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. Author manuscript; available in PMC: 2019 Jun 1.
Published in final edited form as: Cancer Epidemiol Biomarkers Prev. 2018 Mar 21;27(6):696–703. doi: 10.1158/1055-9965.EPI-17-0769

Physical activity and outcomes in patients with stage III colon cancer: A correlative analysis of phase III trial NCCTG N0147 (Alliance)

Amanda I Phipps 1,2, Qian Shi 3, Tyler J Zemla 3, Efrat Dotan 4, Sharlene Gill 5, Richard M Goldberg 6, Sheetal Hardikar 1,2, Balkrishna Jahagirdar 7, Paul J Limburg 8, Polly A Newcomb 1,2, Anthony Shields 9, Frank A Sinicrope 8, Daniel J Sargent 3, Steven R Alberts 8
PMCID: PMC5984710  NIHMSID: NIHMS954401  PMID: 29563133

Abstract

Background

Prior studies have supported an inverse association between physical activity and colon cancer risk, and suggest that higher physical activity may also improve cancer survival. Among participants in a phase III adjuvant trial for stage III colon cancer, we assessed the association of physical activity around the time of cancer diagnosis with subsequent outcomes.

Methods

Before treatment arm randomization (FOLFOX or FOLFOX+cetuximab), study participants completed a questionnaire including items regarding usual daily activity level and frequency of participation in recreational physical activity (N=1992). Using multivariable Cox models, we calculated hazard ratios (HR) for associations of aspects of physical activity with disease-free (DFS) and overall survival (OS).

Results

Over follow-up, 505 participants died and 541 experienced a recurrence. Overall, 75% of participants reported recreational physical activity at least several times a month; for participants who reported physical activity at least that often (vs. once a month or less), the HRs for DFS and OS were 0.82 (95% CI: 0.69-0.99) and 0.76 (95%CI: 0.63-0.93), respectively. There was no evidence of material effect modification in these associations by patient or tumor attributes, except that physical activity was more strongly inversely associated with OS in patients with stage T3 vs. T4 tumors (P-interaction=0.03).

Conclusions

These findings suggest that higher physical activity around the time of colon cancer diagnosis may be associated with more favorable colon cancer outcomes.

Impact

Our findings support further research on whether colon cancer survival may be enhanced by physical activity.

Keywords: colon cancer, physical activity, survival, BRAF, KRAS, mismatch repair

INTRODUCTION

Each year in the United States, greater than 50,000 deaths are attributed to colorectal cancer (1). Many more such deaths are likely prevented by virtue of early detection and curative therapy. To further reduce the mortality burden of colorectal cancer, it is important to identify factors associated with prognosis among colon or rectal cancer patients, particularly factors that may be intervened upon or modified. Although stage at diagnosis remains the strongest known predictor of colorectal cancer survival outcomes (1, 2), and certain tumor attributes (e.g., DNA mismatch repair status, BRAF mutation status) have also been consistently associated with prognosis (2–7), increasing evidence suggests that modifiable lifestyle factors may also play a role survival (8–13). One such factor that may plausibly be associated with colorectal cancer survival is physical activity (12–14).

A sizable literature supports the association between physical activity and reduced risk of developing colon cancer (15, 16). Among numerous plausible mechanisms underlying this association with risk, physical activity contributes to reductions in circulating levels of insulin and insulin-like growth factor-1, both of which inhibit apoptosis and promote cell proliferation in colon tumor cells (17–23). Such mechanisms could also be expected to contribute to a relationship between physical activity and colon cancer survival. In a recent meta-analysis, Wu et al. found significantly more favorable disease-specific and overall survival after colorectal cancer diagnosis associated with any vs. no exercise and with high vs. low physical activity levels, regardless of whether physical activity was ascertained with regard to the time period before or after cancer diagnosis (14). However, questions remain as to whether the association between physical activity and colon cancer survival outcomes varies across case groups defined by patient and/or tumor characteristics.

Using data from a large, multicenter clinical trial of adjuvant chemotherapy for stage III colon cancer, we evaluated the association of physical activity patterns with disease-free survival, overall survival, and time-to-recurrence, with consideration for possible heterogeneity according to tumor and patient attributes.

