Abstract
Background
One in three patients with stage III colon cancer will experience tumor recurrence. It is uncertain if physical activity during and after postoperative chemotherapy for stage III colon cancer improves overall survival after tumor recurrence.
Methods
We conducted a prospective cohort study nested within a randomized multicenter trial of patients initially diagnosed with stage III colon cancer who experienced tumor recurrence (N=399). We measured postoperative physical activity before tumor recurrence. Physical activity energy expenditure was quantified using metabolic equivalent task hours per week (MET-h/wk). The primary endpoint was overall survival after tumor recurrence. Multivariable flexible parametric survival models estimated relative and absolute effects with two-sided hypothesis tests.
Results
Compared with patients expending <3.0 MET-h/wk of physical activity (comparable to <1.0 h/wk of brisk walking), patients with ≥18.0 MET-h/wk of physical activity (comparable to 6 h/wk of brisk walking) had a 33% relative improvement in overall survival time after tumor recurrence [hazard ratio: 0.67 (95% CI: 0.42, 0.96)]. The overall survival rate at three years after tumor recurrence was 61.3% (95% CI: 51.8, 69.2) with <3.0 MET-h/wk of physical activity and 72.2% (95% CI: 63.1, 79.6) with ≥18 MET-h/wk of physical activity [risk difference: 10.9 percentage points (95% CI: 1.2, 20.8)].
Conclusions
Higher postoperative physical activity is associated with improved overall survival after tumor recurrence in patients initially diagnosed with stage III colon cancer. These data may be relevant to patients who, despite optimal postoperative medical therapy, have a high risk of tumor recurrence.
Precis:
Among patients initially diagnosed with stage III colon cancer enrolled in a trial of postoperative treatment, higher postoperative physical activity is associated with improved overall survival after tumor recurrence. Oncologists may wish to include counseling about the potential benefits of physical activity in their postoperative treatment consultations.
INTRODUCTION
One in three patients with stage III colon cancer will experience tumor recurrence.1 Tumor recurrence after colon cancer often manifests as distant metastases to the liver or lung.2 The treatment of recurrence with curative-intent surgery is often not feasible,3 and most patients receive chemotherapy plus monoclonal antibodies,4 which extends median overall survival to 30 months.4, 5 Modifiable risk factors of overall survival after recurrence are unknown.6, 7
Physical activity after surgical resection for stage III colon cancer is associated with longer disease-free survival.8, 9 Physical activity during and after postoperative chemotherapy may improve disease-free survival by preventing tumor recurrence in some patients, which confers an overall survival benefit.10 Conversely, physical activity during palliative chemotherapy in patients with metastatic colorectal cancer (80.6% with synchronous metastases) is not associated with improved overall survival.11 A prior study of 237 patients with stage III colon cancer concluded that physical activity after postoperative chemotherapy might be associated with longer overall survival after tumor recurrence;12 however, this association was not statistically significant (P=0.052), and no studies have attempted to replicate this initial hypothesis-generating observation.
In a cohort of patients with stage III colon cancer enrolled in a randomized multicenter trial of postoperative treatment sponsored by the National Cancer Institute,13 we conducted a secondary analysis to examine the association of physical activity during and after postoperative chemotherapy with overall survival after tumor recurrence. Within this trial, we prospectively collected measures of recreational physical activity, body mass index, and dietary patterns that were updated during the trial. Moreover, because data on pathologic tumor stage, performance status, treatment, and follow-up were carefully measured in this trial, the effect of disease characteristics could be assessed. We hypothesized that physical activity during and after postoperative chemotherapy would be associated with a statistically significant improved overall survival after tumor recurrence.
METHODS
Study Design
The Cancer and Leukemia Group B (CALGB; now part of the Alliance for Clinical Trials in Oncology) and Southwest Oncology Group (SWOG) trial 80702 was designed with the National Cancer Institute. The trial used a 2×2 double-blind factorial design to test the primary hypothesis of the superiority of celecoxib compared with placebo,13 and the secondary hypothesis of the noninferiority of three months compared with six months of chemotherapy as part of an international pooling project.14, 15 At trial enrollment, patients were offered the option to participate in a nested cohort study of lifestyle factors that required completing physical activity assessments at specified time intervals (described below). Institutional review board approval was obtained at all participating centers, and all patients provided written informed consent.
