Physical Activity and Risk of Hepatocellular Carcinoma Among U.S. Men and Women

In the United States, the relative incidence and mortality of hepatocellular carcinoma (HCC) are increasing more rapidly than those for any other cancers (1). HCC incidence has tripled since the early 1980s (2), and annual deaths due to HCC increased from 5,112 in 1999 to 11,073 in 2016 (3). By 2030, liver cancer is projected to be the third leading cause of cancer-related death in the United States (4). Thus, effective preventive strategies are needed to reduce the risk of developing HCC.

According to the American Cancer Society recommendations, physical activity for maintaining health includes both moderate and vigorous-intensity activity (5, 6). Evidence suggested a potential protective benefit of physical activity on obesity (7), insulin sensitivity (8), and nonalcoholic fatty liver disease (NAFLD; refs. 9, 10), which are known predisposing factors for HCC. Previous studies, including two meta-analyses (11, 12), have shown the benefit of physical activity on liver cancer but most focused on vigorous-intensity activities (13–18). Hence, evidence for the potential benefit of moderate-intensity activity, such as brisk walking (at least 3 miles per hour), on HCC risk remains limited. To date, only two studies conducted in Japan examined walking duration, but not walking intensity or other physical activities, with liver cancer incidence and mortality (19, 20). In addition, physical activity was measured at a single time point in all previous studies, but repeated assessments may provide additional useful information by accounting for the changes in physical activity over time.

Therefore, in this study, we examined the association of moderate- and vigorous-intensity activity with HCC risk by utilizing data from two large prospective cohort studies, the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS).

The NHS was initiated in 1976 including 121,700 female registered nurses ages 30 to 55 years. The HPFS was initiated in 1986 including 51,529 male health professionals (dentists, pharmacists, optometrists, osteopath physicians, podiatrists, and veterinarians) ages 40 to 75 years. In each cohort, information on demographics, lifestyle factors, and medical history was collected at baseline and updated biennially. The follow-up rate has been over 90% for each cohort, and causes of death are ascertained for over 98% of deceased participants. This study was approved by the Institutional Review Boards at Brigham and Women's Hospital and the Harvard T.H. Chan School of Public Health in Boston, MA, and those of participating registries as required.

In the NHS and HPFS, physical activity was assessed and updated through biennial questionnaires beginning in 1986, except for 2002 in the NHS. The participants were asked to select a category for the average hours they spent each week over the prior year doing any of the following physical activities: walking (e.g., for exercise or to work), jogging, running, swimming, bicycling, calisthenics and other aerobic exercises (e.g., aerobics, aerobic dance, and rowing machines), squash/racquetball, tennis, lower-intensity exercise (e.g., yoga, stretching, and toning; beginning in 1992 in the NHS and 2010 in the HPFS), weight lifting (beginning in 2000 in the NHS and 1990 in the HPFS), and outdoor work (chopping/digging for men beginning in 1988 and lawn mowing for women beginning in 1992). In both cohorts, participants were also asked about the number of stairs climbed per day. In the NHS, participants chose one of 10 categories that ranged from 0 to 11 hours/week or more. In the HPFS, 13 response categories ranging from 0 to >40 hours/week activities for physical activity. Participants also reported their usual walking pace (easy/casual, <2 mph; normal/average, 2–2.9 mph; brisk, 3–3.9 mph; very brisk/striding, ≥4 mph). If a participant reported walking 1 hour/week and the walking pace as brisk or very brisk, the participant was assigned 1 hour/week of brisk walking. We combined “brisk pace” and “very brisk pace” because only 3% of men and women reported a “very brisk pace.”