MATERIALS AND METHODS

Study Population

N0147, led by the North Central Cancer Treatment Group (NCCTG) (now a part of the Alliance for Clinical Trials in Oncology), is a multicenter phase III randomized trial of adjuvant 5-fluorouracil, oxaliplatin, and leucovorin (FOLFOX) with or without cetuximab in patients with resected stage III colon cancer (24). A total of 3,397 patients were enrolled, including 2,686 who were randomized to the primary treatment comparison arms (FOLFOX vs. FOLFOX plus cetuximab). The present study is limited to N0147 participants enrolled in the primary treatment comparison arms who had completed a patient questionnaire at the baseline study visit, and, specifically, answered physical activity questions (N=1,992). All participants signed Institutional Review Board-approved, protocol-specific informed consent forms in accordance with federal and institutional guidelines.

Ascertainment of Physical Activity

A patient questionnaire eliciting information on a variety of risk factors, including smoking history, alcohol consumption patterns, and usual physical activity patterns was administered to N0147 participants prior to treatment. With respect to physical activity, participants were asked to report on their usual level of physical activity “during a routine day” (almost none/mild activity/moderate/heavy activity). They were also asked to report on how often during their “free time” they took part in “any” physical activity (never/about once a month/several times a month/several times a week/daily). In addition to the question of any free-time physical activity, participants were asked separate questions about the frequency of their participation in “moderate” physical activity (e.g., golf, gardening, long walks, bowling) and “vigorous” physical activity (e.g., jogging, racket sports, swimming, aerobics) during their free time. A specific reference time point was not provided in the physical activity questionnaire items; however, these questions were administered at a time shortly following surgical resection for stage III colon cancer, and prior to receipt of chemotherapy.

Tumor Characteristics

Tumor tissue blocks were collected from the original surgical resection for study participants. Testing for DNA mismatch repair status (MMR), as well as KRAS- and BRAF-mutation status, was conducted centrally at the Mayo Clinic using previously described methods. Briefly, MMR status was determined by immunohistochemical assessment of hMLH-1, hMSH-2, and hMSH-6 (25); patients with tumors exhibiting a loss of expression for any of these proteins were classified as having tumors with defective MMR (dMMR), whereas patients with no loss of expression were classified as having tumors with proficient MMR (pMMR). DNA isolated from tumor specimens was used to test for 7 mutations in KRAS exon 2 hotspot codons 12 and 13, and for the BRAF V600E mutation (26).

Classification of Outcomes

We evaluated associations with respect to three overlapping clinical outcomes: time-to-recurrence (TTR), overall survival (OS), and disease-free survival (DFS). TTR was defined as the time from randomization to first documented disease recurrence; participants who died before a recurrence were censored at their last disease assessment date. OS was defined as the time from randomization to death from any cause. DFS was defined as the time from randomization to the first documented cancer recurrence or death from any cause, whichever came first. Patients were censored at 5 years post-randomization in analyses of DFS and TTR, and censored at 8 years post-randomization in analyses of OS. The present analysis was based on follow-up through December 3, 2014.

Statistical Analysis

We evaluated associations between the following self-reported physical activity attributes and colon cancer outcomes: usual daily physical activity, frequency of any free-time physical activity, frequency of moderate intensity physical activity, frequency of vigorous physical activity. For the latter three frequency variables, based on observed similarities in point estimates and small numbers, we grouped together exposure categories for those who reported never participating in physical activity and those who participated only about once a month; similarly, we grouped together exposure categories for those who reported participating in free-time physical activity several times a month to daily.