Study Population
Eligible patients had curatively resected (margin-negative), histologically proven adenocarcinoma of the colon. Patients had at least one pathologically confirmed metastatic lymph node or N1c designation, defined as tumor deposit(s) in the subserosa, mesentery, or nonperitonealized pericolic tissue without regional lymph node metastases. Patients were at least 18 years of age, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and had normal hepatic, renal, and hematologic values.13
Patients in the analysis presented herein had biopsy-proven recurrent colon cancer. Recurrence was assessed in all patients by history, physical examination, and carcinoembryonic antigen measures every three months for three years following the commencement of postoperative therapy and subsequently every six months for six years after enrollment or until disease recurrence, whichever came first. All patients had surveillance imaging of the chest, abdomen, and pelvis every six months for at least three years and then yearly for three years or until disease recurrence.
Physical Activity Assessment
Patients recalled their average weekly time spent on recreational physical activities during the past two months using a validated questionnaire.16 Patients reported their physical activity once during postoperative chemotherapy and after completing postoperative chemotherapy. Each physical activity was assigned an energy expenditure metabolic equivalent (MET) value according to standardized criteria.17, 18 We calculated the MET hours per week (MET-h/wk) for each activity by multiplying the MET value by the patient’s reported number of hours of physical activity each week. Total recreational physical activity volume was quantified as the sum of the MET-h/wk for all aerobic and muscle-strengthening activities. Light-intensity to moderate-intensity physical activities were <6 METs and vigorous-intensity activities were ≥6 METs.18
Study Endpoint
The primary endpoint of this analysis was overall survival after tumor recurrence, defined as the time from the date of documented recurrence to death from any cause. Patients without reported deaths were censored at their last known follow-up. The exploratory endpoint was colon cancer–specific survival, defined as the time from the date of documented recurrence to death attributed to colon cancer. Time to recurrence was defined as the interval from completing the first physical activity questionnaire to the date of tumor recurrence.7
Covariates
Data for patient demographic factors, including age, sex, race, and ethnicity, were self-reported. Clinical factors, including the extent of tumor invasion through the bowel wall (T-stage), the extent of lymph node metastases (N-stage), pathologic risk group [low (T1, T2, or T3, N1) or high (T4, N2, or both)], tumor location, performance status, and low-dose aspirin use, were obtained from a combination of physician assessment and the medical record. Smoking history was self-reported. Body mass index was abstracted from a combination of the electronic medical record and self-report. Diet was assessed using a 131-item food frequency questionnaire;19 prudent and western dietary patterns were defined using validated factor loadings.20 Body mass index and diet were updated when physical activity was reassessed.
Statistical Analysis
The analytic sample was a priori restricted to patients with one or more physical activity measures obtained before the diagnosis of tumor recurrence. To test for differences in baseline patient characteristics by categories of physical activity volume, the χ2 was used for categorical variables, and analysis-of-covariance was used for continuous variables. Physical activity was modeled using cumulative averaging, quantifying the time-weighted average of all reported physical activity.20, 21 The statistical analysis did not include physical activity measures obtained after tumor recurrence. We updated physical activity based on the results of the second questionnaire (if the patient had not yet experienced tumor recurrence), which was weighted proportional to the time between the first and the second questionnaire and the time between the second questionnaire and the recurrence-free survival period. Repeatedly measured variables (e.g., body mass index and dietary patterns) were considered time-varying covariates.
Flexible parametric proportional hazards survival models were used to quantify the association between physical activity and overall survival after tumor recurrence.22 Parametric survival models allow for smooth predictions and the estimation of relative and absolute effects while permitting flexibility in the shape of the baseline hazard function.23, 24 Relative effects are presented as the hazard ratio (HR) in a time-to-event framework, and absolute effects are presented as the risk difference (RD) at two and three years after tumor recurrence, as these landmarks are meaningful for overall survival after tumor recurrence.4, 7 Confidence intervals for the RD were calculated with 1,000 bootstrap replicates.25 The number needed to treat (e.g., the number of patients needing to increase their postdiagnosis physical activity from < 3.0 MET-h/wk to ≥ 18.0 MET-h/wk to prevent one death after tumor recurrence) was quantified as the inverse of the absolute risk difference. We conducted one sensitivity analysis restricted to the subset of patients with two physical activity measures (e.g., during and after postoperative chemotherapy) obtained before the diagnosis of tumor recurrence.
