1 R1
Exploring the effect of a lifestyle intervention on cancer risk: 43-year follow-up of the randomized Oslo diet and antismoking study
Running headline: Lifestyle intervention and cancer
Authors: Edoardo Botteri1,2, Thomas de Lange1,3,4, Serena Tonstad5,6, Paula Berstad1
Affiliations:
1Department of Bowel cancer screening, Cancer Registry of Norway, Oslo, Norway
2Norwegian National Advisory Unit for Women's Health, Women’s Clinic, Oslo University Hospital, Oslo, Norway
3Unit for Research, Innovation and Education, Oslo University Hospital, Oslo, Norway
4Institute of Clinical Medicine, University of Oslo, Oslo, Norway
5Department of Preventive Cardiology, Oslo University Hospital, Oslo, Norway
6School of Public Health, Loma Linda University, Loma Linda, CA, USA
2 Abstract
Background/objectives. The Oslo diet and antismoking study showed that counselling for a healthy lifestyle reduced lifelong coronary mortality in high-risk men. We explored whether the same counselling reduced also cancer risk.
Methods. The study randomly allocated males at high coronary risk to either a 5-year intervention for lifestyle changes (cholesterol-lowering dietary changes, weight loss and stopping smoking) or a control group (1:1) in 1972/73. We explored the incidence and mortality of all cancers and cancer forms related to smoking, BMI or diet up to 43 years after randomization.
Results. 595 men in the intervention and 621 in the control group were included. At inclusion median age was 45 years, 588 (48.4%) subjects were overweight (BMI>25 kg/m2) and 925 (76.1%) current smokers.
The intervention did not reduce the risk of cancer after 43 years (adjusted hazard ratio (HR) 0.96, 95%
confidence interval (CI) 0.80-1.15). In the first 25 years of follow-up, among the 1,088 (89.5%) men who were overweight/obese and/or smokers, the intervention reduced the incidence of those cancer forms related to smoking, BMI or diet (including carcinoma of the respiratory, digestive and urinary tracts;
adjusted HR 0.69; 95% CI 0.49-0.99). The intervention had no significant effect on incidence beyond 25 years, or on mortality.
Conclusions. The five-year counselling for a healthy lifestyle did not reduce the overall cancer risk in the very long term. However, in the first 25 years, the counselling reduced the risk of relevant cancer types in overweight/obese subjects and smokers.
Keywords: intervention, cancer, cancer mortality, prevention, diet, smoking
3 Introduction
Three of the most prevalent modifiable risk factors for cancer are tobacco, body fatness and diets low in fruit, vegetables, whole grain, nuts and seeds [1]. It is estimated that the total cancer risk is 24-28%
lower in individuals with the highest, compared to the lowest compliance to health guidelines [2]. The risk reduction is even larger for those cancer forms closely related to lifestyle factors, such as lung and colorectal cancer, two of the cancer types that take most lives [3]. Of the many intervention trials for cancer prevention in average-risk individuals, only the Women's Health Initiative (WHI) Dietary Modification Randomized Controlled Trial has succeeded in reducing incidence of some cancer types [4].
A few successful intervention trials showed some cancer risk reduction in high-risk populations, such as smoking cessation intervention in smokers [5] and dietary intervention in individuals with colorectal pre- cancer lesions [6] or patients with myocardial infarction [7]. The lack of effect of lifestyle intervention on cancer risk in the majority of randomized trials is probably due to low compliance and too short follow-up times. There is an urgent need of cancer prevention trials to define the most effective intervention strategies and to identify individuals most likely to benefit [8].
The Oslo diet and antismoking study was a randomized controlled trial (RCT) which recruited men in their 40’s at high risk of coronary heart disease (CHD) in 1972-73. It showed that a comprehensive dietary and smoking cessation intervention was effective in reducing cardiovascular events and mortality through 40 years [9, 10] The intervention was also associated with lower total mortality at 15 years of follow-up [10]. Compliance to dietary intervention was long-lasting; difference in dietary habits between the survivors of the two groups were visible 25 years later [11]. Since lifestyle risk factors for cardiovascular disease (CVD) and cancer overlap to a large degree, we aimed in this exploratory study to investigate whether this intervention had an effect on cancer incidence and mortality during the following 43 years.
