台灣癌症醫誌 (J. Cancer Res. Pract.) 30(1),3-10, 2014 Review Article journal homepage:www.cos.org.tw/web/index.asp Weight Loss and Cancer Risk Reduction Yi-Yang Chen, Kuan-Der Lee* Division of Hematology Oncology, Department of Medicine, Chang Gung Memorial Hospital-Chiayi, Chiayi, Taiwan Abstract. Both obesity and cancer are significant public health issues in Taiwan, as well as in other developed countries. In particular, obesity has numerous well-known comorbidities including hypertension, diabetes, and heart disease. Since the first large study focusing on the association between cancer and obesity was performed by the International Agency for Research on Cancer (IARC) in 2002, there has been an increasing number of reports of the possible mechanisms underlying this relationship in the literature. We hereby review the current literature to assess the effect of intentional loss of body weight on cancer risk. We found that despite current evidence indicating that body weight loss may decrease the risk of certain malignancies, much of this data arises from patients treated by bariatric surgery. For those patients without morbid obesity, the results of these studies should be cautiously interpreted before more comprehensive clinical guidance is proposed for the general population. 綜合評論 Keywords : obesity, intentional weight loss, cancer risk reduction 減重與降低癌症風險 陳苡揚李冠德 * 財團法人嘉義長庚紀念醫院血液腫瘤科 中文摘要肥胖與癌症已經成為台灣及其他已開發國家重要的健康議題 目前已知肥胖與許多疾病有著密切的關係, 像是高血壓, 糖尿病或心臟病 自 2002 年 International Agency for Research on Cancer (IARC) 釋出的第一份有關肥胖與癌症之間關係的報告以來 愈來愈多的文章探討肥胖與癌症之間的關係及相關的機轉 隨著近幾年來台灣肥胖及癌症的盛行率不斷的上升, 儼然成為我國公共衛生重要的議題 目前為止, 大部份文獻著重於體重增加及癌症風險的上升, 較少有文章探討減重是否能降低癌症的風險 本篇文章回顧了這方面有限的文獻, 發現減重似乎與某些癌症的風險有關 但是這部份的資料大多來自於減重手術術後的追蹤調查, 接受手術的病人其術前的體重較一般肥胖病患有著相當大的差距 因此此研究結果對一般非病態性肥胖病人的詮釋上必需要更加的小心 關鍵字 : 肥胖 減重 降低罹癌風險
4 Y. Y. Chen et al./jcrp 30(2014) 3-10 INTRODUCTION Overweight status and obesity have multiple comorbidities, including hypertension, diabetes mellitus, and acute coronary syndrome, and have therefore become important issues for our health insurance system. A study by the Nutrition and Health Survey in Taiwan (NAHSIT) reported that the prevalence of overweight status and obesity increased from 33.4% to 50.8% in men and 31.7% to 36.9% in women from 1996 to 2008 [1]. In addition to obesity, cancer is also a major public health issue in Taiwan, and was responsible for 28.4% of deaths in 2010 [2]. Many recent studies have indicated an association between overweight/obesity and cancer. For example, studies by the International Agency for Research on Cancer (IARC) in 2002 [3] and the World Cancer Research Fund and American Institute for Cancer Research (WCRF/AICR) in 2003 [4] indicated that obesity is a major risk factor in many different cancers, including cancers of the breast, endometrium, colon, esophagus, pancreas, kidney, and probably the gall bladder [3,4]. Both of these studies examined the association of cancer risk and body mass index (BMI), but did not examine the effect of weight loss on the change in cancer risk. Thus, the relationship between obesity and cancer is well-known, yet it is not known if intentional weight loss reduces the risk of cancer. The current paper reviews existing evidence of the relationship between obesity and cancer, to determine if the findings in earlier studies support the hypothesis of an association between intentional weight loss and cancer risk reduction. Since the IARC review in 2002 [3], many researchers have examined the relationship between *Corresponding author: Kuan-Der Lee M.D., Ph.D. * 通訊作者 : 李冠德教授 Tel: +886-5-3621000 ext.2852 Fax: +886-5-3623002 E-mail: kdlee@cgmh.org.tw cancer and obesity by use of animal studies, clinical studies, epidemiological studies, and physiological studies. Many hypotheses explain the connection of obesity with different types of malignancies (Table 1), and the underlying mechanism may involve insulin, insulin-like growth factor (IGF), endogenous steroid sex hormones, inflammation, and liposoluble toxin/ carcinogen. Insulin and steroid sex hormones appear to be particularly important in the connection of obesity and cancer. In particular, insulin and the IGF pathway appear to be involved in colon cancer [5,6], pancreatic cancer [7], prostate cancer [8], endometrial cancer [9], and breast cancer [10,11]. Endogenous steroid sex hormones such as estrogen, androgens, and progesterone are known to be involved in the pathogenesis of breast cancer, endometrial cancer, and prostate cancer. Endometrial cancer is the first cancer found to be related to steroid sex hormones [12-15]. Although most previous studies only examined