The distribution of patient and tumor attributes was tabulated and compared across grouped categories of physical activity frequency using Wilcoxon (27) (continuous) and chi-squared (28) (categories) tests. We used Cox proportional hazards regression models (29, 30) to assess associations between physical activity variables and study outcomes, with adjustment for the following attributes: age at diagnosis, sex, T-stage, N-stage, Eastern Cooperative Group performance score, histologic grade, tumor location, KRAS-mutation status, BRAF-mutation status, MMR status, body mass index (BMI), smoking frequency, alcohol use, and treatment assignment. Confounders were selected a priori and were included in the analytic model as parameterized in Table 1. Participants with missing data on model covariates were excluded from multivariable analyses (N=211). We also conducted analyses stratified by each of the aforementioned adjustment variables and evaluated potential interaction by these variables in the association between physical activity and patient outcomes. Proportional hazards assumptions were verified by testing for a non-zero slope of the scaled Schoenfeld residuals on ranked failure times (31). Two-sided p-values <0.05 were considered statistically significant.

TABLE 1.

Characteristics of study participants from North Central Cancer Treatment Group Trial N0147 according to reported participation in free time physical activity*

Total
(N=1992)
N (column %)		 Never/About once a month
(N=487)
N (column %)		 More than once a month
(N=1505)
N (column %)		 P value
Treatment 0.73
 FOLFOX 1020 (51%) 246 (51%) 774 (51%)
 FOLFOX+cetuximab 972 (49%) 241 (49%) 731 (49%)
Age at randomization 0.04
 Mean (SD) 58.1 (11.3) 59.1 (10.9) 57.8 (11.4)
 Range (19.0-86.0) (25.0-86.0) (19.0-85.0)
Race 0.006
 White 1721 (86%) 407 (84%) 1314 (87%)
 Non-white 243 (12%) 77 (16%) 166 (11%)
 Unknown 28 (1%) 3 (1%) 25 (2%)
Gender <0.001
 Female 952 (48%) 265 (54%) 687 (46%)
 Male 1040 (52%) 222 (46%) 818 (54%)
Tumor site 0.51
 Missing 26 5 21
 Proximal 935 (48%) 223 (46%) 712 (48%)
 Distal 1031 (52%) 259 (54%) 772 (52%)
T-Stage 0.16
 Missing 1 1 0
 T1/T2 282 (14%) 64 (13%) 218 (14%)
 T3 1492 (75%) 379 (78%) 1113 (74%)
 T4 217 (11%) 43 (9%) 174 (12%)
Lymph node involvement 0.58
 1-3 1179 (59%) 283 (58%) 896 (60%)
 ≥4 813 (41%) 204 (42%) 609 (40%)
Performance score 0.003
 0 1522 (76%) 348 (71%) 1174 (78%)
 1-2 470 (24%) 139 (29%) 331 (22%)
Mismatch repair status (MMR) 0.38
 Missing 83 25 58
 Proficient 1679 (88%) 401 (87%) 1278 (88%)
 Deficient 230 (12%) 61 (13%) 169 (12%)
KRAS/BRAF mutation status 0.58
 Missing 144 32 112
 KRAS-wildtype/BRAF-wildtype 941 (51%) 222 (49%) 719 (51%)
 KRAS-mutated/BRAF-wildtype 653 (35%) 168 (37%) 485 (35%)
 KRAS-wildtype/BRAF-mutated 254 (14%) 65 (14%) 189 (14%)
Body mass index (kg/m2) <0.001
 Missing 7 1 3
 <20 77 (4%) 15 (3%) 62 (4%)
 20-24.9 479 (24%) 88 (18%) 391 (26%)
 25-29.90 731 (37%) 165 (34%) 566 (38%)
 ≥30.0 698 (35%) 218 (45%) 480 (32%)
Smoking history 0.07
 Missing 9 3 6
 Never 935 (47%) 216 (45%) 719 (58%)
 Former 900 (45%) 221 (46%) 679 (45%)
 Current 148 (7%) 47 (10%) 101 (7%)
Alcohol consumption <0.001
 Missing 7 3 4
 Never 604 (30%) 165 (34%) 439 (29%)
 Former 597 (30%) 166 (34%) 431 (29%)
 Current 784 (39%) 153 (32%) 631 (42%)
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*

Table excludes N=47 participants who completed the study questionnaire but did not answer the study question pertaining to participation in any free-time physical activity, some of whom provided responses to other physical activity questions.

