pfizer, Pierre Fabre, AstraZeneca, Novartis, and the

National Institute for Health and Care Research,

having a patent issued for a neuropathy device,

and holding stock in iQ HealthTech outside the

submitted work. Dr I. Gögenur reported receiving

personal fees from Boehringer Ingelheim,

Pharmacosmos, Ethicon, and MSD and grants from

Pharmacosmos outside the submitted work.

No other disclosures were reported.

Data Sharing Statement: See Supplement 4.

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