Introduction
Bladder cancer is the sixth leading cancer in the USA, with an estimated 81,190 new cases and 17,240 deaths in 2018. Over 75% of all patients are still alive after 5 years [
1]. Moreover, bladder cancer has high recurrence and is the most expensive malignancy to treat, accounting for > 3% of all cancer-related medical payments in the USA [
2]. At present the better established risk factors associated with developing bladder cancer include smoking, age, male sex, occupation, and to a lesser extent obesity and physical inactivity [
3‐
5]. Since most of the metabolites of ingested food come into direct contact with the bladder mucosa, diet might also play a role in the development of bladder cancer [
6].
Previous studies of diet-related bladder cancer risk factors have tended to focus on single food items [
7,
8]. For example, the Multiethnic Cohort (MEC) study, which included a total of 185,885 participants and 1137 incident bladder cancer cases, reported a hazard ratio (HR) of 0.40 (95% CI 0.23–0.69) comparing highest and lowest quartiles of vegetable intake [
9]. Also, the Los Angeles Bladder Cancer (case–control) Study involving 3246 participants, including 1660 cases, reported a positive association between intake of red meat (salami, pastrami and beef) and bladder cancer risk (comparing highest and lowest quintile: OR 1.33, 95% CI 1.02–1.74) [
10]. Emerging evidence suggests that total dietary patterns may provide stronger evidence for diet–disease associations than individual dietary items [
11].
The Mediterranean diet has been reported to be effective for preventing non-communicable diseases [
12‐
15] and reducing overall mortality and the incidence of several cancers [
16,
17]. It is generally characterized by a high consumption of fruits, vegetables, legumes and cereals, moderate-to-high consumption of fish, moderate consumption of alcohol (mostly wine), low-to-moderate consumption of milk and dairy products, and low consumption of meat and meat products [
18]. The diet distinguishes itself from other dietary recommendations and indices such as the Healthy Eating Index [
19], the World Cancer Research Fund and American Institute for Cancer Research (WCRF/AICR) diet recommendations [
20] and the Diet Inflammatory Index [
21], by its higher levels of dietary fat, mainly monounsaturated fat from olive oil, and higher alcohol consumption, mainly from wine, although alcohol is a risk factor for several cancers [
22‐
26].
To date, few studies [
27,
28] have investigated the association between Mediterranean diet and bladder cancer. The European Prospective Investigation into Cancer and Nutrition (EPIC) cohort study, including 477,312 participants (of which 1425 were incident cases), found an inverse but non-significant association comparing a high with a low Mediterranean diet score (MDS) and urothelial cell carcinoma (UCC) overall (HR 0.84 [95% CI 0.69, 1.03]), and for risk of aggressive (HR 0.88 [95% CI 0.61, 1.28]) and non-aggressive disease (HR 0.78 [95% CI 0.54, 1.14]). The association was statistically significant for current smokers (HR 0.66 [95% CI 0.47, 0.93]) [
27]. Researchers from the Melbourne Collaborative Cohort Study (MCCS), which included 37,442 participants at time of recruitment (379 incident cases), reported an inverse association for both sexes between the MDS and invasive UCC (HR 0.86 [95% CI 0.74, 1.00]) [
28].
Our primary aim was to build on the results of the EPIC cohort study and the MCCS, and to investigate prospectively the potential association between Mediterranean diet and the risk of developing bladder cancer, by aggregating data from 13 cohort studies in a pooled analysis using a meta-analysis approach. Our secondary aims were to examine heterogeneity in any association by sex and disease sub-type (non-muscle-invasive and muscle-invasive bladder cancer).
Results
Dietary data from 646,222 study participants, including 3639 incident cases and 642,583 non-cases were analysed. Disease sub-type was known for 2425 cases, of which 945 (39%) were muscle-invasive bladder cancer (MIBC) and 1480 (61%) were non-muscle-invasive bladder cancer (NMIBC). Compared with non-cases, bladder cancer cases were more likely to be male (74%) and to be current or former smokers (79%). Of all cases, 22% originated from Scandinavian countries, 12% from Mediterranean regions, and 42% from other countries in Western Europe. The remaining 24% of the cases were living in the USA (10%) or Australia (14%); the Australian study (MCCS) oversampled people born in Greece or Italy [
42,
43] (Table
1).
