Diabetes and beta-adrenergic blockage are risk factors for metastatic prostate cancer
© The Author(s). 2017
Received: 4 October 2016
Accepted: 8 February 2017
Published: 21 February 2017
We evaluated the influence of comorbidity inferred risks for lymph node metastasis (pN1) and positive surgical margins (R1) after radical prostatectomy in order to optimize pretherapeutic risk classification.
We analyzed 454 patients after radical prostatectomy (RP) between 2009 and 2014. Comorbidities were defined by patients’ medication from our electronic patient chart and stratified according to the ATC WHO code. Endpoints were lymph node metastasis (pN1) and positive surgical margins (R1).
Rates for pN1 and R1 were 21.4% (97/454) and 29.3% (133/454), respectively. In addition to CAPRA and Gleason score, we identified diabetes as a significant medication inferred risk factor for pN1 (OR 2.9, p = 0.004/OR 3.2, p = 0.001/OR 3.5, p = 0.001) and beta-blockers for R1 (OR 1.9, p = 0.020/OR 2.9, p = 0.004). Patients with diabetes showed no statistically significant difference in Gleason score, CAPRA Score, PSA, and age compared to non-diabetic patients.
We identified diabetes and beta1 adrenergic blockage as significant risk factors for lymph node metastasis and positive surgical margins in prostate cancer (PCa). Patients at risk will need intensive pretherapeutic staging for optimal therapeutic stratification.
KeywordsProstate cancer Metastasis Diabetes Beta-adrenergic blockage
Prostate cancer (PCa) is the second most common cancer and third most leading cause of death of men in the western world . Correct risk stratification is crucial for optimal of high-risk patients and avoiding overtreatment in low-risk patients. Risk stratification is based on histologic analysis of invasive prostate biopsies, which are indicated by elevated prostate-specific antigen (PSA) levels or suspicious digital rectal examination (DRE) findings. Several risk classification tools exist for pretherapeutic stratification such as Kattan normograms , D’Amico score [3, 4] or CAPRA (Cancer of Prostate Risk Assessment) score [5–7]. All scores are based primarily on PSA levels (ng/ml), Gleason score, and age (years) and have biochemical recurrence within 5 years after radical prostatectomy as primary endpoint. The mentioned scores stratify patients into low-, intermediate-, and high-risk groups. However, identifying patients with preexisting lymph node metastases (cN1) or non-organ defined tumors (R1) remains difficult, but these parameters significantly determine the therapeutic strategy. Imaging which provide detailed information for cN status and R status, such as magnetic resonance imaging (MRI) or positron emission computer tomography (PET/CT) (e.g., PSMA-PET/CT), cannot be performed in every patient for economic and availability reasons. cN1 status would require extended lymphadenectomy during radical prostatectomy or extended field radiation in primary radiation therapy. Extended staging using MRI is recommended for high-risk patients with PSA > 10 ng/ml or Gleason score ≥ 8–10  only in the European guidelines for prostate cancer. In order to find further risk stratifier, comorbidities have come into the focus with possible implications on cancer genesis, stage, progression, and therapy [9, 10]. Data are still conflicting, and exact mechanism regarding stage and prognosis are not understood. Among the comorbidities, diabetes is one of the better examined and most common diseases with an estimated 269 million people affected worldwide . Interestingly, a reduced risk for developing PCa has been described for diabetes patients ; however, little is known about the impact on cancer stage. We have therefore used our electronic patient chart to generate the prostate cancer patients’ comorbidity profile by the self-medication during hospitalization for radical prostatectomy. We assessed the comorbidity profile’s impact on cancer stage at diagnosis represented by R status and pN status as the key determinants of primary and adjuvant therapeutical strategy.
We included 454 patients with prostate cancer, who were treated with radical prostatectomy (RP) between 2009 and 2014 (median age 66 years, interquartile range (IQR 61.0–71.0). The same surgical team operated these patients with equal experience. Comorbidities were defined by patients’ self-medication during hospitalization for radical prostatectomy. Medications were generated from our electronic patient chart (Meona©) and stratified according to the ATC (Anatomic Therapeutic Chemical) WHO code at the time of the RP.
Anatomical Therapeutic Chemical (ATC) classification system divides the active substances into different groups according to the organ or system on which they act and their therapeutic, pharmacological, and chemical properties. Drugs are classified in groups at five different levels. The drugs are divided into 14 main groups (1st level), with pharmacological/therapeutic subgroups (2nd level). The 3rd and 4th levels are chemical/pharmacological/therapeutic subgroups, and the 5th level is the chemical substance .
Cancer of the Prostate Risk Assessment CAPRA [13–16] score was used for pretherapeutic risk classification. The score includes PSA at diagnosis (ng/ml), Gleason pattern of the biopsy (primary/secondary), age (years), and positive biopsy cores (percent of total number of biopsies) as variables (Additional file 1: Table S1), which are weighted differently according to the value.
Endpoints were lymph node metastasis (pN1) and positive surgical margins (R1) after radical prostatectomy based on the histopathologic analysis of the radical prostatectomy specimens including lymph nodes. Specimens were routinely processed, and analysis was performed on paraffin embedded, cut, and H&E-stained samples.
Descriptive statistics was done by calculating mean ± standard deviation (SD), median, and interquartile range (IQR). Logistic and linear regression analyses were used for identifying risk factors using SPSS© software (SPSS statistics 22, IBM) calculated as odds ratio (OR) and p value.
