CHAPTER 5: DISCUSSION
5.5 Cancer of the Rectum, Recto-sigmoid and Anus
As mentioned earlier, there were only 3 cases of cancer of the anus in our study, thus, our findings basically reflect relationships between BMI and cancer of the rectum and recto-sigmoid. Our results suggest that increase BMI is associated with increased risk of this type of cancers. This is observed in both men and women, but is slightly stronger in men than in
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women. However, the observed associations are neither statistical significant in men nor women (Table 14). Unlike in colon cancer, menopausal status appeared to have no effect modification on the risk of rectal and recto-sigmoid cancers.
The positive association between obesity and the risk of rectal and recto-sigmoid cancers was also found in similar other studies. Some studies reported that the association was stronger in men than in women (74, 75), while others reported it was limited to only men (76-78), and some found no association in both genders (79).
The tentative biological mechanism involving insulin, IGF, sex hormones and adipokines earlier expounded in respect of colon cancer may also be tenable for the relationship observed here. Furtherance to that, that increased BMI and cancer risk is stronger for colon than rectal cancer may mean that these or other mechanisms related to obesity are stronger for colon than for rectal cancer (78), and several studies have reported that the level of C-peptide and leptin (an adipokine) were more strongly and positively associated with risk of colon cancer than rectal cancer (78).
5.6 Colorectal Cancers
Our results suggest that increase BMI is associated with increased risk of colorectal cancers in men, whereas there are no substantial changes in the risk in women, except a relatively small (but statistically not significant) increased risk in the obese (Table 16 and Figure 11).
The findings were grossly similar to what were observed in the BMI-colon cancer relationship, especially in men.
The relatively small increased risk in obese women becomes more profound when the analyses are limited to women less than 36 years old at baseline. Moreover, the linear
45
relationship between BMI and the risk of colorectal cancer in the women less than 36 years in age, though not statistically significant, may also indicate the possible modifying effect of the menopausal status in women regarding the risk of colorectal cancer, or may actually be a reflection of the colon cancers present in the analyses.
Meta-analyses have indicated that BMI may be more strongly associated with colon cancer than rectal (81, 82) cancer incidence. Our findings were consistent with previous studies where stronger positive relationship for BMI and colorectal cancer risk were found in men compared to women (83, 84). When we restricted the analyses in women to those aged 36 years and below, our results were similar to that of Terry et al (2001) conducted in Sweden (72).
The biological mechanism by which increased BMI increases colorectal cancer risks are largely unclear (71), but the speculative explanations previous provided under colon cancer may equally be accountable here. In addition, the possible mechanism(s) for gender difference is thought to be probably related to testosterone concentration. Studies have shown that increased BMI is inversely related to testosterone concentration in men (39) while it is directly related in women (80). Therefore, a reduction in testosterone concentration caused by obesity may be one reason for stronger association of increased BMI with colon and rectal cancer risk in men than in women (78). However, as recently argued by Kitachara et al (2013), additional studies are needed for better understanding of the biologic mechanism(s) underpinning these associations (71).
Our findings further highlighted the importance of early adulthood weight control in both men and women.
46 5.7 Limitations and Strengths of the Study
We need to acknowledge some limitations in this study. Some invited participants within the stipulated birth cohorts did not attend Tromsø 3 survey; we do not have knowledge of the BMI of these non-attendees. Even though the participants were at liberty to attend at suitable time within the timeframe of about a year, non-attendees were 25 per cent of the total invitees. This estimate is lower (approximately 20 per cent) if people who gave reasons for not attending are taken in to consideration (19). This may be a possible source of selection bias in the study. However, Montgomery et al (2010) posited in their study that the differences between participants and non-participants in prospective cohort study are generally small, and they did not find significant evidence of selection bias (85). In another study by Knudsen et al (2010), they also opined that non-participation in the study of association between exposure and outcome may not have any serious threat to the validity of the results (86). Thus, we do not consider that the 25 per cent non-attendees in Tromsø 3 survey would have introduced any substantial selection bias into our results. Moreover, prospective studies like ours, where the outcome is unknown at the time of enrolment are less susceptible to selection bias (87).
BMI is a surrogate measure of body fat and the measurement relies solely on the weight and height. Accordingly, BMI usually overestimates the adipose tissue (body fat) in people with more lean body mass, such as muscular people and athletes (88), while it underestimates the body fats in people with less lean body mass such as the elderly and people having eating disorder like in anorexia nervosa and bulimia nervosa (88). Therefore, some group of people who are fit and athletic or body builders could have been misclassified as overweight, while some old individuals or in muscle wasting disorders may
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have also been misclassified as low weight. This may potentially lead to bias of misclassification of exposure (87). There were, however, no elderly (65 years and above) and probably very few muscular subjects and patients with eating or muscle wasting disorders in the sample.
Other anthropometric measures reflecting the body fat (such as waist circumference, waist-to-height ratio, and waist-to-hip ratio) have been suggested and used in some studies.