Table 1
Characteristics of the 13 eligible studies according to subject status, sex, age, TNM stage, and smoking status
Subject status |
Total | 56,005 | 100 | 64,866 | 100 | 49,457 | 100 | 25,268 | 100 | 45,204 | 100 | 37,102 | 100 | 33,856 | 100 |
Cases | 411 | < 1 | 31 | < 1 | 218 | < 1 | 50 | < 1 | 192 | < 1 | 119 | < 1 | 24 | < 1 |
Non-cases | 55,594 | > 99 | 64,835 | > 99 | 49,239 | > 99 | 25,218 | > 99 | 45,012 | > 99 | 36,983 | > 99 | 33,832 | > 99 |
Sex |
Men | 26,764 | 48 | 0 | 0 | 21,551 | 44 | 10,438 | 41 | 14,084 | 31 | 9801 | 26 | 0 | 0 |
Women | 29,241 | 52 | 64,866 | 100 | 27,906 | 56 | 14,830 | 59 | 31,120 | 69 | 27,301 | 74 | 33,856 | 100 |
Age |
< 50 | 0 | 0 | 27,158 | 42 | 23,661 | 48 | 10,715 | 42 | 21,565 | 48 | 16,161 | 43 | 21,301 | 63 |
50–59 | 40,996 | 73 | 26,392 | 41 | 16,978 | 34 | 5542 | 22 | 17,791 | 39 | 14,720 | 40 | 12,555 | 37 |
60–69 | 15,009 | 27 | 11,286 | 17 | 8817 | 18 | 6455 | 26 | 5647 | 13 | 6217 | 17 | 0 | 0 |
≥ 70 | 0 | 0 | 30 | < 1 | 1 | < 1 | 2556 | 10 | 201 | < 1 | 4 | < 1 | 0 | 0 |
TNM stage |
Invasive | 44 | 24 | 5 | 12 | 40 | 26 | N/A | N/A | 20 | 20 | 23 | 20 | N/A | N/A |
Non-invasive | 138 | 76 | 22 | 78 | 114 | 74 | N/A | N/A | 104 | 80 | 93 | 80 | N/A | N/A |
Smoking status |
Never smoker | 19,624 | 35 | 45,797 | 71 | 22,658 | 46 | 14,060 | 56 | 20,540 | 45 | 14,171 | 38 | 12,057 | 36 |
Former smoker | 17,070 | 31 | 13,121 | 20 | 16,386 | 33 | 4232 | 17 | 12,096 | 27 | 11,572 | 31 | 10,438 | 31 |
Current smoker | 19,311 | 34 | 5948 | 9 | 10,413 | 21 | 6976 | 27 | 12,568 | 28 | 11,359 | 31 | 11,361 | 33 |
MDS |
0–3 | 12,595 | 22 | 30,882 | 48 | 19,758 | 40 | 6895 | 27 | 13,935 | 31 | 16,255 | 44 | 12,147 | 36 |
4–5 | 25,549 | 46 | 28,380 | 44 | 22,919 | 46 | 12,073 | 48 | 23,186 | 51 | 16,484 | 44 | 15,600 | 46 |
6–9 | 17,861 | 32 | 5604 | 8 | 6780 | 14 | 6300 | 25 | 8083 | 18 | 4363 | 12 | 6109 | 18 |
Subject status |
Total | 40,782 | 100 | 49,328 | 100 | 75,035 | 100 | 76,433 | 100 | 5,632 | 100 | 38,263 | 100 |
Cases | 154 | < 1 | 303 | < 1 | 250 | < 1 | 378 | < 1 | 940 | 17 | 520 | 1 |
Non-cases | 40,628 | > 99 | 49,025 | > 99 | 74,785 | > 99 | 76,055 | > 99 | 4692 | 83 | 37,743 | 99 |
Sex |
Men | 15,439 | 38 | 22,546 | 46 | 22,476 | 30 | 36,792 | 52 | 3052 | 54 | 15,798 | 41 |
Women | 25,343 | 62 | 26,782 | 54 | 52,559 | 70 | 40,089 | 48 | 2580 | 46 | 22,465 | 59 |
Age |
< 50 | 22,824 | 56 | 19,136 | 39 | 39,461 | 52 | 0 | 0 | 0 | 0 | 12,047 | 32 |
