Originally published as JCO Early Release 10.1200/JCO.2006.06.0855 on July 5 2006

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Physical Activity and Survival After Colorectal Cancer Diagnosis

Jeffrey A. Meyerhardt, Edward L. Giovannucci, Michelle D. Holmes, Andrew T. Chan, Jennifer A. Chan, Graham A. Colditz, Charles S. Fuchs

From the Division of Medical Oncology, Dana-Farber Cancer Institute; Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; Harvard School of Public Health; Department of Medicine, Massachusetts General Hospital, Boston, MA

Address reprint requests to Jeffrey A. Meyerhardt, MD, MPH, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: jmeyerhardt{at}partners.org

	ABSTRACT

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PURPOSE: Physically active individuals have a lower risk of developing colorectal cancer but the influence of exercise on cancer survival is unknown.

PATIENTS AND METHODS: By a prospective, observational study of 573 women with stage I to III colorectal cancer, we studied colorectal cancer–specific and overall mortality according to predefined physical activity categories before and after diagnosis and by change in activity after diagnosis. To minimize bias by occult recurrences, we excluded women who died within 6 months of their postdiagnosis physical activity assessment.

RESULTS: Increasing levels of exercise after diagnosis of nonmetastatic colorectal cancer reduced cancer-specific mortality (P for trend = .008) and overall mortality (P for trend = .003). Compared with women who engaged in less than 3 metabolic equivalent task [MET] -hours per week of physical activity, those engaging in at least 18 MET-hours per week had an adjusted hazard ratio for colorectal cancer–specific mortality of 0.39 (95% CI, 0.18 to 0.82) and an adjusted hazard ratio for overall mortality of 0.43 (95% CI, 0.25 to 0.74). These results remained unchanged even after excluding women who died within 12 and 24 months of activity assessment. Prediagnosis physical activity was not predictive of mortality. Women who increased their activity (when comparing prediagnosis to postdiagnosis values) had a hazard ratio of 0.48 (95% CI, 0.24 to 0.97) for colorectal cancer deaths and a hazard ratio of 0.51 (95% CI, 0.30 to 0.85) for any-cause death, compared with those with no change in activity.

CONCLUSION: Recreational physical activity after the diagnosis of stages I to III colorectal cancer may reduce the risk of colorectal cancer–specific and overall mortality.

	INTRODUCTION

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In both prospective^1-11 and retrospective^12-20 studies, physical activity is associated with a significant likelihood of developing colorectal cancer. The International Agency for Research on Cancer concluded that the evidence supports a causal relation between inactivity and colorectal cancer risk.²¹ However, it is largely unknown whether exercise influences survival of patients with established cancer.^22,23

Cancer patients often inquire about the utility of lifestyle changes beyond standard therapies.²⁴ Recent data suggest that physically active breast cancer survivors experience a superior survival compared with those who are more sedentary.²⁵ In a recent study of stage III colon cancer patients participating in an adjuvant chemotherapy trial, increasing postdiagnosis physical activity was associated with significant reductions in cancer recurrence and mortality.²² In the latter study, because data on activity before diagnosis were not available, the relative influence of prediagnosis and postdiagnosis exercise or change in activity could not be assessed.

We studied the impact of recreational physical activity among women with local and regional colorectal cancer who were participating in a large, prospective cohort study that was initiated before cancer diagnosis (the Nurses' Health Study).

	PATIENTS AND METHODS

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Study Population
In 1976, the Nurses' Health Study (NHS) cohort was established when 121,700 female registered nurses answered a mailed questionnaire on risk factors for cancer and cardiovascular disease.^26,27 Every 2 years, participants receive follow-up questionnaires to update information on potential risk factors and report new cancer and disease diagnoses. This study was approved by the Human Subjects Committee at Brigham and Women's Hospital.

Measurement of Colon Cancer
On each biennial follow-up questionnaire, participants were asked whether they had had a diagnosis of colorectal cancer during the prior 2 years. When a participant (or next of kin for decedents) reported colorectal cancer, we sought permission to obtain records and pathology reports. Study physicians, blinded to exposure data, reviewed all records related to colorectal cancer and recorded stage, histology, and tumor location. For nonresponders, we searched the National Death Index to discover deaths and ascertain any diagnosis of colorectal cancer that contributed to death or was a secondary diagnosis. We estimate that 96% of the cases of colorectal cancer were identified through these various methods.²⁸ The individuals in this analysis were NHS participants with stage I to III colorectal cancer diagnosed between 1986 (when physical activity was first assessed) and 2002.

