Physical activity patterns and the risk of colorectal cancer in the Norwegian Women and Cancer study: a population-based prospective study

Colorectal cancer (CRC) remains the second most common cancer in women worldwide [1]. This is also true in Norway, where CRC is the second most common cancer in women [2]. In 2018, it was estimated that Norway had the highest incident rate of CRC in women worldwide, at 39.3 per 100,000, compared to 24.2 per 100,000 in the rest of Europe (World age-standardised rate) [1, 3]. The average annual number of new cases in women in Norway has been on the increase in the past few years, with 1706 in 2002–06; 1833 in 2007–11; and 2049 in 2012–16 [2].

There is convincing epidemiological evidence suggesting that a healthy lifestyle, body weight, and diet could substantially prevent the development of CRC [4], and several epidemiological studies have demonstrated a risk-reducing association between physical activity (PA) and CRC [5–8]. The Continuous Update Project on colorectal cancer by the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) published in September 2017 concluded that all domains of PA (occupational, household, transport, and recreational) reduce the risk of CRC [9]. However, this has only been demonstrated consistently in men, while results of such studies in women have been largely equivocal [10, 11]. Considering only prospective studies that either included women alone or presented sex-specific findings, 13 studies reported no associations between PA and CRC among women with relative risks ranging from 0.69 to 1.15 [10–22]. Six studies reported statistically significant inverse associations among women with relative risks ranging from 0.54 to 0.90 [6–8, 23–25], which were consistent with the findings of most studies in men. However, the associations in women were weaker than those in men, and some of the significant observations in women were only present in sub-analyses [11, 26].

These discrepancies may have stemmed from methodological differences, such as relatively small sample sizes, deficient or poor assessment methods for PA, or assessment of different domains of PA by methods of unknown validity or reproducibility. It may be that the assessment of PA in women has more intricacies than that in men, as inclusion of household PA in women may be under- (or over-) rated [27]. It is also plausible that a sex difference exists in the physio-biological response to PA [28, 29].

The aim of the present study was to further examine the relationship between PA patterns and the risk of CRC in women, using a validated, single-item, self-administered questionnaire and repeated measurements, in a nationally representative cohort of Norwegian women.

During an average of 14.6 years of follow-up and 1.16 million person-years, 885 cases of colon cancer and 426 cases of rectal cancer were diagnosed. The median age of the cohort at baseline was 51 years, while the median age at diagnosis was 65 years, ranging from 43 to 87 years.

Intriguingly, those who were “consistently active” were at an increased risk of rectal cancer when compared to women who were “consistently moderately active” (HR = 1.57, 95% CI 1.02–2.42) (Table 4).

In this nationally representative prospective study of Norwegian women, we did not find an association between PA level and the risk of CRC. These findings remained the same regardless of whether we used baseline data or repeated measurements, and after adjusting for known CRC risk factors. We also examined the influence of change in PA level on the risk of CRC and found that those who increased their PA from baseline to follow-up had a lower risk of colon cancer.

There is an established inverse relationship between PA and the risk of CRC, and several plausible explanatory biological mechanisms and hypotheses have been proposed [37, 38]. These mechanisms are not completely clear, however, the existing plausible hypotheses include the involvement of PA in the reduction of intestinal fecal transit time; increase production of motility-inducing prostaglandin F2α; alterations in sex hormones; reduction in insulin resistance and hyperinsulineamia; improved immune function; changes in free radical generation; and changes in body fat [37, 38]. There could be sex-specific differences in the physiological responses in some of these mechanisms that may place women at a disadvantage, or PA may also interact with other sex-specific factors influencing the responses [28, 29]. The Continuous Update Project on CRC by the WCRF/AICR recently inferred that PA of all types reduces the risk of CRC [9]. However, most of the epidemiological studies that corroborate this relationship have been conducted in men [11]. Results of studies in women have been largely inconsistent and less conclusive [10, 11, 14, 24].

As the exposure of interest, PA may be an intricate and difficult parameter to measure, especially in population-based studies. Inconsistencies may be associated with variations in PA instruments (assessment methods), the use of different domains of PA (occupational, household, transport, and recreational) with the frequency, duration, and intensity of PA in the investigation of the relationship. Nevertheless, the same heterogeneity in the assessment of PA in women also exist in the studies of the PA-CRC relationship in men; whereas the findings in men have been more consistent and largely conclusive [11, 13, 14, 24].

