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Physical activity and cancer risk: dose-response and cancer, all sites and site-specific

THUNE, INGER; FURBERG, ANNE-SOFIE

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Medicine and Science in Sports and Exercise: June 2001 - Volume 33 - Issue 6 - p S530-S550
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Abstract

Environmental exposure has been accepted as a major causal factor of cancer (80–90%) (67). Our genetic constitution was selected for a lifestyle characterized by physical activity. People who have a sedentary Western lifestyle in the year 2000 may be about 0.003% different genetically from late Stone Age people of 10,000 yr ago (104). Consequently, a sedentary lifestyle may be one explanation for the variation in cancer incidence rates and changes in incidence rates observed in migration studies between and within countries and among subgroups of people.

Although Rammazzini 300 yr ago suggested that physical activity played a role in human cancer etiology (95), it is mainly in the last decade that investigators, encouraged by the findings of animal studies, have linked physical activity to human cancer risk (101). This evidence comes from observational studies, as no intervention studies so far have been conducted on physical activity for the primary prevention of cancer. Although many studies suggest an association between physical activity and cancer risk (overall and site-specific), the precise quantitative characteristics of a potential threshold effect or the dose-response remains undefined. Therefore, the aim of the present study was to examine whether there is a dose-response between total volume of physical activity and indexes of morbidity and mortality of overall and site-specific cancer risk and, furthermore, to elucidate quantitative characteristics of the identified dose-response relations of importance in primary prevention. Even a small protective effect of physical activity on cancer risk may be of considerable importance for public health as the population ages and a sedentary lifestyle increases worldwide.

METHODS

Studies were identified through a systematic review of published literature available on the MEDLINE and PubMed literature databases and also by hand searching relevant journals through August 2000. The general inclusion criteria were 1) studies focusing on primary prevention of overall and/or site-specific cancer; 2) a quantitative description of the physical activity variable was described; and 3) the outcome measures including indexes of morbidity and mortality for overall and/or site-specific cancer.

A dose-response relationship was especially elaborated in relation to colon and breast cancer in studies including > 100 cases, respectively. Multiple results from the same study were included only if they contained other characteristics of the exposure variable (physical activity) or the relevant cancer type. Comparisons are made between studies using a great variety of, sometimes crude, physical assessments and a great variety in the characteristics of the populations studied.

Physical Activity and Overall Cancer Risk

Physical activity has marked effects on many functions of the human body, which may influence overall cancer risk (54). These effects include direct mechanical processes such as improved circulation, ventilation and bowel transit time, improved energy balance and immune function, and possibly the capacity to perform DNA repair (Fig. 1).

FIGURE 1
FIGURE 1:
Hypothesis of the influence of dose of physical activity (type, duration, intensity, frequency) on possible biological mechanisms operating on cancer development.

Among the 17 observational studies identified (Table 1), all were follow-up studies, most contained information on cancer mortality (4,8,16,32,50,52,63,79,89,92,93,107,115, 127), and some contained information on overall cancer incidence (1,19,108). Populations in North America (11 studies), Europe (seven studies), and Asia (one study) were included, and only seven studies included women (Table 1). Taylor and colleagues observed as early as 1962 that sedentary workers were at increased risk of developing cancer compared with active men, indicating the role of occupational physical activity (OPA) in relation to overall cancer risk (115). A significant protective effect of leisure time or OPA was observed in 10 studies (1,8,19, 50,89, 92,107,108, 115,127), whereas six studies suggested a protective effect and one study observed a suggestive increased risk (93) (Table 1). A weaker association between physical activity and cancer mortality, or overall cancer incidence, was reported for women compared with men. An estimation of the effect of leisure time physical activity (LPA) and OPA on overall cancer risk has been performed in a meta-analysis and suggested a 30% independent protective effect of OPA and LPA, respectively, on overall cancer risk for men, with no association for women (101).

Table 1
Table 1:
Studies on physical activity and overall cancer risk, dose-response.

A more detailed quantitative description of the volume of physical activity was included in 14 studies (1,4,8,16,19,50, 52,63,79,89,92,107,108,127), and an inverse crude graded dose-response relationship was observed in eight (1,8,19, 50,89,107,108,127) of nine studies in which this was elaborated. Studies in which physical activity was expressed as physical fitness, college athletics, or resting heart rate (8,50) observed a stronger dose-response relationship than those including only self-reported LPA (1) or OPA (108). The observed association between physical activity and overall cancer incidence/mortality in terms of how much physical activity (type, intensity, duration, and frequency) was observed in the Whitehall study was as follows: men who were engaged in regular vigorous activities, e.g., athletics, had a 20% reduction in overall cancer risk compared with sedentary men (107).