To quantify the intensity of physical activities, each specific activity was assigned a metabolic equivalent task (MET) score based on a compendium of physical activities (21). We calculated the MET-hours/week for each activity by multiplying the MET score assigned for that activity by the average number of hours per week reported by the participants. Total physical activity was defined as the sum of specific MET-hour/week for each reported activity. The vigorous-intensity activity was restricted to activities with a MET score of 6 or greater, including jogging, running, bicycling, swimming, tennis, squash/racquetball, outdoor work (only for NHS), and calisthenics and other aerobic exercises. Moderate-intensity activities (3 ≤ MET score < 6) included brisk walking, lower-intensity exercise (e.g., yoga, stretching, and toning), weight training, and outdoor work (only for HPFS). Consistent with the previous study (22), brisk walking required an energy expenditure of over 4 MET and was defined as the moderate-intensity activity.

The reproducibility and validity of the physical activity data were comprehensively evaluated in these cohorts (23, 24). Briefly, the correlation between activities reported on the questionnaire and those recorded in four 1-week diaries was 0.62 in the NHS and 0.58 in the HPFS, and the correlation was 0.79 in the NHS and 0.53 in the HPFS for physical activity reported on the questionnaire and those recalled after 1 week (23, 24).

Covariates in this study were selected on the basis of their putative associations with physical activity and HCC in previous studies (25–31). Biennial follow-up questionnaire updated information on age, body weight, type 2 diabetes mellitus (T2D), smoking status, and aspirin use. Age was calculated from birth date to questionnaire return date. The race was first assessed in 1992 and 1986 in the NHS and HPFS, respectively. Participants reported height at enrollment in each cohort. We calculated body mass index (BMI; kg/m²) in each cycle using self-reported height and weight. We also collected and derived dietary factors every 4 years using semiquantitative food frequency questionnaires (FFQ) in each cohort (32, 33), including total calorie intake (kcal/day), coffee consumption (cup/day), alcohol consumption (g/day), and Alternate Healthy Eating Index-2010 (AHEI-2010) score (as an overall measure of diet quality; ref. 34).

We identified HCC cases through follow-up questionnaires in both cohorts. Participants, who reported a new diagnosis from the biennial questionnaires, were asked for permission to access medical records to confirm the diagnosis. Considering potential unreported cancers, we further searched State Cancer Registries and the National Death Index (35). For all deaths attributable to liver cancer, we requested permission from next-of-kin to review medical records. Blinded to exposure status, study physicians further confirmed and extracted all possible information on HCC cases, including the histological types of cancer (e.g., HCC vs. intrahepatic cholangiocarcinoma), the presence of viral hepatitis (e.g., HBV/HCV infections), the presence of underlying cirrhosis. Additional data on HBV/HCV infection status were available from a nested case–control study of HCC in the NHS/HPFS, which were derived from laboratory blood tests (36).

In this analysis, we used 1986 as the baseline for NHS and HPFS when detailed physical activity information was first available. Participants were excluded if they had a history of cancer (except for nonmelanoma skin cancer) or had missing data on physical activity at baseline, leaving 122,075 participants (77,535 women and 44,540 men) in the final analyses. The person-time of follow-up was calculated from the date of return of the baseline questionnaires to the dates of HCC diagnosis, death, or the end of follow-up (June 1, 2012, in the NHS and January 31, 2012, in the HPFS), whichever came first. Cox proportional hazard model was used to estimate age-adjusted and multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the association of total physical activity as well as moderate- and vigorous-intensity activity with risk of HCC, stratified by age (months) and study period (2-year interval). We stopped updating physical activity when an individual reported unable to walk. To better represent the long-term physical activity level and minimize within-person variations, we calculated the cumulative average of the amount of energy expenditure (MET-hours/week) and hours per week. For example, for HCC incidence from 1988 to 1990, we calculated the average amount and duration of physical activity per week from 1986 to 1988. Similarly, for HCC cases that occurred between 1990 and 1992, we calculated the average amount and duration of physical activity from 1986 until 1990. No violation of the proportional hazard assumption was found after testing an interaction term between total physical activity and follow-up time (P = 0.68). To maximize the statistical power, we combined NHS and HPFS to examine the association between total physical activity and HCC risk because of no significant heterogeneity by cohort (P_{heterogeneity} = 0.79). We categorized the energy expenditure of total physical activity as well as moderate- and vigorous-intensity activity into tertile categories based on the distribution of each cohort. For moderate- and vigorous-intensity activity, we also used the hours' cutoffs recommended by the American Cancer Society (e.g., 0, 0.1–2.4, and ≥2.5 hours/week for moderate-intensity activity; 0, 0.1–1.24, and ≥1.25 hours/week for vigorous-intensity activity; ref. 6).

