World Journal of Urology https://doi.org/10.1007/s00345-018-2240-8
ORIGINAL ARTICLE
Obesity paradox in prostate cancer: increased body mass index was associated with decreased risk of metastases after surgery in 13,667 patients Jonas Schiffmann1 · Pierre I. Karakiewicz2,3 · Michael Rink4 · L. Manka1 · Georg Salomon5 · Derya Tilki4,5 · Lars Budäus5 · Raisa Pompe2,5 · Sami‑Ramzi Leyh‑Bannurah4 · Alexander Haese5 · P. Hammerer1 · Hartwig Huland5 · Markus Graefen5 · Pierre Tennstedt5 Received: 12 November 2017 / Accepted: 16 February 2018 © Springer-Verlag GmbH Germany, part of Springer Nature 2018
Abstract Introduction Obesity might negatively affect prostate cancer (PCa) outcomes. However, evidence according to the associations between obesity and metastases-free survival after radical prostatectomy (RP) is still inconsistent. Methods We relied on PCa patients treated with RP at the Martini-Klinik Prostate Cancer Center between 2004 and 2015. First, multivariable Cox regression analyses examined the impact of obesity on metastases after RP. Last, in a propensity score matched cohort, Kaplan–Meier analyses assessed metastases-free survival according to body mass index (kg/m 2) (BMI) strata (≥ 30 vs. < 25). Results Of 13,667 individuals, 1990 (14.6%) men were obese (BMI ≥ 30). Median follow-up was 36.4 month (IQR 13.3– 60.8). Obese patients were less likely to exhibit metastases after RP (HR 0.7, 95% CI 0.5–0.97, p = 0.03). Similarly, after propensity score adjustment, obesity was associated with increased metastases-free survival (log rank p = 0.001). Conclusion We recorded the obesity paradox phenomenon in PCa patients. In particular, high BMI (≥ 30) was associated with decreased risk of metastases after RP, despite an increased risk being anticipated. Whether statin use might have affected the results was not assessed. Further research is needed to unravel the controversially debated association between obesity and PCa. Keywords BMI · Body mass index · Metastases · Obesity · Obesity paradox · Outcomes · Prostate cancer · Radical prostatectomy · Survival
Introduction
* Jonas Schiffmann
[email protected] 1
Department of Urology, Academic Hospital Braunschweig, Salzdahlumerstrasse 90, 38126 Brunswick, Germany
2
Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, Canada
3
Department of Urology, University of Montreal Health Center, Montreal, Canada
4
Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
5
Martini‑Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Obesity contributes to the risk and mortality of several cancer primaries, including prostate cancer (PCa) [1]. Since the prevalence of obesity increased dramatically over the last decades, the interest in its potential detrimental effects on cancer or cancer control measures has also increased [2]. Basic research demonstrated that obesity contributes to tumorigenesis and local spread of the disease [3, 4]. Consequently, higher rates of advanced disease at time of diagnosis are expected [5, 6]. Whether obesity might also be associated with cancer control outcomes quantified as metastatic progression after radical prostatectomy (RP) is critically debated [7]. Despite relatively robust data supporting the association between obesity and various PCa metrics, specific longterm longitudinal oncologic outcomes after RP, including
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metastases-free survival, suggest little if any effect of body mass index (BMI) [8–10]. Based on the existing evidence, it remains inconclusive whether obese men might need closer follow-up after surgery according to increased risk of PCa progression. To provide further data according to this highly important clinical question, we decided to investigate the Martini-Klinik Prostate Cancer Center database and focused on the association of obesity on PCa progression after RP.
Materials and methods Study population We relied on the Martini-Klinik Prostate Cancer Center database. We included PCa patients treated with RP between January 2004 and March 2015. Patients with neoadjuvant androgen deprivation therapy, those with missing data, as well as those with palliative or salvage RP were excluded. This resulted in 13,667 assessable patients.
Covariates BMI (kg/m2) at time of surgery, age, year of surgery, prostate specific antigen (PSA), pathological Gleason score, pathological tumor stage (pT), nodal stage (Nx vs. pN0 vs. pN1), margin status (R0 vs. R1), surgical approach [robot-assisted RP (RARP) vs. open RP (ORP)], and administration of adjuvant androgen deprivation therapy (ADT) were tabulated. Metastatic progression was assessed during follow-up.