4 Methods
Recruitment in the Oslo study
The study is described in more details by Hjermann et al [9]. Briefly, all men living in Oslo in 1972-1973 who were born in 1923-1932 were invited for screening of coronary risk factors. Of the men who participated (65% of the invited, n=16 203), those without self-reported CVD and diabetes were further invited to two baseline examinations for inclusion in the Oslo diet and antismoking study. Men in the upper quartile of a coronary risk score based on blood pressure, serum total cholesterol concentration and cigarette smoking were invited to participate in the intervention trial. Subjects with very high serum total cholesterol concentration (above 9.0 mmol/l) and a healthy diet, based on a short dietary history, were excluded. This trial randomized 1,232 men at high cardiovascular risk profile to a five-year intervention or control (1:1) in 1972-1973.[9] Fourteen men were excluded from the present analysis because they did not consent to studies other than the main study and two more because of previous history of cancer (Fig.
1). The South-East Norway Regional Ethics Committee approved the study (reference 2016/1442).
Intervention and follow-up
Participants were randomized to either lipid-lowering diet and antismoking counselling, or no intervention (control group) (1:1). The dietary counseling aimed to lower serum cholesterol levels, and thus included advice to reduce intake of saturated fat and cholesterol, and to increase intake of polyunsaturated fat, fish, vegetables and fruit. Weight reduction was recommended for overweight men, as well as reduced consumption of sugar rich foods and drinks, and alcoholic beverages. Smokers were advised to stop smoking. Men in the intervention group participated in individual counseling and follow-up examinations every six months, and also in group meetings addressing diet and smoking together with their wives. Men in the control group met for follow-up examinations every year for five years and did not receive any intervention. At the end of the 5-year intervention period, the same short dietary history as at start of the
5 trial was collected in a random sample of half the men in the intervention group. Large 5-year shift from saturated to polyunsaturated fat intake was observed within the intervention group. The dietary changes were reflected in the serum total cholesterol levels [9]. After 8.5 years from the inclusion in the study, all survivors were recalled to a follow-up examination. At this time point only, men in the control group were given advices about dietary change and smoking cessation as given to the men in the intervention group.
Merging with cancer data
In the present study, we merged data from the Cancer Registry of Norway and the Norwegian Cause of Death Registry to the data of the Oslo study. We collected data on cancer incidence and cancer deaths from the date of inclusion in 1972/73 to the end of 2015.
Endpoints
We analyzed four main primary endpoints: 1) incidence of cancer; 2) incidence of the group of cancers related to smoking, diet or BMI; 3) death from cancer; 4) death from the group of cancers related to smoking, diet or BMI. The group of cancers related to smoking, diet or BMI included, iIn accordance to the International Agency for Research on Cancer [12], the group of cancers related to smoking, diet or BMI included carcinomas of the oral cavity (codes C00 to C05, International Classification of Diseases for Oncology (ICD-O), third edition), oropharynx (C10), esophagus (C15), stomach (C16), colorectum (C18 to C20), liver and intrahepatic bile ducts (C22), pancreas (C25), larynx (C32), trachea, bronchus and lung (C33- C34), urinary tract (C64-C67) and thyroid gland (C73). Secondary endpoints were incidence and mortality of lung (C34), gastro-intestinal tract (GI) (C15 to C25), urinary tract (C64-C67) and prostate (C61) carcinoma.
Statistical methods
6 The Chi-square test, the Chi-square test for trend and the T-test were used to evaluate the differences in categorical, ordinal and continuous variables, respectively, between the intervention arm and the control arm. If a subject had several cancer diagnoses, only the first diagnosis was included in the analysis.
Cumulative incidences were calculated in a competing risk framework. For example, to calculate the cumulative incidence of the group of cancers related to smoking, diet or BMI, those cancers were
counted as events, while other cancers and deaths from any cause were treated as competing events. To estimate the effect of the intervention on the primary endpoints, univariate and multivariable Cox regression models were fitted, adjusting for age, marital status, body mass index (BMI), smoking status, and physical activity (both in free time and physical activity at work), all measured at baseline. Due to the limited number of events, only univariate Cox regression models were fitted for secondary endpoints.