50–59 | 12,936 | 32 | 16,794 | 34 | 17,049 | 23 | 35,262 | 46 | 2058 | 37 | 12,560 | 33 |
60–69 | 5022 | 12 | 11,150 | 23 | 12,553 | 17 | 26,685 | 35 | 3534 | 63 | 13,108 | 34 |
≥ 70 | 0 | 0 | 2248 | 4 | 5972 | 8 | 14,934 | 19 | 40 | < 1 | 548 | 1 |
TNM stage |
Invasive | 7 | 14 | N/A | N/A | 6 | 86 | 121 | 35 | 443 | 52 | 232 | 45 |
Non-invasive | 50 | 86 | N/A | N/A | 1 | 14 | 229 | 65 | 409 | 48 | 288 | 55 |
Smoking status |
Never smoker | 22,599 | 55 | 24,205 | 49 | 41,948 | 56 | 36,478 | 47 | 1848 | 33 | 22,057 | 58 |
Former smoker | 7207 | 18 | 13,410 | 27 | 23,924 | 32 | 33,931 | 44 | 2018 | 36 | 11,848 | 31 |
Current smoker | 10,976 | 27 | 11,713 | 24 | 9163 | 12 | 6490 | 9 | 1766 | 31 | 4358 | 11 |
MDS |
0–3 | 20,067 | 49 | 13,466 | 27 | 24,162 | 32 | 29,434 | 39 | 2181 | 39 | 22,326 | 59 |
4–5 | 17,231 | 42 | 25,798 | 52 | 29,122 | 39 | 29,194 | 39 | 2409 | 43 | 10,411 | 27 |
6–9 | 3484 | 9 | 10,064 | 21 | 21,751 | 29 | 15,921 | 22 | 1042 | 18 | 5314 | 14 |
The overall HR estimates for bladder cancer associated with MDS, after adjustment for total energy intake, smoking status, and sex, are presented in Table
2. A total of 6,577,179 person years, including 3581 cases, were analysed. Overall, high adherence to the Mediterranean diet was associated with a decrease in bladder cancer risk compared with low adherence (HR
high 0.85 [95% CI 0.77, 0.93]). A decreased bladder cancer risk was also found for medium compared with low adherence to the Mediterranean diet (HR
medium 0.91 [95% CI 0.85, 0.99]). In addition, an inverse linear association was found between a one-unit increase in adherence to the Mediterranean diet and risk of developing bladder cancer (HR
continuous 0.96 [95% CI 0.94, 0.98]). Although the proportional hazards assumption was violated, the results were similar when considering only those younger than 70 years at entry in the study (HR
high 0.80, [95% CI 0.72, 0.89], HR
medium 0.90, [95% CI 0.83, 0.98]) separately from those older than 70 years at entry in the study (HR
high 0.86, [95% CI 0.57, 1.29], HR
medium 0.82, [95% CI 0.60, 1.14]), indicating that the presented HRs in Tables
2 and
3 were probably not heavily influenced by this violation. Furthermore, residual confounding by smoking seemed minimal as the results in never smokers (HR
high 0.84, [95% CI 0.68, 1.04], HR
medium 0.84, [95% CI 0.71, 0.99]) were similar to those in ever smokers (HR
high 0.80, [95% CI 0.71, 0.89], HR
medium 0.90, [95% CI 0.83, 0.98]).