Statistical analyses Our statistical analyses consisted of four steps. First, we investigated differences in clinical, pathological and treatment characteristics according to different BMI strata (≥ 30 vs. 25–30 vs. < 25). Second, in multivariable Cox regression analyses, we tested the effect of obesity on the rates of metastases (events = 387) after RP. Third, we applied propensity score matching to obese (BMI ≥ 30) and non-obese (BMI < 25) patients. The propensity-matched cohort was balanced according to clinical and pathological characteristics, such as age, PSA, year of surgery, pT, pN, surgical margin status, pathological Gleason score, and ADT administration, respectively. Finally, Kaplan–Meier analyses then tested for the effect of obesity (BMI ≥ 30 vs. BMI < 25) on rates of metastases-free survival after RP. All statistical tests were performed using R. All tests were 2-sided with a significance level set at p < 0.05.
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Results Baseline descriptives Overall, 13,667 PCa patients treated with RP were identified. Of those, 1990 (14.6%) were obese (BMI ≥ 30), 7041 (51.5%) men were overweight (BMI 25–30), and 4636 (33.9%) had a BMI < 25, respectively (Table 1). We recorded statistically significant differences in clinical, pathological and treatment characteristics according to BMI strata (≥ 30 vs. 25–30 vs. < 25). Specifically, obese patients (BMI ≥ 30) were younger than their non-obese counterparts (median age: 64 vs. 65 vs. 65 years, p < 0.001). Conversely, obese man had higher median PSA (7.2 vs. 6.9 vs. 6.9 ng/ ml, p = 0.02), and more frequently harbored Gleason ≥ 4 + 4 at final pathology (8.7 vs. 5.9 vs. 5.2%, p < 0.001). Obese men were also more likely to harbor unfavorable pathological tumor stage ≥ pT3b (15.1 vs. 11.6 vs. 11.1%, p < 0.001), and lymph node metastases (9.3 vs. 7.5 vs. 7.2%, p = 0.02) at final pathology, respectively. Additionally, obese men more frequently exhibited a positive surgical margin (23.7 vs. 17.6 vs. 15.8%, p < 0.001). Finally, obese men were more likely to be treated with RARP instead of ORP than non-obese patients (22.1 vs. 15.0 vs. 13.9%, p < 0.001; Table 1).
Cox regression analyses testing the association of obesity on metastases after RP, without propensity score adjustment In multivariable Cox regression analyses, where at 60 months, 3978 men were at risk, BMI was an independent predictor of metastases after RP. Specifically, obese patients (BMI ≥ 30) were associated with lower risk of metastases after RP than their non-obese counterparts (BMI < 25) [hazard ratio (HR) 0.7; 95% CI 0.5–0.97; p = 0.03; Table 2].
Propensity score adjustment The propensity score matched cohort consisted of 3454 PCa patients treated with RP. Of those, 1727 (50.0%) men were obese (BMI ≥ 30) and 1727 (50.0%) patients were non-obese (BMI < 25), respectively. No significant differences according to age, PSA, year of surgery, pT-stage, nodal stage, pathological Gleason score, surgical margin status, and ADT administration existed between obese and non-obese patients (all p > 0.05).