Results were reported as hazard ratio (HR) and 95% confidence interval (CI). All analyses were carried out with the SAS software (SAS Institute, Cary, NC) and the R (http://cran.r-project.org/) software. All the reported P values were two-sided.
Results
We included 595 men in the intervention arm and 621 in the control arm (Fig. 1, Table 1). At randomization, mean age was 45.2 years; 588 (48.8%) subjects were overweight or obese, 925 (76.1%) were current smokers and 1,088 (89.5%) were overweight/obese and/or current smokers. Age, marital status, BMI (categorical), smoking status, and physical activity in free time and at work were similarly distributed between the two arms. BMI as a continuous variable was higher in the control arm compared to the intervention arm (0.4 kg/m2 mean difference).
Cancer incidence
7 The number of incident cancer cases and the effect of intervention on cancer incidence at different time points during the follow-up are shown in table 2. At 43 years of follow-up, we observed 235 cancers in the intervention arm and 247 in the control arm (cumulative incidence 40.2% and 40.0%, respectively;
adjusted HR 0.96, 95% CI 0.80 to 1.15). We observed 128 cancers related to smoking, diet or BMI in the intervention arm and 141 in the control arm (cumulative incidence 21.8% and 23.0%; adjusted HR 0.93, 95% CI 0.73 to 1.18). When we limited the analysis to the 1,088 men who were overweight/obese and/or current smokers at baseline, we observed 112 cancers related to smoking, diet or BMI in the intervention arm and 129 in the control arm (cumulative incidence 21.5% and 23.4%, respectively; adjusted HR 0.87, 95% CI 0.68 to 1.13).
Approximately 18 years after the randomization, the cancer incidence rate started to increase more in the control group than in the intervention group, but after 25 years the incidence A proportional development of risk took place approximately only between 18 and 25 years, and after 25 years the curves were parallel and eventually approached (Fig. 2a and 2b). Within 25 years from randomization we observed 58 cancers related to smoking, diet or BMI in the intervention arm and 81 in the control arm (cumulative incidence 9.8% and 13.0%, respectively; adjusted HR 0.73, 95% CI 0.52 to 1.03). Among men who were overweight/obese and/or smokers at baseline, we observed 51 cancers related to smoking, diet or BMI in the intervention arm and 76 in the control arm (cumulative incidence 9.7% and 13.6%, respectively; adjusted HR 0.69, 95% CI 0.49 to 0.99, Table 2, Fig. 2b). There was not statistically significant effect of the intervention on cancer risk after 25 years from randomization.
Among men who were overweight and/or current smokers at baseline, there was evidence showing that the intervention decreased the risk of GI cancers within 25 years from randomization (HR 0.55, 95% CI 0.30 to 0.99; supplementary table 1 and fig 3a), and cancer of the urinary tract (HR 0.36, 95%
CI 0.13 to 1.01; Supplementary Table 1 and Fig. 3b) while it showed no effect on the risk of lung cancer
8 (HR 1.05, 95% CI 0.60 to 1.83; Supplementary Table 1 and Fig. 3c); and prostate cancer (HR 1.04, 95% CI 0.69 to 1.57).
Cancer mortality
At 43 years of follow-up, we observed 161 cancer deaths in the intervention arm and 155 in the control arm (adjusted intervention vs control HR 1.09; 95% CI 0.87 to 1.36), 104 smoking, diet or BMI -related cancer deaths in the intervention arm and 106 in the control arm (HR 1.04; 95% CI 0.79 to 1.37). Among the 1,088 overweight men and/or current smokers at baseline, we observed 90 smoking, diet or BMI - related cancer deaths in the intervention arm and 96 in the control arm (HR 0.99; 95% CI 0.74 to 1.32).
The intervention showed some possible beneficial effect only on mortality from GI cancer: by the end of the study, we observed 27 deaths in the intervention arm and 40 in the control arm. HRs for intervention vs control at 30, 35 and 43 years of follow-up were, respectively, 0.59 (95% CI 0.34 to 1.03), 0.55 (95% CI 0.29 to 1.06) and 0.68 (95% CI 0.42 to 1.12).