Physical Activity and Site-Specific Cancer Risk

Colorectal, colon, and rectal cancer.

Physical activity may shorten the fecal transit time and thereby reduce the period of contact between carcinogens and mucosal cells, inducing favorable effects on insulin, prostaglandin, and bile acid levels, which may influence the growth and proliferation of colonic cells.

Cancer of the large bowel is the most frequently investigated cancer in relation to physical activity, and includes at present more than 40,000 colon/colorectal cancer cases in 48 studies (23 cohort studies and 25 case-control studies) conducted in most continents among both sexes (47studies of men, 28 studies of women) and in different population groups (1,3,5,6,9–11,18,19,25,27,29,35–39,46,51,55,57,58, 60,61,66,69,71,72,74–76,89,91,100,105,106,108,110,113, 114,117,119,123,124,129,130,132,133) (Table 2). The majority of the studies (35 of 48) observe a significant independent protective effect between 10 and 70% on overall colon/colorectal cancer risk (Fig. 2A) for either LPA, OPA, or both activities combined (Fig. 2A). A significant inverse crude graded dose-response association between LPA and colon cancer was observed in 21 (6,10,11,18,19,25,39,57, 66,74,76,91,106,113,114,118,119,124,129,130,132) of 33 observational studies (Table 2, Table 7, and Fig. 2B). When including studies with at least 100 cases, the dose-response associations seems to be especially dependent on moderate-heavy-vigorous physical activity (76) (Fig. 2B). This situation can be illustrated in studies using MET-hours per week (39,76). These observations are demonstrated for both men and women, with a somewhat stronger dose-response relationship for men compared with women (Fig. 2B), without suggesting publication bias (101). Those men and women who reported that more than 1000 kcal·wk-1 of energy were expended in vigorous activity through at least three time periods in their lives were observed to have a 40% reduction in colon cancer risk (106). Men who were highly active (energy expenditure of >2500 kcal·wk-1 at two assessments) had half the risk of developing colon cancer relative to inactive men (1000 kcal·wk-1). In another study, 21 MET-hours per week were associated with a 50% reduction in colon cancer risk (76) (Fig. 2B), which reflects the fact that approximately 4 h of moderate or 3 h of high-intensity LPA weekly is necessary to reduce colon cancer risk in middle-aged American women. Some studies suggest a greater protective effect on the left than on the right colon (38), and in lean than in obese persons (119), which is also observed to differ by sex (119).

FIGURE 2
FIGURE 2:
(A) Relative risk of colon cancer with 95% confidence intervals among persons with high versus low physical activity (LPA and OPA) in cohort (•) and case-control studies (○ (see references). (B) The dose-response relationship between LPA (categories and MET-hours per week) and colon cancer risk in cohort and case-control studies (see references) including > 100 colon cancer cases. Males (dashed lines): cohort studies (•) and case-control studies (○. Females (solid lines): cohort studies (•) and case-control studies (○.
Table 2
Table 2:
Studies on physical activity and colorectal, colon, and rectal cancer risk, dose-response.
Table 2
Table 2:
Continued
Table 2
Table 2:
Continued
Table 7
Table 7:
Studies on physical activity and testicular cancer risk, dose-response.

No effect of physical activityrelated to time period or susceptible period of exposure has been observed. However, lack of influence of physical activity during adulthood (25,72,89) and an increased effect observed for long-term activity in a cohort study (58) suggest that continuous, rather than short-term activity is of importance.

A reduction in bowel transit time because of physical activity may account for the observed effect on colon cancer and the absence of a relationship between physical activity and rectum cancer. In 80% of the 24 studies identified, including 12,055 cancer cases localized in the rectum, no association between physical activity and rectal cancer was observed (Table 2).

Breast, endometrial, and ovarian cancer.

Endogenous sex hormones (estradiol, progesterone) are strongly implicated in the etiology of breast and endometrial cancer and possibly also ovarian cancer. Given that physical activity may modulate production, metabolism, and excretion of these hormones, protection against these cancers by means of physical activity is biologically plausible.