World Journal of Urology Table 1 Baseline characteristics of 13,667 prostate cancer patients treated with radical prostatectomy between 2004 and 2015 at the Martini-Klinik Prostate Cancer Center stratified according to different body mass index strata: ≥ 30, 25–30, and < 25 kg/m2
Parameter
Overall
Patients, n (%) 13,667 Age (years) Median (IQR) 65 (60; 69) PSA (ng/ml) Median (IQR) 6.9 (5.0–10.3) Year of surgery, n (%) 2004 179 (1.3) 2005 608 (4.4) 2006 825 (6.0) 2007 1099 (8.0) 2008 1270 (9.3) 2009 1319 (9.7) 2010 1591 (11.6) 2011 1727 (12.6) 2012 1778 (13.0) 2013 1580 (11.6) 2014 1316 (9.6) 2015 375 (2.7) pT-stage, n (%) pT2 9179 (67.2) pT3a 2844 (20.8) ≥ pT3b 1630 (11.9) pN-stage, n (%) Nx 4089 (30.0) pN0 8505 (62.3) pN1 1047 (7.7) Gleason score, n (%) 3 + 3 2433 (17.8) 3 + 4 7983 (58.4) 4 + 3 2400 (17.6) ≥ 4 + 4 828 (6.1) Surgical margin, n (%) R0 11,214 (82.1) R1 2447 (17.9) Surgical approach, n (%) RARP 2141 (15.7) ORP 11,526 (84.3) Follow-up (month) Median (IQR) 36.4 (13.3; 60.8) Adjuvant ADT, n (%) 233 (1.7)
BMI ≥ 30
BMI 25–30
BMI < 25
1990 (14.6)
7041 (51.5)
4636 (33.9)
p value
64 (59; 68)
65 (60; 69)
65 (60; 69)
< 0.001
7.2 (5.0–11.0)
6.9 (5.1–10.2)
6.9 (4.9–10.0)
16 (8.9) 75 (12.3) 103 (12.5) 153 (13.9) 147 (11.6) 183 (13.9) 231 (14.5) 243 (14.1) 290 (16.3) 260 (16.5) 237 (18.0) 52 (13.9)
91 (50.8) 304 (50.0) 413 (50.1) 551 (50.1) 667 (52.5) 687 (52.1) 819 (51.5) 907 (52.5) 925 (52.0) 803 (50.8) 668 (50.8) 206 (54.9)
72 (40.2) 229 (37.7) 309 (37.5) 395 (35.9) 456 (35.9) 449 (34.0) 541 (34.0) 577 (33.4) 563 (31.7) 517 (32.7) 411 (31.2) 117 (31.2)
< 0.001
1245 (62.7) 440 (22.2) 300 (15.1)
4731 (67.2) 1486 (21.1) 818 (11.6)
3203 (69.1) 918 (19.8) 512 (11.1)
< 0.001
554 (27.9) 1245 (62.8) 185 (9.3)
2112 (30.0) 4391 (62.4) 530 (7.5)
1423 (30.8) 2869 (62.0) 332 (7.2)
0.016
290 (14.6) 1139 (57.4) 384 (19.3) 172 (8.7)
1232 (17.5) 4136 (58.9) 1247 (17.7) 417 (5.9)
911 (19.7) 2708 (58.5) 769 (16.6) 239 (5.2)
< 0.001
1516 (76.3) 471 (23.7)
5797 (82.4) 1242 (17.6)
3901 (84.2) 734 (15.8)
< 0.001
439 (22.1) 1551 (77.9)
1057 (15.0) 5984 (85.0)
645 (13.9) 3991 (86.1)
< 0.001
0.009
34.1 (12.7; 59.9) 36.4 (13.1; 60.7) 36.8 (14.2; 62.0) < 0.001 47 (2.4) 126 (1.8) 60 (1.3) 0.007
All statistical tests were performed using R. All tests were 2-sided with a significance level set at p < 0.05. BMI body mass index, IQR interquartile range, PSA prostate specific antigen, pT pathological tumor stage, pN nodal stage at final pathology, RARP robot-assisted radical prostatectomy, ORP open radical prostatectomy, ADT androgen deprivation therapy
Kaplan–Meier analyses of metastases‑free survival after propensity score adjustment In Kaplan–Meier analyses, we recorded significant
differences according to metastases-free survival between obese and non-obese patients (log rank p = 0.01, Fig. 1), evidenced by metastases-free survival rates at 8 years after
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Table 2 Multivariable Cox regression analyses predicting metastatic progression (387 events) in 13,608 prostate cancer patients treated with radical prostatectomy at the Martini-Klinik Prostate Cancer Center
RP of, respectively, 95.8 and 93.0% in obese and nonobese patients (Fig. 1).