In the multivariable models, we adjusted for race (white, nonwhite), aspirin use (yes, no), smoking status (never, past, current), total calorie intake (kcal/day, tertiles), alcohol intake (g/day, tertiles), coffee consumption (never or 1, 2–3, 4+ cups/day), and AHEI-2010 (tertiles). Covariates were updated prospectively over each interval of follow-up. We used cumulative average updated variables for diet and alcohol consumption, to better reflect the long-term pattern and to minimize measurement error. Because physical activity reduces the risk of obesity and T2D, which may be in the causal pathway between physical activity and HCC risk, we additionally adjusted for BMI and T2D in separate models. The trend tests were performed using a median of each category as a continuous variable.

To examine the association between brisk walking and HCC risk, we categorized brisk walking hours per week into three categories (none, ≤1 hour/week, and >1 hour/week) based on the data distribution in this study. These categories roughly correspond to the tertile categories in each cohort. We also assessed this association among participants who did not perform vigorous-intensity activity regularly (e.g., <1 hour/week; ref. 37). Furthermore, we conducted exploratory stratified analyses a priori to assess whether the association between brisk walking and HCC risk varied across levels of major risk factors, including age, BMI, T2D, smoking status, aspirin use, and alcohol consumption. We tested the significance of interaction using the log-likelihood ratio test. We also conducted several sensitivity analyses. We performed sensitivity analyses with a 2-, 4-, and 6-year lag to address potential concerns that liver diseases or cancer symptoms may limit the ability to exercise. For example, in a 2-year lag analysis, the cumulative average of brisk walking reported in 1986 and 1988 would be used for the 1990 to 1992 follow-up period. Second, we performed analyses after excluding HCC cases with known HBV/HCV infections. Third, the association of total physical activity with HCC was assessed separately by a history of preexisting cirrhosis status (cirrhotic vs. noncirrhotic HCC). In addition, among participants with viral infection data, Spearman correlation analysis was conducted between brisk walking and HBV/HCV status. All analyses were performed in SAS version 9.4 (SAS Institute), and a P value less than 0.05 was considered to be statistically significant.

After an average 23-year follow-up, we documented a total of 138 HCC cases (65 women and 73 men). Participants who reported more physical activity were more likely to be leaner and aspirin users, drink more alcohol, and have a higher AHEI-2010 score, but were less likely to be current smokers and have a history of T2D (Table 1). Similar patterns were observed in each cohort (Supplementary Table S1).

Although total physical activity was not associated with HCC risk, we observed a significant association with HCC risk for moderate-intensity activity (Table 2; top vs. bottom tertile, HR = 0.60; 95% CI, 0.38–0.94; P_trend = 0.04). This inverse association was attenuated after adjusting for BMI and T2D (HR = 0.70; 95% CI, 0.44–1.12; P_trend = 0.13). There was a nonsignificant inverse association between vigorous-intensity activity and HCC risk (HR = 0.88; 95% CI, 0.56–1.37; P_trend = 0.74). The results did not materially change when using the cutoffs of moderate- and vigorous-intensity activity hours per week (Supplementary Table S2).

More time spent on brisk walking was associated with a decreased risk of HCC (Table 3). Comparing participants who spent over 1 hour/week of brisk walking with non-brisk walkers, the multivariable HR was 0.50 (95% CI, 0.31–0.78; P_trend = 0.006) in the pooled analysis. This inverse association was attenuated after adjusting for BMI and T2D but remained significant (>1 hour/week vs. no brisk walking, HR = 0.56; 95% CI, 0.35–0.90; P_trend = 0.02). For the same comparison, the multivariable-adjusted HR for HCC associated with brisk walking among participants who did not perform vigorous exercise regularly (<1 hour/week) was 0.55 (95% CI, 0.30–1.01; P_trend = 0.06; Supplementary Table S3).