Potential confounding variables were identified based on prior analyses8, 12 and expert knowledge as potentially causally related to physical activity, tumor recurrence, or both.26 Multivariable (e.g., confounder-adjusted) models were fit to achieve parsimony based on stepwise selection, relative change-in-estimates, and minimization of the Akaike Information Criterion (AIC).27 Sensitivity analyses were conducted to quantify an unmeasured confounder’s strength to explain the observed association.28 A two-sided P<0.05 was considered statistically significant. Reported P values are not adjusted for multiplicity. Data were collected by the Alliance Statistics and Data Management Center. Data quality was ensured by review of data by the Alliance Statistics and Data Management Center and by the study chairperson following Alliance policies. Data analysis was conducted by the Alliance Statistics and Data Management Center using SAS (Version 9.4) and R (Version 4.2.1) on a data set locked on August 10, 2020.
RESULTS
Between June 2010 and November 2015, 2,524 patients from 654 academic and community oncology centers in the United States and Canada were eligible and enrolled in CALGB/SWOG 80702; 1,707 (67.6%) were enrolled in the nested cohort of diet and lifestyle study. As previously reported, patients enrolled in the nested cohort study were more often white and non-Hispanic, and more likely to use low-dose aspirin.9 Three hundred ninety-nine patients (23.4%) experienced tumor recurrence after completing the first physical activity questionnaire and were analyzed (Supplementary Figure 1). The median time from the first physical activity questionnaire to tumor recurrence was 17.2 [11.2, 26.2] months. Patients who experienced tumor recurrence were more likely to be male (60.7 vs. 54.1%; P=0.020), with T4 colonic lesions (26.3 vs. 11.1%; P<0.001), N2 nodal staging (43.1 vs. 22.0%; P<0.001), high pathologic risk based on the combination of T- and N-stage (56.7 vs. 30.4%; P<0.001), and lower postdiagnosis physical activity [13.2 vs. 16.9 MET-h/wk; P=0.006) Supplementary Table 1].
Patients with higher postdiagnosis physical activity were more likely to be male (66.7 vs. 52.0%; P=0.02), white race (91.1% vs. 72.4%; P=0.006), with better performance status (83.3 vs. 62.5% with ECOG of zero; P=0.002), a lower body mass index (26.8 vs. 29.1 kg/m2; P=0.017), and more likely to consume a prudent diet [(65.6 vs. 47.4%; P=0.003); Table 1].
Table 1.
Baseline characteristics of subjects who had recurrence, stratified by physical activity category
| Physical Activity Volume (MET-h/wk) |
||||
|---|---|---|---|---|
| Characteristic | < 3.0 N = 152 (38.1%) |
3.0–17.9 N = 157 (39.4%) |
≥ 18.0 N = 90 (22.6%) |
P |
|
| ||||
| Demographic factors | ||||
| Age, y, mean (SD) | 61.0 (11.6) | 60.9 (10.4) | 59.9 (11.5) | 0.72 |
| Sex, n (%) | 0.020 | |||
| Male | 79 (52.0) | 103 (65.6) | 60 (66.7) | |
| Female | 73 (48.0) | 54 (34.4) | 30 (33.3) | |
| Race, n (%) | 0.006 | |||
| White | 110 (72.4) | 131 (83.4) | 82 (91.1) | |
| Black or African American | 32 (21.1) | 17 (10.8) | 3 (3.3) | |
| Asian | 4 (2.6) | 3 (1.9) | 3 (3.3) | |
| All others or not reported | 6 (3.9) | 6 (3.8) | 2 (2.2) | |
| Hispanic or Latino, n (%) | 10 (6.6) | 7 (4.5) | 7 (7.8) | 0.53 |