Unfortunately we do not have any of these in Tromsø 3 survey either as alternatives or for comparison to BMI measurement. Howbeit, studies have shown that BMI correlates sufficiently high enough with body fat (89) to minimise misclassification mentioned above, and therefore, we do not suppose this could have compromised our results.
Measurement of BMI close to the time of diagnosis of cancer may be lower than the preclinical values, and may also have led to misclassification. To assess the possibility of this effect (if any), each BMI-cancer analysis was further verified by excluding cases diagnosed within the first 3 or 5 years of the follow-up (as deemed appropriate), and we checked for attenuation or complete alteration of the results or patterns previously observed. Our results did not suggest that the preclinical disease had any significant impact on our results or on the conclusions.
Changes in BMI after the study began were not factored in in the study. However, even though BMI tends to increase with age, and more strongly in relatively young adults than older subjects, there is a strong tracking with regards to BMI; the correlation between BMI at baseline and after, for instance after 10 years, is high (92). Furthermore, the classification with regards to confounders (such as smoking) may have changed during follow-up period.
These changes may have had effects on the possible outcome of the participants (having
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incident cancer or not), and some residual confounding is likely. In addition, we did control for smoking status in all our analyses, but, we could not assess the contribution of environmental tobacco smoke (ETS) exposure in these BMI-cancer relationships. The amount of ETS exposure in never-smokers may be essential for ascertaining the cancer risks related to ETS exposure (90).
The possible effects of family history of obesity and cancer were not explored in this study.
Both obesity and cancer are known to correlate within families (91), but we do not have adequate information suitable for analyses for both in our study. Likewise, information on dietary intake (such as red or processed meat) was also not available. As BMI and dietary habits are linked in different (and sometimes quite complicated) ways, this may be a weakness in our study.
Regardless of the above, our study had the evident strength of a population-based prospective design, with a comparatively long follow-up time (1986 to 2010). There was relatively high attendance rate (about 75%) and minimal loss to follow-up (19). Baseline information including weight and height of participants were collected beforehand, thus avoiding the exposure-recall bias which is an integral of case-control studies. The cohorts used in the study were based on birth-year and not based on professional affiliation (e.g.
nurses) or church membership (e.g. Adventist) as in some studies, which could introduce possibilities of bias. The study also enjoyed the advantage of measured (not self-reported) values of height and weight, and the reliability of the connected Norwegian registries for cancer diagnosis, death, and emigration. Thus, body mass index at baseline was measured with high validity and the follow-up of deaths and incident cancers with histologic confirmations were mostly assured and complete.
49 5.8 External Validity
The findings in this study may be generalizable to cities similar to Tromsø municipality in population homogeneity, and to the rest of Norway, Europe or any similar population that is predominantly Caucasian. However, the generalizability may not extend to Asia and Africa because, for instance, Asians have more body fat at any given BMI compared to Caucasians (93). Increased risks of diabetes and cardiovascular diseases may thus start at lower BMI in Asian population compared to Caucasians and this may extend to cancer risks as well (84).
Therefore, the BMI cut-offs for overweight and obesity may be expected to be different in Asians.
5.9 Recommendation for Future Studies
Obesity-related cancers are diverse and there still exist much knowledge gaps in the mechanism(s) underpinning the association between obesity and cancers, and what is actually responsible for the gender difference observed in some cancer incidents. More studies are still required in this area for better understanding. A better understanding may lead to improved or development of new public health approach to the prevention and treatment of BMI-related cancers.
It has also been implied that waist circumference, waist-hip-ratio and waist-to-height ratio (as measure of obesity) may be better predictors of future health risk than BMI (94).
However, there is need for big cohort studies to evaluate these measures alongside BMI as regards the risk of cancers, and the associated gender variations in some of the cancer incidents.
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51
CHAPTER 6: CONCLUSION
The purpose of this current study was to determine the relationship between BMI and the total cancer incidence as well as its relationships with some common specific cancers. This was done in relatively young subjects (in cancer research perspective).
The findings demonstrated that both the underweight and obese men were at increased risk of total incident cancer while the women were not. Thus, our first hypothesis that low and high BMIs increase the risk of total incident cancers holds in men but not in women. For specific cancers, adiposity may be a threat to the men as regards colon and colorectal cancers, and similarly to the relatively young premenopausal women, but not to the older women. Low weight and obese subjects may be at increased risk of lung cancer, whereas prostate cancer appeared to be indifferent to adiposity. Thus, our second hypothesis that low and high BMIs increase the risks of common cancers is gender specific and holds for some specific cancers (such as lungs and colon), but fell for others (such as prostate).
Our findings confirmed previous studies and contributed additional evidence in respect of BMI and total incident cancer risk, colon and colorectal cancer risks, and the possible modifying effect of menopausal status in the risk of colon cancer in women. Our study also supported the existing knowledge that underweight individuals who smoke may be at higher risk of lung cancer.
These results suggested that the safest body weight in respect of reducing ones cancer risks may be the “normal” weight, as both ends of the BMI spectrum may be at increased risk of future cancer development. Therefore, public health policies directed at reducing incidence of cancers should address both the obese and the underweights in the community.
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