the effect of obesity on cancer risk, few of these studies examined the effect of weight loss on cancer risk reduction, which is the purpose of this review. WEIGHT LOSS AND REDUCTION OF CANCER RISK There have been several studies focusing on the effect of intentional weight loss on the risk reduction of certain malignancies, such as those of the colon, breast, and prostate. However, many of these inquiries were follow-up studies of those patients after bariatric surgery in America and Sweden, which are here listed below. Colon Cancer The prevalence and incidence of colon cancer in Taiwan has been steadily increasing. According to data from the Department of Health, about 8000 people were diagnosed with colon cancer annually, and 4000 people die of colon cancer every year. The IARC and WCRF/AICR have presented compelling data on the connection of obesity and colon cancer [3,4]. Thus,
Y. Y. Chen et al./jcrp 30(2014) 3-10 5 Table 1. Relative risk for cancer with increase body mass index (BMI) every 5kg/m 2 [3,16,19,20] Cancer type Relative risk in men & women Possible mechanism Colon Men : 1.24 (CI: 1.20-1.28) Insulin growth factor Women : 1.09 (CI: 1.05-1.13) Rectal Men : 1.09 (CI: 1.06-1.12) Unknown Liver Men : 1.24 (CI: 0.95-1.62)* Fatty liver related liver cirrhosis Women : 1.07 (CI: 0.55-2.08)* Pancreas Men : 1.07 (CI: 0.93-1.23)* Possible insulin pathway Women : 1.12 (CI: 1.02-1.22) Esophageal adenocarcinoma Men : 1.52 (CI: 1.33-1.74) Reflux esophagitis and chronic Women : 1.51 (CI: 1.31-1.74) irritation Esophageal squamous carcinoma Men : 0.71 (CI: 0.60-0.85) Smoking Women : 0.57 (CI: 0.47-0.69) Kidney Men : 1.24 (CI: 1.15-1.34) Inflammation or other growth factor, Women : 1.34 (CI: 1.25-1.43) partially due to hypertension Thyroid Men : 1.33 (CI: 1.04-1.70) Unknown Women : 1.14 (CI: 1.06-1.23) Gallbladder Men : 1.09 (CI: 0.99-1.21)* Gallbladder stone and chronic Women : 1.59 (CI: 1.02-2.47) irritation Lung Men : 0.76 (CI: 0.70-0.83) Smoking Women : 0.8 (CI: 0.66-0.97) Leukemia Men : 1.08 (CI: 1.02-1.14) Unknown Women : 1.17 (CI: 1.04-1.32) Non-Hodgkin s lymphoma Men : 1.06 (CI: 1.03-1.09) Chronic Women : 1.07 (CI: 1.00-1.14)* inflammation (Interleukin-6) Multiple myeloma Men : 1.11 (CI: 1.05-1.18) Chronic Women : 1.11 (CI: 1.07-1.15) inflammation (Interleukin-6) Breast postmenopausal Women : 1.12 (CI: 1.08-1.16) Endogenous estrogen Breast premenopausal Women : 0.92 (CI: 0.88-0.97) Hormone or irregular menstrual cycle Endometrium Women : 1.59 (CI: 1.50-1.68) Endogenous estrogen Prostate Men : 1.03 (CI: 1.00-1.07)* Unknown Malignant melanoma Men : 1.17 (CI: 1.05-1.30) Unknown *p 0.05 Based on body-mass index and incidence of cancer: A systematic review and meta-analysis of prospective observational studies. Lancet 2008; 371:569-578 certain lifestyle modifications are thought to reduce the risk of colon cancer, such as increasing physical activity and maintaining an ideal body weight [16]. However, most studies examined the effect of body weight increase and cancer risk, but very few examined the effect of intentional weight loss and cancer risk. A cohort study in Canada reported that an increase in body weight after adulthood is associated with a moderately increased risk of colorectal cancer in males. A subsequent case-control study in Canada
6 Y. Y. Chen et al./jcrp 30(2014) 3-10 Table 2. Relationship between intentional weight loss from bariatric surgery and cancer incidence & mortality Study Time Number Mean follow-up time Population Reduction of cancer incidence Reduction or cancer mortality Swedish (prospective controlled cohort study) [30,31] U.S.A. (retrospective cohort study) [29] Canada (observational-2 cohort study) [32] 1987-2001 4047 10.9 years All 33% Men 3% Women 42% 1984-2007 16038 7.1 years All 24% 46% Men 2% 30% Women 27% 62% 1986-2002 6781 < 5years All 78% indicated that men who gained more than 21 kgw after the age of 20 years have a 60% higher risk of colon cancer than those who gained only 1~5 kg, and that the difference in risk is even greater if rectal cancer is excluded [17]. This result indicates that previous researchers may have underestimated the strength of the relationship between colon cancer and overweight/ obesity. Another study reported that an increased BMI at age 30~50 years increased the risk for colorectal cancer by 25~35% in men and women [18]. Our literature search indicated that many studies of overweight/obesity and colorectal cancer failed to report an association for women, possibly because the benefit of a higher level of estrogens in obese women counters the harmful effect of insulin pathway activation in