All statistical analyses were performed by the Alliance Statistics and Data Center. Analyses were conducted using SAS version 9.3 (SAS Institute, Cary, NC).

RESULTS

Approximately 75% of study participants reported participating in any physical activity during their free time at least several times a month; more specifically, 68% reported participating in moderate intensity physical activity more than once a month and 16% reported participating in vigorous intensity physical activity more than once a month. Compared to those who reported no participation in free-time physical activity or participation only once a month, participants who took part in any physical activity more than once a month were slightly younger (P=0.04), more likely to be male (P<0.001), had lower ECOG performance scores (P=0.003), were more likely to consume alcohol (P<0.001), and had a lower BMI (P<0.001) (Table 1).

Over the course of study follow-up, 28% (N=505) of study participants died and 30% (N=541) experienced a disease recurrence (89% of whom subsequently died during follow-up). The median follow-up time was 6.9 years (IQR: 6.1 – 7.6 years). After multivariable adjustment, there was no association between usual daily activity level and any of the evaluated outcomes (Table 2). However, reported participation in free-time physical activity more than once a month versus once a month or less was significantly associated with OS [hazard ratio (HR)= 0.76, 95% confidence interval (CI): 0.63-0.93, P=0.007) and DFS (HR=0.82, 95% CI: 0.69-0.99, P=0.04); these associations persisted when we restricted the comparison group to those who reported no participation in any free-time physical activity (HR=0.73 and HR=0.77, respectively). Reported participation in moderate intensity physical activity more than once a month was similarly associated with outcomes, particularly with respect to OS (HR=0.80, 95% CI: 0.66-0.96, P=0.02). Observed associations between vigorous intensity physical activity and patient outcomes were more modest and not statistically significant, as were associations between any or moderate intensity physical activity and TTR.

TABLE 2.

Association of daily activity levels and participation in physical activity with colon cancer outcomes*

Overall Survival
Disease-Free Survival
Time-to-Recurrence
N Events/Total N HR (95% CI) N Events/Total N HR (95% CI) N Events/Total N HR (95% CI)
Usual daily activity level
Almost no activity 23/84 1.0 (ref) 30/84 (ref) 30/84 1.0 (ref)
Mild activity only 220/738 1.20 (0.78-1.86) 253/738 1.12 (0.76-1.64) 253/738 1.15 (0.76-1.74)
Moderate activity 207/755 1.10 (0.71-1.71) 251/755 1.09 (0.74-1.61) 251/755 1.16 (0.76-1.75)
Heavy activity 61/225 1.06 (0.65-1.73) 70/225 0.99 (0.64-1.54) 70/225 1.05 (0.66-1.68)
p-value 0.66 0.80 0.83
Participation in any free-time physical activity
Never/once a month 156/440 1.0 (ref) 173/440 (ref) 173/440 1.0 (ref)
At least several times a month 349/1341 0.76 (0.63-0.93) 426/1341 0.82 (0.69-0.99) 426/1341 0.86 (0.70-1.04)
p-value 0.007 0.04 0.12
Participation in moderate-intensity free-time physical activity
Never/once a month 199/580 1.0 (ref) 218/580 1.0 (ref) 218/580 1.0 (ref)
At least several times a month 308/1219 0.80 (0.66-0.96) 383/1219 0.88 (0.74-1.05) 383/1219 0.93 (0.77-1.12)
p-value 0.02 0.16 0.46
Participation in vigorous-intensity free-time physical activity
Never/once a month 442/1517 1.0 (ref) 524/1517 1.0 (ref) 524/1517 1.0 (ref)
At least several times a month 68/290 0.93 (0.72-1.22) 81/290 0.89 (0.70-1.13) 81/290 0.91 (0.71-1.17)
p-value 0.62 0.34 0.47
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*

Hazard ratios (HR) adjusted for age, sex, T-stage, N-stage, performance score, histologic grade, tumor location, KRAS/BRAF somatic mutation status, mismatch repair status, body mass index, smoking history, and alcohol consumption. Participants with missing data on model covariates or physical activity variables are excluded from multivariable analyses and table counts. Sample size differs across variables due to variability in missingness of physical activity variables.