Observations from 26 (7, 13, 15, 21, 23, 28, 31, 43, 53, 65, 77, 80, 82, 85, 86, 94, 97, 102, 112, 120, 122, 124, 126, 134) of 41 studies (1, 7, 12, 13, 15, 17, 20–25, 28, 30, 31, 34, 43, 47, 53, 65, 73, 77, 80, 82, 83, 85, 86, 89, 94, 96, 97, 99, 102, 108, 112, 120, 122, 124, 126, 134, 136) including 108,031 breast cancer cases demonstrate that both OPA and LPA are associated with about a 30% reduction in breast cancer risk in pre-, peri-, and postmenopausal women, with a graded dose-response relationship reported in 16 (7,13,21,23,65,77,80,82,85,86,97,99,102,120,122,126) of 28 studies (Table 3 and Fig. 3 B). Findings are less consistent than for colon cancer, and the magnitude of the reported associations is generally lower, which may reflect a genuinely weaker relationship. An alternative explanation is that the strength of the physical activity–breast cancer association varies across the lifespan and in subgroups, as it does for more established risk factors (e.g., reproductive factors, body mass index). The actual amount of physical activity that is needed to reduce breast cancer risk has in several studies been reported as leisure time physical activity for at least 4 h·wk-1(7,97,120) of at least moderate intensity (4–5 MET) (126) or continuous vigorous activity (24.5 MET-h·wk-1) (13). A dose-response relationship was especially observed in case-control studies in where MET-hours per week was assessed (Fig. 3 B). LPA during puberty (73,126) may be particularly important for reducing breast cancer risk. However, continuous high levels of LPA throughout life may be just as important as physical activity in puberty (28,73,126).

Table 3
Table 3:
Studies on physical activity and breast cancer risk, dose-response.
Table 3
Table 3:
Continued
FIGURE 3
FIGURE 3:
(A) Relative risk of breast cancer with 95% confidence intervals among persons with high versus low physical activity (LPA and OPA) in cohort (•) and case-control studies (○ (see references). (B) The dose-response relationship between LPA (categories and MET-hours per week) and breast cancer risk in cohort and case-control studies (see references) including > 100 breast cancer cases. Females—cohort studies (•) and case control studies (○.

Of 12 studies (25,41,44,49,64,84,88,94,103,109,116,136) of populations in North America, Europe, and Asia, a link between physical activity and endometrial cancer risk was observed in 8 studies (44,49,64,84,88,94,109,116), with a significant (20–80%) reduced risk of endometrial cancer (Table 4). A graded dose-response association was observed in two studies (64,116). In a cohort study, hard LPA was observed to reduce endometrial cancer by 80%, whereas occasional exercise gave the same risk reduction as at least three to four times per week in another study (44). Occupational physical activity appeared to be protective only among women aged 50–69 yr (84).

Table 4
Table 4:
Studies on physical activity and endometrial cancer risk, dose-response.

Only four studies (25,81,94,136) have been identified that focus on the association between physical activity and ovarian cancer. One study has observed a significant increased risk attributable to high LPA (81), whereas others have observed a decreased risk (136), but no dose-response relationship has been demonstrated (Table 5).

Table 5
Table 5:
Studies on physical activity and ovarian cancer risk, dose-response.

Prostate and testicular cancer.

The observation that athletes display lower levels of circulating testosterone than nonathletes, and the role of testosterone in relation to prostate and testicular cancer, has led to the hypothesis that physical activity might protect against the development of these two cancer types. However, trauma in sports may be hypothesized to increase testicular cancer risk (121).

Of 28 published studies (1, 2, 11, 14, 19, 25, 40, 42, 45, 48, 56, 59, 60, 68, 70, 87, 89, 90, 93, 100, 108, 111, 118, 124, 125, 128, 131, 135) including 22,521 prostate cancer patients in North America, Asia, and Europe, 14 studies (1, 2, 11, 14, 40, 42, 60, 70, 89,90,118,124,125,135) demonstrated that either OPA or LPA, or both activities combined, significantly decreased prostate cancer risk by 10–70%, but an inverse graded dose-response association was only observed in 10 of 19 studies (Fig. 4 and Table 6). In one study, at least 12 kJ·min-1 for occupational activity was required for a reduction in prostate cancer risk (45). Men who expended at least 1000 kcal·wk-1 and up to 3000 kcal·wk-1 had at most a 70% reduction in risk. However, the data are inconsistent, as three studies observed a significantly increased risk among physically active men (14,48,56). These studies related to prostate cancer are hampered by variation in detection of latent disease.

FIGURE 4
FIGURE 4:
Relative risk of prostate cancer with 95% confidence intervals among persons with high versus low physical activity (LPA and OPA) in cohort (•) and case-control studies (○ (see references).
Table 6
Table 6:
Studies on physical activity and prostate cancer risk, dose-response.
Table 6
Table 6:
Continued

Data for testicular cancer show the same discrepancies as for prostate cancer (11,25,26,33,90,98,118), with a recent study observing an increased risk among physically active men (98), which contrasts with the U.K. testicular group’s findings that suggest a decreased risk (26). Three of five studies observed a graded inverse dose-response relationship (Table 7).