| Clinical factors | ||||
| Extent of invasion through the bowel wall, n (%)a | 0.86 | |||
| T1 or T2 | 11 (7.2) | 13 (8.5) | 8 (8.9) | |
| T3 | 100 (65.8) | 97 (63.4) | 62 (68.9) | |
| T4 | 41 (27.0) | 43 (28.1) | 20 (22.2) | |
| Missing | 0 | 4 | 0 | |
| Nodal stage, n (%)b | 0.37 | |||
| N1 | 80 (52.6) | 92 (58.6) | 55 (61.1) | |
| N2 | 72 (47.4) | 65 (41.4) | 35 (38.9) | |
| Risk group, n (%) | 0.18 | |||
| Low (T1, T2, or T3, N1) | 57 (37.5) | 71 (46.4) | 43 (47.8) | |
| High (T4, N2, or both) | 95 (62.5) | 82 (53.6) | 47 (52.2) | |
| Missing | 0 | 4 | 0 | |
| Tumor location, n (%) | 0.19 | |||
| Left | 67 (44.4) | 82 (53.6) | 52 (57.8) | |
| Right/Transverse/Multiple | 84 (55.6) | 71 (46.4) | 38 (42.2) | |
| Missing | 1 | 4 | 0 | |
| ECOG performance status, n (%)c | 0.002 | |||
| 0 | 95 (62.5) | 114 (72.6) | 75 (83.3) | |
| 1–2 | 57 (37.5) | 43 (27.4) | 15 (16.7) | |
| Low dose aspirin use, n (%) | 29 (19.1) | 42 (26.8) | 22 (24.4) | 0.27 |
| Behavioral factors d | ||||
| Body mass index, kg/m2, mean (SD) | 29.1 (6.4) | 28.2 (6.1) | 26.8 (5.2) | 0.017 |
| Smoking history, n (%) | 0.25 | |||
| Never | 65 (42.8) | 71 (45.2) | 52 (57.8) | |
| Former | 67 (44.1) | 68 (43.3) | 32 (35.6) | |
| Current | 18 (11.8) | 16 (10.2) | 4 (4.4) | |
| Not reported | 2 (1.3) | 2 (1.3) | 2 (2.2) | |
| Western dietary pattern, n (%) | 0.63 | |||
| < Median | 73 (48.0) | 83 (52.9) | 43 (47.8) | |
| ≥ Median | 79 (52.0) | 74 (47.1) | 47 (52.2) | |
| Prudent dietary pattern, n (%) | 0.003 | |||
| < Median | 80 (52.6) | 88 (56.1) | 31 (34.4) | |
| ≥ Median | 72 (47.4) | 69 (43.9) | 59 (65.6) | |
| Physical activity | ||||
| Mean (SD), MET-h/wk | 0.75 (0.92) | 8.5 (4.1) | 42.3 (29.6) | <0.001 |
| Median [IQR], MET-h/wk | 0.25 [0.03,1.6] | 7.6 [5.0,11.4] | 35.8 [25.4,50.1] | |
| Randomization groups | ||||
| Chemotherapy, n (%) | 0.44 | |||
| 3 Months | 80 (52.6) | 87 (55.4) | 55 (61.1) | |
| 6 Months | 72 (47.4) | 70 (44.6) | 35 (38.9) | |
| Pharmacotherapy, n (%) | 0.76 | |||
| Celecoxib | 75 (49.3) | 74 (47.1) | 40 (44.4) | |
| Placebo | 77 (50.7) | 83 (52.9) | 50 (55.6) | |
| Recurrence details | ||||
| Time from randomization to recurrence | ||||
| Mean (SD), months | 20.7 (14.1) | 22.8 (14.8) | 21.3 (12.2) | 0.39 |
| Median [IQR], months | 17.0 [11.0,26.0] | 19.0[12.0,30.0] | 18.0 [13.0,26.0] | 0.29 |
| Time from Q1 to recurrence | ||||
| Mean (SD), months | 20.0 (14.1) | 22.0 (14.8) | 20.7 (12.1) | 0.45 |
| Median [IQR], months | 16.0 [10.3,25.3] | 17.9 [11.1,28.8] | 17.5 [12.5,25.7] | 0.30 |
| Categorical, n (%) | 0.091 | |||
| 0–12 months | 52 (34.2) | 44 (28.0) | 21 (23.3) | |
| 12–24 months | 55 (36.2) | 63 (40.1) | 42 (46.7) | |
| 24–36 months | 25 (16.4) | 27 (17.2) | 18 (20.0) | |
| 36–48 months | 10 (6.6) | 4 (2.5) | 6 (6.7) | |
| ≥ 48 months | 10 (6.6) | 19 (12.1) | 3 (3.3) | |
| Time from Q2 to recurrence e | ||||
| Mean (SD), months | 14.4 (14.3) | 14.1 (12.6) | 12.4 (10.6) | 0.62 |
| Median [IQR], months | 9.5 [3.0, 22] | 9.5 [4.0, 20] | 10.0 [4.0, 18] | 0.92 |
| Site of recurrence, n (%)f | ||||
| Liver | 55 (36.2) | 58 (36.9) | 35 (38.9) | 0.91 |
| Lung | 36 (23.7) | 40 (25.5) | 28 (31.1) | 0.44 |
| Local | 20 (13.2) | 23 (14.6) | 12 (13.3) | 0.92 |
| Other | 63 (41.4) | 66 (42.0) | 36 (40.0) | 0.95 |
ECOG, Eastern Cooperative Oncology Group.