In stratified analyses, the association between reported participation in any free-time physical activity more than once a month (vs. once a month or less) and more favorable OS appeared to be restricted to those with smaller tumors (stage T3 vs. T4, P-interaction=0.03). This association was also suggestively but not significantly stronger among those who were normal weight or obese (but not overweight, P-interaction=0.07), among those with tumors not exhibiting mutations in BRAF or KRAS (vs. with a somatic mutation in either gene, P-interaction=0.20), and among those who received FOLFOX without cetuximab (vs. with cetuximab, P-interaction=0.16) (Figure 1). Similar patterns of difference were evident in analyses of DFS (Figure 2).

Figure 1. Physical activity and overall survival.

Figure 1

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provides a comparison of overall survival between participants who reported taking part in any free-time physical activity more than once a month (vs. once a month or less) according to patient and tumor characteristics. Analyses are adjusted for age, treatment, sex, smoking history, performance score, alcohol consumption, and body mass index. Overall survival is defined as the time from randomization to death from any cause, whichever came first. Abbreviations: wt, wildtype; mut, mutated; pMMR, proficient mismatch repair; dMMR, deficient mismatch repair.

Figure 2. Physical activity and disease-free survival.

Figure 2

Open in a new tab

provides a comparison of disease-free survival between participants who reported taking part in any free-time physical activity more than once a month (vs. once a month or less) according to patient and tumor characteristics. Analyses are adjusted for age, treatment, sex, smoking history, performance score, alcohol consumption, and body mass index. Disease-free survival is defined as the time from randomization to the first documented cancer recurrence or death from any cause, whichever came first. Abbreviations: wt, wildtype; mut, mutated; pMMR, proficient mismatch repair; dMMR, deficient mismatch repair.

DISCUSSION

In this cohort of clinical trial participants with stage III colon cancer, we observed a modest association between physical activity and colon cancer outcomes, suggesting more favorable DFS and OS in individuals who reported participating in recreational physical activity more than once a month around the time of colon cancer diagnosis. These associations were consistent across most participant subgroups defined by demographic, tumor, and lifestyle factors.

Similar to our overall findings, most previous studies into the association between pre-diagnostic physical activity and subsequent colorectal cancer outcomes have suggested modestly more favorable survival in those who were physically active than in those who were not active or minimally active during this time (12, 13, 32–38). Most recently, Walter et al. reported a significant inverse association between average leisure time activity in the years immediately preceding colorectal cancer diagnosis and subsequent OS, and a more modest, borderline significant inverse association with DFS (38). Although physical activity was parameterized in quartiles of MET-hours/week in that study, point estimates comparing outcomes for those in upper quartiles of physical activity to those in the lowest quartile (HROS=0.64 to 0.81, HRDFS=0.78 to 0.92) are within the range of point estimates reported here. Previous meta-analyses have similarly reported modestly more favorable OS and disease-specific survival associated with participation in any vs. no physical activity among individuals with colorectal cancer, with summary point estimates of 0.74 for OS and 0.75 for disease-specific survival (32–34). However, this pattern of association has not been uniformly observed across all studies (39).

To our knowledge, only one prior study has investigated the association between physical activity and colon cancer outcomes with consideration for the tumor attributes evaluated here (13). In contrast to our findings, Hardikar et al. reported suggestive evidence that the association between pre-diagnostic physical activity and subsequent colorectal cancer survival may be slightly stronger among those with tumors exhibiting high levels of microsatellite instability (mimicking the dMMR profile evaluated in this study); their results also indicated no difference in the magnitude of association by BRAF/KRAS somatic mutation status (13). Other analyses of post-diagnostic physical activity in relation to colorectal cancer outcomes have suggested that the benefits of physical activity may be greater among individuals with colorectal tumors that were negative for nuclear cadherin-associated protein β1 (CTNNB1) (40), positive for PTGS2 expression (41), and negative for expression of insulin receptor substrate 1 (IRS1) (42). Although CTNNB1, PTGS2, and IRS1 expression levels were not assayed in the N0147 study population, these prior studies highlight potential heterogeneity in the association between physical activity and cancer outcomes. Thus, although the broad-range benefits of physical activity are well established, it is plausible that the magnitude of that benefit may vary across the population of colon cancer patients.