Measurement of Mortality
Women were observed until death or June 2004, whichever came first. Ascertainment of deaths included reporting by the family or postal authorities. In addition, the names of persistent nonresponders were searched in the National Death Index.²⁹ The cause of death was assigned by physicians blinded to exposures. In the case of a woman who died as a result of colorectal cancer not previously reported, we obtained medical records of the colorectal cancer diagnosis after permission from next of kin. More than 98% of deaths in the NHS have been identified by these methods.³⁰

Exclusions
Women were excluded if they presented with metastatic colorectal cancer at time of initial diagnosis or were diagnosed with any other cancer (other than nonmelanoma skin cancer) within 3 years of their colorectal cancer. Moreover, to minimize bias by occult recurrence or other undiagnosed major illnesses, we excluded women who died within 6 months of their postdiagnosis physical activity assessment. There were 573 women eligible for analysis.

Exposure Assessment
We assessed leisure-time physical activity in metabolic equivalent task (MET) -hours per week beginning in 1986, as briefly described.^2,25 Participants reported duration of participation (range, 0 to 11 or more hours per week) in walking (along with usual pace), jogging, running, bicycling, swimming laps, racket sports, other aerobic exercises, lower intensity exercise (yoga, toning, stretching), or other vigorous activities.

Although we only included women with stage I to III cancer, we presumed that those who eventually died as a result of colorectal cancer had metastatic disease before death. To avoid bias due to declining activity immediately before and after diagnosis of metastatic cancer, physical activity was not updated (thereby a single prediagnosis and single postdiagnosis measurement was determined).

Each activity on the questionnaire was assigned a MET score.³¹ One MET is the energy expenditure for sitting quietly. MET scores are defined as the ratio of the metabolic rate associated with specific activities divided by the resting metabolic rate. The values from the individual activities were summed for a total MET-hours per week score. Categories of MET-hours per week were predefined as less than 3, 3 to 8.9, 9 to 17.9, 18 or more, to correspond to the equivalent of less than 1, 1 to less than 3, 3 to less than 6, 6 or more hours per week of walking at an average pace, consistent with prior analyses.³² Our activity questionnaire has been validated previously against activity diaries.^33,34

For analyses of prediagnosis physical activity, the response from the immediate prior survey was used (median, 6 months before diagnosis). If a response were missing, one previous assessment would be carried forward; otherwise, the patient was not included in those analyses. For postdiagnosis analyses, the first physical activity assessment collected at least 1 year but no more than 4 years after diagnosis (median, 22 months) was used to avoid assessment during the period of active treatment. For change in activity, patients who changed from a higher to lower category before and after diagnosis, respectively, were categorized as decreasing activity, patients who changed from a lower to higher category were categorized as increasing activity, and patients who remained in the same category were categorized as no change.

Covariates
Stage of disease, grade of tumor differentiation, year of diagnosis, and location of tumor were extracted from the medical record. Beginning in 1993, women were asked methods of treatment in a supplemental questionnaire. The time interval between cancer diagnosis and assessment of activity was also adjusted for in these analyses. Body mass index (BMI) and smoking status (current, past, or never) were also taken from the biennial questionnaire at the time of the respective physical activity assessment.

Statistical Analyses
Cox proportional hazards models were used to calculate hazard ratios (HRs) of death or death as a result of colorectal cancer, adjusted for other risk factors for cancer survival. In the main analysis, death as a result of colorectal cancer was the primary end point and deaths as a result of other causes were censored. In secondary analyses, death as a result of any cause was the end point. The primary exposure of interest was physical activity after the diagnosis of colorectal cancer. In addition, we examined prediagnosis activity and change in physical activity. For the analyses of postdiagnosis physical activity and change in activity, participants were observed from the date of return of postdiagnosis physical activity assessment to either death or June 2004. In the analyses of physical activity before diagnosis, participants were observed from the date of diagnosis of colorectal cancer to either death or June 2004. The two-tailed P value for the linear trend test across categories was calculated by using the median value of each category as a continuous variable, consistent with prior studies.^2,25 Tests of interactions between physical activity categories and potential effect modifiers were assessed by entering in the model the cross product of the median of each physical activity category with the dichotomized covariate. All analyses used SAS version 8.0 (SAS Institute Inc, Cary, NC).