T1 indicates the tumor has grown into the submucosa; T2, growth into the muscularis propria; T3, growth through the muscularis propria and into the subserosa; T4, growth into the surface of the visceral peritoneum or into or has attached to other organs or structures.
N1 indicates 1 to 3 lymph nodes tested positive for cancer (or for this table, N1c: tumor deposit(s) in the subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues without regional lymph node metastases); N2, four or more lymph nodes tested positive for cancer.
Performance status: 0 indicates fully active; 1, restricted in physically strenuous activity but ambulatory and able to carry out light work; and 2, ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50% of waking hours.
Body mass index, western dietary pattern, prudent dietary pattern, and physical activity were calculated using the cumulative average method.
For patients who completed Q2.
Values may not sum to 100% as some patients may have experienced cancer recurrence at more than one site
All multivariable models were adjusted for nodal stage, tumor location, and time from the first physical activity assessment to tumor recurrence. The median follow-up time from tumor recurrence was 47 [36, 55] months. Compared with < 3.0 MET-h/wk of physical activity (comparable to < 1.0 h/wk of brisk walking), patients with ≥ 18.0 MET-h/wk of physical activity (comparable to 6 h/wk of brisk walking) had a 33% relative improvement in overall survival time after tumor recurrence [HR: 0.67 (95% CI: 0.42, 0.96); Table 2]. When analyzed as a continuous variable, higher volumes of physical activity were linearly related (P=0.01) to improved overall survival after tumor recurrence [Supplementary Figure 2]. The overall survival rate two years after tumor recurrence was 74.5% (95% CI: 67.2, 80.4) with < 3.0 MET-h/wk of physical activity and 82.2% (95% CI: 75.7, 87.4) with ≥ 18.0 MET-h/wk of physical activity [RD: 7.7 percentage points (95% CI: 0.8, 14.8); Figure 1]. The overall survival rate three years after tumor recurrence was 61.3% (95% CI: 51.8, 69.2) with < 3.0 MET-h/wk of physical activity and 72.2% (95% CI: 63.1, 79.6) with ≥ 18.0 MET-h/wk of physical activity [RD: 10.9 percentage points (95% CI: 1.2, 20.8)]. Nine patients would need to increase their postdiagnosis physical activity from < 3.0 MET-h/wk to ≥ 18.0 MET-h/wk to prevent one death three years after tumor recurrence. The anatomic site of recurrence did not modify the association between physical activity and overall survival after tumor recurrence (P=0.24).
Table 2.
Association of overall survival after cancer recurrence by physical activity category
| Physical Activity Volume (MET-h/wk) | 2-y OS Rate (95% CI)a,b | 2-y Risk Difference (95% CI)a,c | 3-y OS Rate (95% CI)a,b | 3-y Risk Difference (95% CI)a,c | Hazard Ratio (95% CI)a |
|---|---|---|---|---|---|
|
| |||||
| < 3.0 | 74.5 (67.2, 80.4) | 0.0–Reference | 61.3 (51.8, 69.2) | 0.0–Reference | 1.00–Reference |
| 3.0–17.9 | 76.3 (69.7, 82.2) | 1.8 (−4.4, 8.3) | 63.7 (54.9, 71.7) | 2.4 (−6.1, 11.5) | 0.92 (0.65, 1.21) |
| ≥ 18.0 | 82.2 (75.7, 87.4) | 7.7 (0.8, 14.8) | 72.2 (63.1, 79.6) | 10.9 (1.2, 20.8) | 0.67 (0.42, 0.96) |
| NNTd | — | 13 | — | 9 | — |
Abbreviations: MET-h/wk, metabolic equivalent total physical activity energy expenditure; y, year; OS, overall survival; CI, confidence interval.