Parameter
Discussion
Metastases HR
Age (years) PSA (ng/ml) pT-stage pT3a vs. pT2 ≥ pT3b vs. pT2 pN-stage pNx vs. pN0 pN+ vs. pN0 Gleason score 3 + 4 vs. 3 + 3 4 + 3 vs. 3 + 3 ≥ 4 + 4 vs. 3 + 3 Surgical margin R1 vs. R0 BMI 25–30 vs. < 25 ≥ 30 vs. < 25 Adjuvant ADT Yes vs. no
95% CI
p value
0.99 1.005
0.97–1.005 1.002–1.007
0.17 0.005
1.87 3.49
1.37–2.58 2.5–4.89
< 0.001 < 0.001
0.5 1.68
0.31–0.75 1.31–2.15
< 0.001 < 0.001
3.91 18.12 36.38
1.65–11.77 7.56–54.91 14.85–112.03
0.001 < 0.001 < 0.001
1.15
0.91–1.44
0.24
0.96 0.71
0.77–1.2 0.51–0.97
0.74 0.033
0.79
0.54–1.13
0.21
HR hazard ratio, CI confidence interval, PSA prostate specific antigen, pT-stage pathological tumor stage, pN-stage nodal stage, BMI body mass index, ADT androgen deprivation therapy
Fig. 1 Kaplan–Meier analysis for metastases-free survival comparing propensity score adjusted obese (body mass index ≥ 30) vs. nonobese (body mass index < 25) prostate cancer patients after radical prostatectomy
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Obesity might predispose to local invasion of PCa [4, 11]. Subsequently, obese men are more likely to harbor advanced disease at time of diagnosis [6, 12]. Since obesity affects one-third of the United States population [13] and increasing prevalence of obesity was also recorded in Europeans [14], the suggested impact on PCa outcomes beyond RP might represent a major challenge to current and future health care systems. However, the association between obesity and various PCa outcomes is still debatable, since several reports were not able to validate the negative associations between obesity and various PCa metrics [8–10, 15]. To evaluate the association of obesity on surgically treated PCa patients, we investigated the Martini-Klinik Prostate Cancer Center database. We relied on 13,667 men treated with RP and assessed the association of obesity on metastatic progression after surgery. Our analyses uncovered several important results. According to multivariable Cox regression analyses, we recorded that obesity (BMI ≥ 30) was associated with a decreased risk of metastases after RP (HR 0.7, 95% CI 0.5–0.97, p = 0.03, Table 2). Similarly, Kaplan–Meier analyses recorded increased metastases-free survival in obese men after propensity score adjustment (log rank p = 0.01, Fig. 1). It is of note that there is a paucity of studies reporting on the association of obesity on metastases-free survival after RP [7, 16]. To the best of our knowledge, no previous study recorded a negative association between obesity and risk of metastases after RP. In particular, the Mayo Clinic recorded no impact of obesity on metastases-free survival within 5313 RP patients after a median follow-up of 10.1 years [8]. Conversely to our study, as well as to the Mayo Clinic data, Gong et al. recorded an increased risk of metastases in obese PCa patients [17]. However, the value of that study was compromised by non-negligible biases according to patient selection, with the inclusion of multiple cancer treatments [e.g., RP ± androgen deprivation therapy (ADT), radiation therapy ± ADT, watchful waiting or ADT alone], and underpowered analyses, with only 66 events. It is noteworthy that obesity was recorded as independent risk factor for distant metastases in PCa patients
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treated with radiation therapy [18]. However, available evidence according to the link between obesity and oncological outcomes in PCa patients treated with radiation therapy revealed inconsistent results as well [19]. These inconsistent data according to the link between obesity and metastatic progression might document, that such possible association might be far more complex than expected. A further dimension to this association is the emerging topic of the obesity paradox [20]. Such paradox is the observation of an apparent risk reduction associated with increased BMI, despite an increased risk is anticipated. This phenomenon is well-recognized in cardiovascular and diabetes research, and currently emerges in the field of oncology [21–23]. However, to the best of our knowledge, this study is the first describing such a paradox phenomenon in PCa research. Consequently, our data provide highly important information on the present topic, and shed a different light on the assumed association between obesity and metastatic progression after RP [2]. The increased metastases-free survival in obese patients might be a consequence of improved medical treatment of diabetes, which might be more frequently present in obese men. Since glucose metabolism and the insulin/insulin like growth factor-1 (IGF-1) axis might represent a mechanism which underlies the possible link between obesity and PCa progression, improvements in medical treatment of diabetes (e.g., metformin) might subsequently have positively affected the current study results [24, 25]. Additionally, statin use might play a protective role in PCa [26]. Despite the case that high BMI patients might frequently take statins, statin use was not assessed in the current study. However, these hypotheses are highly speculative and cannot be validated within our