increasing the risk for cancer [19]. These were only from a cohort study in Austria, which found a trend between intentional weight loss and risk reduction in colon cancer among men (hazard ratio = 0.50, 95% CI=0.29-0.87, p for trend=0.58) [20]. Breast Cancer Breast cancer is the most common malignancy among woman, and the second leading cause of cancer death in women. Both IARC and WCRF/AICR have documented that obesity, weight gain, and adiposity increase the risk for post-menopausal breast cancer. A meta-analysis indicated that there was a 5% increase in the risk of post-menopausal breast cancer for every 5 kgw of weight gain [3,4]. Few studies have examined the physiological basis for the connection between body weight and breast cancer, and this mechanism must be understood in order to determine if lifestyle modification can reduce cancer risk. The levels of endogenous hormones, especially circulating estradiol, have important effects on the occurrence of postmenopausal breast cancer [21]. A randomized study of activity among the postmenopausal women indicated a decrease in the level of estrogen among postmenopausal women who lost body fat via exercise [22]. In addition to the important effect of estrogen on breast cancer, a prospective cohort study within the Nurses Health Study in 2006 indicated a decrease in the incidence of postmenopausal invasive breast cancer after weight loss [23]. In addition, a loss of 10 kgw in body weight after menopause reduced the risk of breast cancer by nearly 50% [24]. The same study also estimated that weight gain after adulthood or after menopause accounted for 24% and 7% of postmeno-
Y. Y. Chen et al./jcrp 30(2014) 3-10 7 pausal breast cancer in patients using no postmenopausal hormone therapy, respectively. Prostate Cancer The initial review of the IARC indicated insufficient evidence regarding the relationship between obesity and prostate cancer. Some studies indicated that obese men had a lower overall incidence of prostate cancer, but a higher incidence of fatal and aggressive prostate cancer [25,26]. A recent meta-analysis indicated a weak but statistically significant relationship between high BMI and risk of advanced prostate cancer [27]. There are limited data about the association between weight loss and the risk of prostate cancer. A cohort study in the Cancer Prevention Study II Nutrition Cohort indicated that weight loss of more than 11 lbs after adulthood was associated with a decreased risk of high grade prostate cancer relative to stable body weight (change 5 lbs) [26]. Another study reported a similar trend for patients older than 50 years of age [27]. BARIATRIC SURGERY The aforementioned studies focused on the effect of overweight/obesity on a specific malignancy or even a specific gender. In Western countries, patients with morbid obesity may be treated by bariatric surgery, also known as weight-loss surgery. This surgery may be performed by a variety of procedures, such as gastric banding or gastric bypass. This type of surgery can be traced back to 1954, when Dr. A.J. Kremen performed the first bariatric procedure via intestinal bypass [28]. In the past decades, bariatric surgery has become popular, and there is strong evidence that it effectively decreases the body weight of obese patients and allows most patients to maintain a reduced weight. However, it is not yet clear if bariatric surgery can reduce the mortality rate and comorbidities of obese patients. Follow-up studies of bariatric surgery patients have been conducted in America and Sweden [29,30], and these studies provided important insight about the effect of sustained weight loss on cancer risk. The prospective, controlled study of obese subjects from Sweden enrolled 4047 patients from 1987 to 2001, with a mean follow-up time of nearly 11 years. Patients receiving surgery had a sustained mean weight reduction of 19.9 kg over 10 years. The number of cancers was significantly lower in the surgery group than in the control group (117 patients vs. 169 patients, HR=0.67, 95% CI=0.53-0.85, p=0.0009). Subgroup analysis indicated that this effect was significant in women (HR=0.58, 95% CI=0.44-0.77, p=0.0001), but not in men (HR=0.97, 95% CI=0.62-1.52, p=0.90). This effect was also significant in postmenopausal women (HR=0.56; 95% CI=0.36~0.86, p=0.0088), patients with diabetes (HR=0.68, 95% CI=0.53~0.87, p=0.0021) and non-smoking patients (HR=0.61, 95% CI=0.46~0.82, p=0.0009) [30,31]. The American study reported similar trends. This study was a retrospective observational study that enrolled 15,850 obese patients with mean follow-up duration of 7.1 