Adjusted for nodal stage, tumor location, time from Q1 to recurrence. Continuous covariates were modeled linearly, and categorical covariates were modeled using the categories presented in Table 1.
Covariates for predicting survival rates were set to the mean of the study population for continuous variables and most common categories for categorical variables.
95% confidence intervals were calculated via the bootstrap method with 1,000 replicates.
The number needed to treat (NNT) was calculated as 1/ Risk Difference comparing < 3.0 MET-hr/wk to ≥ 18.0 MET-hr/wk. The NNT quantifies the number of patients who need to become physically active to prevent one death after cancer recurrence.
Figure 1.
Multivariable-adjusted overall survival after colon cancer recurrence by physical activity category
For light- and moderate-intensity activities, compared with 0.0 h/wk, patients with ≥ 1.5 h/wk had a 58% relative improvement in overall survival time after tumor recurrence [HR: 0.42 (95% CI: 0.22, 0.69; Supplementary Table 2]. For brisk walking, compared with < 1.0 h/wk, patients with ≥ 3.0 h/wk, had a 50% relative improvement in overall survival time after tumor recurrence [HR: 0.50 (95% CI: 0.28, 0.81)]. Vigorous-intensity activity [HR: 0.80 (95% CI: 0.57, 1.04)] and muscle-strengthening activity [HR: 1.17 (0.80, 1.58)] were not associated with overall survival time after tumor recurrence.
Sensitivity analyses indicated that an unmeasured confounder would need an HR larger than 2.0 to explain away the above-described associations, independent of all other variables included in the regression models. The sensitivity analysis restricted to the subset of patients with both physical activity measures obtained before the diagnosis of tumor recurrence produced associations of similar magnitude to the primary analysis [Supplementary Table 3]. Sensitivity analysis with the exploratory endpoint of death attributed to colon cancer was identical to that presented (results not shown); only six patients had deaths unrelated to cancer: three due to cardiovascular events and three due to other causes.
DISCUSSION
In this nested cohort study of 399 patients initially diagnosed with stage III colon cancer, physical activity during and after postoperative chemotherapy was associated with improved overall survival after tumor recurrence. Patients with ≥ 18.0 MET-h/wk of physical activity (the energy expenditure equivalent of 4.5 hours of brisk walking per week) had a 10.9 absolute percentage point higher overall survival rate three years after tumor recurrence as compared with patients with < 3.0 MET-h/wk of physical activity (the energy expenditure equivalent of less than one hour of brisk walking per week). In a time-to-event analysis, higher physical activity was associated with a 33% relative improvement in overall survival time after tumor recurrence. The results of this analysis may be particularly relevant to patients who, despite optimal postoperative medical therapy, have a high risk of tumor recurrence (e.g., those with T4 primary lesions with N2 nodal staging).
This analysis confirms the hypothesis generated by a prior study that physical activity after postoperative chemotherapy is associated with improved overall survival after tumor recurrence.12 In that prior study of 237 patients with stage III colon cancer with tumor recurrence, ≥ 18.0 MET-h/wk of physical activity was associated with a 29% relative improvement in overall survival time after tumor recurrence, compared with < 3.0 MET-h/wk; however, this effect was not statistically significant [HR: 0.71 (95% CI: 0.46, 1.11)]. In our analysis of 399 patients, ≥ 18.0 MET-h/wk of physical activity was associated with a 33% relative improvement in overall survival time after tumor recurrence, compared with < 3.0 MET-h/wk, an effect that was statistically significant [HR: 0.67 (95% CI: 0.42, 0.96)]. The hazard ratio estimates are comparable between these two studies (0.71 vs. 0.67); however, the larger sample size in the current analysis allowed for narrower confidence intervals and greater statistical power.
Before this analysis, it was uncertain if physical activity was associated with overall survival after tumor recurrence. Postdiagnosis physical activity may improve overall survival among patients with stage III colon cancer by preventing a subset of patients from experiencing tumor recurrence.29 However, this analysis indicates that preventing tumor recurrence does not entirely mediate the overall survival benefit of physical activity after a colon cancer diagnosis.