	RESULTS

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Baseline Characteristics by Physical Activity Category
Among the 573 eligible participants with stage I, II, or III colorectal cancer, there were 132 deaths, of which 80 were classified as colorectal cancer–specific deaths. The median time of follow-up from date of diagnosis of women who are alive was 9.6 years (with 95% observed for 5 or more years). Baseline characteristics of the 573 patients are shown according to categories of both prediagnosis and postdiagnosis physical activity (Table 1). In general, women who were more active had a lower BMI and were less likely to have smoked cigarettes.

For the analysis of 5-year survival, activity levels were collapsed into three categories (< 3, 3 to 17.9, and 18 MET-hours per week) based on the results described above (Figs 1 and 2). Of note, follow-up in this analysis begins at the time of completion of the questionnaire that assessed physical activity to reduce bias rather than the date of diagnosis of colorectal cancer, as is typically derived for studies for adjuvant chemotherapy. Nonetheless, the proportion of patients with colorectal cancer–specific deaths at 5 years (Fig 1) was 14.1% for patients who engaged in less than 3 MET-hours per week, 14.4% for patients who engaged in 3 to 17.9 MET-hours per week, and 6.2% for patients who engaged in 18 or more MET-hours per week (P log-rank = .004). There was also a statistically significant difference in overall survival across physical activity tertile (P = .02, Fig 2).

View larger version (14K): [in this window] [in a new window]   Fig 1. Cumulative incidence curve of colorectal cancer–specific deaths by level of postdiagnosis physical activity. MET, metabolic equivalent task.

View larger version (14K): [in this window] [in a new window]   Fig 2. Kaplan and Meier curve of overall survival by level of postdiagnosis physical activity. MET, metabolic equivalent task.

View larger version (11K): [in this window] [in a new window]   Fig 3. Impact of change of physical activity before and after colorectal cancer diagnosis. *Compared with no change. Adjusted for body mass index, stage of disease (I, II, III), grade of tumor differentiation, colon or rectal primary, age at diagnosis, year of diagnosis, receipt of chemotherapy (yes, no, unknown), time from diagnosis to physical activity measurement, change in body mass index, smoking status (current, past, never).

	DISCUSSION

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Physical activity has been shown consistently to reduce colon cancer incidence.^1-20 Although the mechanism is unclear, the association with sedentary lifestyle and hyperinsulinemia is a potential etiology.^35-37 Insulin and the insulinlike growth factor family have been associated with enhanced tumor growth and antiapoptosis,³⁵ and colon cancer risk is elevated in individuals with higher circulating levels of insulin or C-peptide (a marker of insulin secretion) and insulinlike growth factor-1.^38-43 Colon cancer recurrences are believed to be growth of micrometastases. Thus, an environment that allows such microscopic tumors to proliferate could be detrimental. Whether insulinlike factors or other mechanisms potentially linked to physical activity would affect this environment is unknown.

In a separate cohort of men and women with stage III colon cancer, we reported a similar reduction in disease-free survival among patients physically active after diagnosis.²² The NHS provide provides several complementary advantages. First, given that patients who are more physical active after cancer diagnosis may have been active before diagnosis, we considered the possibility that physically active individuals who do develop colon cancer simply acquire tumors that are biologically less aggressive. However, physical activity levels before diagnosis were not predictive of cancer survival. Second, the NHS cohort provided a unique opportunity to explore the relationship of change in activity before and after diagnosis. It should be noted that greater than 50% of women changed levels of physical activity appreciably after diagnosis. Although a decrease in activity was not significantly associated with survival, increases in activity did seem to confer a significantly improved survival. The magnitude of benefit of increasing activity seemed similar in women who were both relatively inactive and more active before diagnosis. These analyses also demonstrate that women who were at a relatively higher level of activity before diagnosis should at least maintain such activity, but do not necessarily need to increase beyond that level. Nonetheless, because we do not know the reasons why these women increased their activity levels, these findings need to be confirmed.