Our findings of no association between PA and the risk of CRC in women may be an accurate reflection of a true lack of association, which is consistent with findings from many previous prospective studies among women [10–22]. From the available prospective studies that included only women or gave sex-specific results, we identified 21 studies [6–8, 10–26, 39]. Thirteen of these studies found no association between PA and risk of CRC [10–22], six observed a statistically significant association [6–8, 23–25], while two reported both [26, 39]. The last two studies further underscore the discrepancies in the findings of PA-CRC relationship in women [26, 39].

Out of the 13 prospective studies that found no association, none of them used the same PA instrument we used in our study. Nevertheless, since our PA scale corresponds to total PA, including all the domains in one global score, we can compare our study to others that utilized total PA. For example, the questionnaire used in the National Institutes of Health-American Association of Retired Persons Diet and Health (NIH-AARP Diet and Health) Study [11] assessed participants’ detailed routine throughout the day, at home and work (daily routine activity), and sporting activities. Daily routine activity and sporting activity were analysed separately and neither were statistically significant (HR = 0.84, 95%CI 0.50–1.42, p-trend = 0.714 and HR = 0.87, 95%CI 0.71–1.06, p-trend = 0.536, respectively) in women. Interestingly, the same analyses were statistically significant in the participating men (HR = 0.86, 95%CI 0.66–1.12, p-trend = 0.007 and HR = 0.82, 95%CI 0.71–0.95, p-trend = 0.013, respectively). The Japan Public Health Center-based Prospective Study also found no relationship between total daily PA and CRC in women (HR = 0.82, 95%CI 0.56–1.21, p-trend = 0.198 for colon cancer; HR = 1.79, 95%CI 0.99–3.23, p-trend = 0.077 for rectal cancer) [20]. Corresponding analyses in the participating men from that study were statistically significant for colon cancer (HR = 0.58, 95%CI 0.48–0.79, p-trend < 0.001), but not for rectal cancer (HR = 0.88, 95%CI 0.57–1.36, p-trend = 0.464). The Framingham Study used the summary PA index of daily activity, which also relates to total daily PA. The authors observed no association between total daily PA and large bowel cancer (p-trend 0.89) among women, but they did report an association among men (p-trend 0.06) [18]. Likewise, the Breast Cancer Detection Demonstration Project (BCDDP), which used a PA instrument similar to that of Framingham Study, observed no association between total PA and the risk of colon cancer (HR = 1.15, 95%CI 0.76–1.75, p-trend = 0.77) [10].

The other nine prospective studies, which found no association between PA and CRC in women used various PA instruments and assessed different domains of PA. These ranged from recreational and non-recreational, with HR = 1.60, 95%CI 0.70–3.50 (inactivity-CRC relation) [17]; recreational and occupational, with HR = 0.86, 95%CI 0.77–1.03 [12]; recreational only, with HR = 0.77, 95%CI 0.43–1.38, p-trend = 0.27 [14], HR = 0.90, 95%CI 0.56–1.46, p-trend = 0.68 [15], HR = 0.89, 95%CI 0.50–1.60 [16], HR = 0.95, 95%CI 0.68–1.39, p-trend = 0.75 [22]; non-recreational only, with HR = 0.94, 95%CI 0.40–2.21 [21], amount of time spent walking, with HR = 1.02, 95%CI 0.60–1.75, p-trend = 0.91 [19]; to metabolic equivalent (MET) hours per day, with HR = 1.16, 95%CI 0.76–1.77, p-trend = 0.569 [13]. However, some of these studies observed statistically significant associations among men from the same studies [13, 14, 16, 19].

On the other hand, six prospective studies reported a significant association between PA and colon cancer or CRC [6–8, 23–25]. The Nurses’ Health Study found significant inverse association between recreational PA and incidence of colon cancer in women (HR = 0.54, 95%CI 0.33–0.90, p-trend = 0.03) consistent with results found in men [6]. The Nord-Trøndelag Health Study conducted in Norway also found a significant association among women who reported high recreational PA versus no PA (HR = 0.77, 95% CI 0.53–0.98, p-trend = 0.03). No linear association was found for rectal cancer risk (p-trend = 0.74) [7]. Another population-based cohort study in women in Norway found recreational PA to be associated with decreased risk of colon cancer (HR = 0.62, 95% CI 0.40–0.97, p-trend = 0.25) [8]. However, The California Teachers Study found that lifetime recreational PA reduces colon cancer risk among postmenopausal women who had never taken hormone therapy (HR = 0.51, 95% CI 0.31–0.85, p-trend = 0.02), but not in postmenopausal women with history of hormone therapy use (HR = 0.98, 95% CI 0.66–1.44 p-trend = 0.49) [23]. One thing is conspicuously common to these studies: they all utilized the single domains of either recreational [6–8, 23] or occupational [8, 24, 25] PA. This may have effectively excluded the household (domestic or family care) PA domain, which is mostly important for the female population [27]. This could partly account for the gender bias in the appraisal of PA in epidemiological studies [40]. On the other hand, it may be relatively easy to remember and thus simpler to appraise recreational and occupational PA compared to total PA.