In stratified analyses, although the inverse association between brisk walking and HCC risk was present across all prespecified groups, including age, BMI, T2D, smoking status, alcohol consumption, and aspirin use (Table 4), a stronger inverse association observed for individuals aged less than 65 years (HR = 0.20; 95% CI, 0.04–0.93; P_trend = 0.03), normal-weight participants (BMI < 28 kg/m²; HR = 0.52; 95% CI, 0.30–0.90; P_trend = 0.03), or nondiabetics (HR = 0.57; 95% CI, 0.34–0.94; P_trend = 0.04). When the analysis was repeated with a 2-, 4-, and 6-year lag, results for brisk walking were essentially the same (Supplementary Table S4). The inverse association between brisk walking and risk of HCC did not materially change after excluding the known HCC cases (n = 22) with HBV/HCV infection (HR = 0.45; 95% CI, 0.27–0.75; P_trend = 0.003; Supplementary Table S5). When examining HCC according to the history of cirrhosis, the HRs were 0.84 (95% CI, 0.41–1.73; P_trend = 0.49) for noncirrhotic HCC (n = 49), and 0.28 (95% CI, 0.09–0.83; P_trend = 0.05) for cirrhotic HCC (n = 32; P_{heterogeneity} = 0.12). The Spearman correlation coefficient between brisk walking and HBV/HCV infection status was −0.13.

In these two large prospective cohorts of U.S. men and women, a higher amount of total physical activity appeared not strongly associated with a reduced risk of HCC, although there was a significant inverse association with moderate-intensity activity. Engaging in brisk walking over 1 hour/week was associated with HCC risk reduction by half. This study suggests that brisk walking might offer an accessible and effective way for HCC primary prevention.

Our findings suggest that brisk walking might protect against incident HCC. The possible protective effect of brisk walking on HCC was not well documented, although previous evidence suggested that higher intensity and duration of exercise may be needed (13–17, 38–40). To the best of our knowledge, only two studies have assessed the risk of liver cancer mortality associated with daily walking (19, 20). One study, conducted among 69,752 participants with 267 participants who died of liver cancer from the Japan Collaborative Cohort (JACC) Study, reported a significant inverse association for walking more than 30 minutes per day (HR: 0.77; 95% CI, 0.59–0.99) (19). Similarly, results from the same cohort suggested that those who reported less than 1 hour a week of walking had an increased risk of death from liver cancer (20). Of note, the JACC study lacked updated walking intensity and duration data and did not account for additional relevant physical activities. Our findings extend this evidence by utilizing prospectively updated physical activity assessments over 3 decades and more detailed data with intensity and duration, showing brisk walking was associated with a lower risk of HCC. However, given the limited case numbers, the results in this study may be due to chance. Alternatively, it is plausible that a higher amount of physical activity influences HCC risk by exerting an effect on glucose, glycogen, and lipid metabolism in the liver and might reduce the risk of or reverse NAFLD (41, 42), a risk factor for liver cancer. Brisk walking (at least 3 mph) represents moderate exercise, while causal/normal walking corresponds to low-intensity activity. Higher intensity leads to greater energy expenditure and different physiologic effects. Therefore, our findings lend some support to current recommendations for moderate exercise, but more studies are needed to confirm our results and determine the optimal hours of brisk walking for HCC prevention.