Table 2
Pooled HR and 95% CI for the association between adherence to the Mediterranean diet and risk of developing bladder cancer for all bladder cancer, by sex, and by disease sub-type
All bladder cancerc |
Low (0–3) | 1483/2,460,613 | 1.00 | Reference | 1082/756,521 | 1.00 | Reference | 399/1,703,192 | 1.00 | Reference |
Medium (4–5) | 1479/2,868,685 | 0.91 | 0.85–0.99 | 1113/951,445 | 0.89 | 0.82–0.97 | 340/1,920,564 | 0.84 | 0.73–0.98 |
High (6–9) | 619/1,247,881 | 0.85 | 0.77–0.93 | 498/462,294 | 0.86 | 0.77–0.96 | 149/783,160 | 0.90 | 0.74–1.10 |
MDS continuous | 3581d/6,577,179 | 0.96 | 0.94–0.98 | 2693/2,170,260 | 0.95 | 0.93–0.98 | 888/4,406,918 | 0.96 | 0.92–1.00 |
Non-muscle-invasive |
Low (0–3) | 643/2,156,174 | 1.00 | Reference | 484/652,250 | 1.00 | Reference | 176/1,449,731 | 1.00 | Reference |
Medium (4–5) | 620/2,256,426 | 0.93 | 0.83–1.04 | 446/748,953 | 0.82 | 0.72–0.94 | 138/1,510,539 | 0.86 | 0.68–1.09 |
High (6–9) | 251/933,699 | 0.86 | 0.74–0.99 | 212/370,334 | 0.87 | 0.74–1.03 | 58/614,493 | 0.94 | 0.69–1.29 |
MDS continuous | 1514/5,346,298 | 0.96 | 0.94–0.99 | 1142/1,771,536 | 0.96 | 0.92–0.99 | 372/3,574,763 | 0.97 | 0.92–1.04 |
Muscle-invasive |
Low (0–3) | 408/1,291,420 | 1.00 | Reference | 326/475,555 | 1.00 | Reference | 87/796,549 | 1.00 | Reference |
Medium (4–5) | 355/1,427,419 | 0.88 | 0.76–1.02 | 279/570,121 | 0.80 | 0.68–0.95 | 73/850,470 | 0.99 | 0.70–1.38 |
High (6–9) | 167/625,505 | 0.89 | 0.74–1.07 | 132/290,429 | 0.85 | 0.69–1.05 | 33/316,218 | 1.05 | 0.68–1.60 |
MDS continuous | 930/3,344,345 | 0.94 | 0.90–0.97 | 737/1,336,106 | 0.94 | 0.90–0.98 | 193/2,008,238 | 0.95 | 0.88–1.04 |
Table 3
Pooled HR and 95% CI of the analyses exploring the effects of alcohol and fats on the MDS score
Low (0–3) | 1483 (2,460,613) | 1.00 | Reference | 1478 (2,177,423) | 1.00 | Reference | 1528 (2,705,709) | 1.00 | Reference | 1885 (3,335,869) | 1.00 | Reference |
Medium (4–5) | 1479 (2,868,685) | 0.91 | 0.85–0.99 | 1494 (2,918,929) | 0.91 | 0.84–0.98 | 1405 (2,838,719) | 0.93 | 0.86–1.00 | 1374 (2,618,681) | 0.92 | 0.85–0.99 |
High (6–9) | 619 (1,247,881) | 0.85 | 0.77–0.93 | 609 (1,480,826) | 0.82 | 0.74–0.90 | 396 (796,459) | 0.93 | 0.83–1.04 | 322 (622,627) | 0.88 | 0.78–0.99 |
MDS continuous | 3581 (6,577,179) | 0.96 | 0.94–0.98 | 3581 (6,577,178) | 0.95 | 0.93–0.97 | 3329 (6,340,889) | 0.98 | 0.95–1.00 | 3581 (6,577,178) | 0.95 | 0.93–0.97 |
Results remained consistently below 1.00 for non-muscle-invasive (HR
high 0.86 [95% CI 0.74, 0.99]) and muscle-invasive (HR
high 0.89 [95% CI 0.74, 1.07]) patients after stratification on disease sub-type (Table
2).
Results for men (HR
high 0.86 [95% CI 0.77–0.96], HR
medium 0.89 [95% CI 0.82, 0.97]) and women (HR
high 0.90 [95% CI 0.74–1.10], HR
medium 0.84 [95% CI 0.73, 0.98]) were comparable and in line with the overall estimates. Although total person-time was higher for women, the total number of cases was much higher for men (Table
2).When stratified on both disease sub-type and sex, HRs were consistently below 1.00, except for high compared with low adherence to the Mediterranean diet and risk of muscle-invasive disease for women (HR
high 1.05 [95% CI 0.68, 1.60]) (Table
2).
In the exploratory analysis, we obtained similar results after excluding either fats (HRhigh 0.88 [95% CI 0.78, 0.99], HRmedium 0.92 [95% CI 0.85, 0.99]) or alcohol (HRhigh 0.93 [95% CI 0.83, 1.04], HRmedium 0.93 [95% CI 0.86, 1.00]) from the diet score. Also, consistent results were found in the relation between adherence to the Mediterranean diet and bladder cancer risk when we replaced the lipid ratio (fats from plant sources divided by total fats) with olive oil intake only (HRhigh 0.82 [95% CI 0.74, 0.90], HRmedium 0.91 [95% CI 0.84, 0.98]).