According to our findings, those who increased their PA from baseline to follow-up had a lower risk of colon cancer, thus this lower risk may very well be a marker of a generally healthy lifestyle. However, we found no association between those who were consistently active and the risk of colon cancer. This further portrays that both short and consistent PA over a period of time may not confer protection against colon cancer in women. The association between long-term PA and a reduced risk of colon cancer (consistently active vs consistently inactive) is more often seen in men [39, 41], and even then it is inconsistent [42]. Intriguingly, women who were consistently active were at an increased risk of rectal cancer when compared to those who were consistently moderately active. This result must be interpreted with caution as it could be a spurious finding, which is probably due to another associated factor. This is because the finding on its own has no plausible physio-biological explanations.

The present study has some limitations. Our PA measurement may not have been sensitive enough to detect perhaps small effect of PA on CRC among women. The PA level in our study was self-reported through questionnaires and thus is inevitably susceptible to measurement error [43]. Unfortunately, in large population-based studies, one may not be able to use more accurate PA assessment methods, such as the accelerometer and gyroscope. Furthermore, although the PA assessment used in our study gave a total PA score, this score lacks quantification and distinguishability of the domains involved, the frequencies, durations, and intensities of the PA [32]. The ordinal scale measures self-perceived PA, which is subjected to individual frame of reference, which may differ widely [28]. Thus, one should be cautious of this limitation while interpreting the results. Notwithstanding, the PA instrument we used has been validated, and the results show that the scale is sufficient to differentiate between levels of the total amount of PA. The Spearman correlation coefficient was found to be moderate at 0.36–0.46 with p-value less than 0.001 [32]. This compares well with the International Physical Activity Questionnaire, which reported criterion validity by Spearman correlation of a median of 0.30 in a validation study across 12 countries [44]. The covariates in our study were also self-reported and are therefore prone to the errors inherent to self-reporting. Indeed, self-reporting leads to a tendency for people to overstate desirable behaviours, such as PA, dietary habits, and alcohol consumption habits, thereby introducing some level of misclassification error [45]. We used only one measure of the dietary intakes, taken at enrollment. These intakes likely change over time and may be invalid over the length of the study period [46]; thus, residual confounding cannot be excluded. Nevertheless, the information in the NOWAC Study on PA, BMI, dietary habits, and alcohol consumption habits have been validated with satisfactory results [32, 47–49]. The self-reported duration of education has been compared to the relevant national registries and no statistical differences were found [30]. Accordingly, this self-reporting method is judged to be adequate and pragmatic, especially considering the large sample size of the NOWAC Study. Our study lacked information on family history of CRC. Women who have a familial predisposition to developing CRC may be more health conscious than others, which may cause residual confounding. Likewise, we lacked information on use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) by our participants. Regular use of aspirin and other NSAIDs are suggestive of protection against colon adenoma and cancer [50]. This may also be a source of confounding.

Our study has several strengths. These include the prospective and population-based design, the large sample size, the long follow-up time, information on important confounding factors, and the use of a high-quality national cancer registry to identify cases of CRC [31]. The NOWAC cohort consists of participants who were randomly recruited from the general population and is representative of the Norwegian female population aged 30 to 70 years [32]. The external validity of the NOWAC cohort has been found to be acceptable [30]. We used repeated measurements of PA level, BMI, and smoking status in order to account for changes in these variables over time and to attenuate the risk of measurement error. The availability of data on PA level at two different time points also allowed us to investigate changes in PA levels, which is a vital strength of this study. The self-reported BMI and the food frequency questionnaire in the NOWAC Study have been validated [47–49]. There is a substantial agreement between the self-reported and measured BMI values [49], while 24-h dietary recall studies found the food frequency questionnaire to be reliable [47, 48].

Our data do not support the hypothesis that total physical activity, nor consistent participation in PA over a period of time, is associated with a reduced risk of CRC in women. Thus, women may need to look beyond PA in order to reduce their risk of CRC.