Discussion
In this exploratory long-term follow-up study of men at high coronary risk, which has previously demonstrated a reduction in CVD risk, we found that a five-year dietary and anti-smoking counselling in overweight and/or smoking men reduced the incidence of some cancer forms related to smoking, diet or BMI. The effect was detectable within 25 years of follow-up, meaning that the intervention could prevent both CVD and cancer during the professionally active period of life. Increased odds for avoiding or postponing the occurrence of cancer to the years of retirement can be considered valuable both for the individual and the society. We found, however, no significant effect of the intervention on cancer mortality.
9 The Oslo diet and antismoking study successfully reached its original aim, i.e. to reduce cardiovascular events and mortality in men at high CVD risk [9, 10, 13]. The effect on these endpoints was parallel with the changes in serum total cholesterol [13]. Although the trial was not aimed to test the effect on cancer risk, it seems consistent that the dietary changes have reduced the risk of some cancer forms related to smoking, diet and BMI. We observed this effect only in men who were smokers, overweight or both, that is, those leading a lifestyle with a high cancer risk.
There is only modest evidence from earlier RCTs that lifestyle intervention in high-risk populations may be effective to reduce cancer risk. In the Lyon Diet Heart Study, a lower cancer incidence in myocardial infarction patients was observed four years after an intervention encouraging a cardioprotective Mediterranean diet [7]. In the Whitehall study, anti-smoking advice in smokers was followed by a lower lung cancer incidence during 20 years [5]. In the US Polyp Prevention Trial, the odds of colorectal adenoma recurrence in overweight individuals was reduced by a successful dietary long-term intervention during four years after randomization [6]. To our knowledge, the WHI Dietary Modification Trial is the only RCT in average-risk individuals reporting effect of dietary intervention on cancer incidence. In that trial, a low- fat dietary intervention was followed by a slight decrease in both total number of invasive cancers and ovarian cancer during 8.1 years of follow-up, and pancreatic cancer during 14.7 years of follow-up independently [4, 14]. However, the WHI trial found no effect on the most common GI cancers such as colorectal cancer (CRC) during 8.1 years of follow-up [4, 15]. It seems that the follow-up periods in most studies are too short when considering that the effect in our study was visible not earlier than 18 years after the start. A recent meta-analysis, which summarized the effect of weight-reduction interventions by low-fat and low saturated fat diets in obese individuals on cancer incidence and mortality, did not report a statistically significant effect on any of these, although there was a trend towards a reduced cancer mortality [16].
10 In our study, when we looked at specific cancer sites, we observed a beneficial effect from the intervention on the risk of GI and urinary tract cancer, but not lung cancer in the long-term follow-up. The lack of effect on lung cancer incidence may be explained by the short-term effect of the intervention on smoking cessation. Although a large proportion of participants in the intervention group stopped smoking temporarily, tobacco consumption was similar in the intervention and the control groups 7.5 years after the start of the trial [13]. In addition, during the follow-up period, there have been various political efforts to reduce tobacco consumption in Norway through state policy, and tobacco consumption has been strongly reduced among men of all ages [17, 18]. Lung cancer is the only type of cancer with smoking as the major risk factor, while the risk of GI and urinary tract cancers are also affected by diet and BMI [19, 20]. We can assume that the intervention was effective to reduce the risk of those cancers because of the combined effort targeting smoking, diet and BMI. Epidemiological studies suggest that a combination of several favourable lifestyle behaviours is more powerful in cancer prevention than single factors alone [21- 23]. There is no evidence that dietary fat is associated with cancer risk [24]. We do therefore not assume that the effect of the intervention on GI cancer risk was mediated through the long-term reduction of total or saturated dietary fat which was observable 20 years after the intervention in the survivors [11]. The effect might rather have been mediated through other potential dietary changes as a consequence of higher attention to healthy lifestyle [11]. As both dietary and smoking habits have changed in the general population since the time of inclusion in the 1970’s, the present results challenge future researchers to explore intervention strategies suitable for today’s individuals at high risk for cancer.