years from 1984 to 2006. The cancerrelated mortality was 60% lower in the surgery group (HR = 0.40, 95% CI = 0.25-0.65, p < 0.001), and subgroup analysis indicated that reduction of cancer risk only occurred in women and the amount of weight loss was not proportional to cancer risk reduction. Analysis of females indicated that the risk reduction of different malignancies was mainly in malignancies that are known to be related to obesity (Table 2) [29,32]. In Austria, a large cohort study based on a normal population of more than 65,000 adults was conducted from 1985 to 2003, with a follow-up duration of 7 years [20]. In this study, neither weight loss nor gain was associated with overall incidence of malignancies in men or women. However, subgroup analysis indicated that weight loss (> 0.10 kg/m 2 /year) was associated with a decreased risk of colon cancer in men (HR=0.50, 95% CI=0.29-0.87, p for trend= 0.58) and
8 Y. Y. Chen et al./jcrp 30(2014) 3-10 that weight gain was associated with a decreased overall incidence of prostate cancer, although prostate cancer stage was not considered (HR =0.43, 95% CI=0.24-0.76, p for trend=0.06) [20]. DISCUSSION Obesity and cancer have become major public health issues in Taiwan and other developed countries. This review has identified increasing evidence of an association between obesity and cancer. It is important for clinicians to know whether the risk of cancer can be reduced if overweight/obese patients lose body weight. Unfortunately, due to the insufficiency of current data, the actual beneficial effect of weight loss on cancer risk is not yet conclusive. One of the problems is that such intervention or prevention cancer trials are limited by the challenges of sustaining weight loss over a prolonged period and the duration of follow-up. Over time, non-compliance in the intervention group will reduce the power of the study [33]. This bias has been reported in previous prevention trials, such as those for hormone replacement [34] and diet modification [35]. Another problem is the presence of numerous comorbidities associated with short-term and long- term obesity, such as diabetes, hypertension, coronary artery disease, and those comorbidities associated with diet and physical activity. Comprehensive collection of these data may be difficult due to low levels of adherence by patients enrolled in such trials in the absence of active intervention. Another concern is the feasibility of applying data from bariatric surgery patients to the general population. Numerous factors must be considered, including race/ethnicity, type of surgical intervention, the extent of overweight/obesity, and the amount of weight loss. Because of these issues, it is difficult to conduct prevention trials to document the pure effect of weight loss on cancer risk. Nonetheless, existing evidence suggests that weight loss may be effective in reducing the risk of certain cancers. In addition to these epidemiological studies, numerous studies have also examined the effect of certain cancer-related risk factors such as estrogens, sex hormone binding globulin (SHBG), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), insulin-like growth factor-1 (IGF-1), and IGF binding protein on weight reduction. Review of this literature indicates that body weight loss may increase the level of SHBG and decrease the level of estrogen [36]. For example, free estradiol declines by about one-third with a 10% reduction of body weight; similar declines occur in CRP, IL-6, and TNF-α, although the declines are not as large. In contrast, levels of IGF-1 and IGFBP had no significant changes after body weight loss [19]. CONCLUSIONS In this review, we concluded that the risk of certain malignancies is increased in patients with morbid obesity and can be reduced by intentional weight loss. However, current data remain insufficient to extrapolate this information onto the general population. Further prospective studies are necessary to explore the effect of weight reduction on cancer risk in nonmorbidly obese patients. REFERENCES 1. 行政院衛生署 (2010) 2005~2008 調查成果 取自台灣營養健康狀況變遷調查 http://nahsit. nhri.org.tw/node/1 2. 行政院衛生署 (2011):99 年國人主要死因統計結果分析 取自衛生統計資訊網 http://www. doh.gov.tw/cht2006/dm/dm2_p01.aspx?class_ no=25&level_no=1&doc_no=80728 3. International Agency for Research on Cancer. Weight Control and Physical Activity, Volume 6. Lyon: IARC: 1-315, 2002. 4. Calle EE, Rodriguez C, Walker-Thurmond K, et al. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348: 1625-38, 2008. 5. McKeown-Eyssen G. Epidemiology of colorectal
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