Existing evidence from prospective cohort studies supports a protective role for vigorous-intensity activity on HCC risk. However, our findings did not support a strong association between vigorous-intensity physical activity and HCC risk. The current results are consistent with one recent pooled analysis of nine prospective cohorts, showing that associations for HCC were of no statistical significance for vigorous-intensity activity (43). Of note, the domains of vigorous-intensity activity in our cohorts are somewhat different from others, which may contribute to the nonsignificant results for vigorous-intensity activity. In the current study, vigorous-intensity activities consist of leisure-time physical activities, except for outdoor work among women. However, outdoor work for women generally contributed to <2% of total physical activity. In contrast, vigorous activity in the European Prospective Investigation into Cancer and Nutrition cohort (EPIC) study included household and recreational activity (13). In another cohort study conducted in Japan, vigorous activity was defined as “heavy physical work or strenuous exercise” (16). Similarly, the vigorous-intensity exercise in the NIH and the American Association of Retired Persons (NIH-AARP) study included exercise and physical work (38). Evidence demonstrated that the magnitude of risk reduction for health outcomes varies from domain-specific physical activity (44). Thus, our study might have underestimated the total amount of vigorous-intensity activity and its potentially beneficial effect on HCC prevention. However, given that leisure-time exercise is a modifiable proportion of daily activity, more studies are required to assess whether the leisure-time vigorous-intensity activity is associated with a lower risk of HCC.

This study has multiple strengths, including the prospective study design, repeated assessments of physical activity and other covariates, and validated HCC outcome. Our study also has several limitations. First, although we included two large cohorts with decades of follow-up, the number of incident HCC cases is relatively limited due to the rareness of the disease in the United States. The limited number of HCC cases did not allow us to examine higher levels of brisk walking by using additional cut points (e.g., ≥2.5 hours/week). Physical activity in this study was self-reported and subject to some degrees of misclassifications, as with any observational study. However, questionnaires used in these cohorts have shown reasonable reproducibility and validity (23, 24). Third, we did not have data on chronic HBV/HCV infection status in all participants. However, among a subset of participants in which such data are available, physical activity was not correlated with HBV/HCV infection status. Moreover, results were similar when we excluded HCC cases with known chronic HBV/HCV infections. Thus, our results were less likely to be substantially confounded by HBV/HCV infection status. Finally, our cohorts consist mostly of Caucasians of European origin living in the United States, which may limit the generalizability of our results to other racial/ethnic populations or geographic regions.

In conclusion, this study suggests that moderate-intensity activity (e.g., brisk walking) was associated with a reduced risk of HCC. Brisk walking might be a valuable alternative for individuals who have difficulty adhering to vigorous activity regularly. More research is warranted to confirm our findings and to elucidate the underlying mechanisms. If our findings are confirmed, walking activity, a widely accepted approach for physical activity, can be incorporated into daily life for HCC primary prevention.

No potential conflicts of interest were disclosed.

Conception and design: X. Luo, E.L. Giovannucci, X. Zhang

Development of methodology: X. Zhang

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): X. Luo, A.T. Chan, E.L. Giovannucci, X. Zhang

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): X. Luo, J.A. Meyerhardt, A.T. Chan, X. Zhang

Writing, review, and/or revision of the manuscript: X. Luo, W. Yang, Y. Ma, T.G. Simon, J.A. Meyerhardt, A.T. Chan, E.L. Giovannucci, X. Zhang

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): X. Luo, X. Zhang

Study supervision: A.T. Chan, X. Zhang

The HPFS and NHS were supported by the NCI at the NIH (grant nos. UM1 CA186107, P50 CA127003, P01 CA87969, and U01 CA167552). This work was supported by NIH grants (R01 CA137178 to A.T. Chan, K24 DK098311 to A.T. Chan, K07 CA188126 to X. Zhang, and R21 CA238651 to X. Zhang). A.T. Chan is a Stuart and Suzanne Steele MGH Research Scholar. X. Zhang is also supported by the American Cancer Society Research Scholar Grant (RSG NEC-130476), Dana-Farber Harvard Cancer Center (DF/HCC) GI SPORE Developmental Research Project Award (P50CA127003), and DF/HCC Cancer Center Support Grant (CCSG, 5P30CA006516-55). The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. We would like to thank the participants and staff of the NHS and the HPFS for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data.

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