This study did not find an effect of the intervention on the total cancer mortality, in accordance to the above mentioned trials. We only observed some evidence of a lower GI cancer mortality in the intervention group compared to the control group, which seems to be in accordance to the results on GI cancer incidence. This lack of effect could be due to the non-differential misclassification of the causes of death, which might have biased the association towards the nullhidden a possible true association
11 between the intervention and cancer death. In addition, the relatively high mortality on CVD may explain the lack of effect on cancer mortality. The intervention group had a lower CVD death risk compared to the controls, and therefore a higher probability to die from other causes (e.g. cancer). Another explanation could be that the intervention could not prevent those forms of cancers which are more common and more life-threatening, such as lung cancer. In fact, in our series, approximately one third (data not shown) of the cancer deaths were caused by lung cancer.
The success of the dietary intervention and the long-term follow-up are strengths of this study.
The included individuals had rather poor baseline diet, therefore the dietary improvements were large and clear, as shown in a sub-sample of the intervention group [9]. The main limitation of this study is that the information of the individual 5-year or longer dietary and smoking changes of the participants were not available for the present data merging. Thus, we were unable to analyze the association between the dietary factors or stopping smoking, and cancer outcomes. We had either no individual information of the compliance to the intervention. However, the serum total cholesterol levels and body weight during the 7.5 first years of follow-up [13] and the attitudes towards diet and health at 25 years of follow-up in the survivors [11] indicate long-lasting dietary differences between the intervention and the control group.
Since the study was not designed to detect differences in cancer outcomes, lack of power is potentially a major limitation, especially in subgroup analyses. In our exploratory study subgroup analyses were not pre-specified, but we considered reasonable to explore the risk of lifestyle-related cancers in a high-risk population based on BMI and smoking. Trials with a larger sample size are needed to assess the effect on the risk of specific cancer types, as lifestyle impacts only the risk of certain forms of cancer and not cancer as one disease [24]. Finally, as only males were included in this study, the results cannot be generalized to the total population.
12 Conclusion
The long-term follow-up of the randomized Oslo diet and antismoking study showed that a dietary and antismoking intervention in middle-aged men at high cardiovascular risk can reduce their risk of CVD events as well as the risk of some types of cancers during 25 years.
Conflict of interest statement
The authors have no competing interests to declare.
Acknowledgements
We thank the Norwegian Institute of Public Health for the data on Oslo diet and antismoking study participants.
13 References
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Corresponding author:
Paula Berstad
Cancer Registry of Norway P.O. Box 5313, Majorstuen 0304 Oslo, Norway Phone +47 22928735
E-mail [email protected]
Alternative proof reader among the co-authors:
Edoardo Botteri
E-mail edoardo [email protected]
15 Figure legends
Figure 1. Participant flow diagram Footnote:
CVD; cardiovascular disease
*Assumed, based on previous publications.9-11, 13
Figure 2. Incidence of smoking/diet/BMI-related cancers in all men (a), and high-risk men (limited to men who were current smokers and/or overweight at randomization) (b)
Footnote:
HR: hazard ratio, adjusted for age, civil marital status, body mass index, smoking status, physical activity in free time, and physical activity at work measured at baseline; CI: confidence interval. The group of cancers related to smoking, diet or BMI included carcinomas of the oral cavity, oropharynx, esophagus, stomach, colorectum, liver and intrahepatic bile ducts, pancreas, larynx, trachea, bronchus and lung, urinary tract and thyroid gland.
Figure 3. Incidence of cancers in the gastro-intestinal tract (a), urinary tract (b) and lung (c) in high-risk men
Footnote:
HR: hazard ratio. CI: confidence interval
Analysis limited to men who were current smokers and/or overweight at randomization.