Lung cancer.

It is well established that physical activity improves ventilation and perfusion, which may in turn reduce both the concentration of carcinogenic agents in the airways and the duration of agent–airway interaction. However, the association of physical activity with lung cancer has only been elaborated in 11 studies (1, 11, 19, 25, 60, 62, 89,90,100,108,121) including 7,726 men and women, and most of these studies were conducted in men only (Table 8). Findings from 6 (1,11,60,62,100,121) of these 11 studies (five cohort studies and one case-control study) support a protective effect of both LPA and OPA of 20–60%, with an inverse graded dose-response relationship (Fig. 5). No studies suggested an increased risk attributable to physical activity. These studies indicate that a continuous 4 h·wk-1 of hard leisure time activity in order to keep fit (121), and participation in activities of at least moderate activity (>4–5 MET), but not light activity (<4–5 MET) (62), reduced the lung cancer risk independently after careful adjustments for smoking and other possible risk factors. An effect of physical activity related differently to various histologic types of lung cancer has also been observed (121).

Table 8
Table 8:
Studies on physical activity and lung cancer risk, dose-response.
FIGURE 5
FIGURE 5:
Relative risk of lung cancer with 95% confidence intervals among persons with high versus low physical activity (LPA and OPA) in cohort (•) and case-control (○ studies.

Others.

A small number of studies have elaborated on the effect of physical activity on renal cancer, bladder cancer, stomach cancer, malignant melanoma, brain tumors, and malignant tumors in the lymphatic and hematopoietic tissues (19,25,31,78,89,93,94,100). No clear patterns can be drawn from these studies (see Table 9).

Table 9
Table 9:
Summary for site-specific cancer, type of studies, dose-response.

FUTURE RESEARCH ISSUES

When considering the research field of physical activity and cancer, five different research issues can be delineated.

  • 1. The lack of understanding of the biological mechanisms operating between physical activity and site-specific cancer risk warrants further studies.
  • 2. Assessing biomarkers, intermediate steps, and precancerous lesions for site-specific cancer may give us further insight into the relationship between physical activity and cancer that will be of particular interest for public health recommendations.
  • 3. Improving the quality of physical activity assessment methods is one of the most important methodological issues in the field of research on physical activity and cancer risk. This includes measurements of all types and components of physical activity across the entire lifetime, with attention to susceptible periods, gender, age, cultural, and individual variations.
  • 4. The importance of genetic predisposition to be physically active combined with the knowledge that cancer is a genetic localized disease warrants studies in general populations and high-risk groups alike. This is especially important when considering the improved insights into cellular and molecular levels in the development of malignancy.
  • 5. Controlled randomized clinical trials studying the physical activity–cancer association in relation to biological mechanisms and biomarkers or intermediate steps and cancer types are warranted. Thus, through such studies alternative explanations for the apparent protective effect of this exposure against some cancers can be better explored in relation to confounding factors.

Consequently, discrepancies between studies elaborating the association between physical activity and site-specific cancer risk may be explained by real differences or lack of information on the various components. These components may consist of physical activity (type, intensity, duration), incomplete information about the cancer type studied (localization, histologic type) combined with incomplete understanding of the pathogenesis of most cancer and lack of knowledge regarding possible biological mechanisms operating between physical activity and cancer.

CONCLUSION: CURRENT EVIDENCE AND RESEARCH ISSUES

How should the physician understand and interpret our existing knowledge of the association between physical activity and cancer? Although existing studies are hampered by methodological limitations, the totality of the evidence confirms a protective effect of physical activity with a graded dose-response relationship between physical activity and cancers of the colon and also of the breast, whereas no association has been observed with cancer of the rectum. Further data concerning cancer of other organ cancers are required. Notably, no consistently increased risk has been observed for any cancer type. This emerging knowledge is especially important when considering the observed overall increase in physical inactivity in westernized countries across the lifespan. The optimal permutation of intensity, duration, and frequency of physical activity across the lifespan is unclear, but it is gender, age, and site specific. We need further insight into these dimensions of physical activity, as well as studies of biological mechanisms, biomarkers, and intermediate steps, in order to understand in more detail how physical activity reduces cancer risk.

Address for correspondence: Inger Thune, M.D., Ph.D., Institute of Community Medicine, Faculty of Medicine, University of Troms/o, N-9037 Troms/o, Norway; E-mail; Inger.Thune@ism.uit.no.

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Keywords:

PHYSICAL ACTIVITY; CANCER RISK; BIOLOGICAL MECHANISMS; DOSE-RESPONSE

© 2001 Lippincott Williams & Wilkins, Inc.