Patients who have experienced tumor recurrence continue to derive an overall survival benefit from physical activity completed during and after postoperative chemotherapy. In a study of patients with metastatic colorectal cancer (80.6% with synchronous metastases), physical activity during palliative chemotherapy was not associated with overall survival.11 Therefore, the overall survival benefit of physical activity may vary based on the initial stage of cancer (e.g., III vs. IV) or type of metastases (metachronous vs. synchronous).
Physical activity may have a legacy or long-term effect that confers an overall survival benefit after tumor recurrence. Physical activity is associated with a lower risk of developing colon cancer.30 Among patients with colon cancer, pre- and post-diagnosis physical activity is associated with improved clinical outcomes (e.g., tumor recurrence, cancer-specific survival, overall survival, and survival after tumor recurrence). These associations may be relevant to patient counseling, as a cancer diagnosis is a teachable moment that can inspire behavior change.31
The mechanisms by which physical activity improves overall survival after tumor recurrence are speculative. We previously reported that in stage III colon cancer, physical activity during postoperative chemotherapy is associated with higher dose intensity.9 In patients with metastatic colorectal cancer, physical activity during palliative chemotherapy reduces the risk of chemotherapy dose-limiting toxicity.11 Higher chemotherapy dose intensity is associated with improved overall survival in patients with colon cancer.32 Thus, the benefit of physical activity on overall survival after tumor recurrence may be partly attributed to an improved ability to tolerate chemotherapy administered after tumor recurrence.
Physical activity may improve overall survival after recurrence by enabling the subset of patients with patterns of recurrence that are amenable to tumor resection to maintain a performance status necessary for complex abdominal or thoracic surgery.33 In colon cancer survivors, randomization to aerobic exercise improves physical functioning compared to control.34 Among patients eligible for surgical resection of colorectal cancer liver metastases, randomization to four weeks of exercise before surgery (e.g., prehabilitation) improved cardiopulmonary fitness capacity versus control.35 Cardiopulmonary fitness independently predicts surgical morbidity and morbidity after hepatectomy and lobectomy.36 Physical activity reduces hospital length of stay after complex abdominal surgery.37
Lastly, physical activity may improve overall survival after recurrence by exerting direct effects on the tumor that restrain the location and extent of metastatic progression. Physical activity reduces circulating tumor cells in patients with stage I-III colon cancer.38 Physical activity improves immune surveillance (e.g., NK cell activity),39 and may foster improved distant organ tissue defenses against infiltrating tumor cells.40 Physical activity reduces inflammation and hyperinsulinemia in patients with colon cancer,41, 42 and may limit the availability of niches that can support the metabolic demands for metastatic cell growth.43 Physical activity improves progression-free survival in patients with metastatic colorectal cancer.11 By restraining metastatic progression, these hypothesized effects of physical activity may improve the probability that patients who experience tumor recurrence have limited or isolated metastatic lesions that are appropriate for curative intent surgery or limited tumor burden consistent with improved overall survival.
There are several limitations of the current analysis. Due to the nonrandomized design of our study, we cannot rule out the possibility of residual confounding. However, our analysis accounted for numerous factors we considered confounders.26 Our sensitivity analyses indicated that an unmeasured confounder must be of a moderate magnitude to shift the relative and absolute effect size estimates to the null. Readers should consider the potential for omitted confounders and their impact on our conclusions.
This analysis was nested within a randomized clinical trial. Patients enrolled in randomized trials may differ from the underlying population.44 However, because our study sample was recruited throughout the United States and Canada in academic and community cancer centers, we believe our findings can be generalized to many patients with stage III colon cancer who have experienced tumor recurrence. Readers should consider how the patients in this analysis differ from the patients to whom they wish to apply our conclusions.
Patients in this analysis were all treated with three- or six months of 5-fluorouracil and oxaliplatin (FOLFOX) chemotherapy. It is unknown whether our results apply to patients treated with postoperative capecitabine and oxaliplatin (CAPEOX) or fluoropyrimidine monotherapy. Although we documented the site(s) of postoperative tumor recurrence, we did not record which types of post-recurrence therapy were delivered. These data may have clarified the potential mechanisms by which physical activity improves overall survival after tumor recurrence. Readers should consider how this analysis of patients treated with FOLFOX chemotherapy applies to patients treated with CAPEOX or fluoropyrimidine monotherapy.