Beyond cause of mortality, data on cancer recurrences were not available in this cohort. Nonetheless, given that median survival for metastatic colorectal cancer was approximately 10 to 12 months during much of the time period of this study,⁴⁴ colorectal cancer–specific mortality should be a reasonable surrogate for cancer-specific outcomes. Our cohort was restricted to women; it is possible that these findings might not apply to male patients with colorectal cancer. However, we did not observe a sex interaction in our prior study of postdiagnosis activity.²²

In this cohort, data on the treatment are limited. Two thirds of the women had stage I or II disease, in which surgery alone generally would be standard of care. Furthermore, although there are differences in the likelihood of use of adjuvant chemotherapy based on factors such as socioeconomic class, the fairly homogenous nature of this cohort (professional nurses) would likely increase the probability of at least standard therapy.^45,46 Moreover, as shown in Table 1, chemotherapy use (based on the available data) did not differ according to postdiagnosis physical activity levels. Comorbidities and access to health care may also confound these findings. Given the population studied (professional nurses), we would expect the latter to be relatively diminished. Although comorbidities have been shown to affect mortality in colorectal cancer survivors,^47-49 such diseases are less likely to affect disease recurrence and thereby colorectal cancer–specific mortality.

We cannot completely exclude the possibility that lower levels of physical activity may be reflective of other occult predictors for poor prognosis. However, we did not observe any significant associations between physical activity and other predictors of cancer outcome. Our findings remained unchanged after adjusting for potential risk factors for colorectal cancer mortality. Moreover, we found a consistent benefit for physical activity among patients with either stage I/II or stage III disease. Furthermore, we considered the possibility that sick patients (with cancer recurrences and limited survival) will exercise less. To minimize the bias by occult cancer recurrence, we excluded recurrences or deaths within 6 months of the activity assessment in the primary analysis and continued to observe a positive impact of exercise even when extending this restriction to 12 and 24 months. Finally, we would expect few patients to have undetected recurrences over extended periods of time, given the relatively brief natural history of recurrent colon cancer.

Patients who underwent treatment for colorectal cancer may be considered limited in their ability to exercise. However, Arndt et al⁵⁰ reported that 1 year after surgery of the primary tumor, patients with colorectal cancer reported their physical functioning and global quality of life nearly identical to those of a noncancer population. Furthermore, the distribution of levels of exercise in our study does not vary significantly by stage and is similar to that in other reports from the NHS in women without cancer.²

Our results suggest that physical activity after a colorectal cancer diagnosis may lower the risk of death from that disease. This benefit was seen regardless of age, BMI, stage, or site of disease. Along with our prior findings,²² these data suggest that, in addition to surgery and chemotherapy, increasing physical activity may confer additional benefit to patients with colorectal cancer.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Author Contributions

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Conception and design: Jeffrey A. Meyerhardt, Edward L. Giovannucci, Michelle D. Holmes, Charles S. Fuchs Financial support: Jeffrey A. Meyerhardt, Edward L. Giovannucci, Graham A. Colditz, Charles S. Fuchs Administrative support: Jeffrey A. Meyerhardt Provision of study materials or patients: Edward L. Giovannucci, Graham A. Colditz Collection and assembly of data: Edward L. Giovannucci, Graham A. Colditz, Charles S. Fuchs Data analysis and interpretation: Jeffrey A. Meyerhardt, Michelle D. Holmes, Andrew T. Chan, Jennifer A. Chan, Graham A. Colditz, Charles S. Fuchs Manuscript writing: Jeffrey A. Meyerhardt, Charles S. Fuchs Final approval of manuscript: Jeffrey A. Meyerhardt, Edward L. Giovannucci, Michelle D. Holmes, Andrew T. Chan, Jennifer A. Chan, Graham A. Colditz, Charles S. Fuchs

 

	NOTES

 
Supported in part by a K07 award from the National Cancer Institute (Grant No. K07CA097992-01A1) and an American Society of Clinical Oncology Career Development Award (J.A.M.). The Nurses' Health Study is supported in part by Grant No. P01CA087969 from the National Cancer Institute.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted February 8, 2006; accepted March 23, 2006.

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