data. Moreover, multiple key factors in the interplay between obesity and cancer growth might still be unknown. Subsequently, more research is needed to unravel the complex association between increased BMI and PCa. More evidence exists according to the link between obesity and PCa-specific mortality. Here, Siddiqui and colleagues recorded no impact of obesity on PCa-specific survival after RP [8]. Conversely to our study, obesity is generally assumed as an independent driver of PCa-specific mortality [7, 16]. For example, a current meta-analysis recorded a significant association between obesity and PCaspecific mortality (HR 1.24, 95% CI 1.15–2.33) [27]. Possible explanations for such an impact are multiple changes in the microenvironment of obese patients [7]. In particular, increased insulin levels might be associated with PCa growth [24, 28]. Additionally, specific adipokines (e.g., interleukin-6) might promote PCa progression [7]. However, benchmark studies suggesting an increased risk of PCa-specific mortality in obese patients might harbor
non-negligible biases. For example, the important data from the Cancer Prevention Study II suggested increased risk of cancer-specific death in obese PCa patients (HR 1.2, 95% CI 1.06–1.36, p < 0.001) [1]. However, the corresponding analyses relied on patients from the last millennium and the Cox proportional-hazards model was not adjusted for important PCa variables, such as tumor stage, Gleason score, and PSA, respectively [1]. Additionally, it remained unclear what treatment was administered in the selected patient cohort [1]. Similarly, the study from Ma et al. recorded an increased PCa-specific mortality in obese men (HR 1.95, 95% CI 1.17–3.23, p = 0.004). However, they were not able to adjust their analyses according to important PCa variables, such as pathological tumor stage, pathological Gleason score, and selected treatment, respectively [29]. Consequently, the above mentioned studies might be of limited use according to the important question of the impact of obesity on PCaspecific mortality in RP patients. Despite its strengths, our study is not devoid of limitations. First, we relied on a single-center database from a high-volume center. Consequently, a selection bias might be operational and might not allow to generalize our findings to men treated in other European countries, or even less so in the United States. Second, we relied on exclusively surgically treated PCa patients. Consequently, the current results might not be generalizable to men treated with active surveillance, or radiation therapy, respectively. Third, our study is limited by its retrospective design and recall biases might have affected our results. However, within our analyses, we relied on variables that are generally little if any affected by recall. Additionally, we performed propensity score matching using well-established variables, to even better control for population differences than multivariable models. Fourth, the follow-up was limited. In consequence, more mature data might shed a different light on the tested association between obesity and PCa outcomes. Fifth, neither detailed information according to actual diabetes rates, nor metformin or statin use were available within our study. Sixth, data according to adjuvant and salvage radiation therapy were not included in our analyses. Similarly, testosterone levels were not available within the current study. Finally, clinical data according to diabetes, body fat distribution, blood cholesterol level and hypertension were not available. Consequently, no additional subanalyses according to patients with metabolic syndrome were performed within the current study. In conclusion, we recorded the obesity paradox in surgically treated PCa patients. In particular, increased BMI was associated with a decreased risk of metastases after RP. Despite the latter observation representing a novel finding in PCa research, our data cannot explain the underlying mechanisms. However, our data are very important, since they provide the most contemporary evidence (2004–2015) of the
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link between obesity and PCa. Consequently, more research is needed to unravel the controversially debated association between obesity and PCa. Author contributions JS protocol/project development, data analysis, manuscript writing/editing, data collection or management. PIK manuscript writing/editing. MR data collection or management. LM manuscript writing/editing. GS data collection or management. DT data collection or management. LB data collection or management. RP data collection or management. S-RL-B data collection or management. AH data collection or management. PH manuscript writing/ editing. HH data collection or management. MG data collection or management, protocol/project development. PT data collection or management, protocol/project development, data analysis.
Compliance with ethical standards The study was conducted according to the principles of the declaration of Helsinki. Conflict of interest The authors declare that they have no conflict of interest.
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