The precise mechanisms underlying the association between physical activity and colon cancer outcomes are unknown; however, several factors are likely to contribute. In particular, physical activity has been suggested to lower insulin and insulin-like growth factor (IGF) levels, and to elevate levels of IGF binding proteins, thereby reducing the potential impact of insulin and IGF on tumor growth (43, 44). Other studies have suggested that moderate physical activity is associated with greater T cell proliferation relative to in sedentary individuals (45–48), which may enable an enhanced immune response in colon cancer. Similarly, physical activity has been shown to reduce levels of chronic inflammation and serum prostaglandin levels (44, 49, 50); chronic overproduction of prostaglandins has previously been linked with cancer progression and metastasis (51, 52). Several additional mechanisms may plausibly underlie the observed associations with physical activity, both with respect to OS and disease-specific outcomes (44).

Results from the present analysis should be interpreted in the context of study limitations. In particular, information as to the timing of reported physical activity was non-specific: participants were asked about current physical activity patterns at a time shortly following colon cancer diagnosis, with no specification as to whether or not those patterns had recently changed in response to cancer symptoms, treatment, or life circumstances. Furthermore, because this physical activity information was not updated in follow-up interviews, we were not able to evaluate associations with continued patterns of physical activity after colon cancer diagnosis and treatment. We also lacked information on participation in specific activities (e.g., swimming, running) and the typical duration of activity sessions. As such, we were unable to estimate metabolic equivalent (MET) hours or other metrics of actual energy expenditure from physical activity, as previous studies have done (12–14, 35, 53–55). Given that the present study was conducted within a randomized clinical trial population, the generalizability of study findings to the broader population of all colon cancer patients is not fully known. Patients who enroll in randomized trials represent a more selected population and, thus, their personal characteristics, such as physical activity patterns, may differ from the general population of colon cancer patients. Residual confounding is also a potential concern; for example, we lacked detailed information on income and socioeconomic status, which are plausibly associated with both physical activity (56) and colon cancer outcomes (57). We also lacked information on other co-morbidities (e.g., diabetes, cardiovascular disease) that could also have an impact on OS and also related to physical activity (58, 59). Also, although we were able to investigate heterogeneity by a number of participant and tumor attributes, it is plausible that the association between physical activity and colon cancer outcomes could vary according to attributes not captured by this study (e.g., NRAS mutation status). Last, although the overall included sample size was large, our numbers were limited within some strata defined by patient or tumor characteristics, which reduced our ability to identify heterogeneity in the association between physical activity and colon cancer survival.

Our study also has several important strengths, including the availability of information regarding multiple tumor markers, potential confounders, and standardized treatment data. Incorporating this information allowed us to better disentangle the association between physical activity and outcomes after colon cancer diagnosis. The associations we observed in this context are consistent with the existing literature (13, 36, 37, 53, 60–62), indicating a modest favorable association between physical activity and colon cancer outcomes.

Current guidelines suggest that cancer survivors, including colon cancer survivors, engage in 150 minutes of moderate-intensity or 75 minutes of vigorous-intensity physical activity per week (63, 64). Although we did not collect information on duration of activity, and although physical activity information from our study cannot be clearly classified as reflecting strictly pre- or post-diagnostic patterns, our findings do support these guidelines – suggesting that higher physical activity around the time of colon cancer diagnosis is associated with more favorable colon cancer outcomes.

Acknowledgments

Financial Support: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers K07CA172298; U10CA180821, U10CA180882 and UG1CA189823 (to the Alliance for Clinical Trials in Oncology); U10CA180790; U10CA180850; UG1CA189863; U10CA180820 (ECOG-ACRIN); U10CA180863 and CCSRI #021039 and 704970 (CCTG); U10CA180835 and U10CA180888 (SWOG). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute.

Footnotes

Conflict of interest disclosures: None.

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