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.
Abstract
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
This post hoc analysis of the phase 3 SCOT randomized clinical trial investigates the association between the timing of adjuvant chemotherapy after surgery for colorectal cancer and disease-free survival.
Introduction
Colorectal cancer (CRC) incidence is increasing worldwide, and efforts to reduce recurrence and mortality 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 for Medical 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).9 Three months of adjuvant chemotherapy was noninferior to 6 months of adjuvant chemotherapy across high-risk stage II and stage III CRC, with reduced adverse events in patients randomized to 3 months 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 in Supplement 1, and the post hoc analysis protocol is available in Supplement 2. The study was done in accordance with the Declaration of Helsinki, 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 years without cancer-related factors. Patients with rectal cancer required a total mesorectal excision with negative resection margins (>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.
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 chemotherapy-related 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 analysis was performed using R 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.
Table 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.
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 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 (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).
Figure 1. Unadjusted Disease-Free Survival by Study Group.
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.
In adjusting for sex, age, country of inclusion, WHO performance status, randomization group, tumor localization, 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 disease-free 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).
Figure 2. Subgroup Analysis of the Association of Time to Adjuvant Chemotherapy Start and Disease-Free Survival.
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.
aThe IR is per 10 000 person-years.
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 association was found between treatment starting within 6 weeks 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).
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.
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.11,12,13,14 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 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 time-to-recurrence analysis. Of note, we did see that the association persisted in the subgroups of patients with 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 was modeled 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 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.18 This 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.19 There 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 adjuvant chemotherapy start. Patients were enrolled within 11 weeks without information concerning surgical treatment, including the surgical approach, whether an ERAS approach was used, and postoperative complications. The mean 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.
Trial Protocol
Post Hoc Analysis Protocol
eFigure 1. Consort Diagram
eFigure 2. Schoenfeld Residuals for Included Variables in the Cox Regression Model
eFigure 3. Adjusted Cox Regression Model Where Time to Adjuvant Chemotherapy Was Modeled as an Ordinal Variable With the Levels <=6 Weeks, 6-8 Weeks, 8-10 Weeks, and >10 Weeks
eFigure 4. Subgroup Analysis of the Association of Time to Adjuvant Chemotherapy Start and Adverse Events in the Total Treatment Period
eFigure 5. Subgroup Analysis of the Association of Time to Adjuvant Chemotherapy Start and Adverse Events in the First Cycle of Treatment
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol
Post Hoc Analysis Protocol
eFigure 1. Consort Diagram
eFigure 2. Schoenfeld Residuals for Included Variables in the Cox Regression Model
eFigure 3. Adjusted Cox Regression Model Where Time to Adjuvant Chemotherapy Was Modeled as an Ordinal Variable With the Levels <=6 Weeks, 6-8 Weeks, 8-10 Weeks, and >10 Weeks
eFigure 4. Subgroup Analysis of the Association of Time to Adjuvant Chemotherapy Start and Adverse Events in the Total Treatment Period
eFigure 5. Subgroup Analysis of the Association of Time to Adjuvant Chemotherapy Start and Adverse Events in the First Cycle of Treatment
Data Sharing Statement