There are several strengths of the current analysis. Conducting this analysis within a cohort study nested with a randomized trial offers several advantages over other data sources. Due to eligibility criteria, the disease status of study participants was extensively characterized to maximize patient homogeneity. Chemotherapy dosing, follow-up care, and endpoint ascertainment were standardized within the trial. Prospectively collected detailed information on the baseline and time-varying variables, such as smoking status, body mass index, and diet, permitted comprehensive multivariable adjustment to minimize bias from confounding.
Among patients initially diagnosed with stage III colon cancer enrolled in a trial of postoperative treatment, higher postoperative physical activity is associated with improved overall survival after cancer recurrence. Oncologists may wish to include counseling about the potential benefits of physical activity in their postoperative treatment consultations.
Supplementary Material
Funding:
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821 and U10CA180882 (to the Alliance for Clinical Trials in Oncology), https://acknowledgments.alliancefound.org; UG1CA233180, UG1CA233290, UG1CA233339, UG1CA189954; and U10CA180863 and CCS #707213 to the Canadian Cancer Trials Group; U10CA180820, and UG1CA233234 to the ECOG–ACRIN Cancer Research Group; U10CA180868, UG1CA189867 to NRG Oncology; U10CA180888 and UG1CA233163 to the SWOG Cancer Research Group. Dr. Brown is supported by R00CA218603, R01CA270274, U01CA271279, and OT2CA278684. Dr. Meyerhardt is supported by the Douglas Gray Woodruff Chair fund, the Guo Shu Shi Fund, the Project P fund, Anonymous Family Fund for Innovations in Colorectal Cancer, and the George Stone Family Foundation. The National Cancer Institute was involved in the study’s design, review, and approval of the manuscript; it was not involved in the conduct of the study; collection, management, analysis, and interpretation of the data; and the decision to submit the manuscript for publication. Pfizer participated in the initial protocol development, review, and approval of the final manuscript. Pfizer provided celecoxib and placebo tablets. Pfizer was not involved in collecting, managing, analyzing, and interpreting the data. Neither Pfizer nor the National Cancer Institute had the right to veto publication or to decide to which journal the article was submitted. The content is solely the authors’ responsibility and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
Disclosures: Dr. Brown reported receiving grants from the National Institutes of Health, the American Institute for Cancer Research, and Cancer Research UK paid to his institution. Dr. Shi reported receiving institutional grant support from Celgene–Bristol Myers Squibb and Roche/Genentech; serving as a consultant to Yiviva Inc and Boehringer Ingelheim Pharmaceuticals; and owning stock in Johnson & Johnson, Merck, and Amgen. Dr. Kuebler reported receiving grants from the Columbus National Community Oncology Research Program and the National Institutes of Cancer. Dr. Goldberg reported serving as a paid consultant to Abbvie, Adaptimmune, Astra Zeneca, Bayer, Compass Therapeutics, Eisai, Focus Medical, Genentech, G1Therapeutics, GSK, Haystack Oncology, IQVIA, Inspirna, Merck, Sorrento, Taiho, and UpToDate. Dr. O’Reilly reported receiving research funding paid to her institution from Genentech/Roche, BioNTech, AstraZeneca, Arcus, Elicio, Parker Institute, NIH/NCI, Pertzye; and serving as a consultant or data safety monitoring board member for Boehringer Ingelheim, BioNTech, Ipsen, Merck, Novartis, AstraZeneca, BioSapien, Astellas, Thetis, Autem, Novocure, Neogene, BMS, Tempus, Fibrogen, Merus, Agios (spouse), Genentech-Roche (spouse), Eisai (spouse). Dr. Shields reported receiving grants from National Cancer Institute. No other disclosures were reported. Dr Meyerhardt reported receiving personal fees for serving on the advisory boards of COTA Healthcare and Merck Pharmaceutical. All other authors disclosed no conflicts of interest.
Ethics Approval: Institutional review board approval was obtained at all participating centers.
Patient Consent: All patients provided written informed consent.
ClinicalTrials.gov Identifier
Data Availability:
The data underlying this article will not be shared to protect the privacy of individuals that participated in the study.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data underlying this article will not be shared to protect the privacy of individuals that participated in the study.