16 Table 1. Characteristics of men at baseline in 1972–1973
Variable Intervention
No. 595
Control
No. 621 P-value
Age 0.827a
40-45 300 (50.4) 317 (51.1)
46-50 295 (49.6) 304 (48.9)
Mean (SD) 45.2 (3.0) 45.2 (2.9) 0.944b
Civil Marital status 0.136a
Single 45 (7.6) 44 (7.1)
Married 529 (88.9) 540 (87.0)
Widow/Separated 21 (3.5) 37 (6.0)
Body mass index 0.116c
< 25 315 (53.3) 303 (49.3)
25-29.9 256 (43.3) 284 (46.2)
≥ 30 20 (3.4) 28 (4.6)
Mean (SD) 24.9 (2.7) 25.3 (2.7) 0.023b
Smoking status 0.665b
Never 54 (9.1) 48 (7.7)
Former 89 (15.0) 100 (16.1)
Current 452 (76.0) 473 (76.2)
Physical activity in free time 0.952c
Sedentary 136 (22.9) 142 (22.9)
Light 361 (60.7) 378 (60.9)
Moderate/Heavy 98 (16.5) 101 (16.3)
Physical activity at work 0.736c
Sedentary 274 (46.0) 285 (45.9)
Walking 179 (30.1) 179 (28.8)
Lifting/Heavy work 142 (23.9) 157 (25.3)
a Chi-square test.
b T-test.
c Chi-square test for trend.
17 Table 2. The effect of intervention on cancer incidence at different time points
Length of follow-up 20 years 25 years 30 years 35 years 43 years
All men
Intervention arm n=595; Control arm n=621 All cancers
Events (cumulative incidence)
intervention:control 56 (9.4):68 (11.0) 107 (18.1):132
(21.3) 147 (24.7):161(25.9) 187 (31.6):200
(32.3) 235 (40.0):247 (40.2) HR (95% CI) a 0.83 (0.58-1.19) 0.81 (0.63-1.05) 0.92 (0.73-1.15) 0.95 (0.78-1.16) 0.96 (0.81-1.15) HR (95% CI) b 0.84 (0.59-1.20) 0.82 (0.64-1.06) 0.93 (0.74-1.16) 0.96 (0.79-1.18) 0.96 (0.80-1.15) Smoking/diet/BMI-related cancers c
Events (cumulative incidence)
intervention:control 36 (6.1):41 (6.6) 58 (9.8):81 (13.0) 82 (13.8):94 (15.1) 99 (16.7):117 (18.9) 128 (21.8):141 (23.0) HR (95% CI) a 0.89 (0.57-1.39) 0.72 (0.51-1.01) 0.88 (0.65-1.18) 0.86 (0.66-1.12) 0.92 (0.72-1.16) HR (95% CI) b 0.91 (0.58-1.42) 0.73 (0.52-1.03) 0.89 (0.66-1.20) 0.87 (0.67-1.14) 0.93 (0.73-1.18) High-risk men d
Intervention arm n=530; Control arm n=558 All cancers
Events (cumulative incidence)
intervention:control 52 (10.0):64 (11.4) 95 (18.0):124 (22.2) 128 (24.3):149 (26.7) 163 (31.0):184
(33.0) 205 (39.2):220 (39.7) HR (95% CI) a 0.83 (0.57-1.20) 0.77 (0.59-1.00) 0.86 (0.68-1.09) 0.89 (0.72-1.10) 0.92 (0.76-1-12) HR (95% CI) b 0.84 (0.58-1.21) 0.78 (0.60-1.02) 0.88 (0.69-1.11) 0.91 (0.73-1.12) 0.93 (0.77-1-13) Smoking/diet/BMI-related cancers c
Events (cumulative incidence)
intervention:control 33 (6.2):39 (7.0) 51 (9.7):76 (13.6) 70 (13.2):87 (15.6) 85 (16.1):108 (19.4) 112 (21.5):129 (23.4) HR (95% CI) a 0.86 (0.54-1.37) 0.67 (0.47-0.96) 0.81 (0.59-1.10) 0.79 (0.60-1.05) 0.86 (0.67-1.11) HR (95% CI) b 0.88 (0.55-1.41) 0.69 (0.49-0.99) 0.83 (0.61-1.14) 0.81 (0.61-1.08) 0.87 (0.68-1.13)
BMI: body mass index. HR: hazard ratio. CI: confidence interval.
a Univariate analysis.
18
b Multivariable analysis; adjusted for age, marital status, smoking status, BMI, physical activity in free time and physical activity at work at randomization.
c Carcinomas of the oral cavity, oropharynx, esophagus, stomach, colorectum, liver and intrahepatic bile ducts, pancreas, larynx, trachea, bronchus and lung, urinary tract and thyroid gland.
d Current smokers and/or overweight subjects at randomization.
19 Figures
Figure 1.
20 Figure 2.
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