Patients’ characteristics (n = 454)
Age at radical prostatectomy (years)
PSA at radical prostatcetomy (ng/ml)
Gleason score at biopsy (n)
Gleason score at radical prostatectomy (n)
T stage at biopsy (n)
T stage at radical prostatectomy (n)
CAPRA score at biopsy (n)
6–10 (high risk)
3–5 (intermediate risk)
1–2 (low risk)
Positive lymph nodes (N+) at radical prostatectomy (n)
Positive surgical margin (R+) at radical prostatectomy (n)
A median of 2 (IQR 1–4) medications from 2 (IQR 1–4) comorbidity level 1 classes were taken per patient. 14.9% (68/454), 54.2% (246/454), 29.7% (135/454), and 1.1% (5/454) of the patients took 0, 1–3, 4–9, and 10–15 medications (Table 5). From clinical parameters such as age (years), PSA (ng/ml), Gleason score, and CAPRA score, we identified CAPRA score and Gleason score as significant risk factors for N1 (OR 3.200, p = 0.001/OR 3.454, p = 0.001) and CAPRA score for R1 (OR 2.916, p = 0.004) (Table 4). Patients with diabetes showed no statistically significant difference in Gleason score (p = 0.499), CAPRA score (p = 0.495), PSA (p = 0.668), and age (p = 0.537) compared to non-diabetic patients.
Characteristics of comorbidities (ATC code level 1, distribution and regression analyses)
ATC code level 1
Positive surgical margin (R1)
Lymph node metasasis (N1)
Cardiovascular system C
Alimentary tract A
Blood system B
Urinary system G
Hormonal system H
Nervous system N
Respiratory system R
Sensory system S
Immune system L
Characteristics of comorbidities (ATC code level 2, distribution and regression analyses)
ATC code level 2
Positive surgical margin (R1)
Lymph node metastasis (N1)
Renin angiotensin system
Calcium channel blockers
Functional gastroint, disorders
Anti parkinson drugs
0.0 / 0.999
Logistic regression analysis on ATC code level 1 did not show significantly increased risk for pN1 or R1 status whereas regression analysis on ATC code level 2 did show significantly increased risk for pN1 in patients with diabetes (OR 2.869, p = 0.004) and beta1 blockers for R1 (OR 1.929, p = 0.020). Subgroup analysis showed significantly increased risk for N1 in patients taking metformin (OR 2.989, p = 0.010) and R1 for patients taking beta1 selective blocker metoprolol (OR 2.400, p = 0.010). The number of medications per patient and the number of medicated organ systems per patient did not show statistically significant risk increase for either N1 or R1 (Table 3).
In this study, we identified diabetes (OR 2.869) and beta-blockage (OR 1.929) as significant risk factors for the existence of lymph metastases (pN1) and non-organ confined (R1) prostate cancer in patients at radical prostatectomy. The comorbidity profile of each patient was defined as the self-medication, which is not associated to hospitalization. More comorbidities might have been present within the cohort, which were missed by this method. However, our methods allow for a detailed analysis of the comorbidities on the organ system level down to single medications utilizing the WHO ATC code. Within the diabetes group, e.g., we identified metformin and in the beta1 selective blockage group metoprolol as single risk factors for pN1 and R1, respectively.
Comorbidities have been associated with tumor genesis and progression, results however remain controversial. Several studies show that the effect can be protective or associated with increased cancer risk in different organs . Especially, diabetes and beta-adrenergic signaling have been associated with carcinogenesis for a long time.
Lipscomb et al.  showed that diabetic women (n = 6115) have an increased risk (OR 1.16) for developing lymph node positive breast cancer. Obesity or increased BMI are not associated with increased risk for lymph node metastases  in breast cancer. We could not identify a study, which specifically analyzed the association between diabetes and nodal status of prostate cancer in a PubMed search until today.
Several studies describe a medication inferred decreased risk for developing prostate cancer: Margel et al.  showed in 12,000 prostate cancer patients that, e.g., metformin users had decreased risk (OR 0.66) for developing prostate cancer. Preston et al.  showed in 120,000 diabetic men that metformin was not associated with decreased risk for developing prostate cancer in general or high-grade prostate cancer. A meta-analysis by Bansal et al.  concluded from 8.1 million patients including 120,000 prostate cancer patients that diabetes significantly lowers the risk (RR 0.86) for developing prostate cancer. Li et al.  report opposite results in a cohort of 22,000 men with increased risk for developing high-grade prostate cancer in men with diabetes.
Regression analysis for clinical risk factors
Positive surgical margin (R1)
Lymph node metasasis (N1)
Gleason score (6–10)
CAPRA score (1–5)
Also, beta-adrenergic signaling has been associated with advanced prostate cancer  and beta-blockers have been associated reduced mortality in various tumor types . The prostate, especially the peripheral zone where most of the tumors originate, shows high adrenergic innervation . Especially, beta2 receptor subtypes were detected in the peripheral zone. This could explain a possible protective effect by unselective beta-blockage such as carvedilol; however, the effect in our analysis was statistically not significant. The luminal epithelial cells which are suspected as the originating cells for prostate cancer show high expression for beta-adrenergic receptors in the malignant and benign state and thus connect the nervous system to the tumor . Magnon et al.  showed that beta-adrenergic and cholinergic nerves play an important role in prostate cancer genesis and progression, by actively infiltrating the tumor. Perineural nerve sheath infiltration by the tumor also serves as an independent negative predictor for disease free survival . Furthermore, beta-blockers were associated, we improved survival in prostate cancer patients . Even though beta-blockers seem to have protective effects on long term survival, the underlying disease with an activated adrenergic system could well explain the increased risk for R1 disease in prostate cancer patients in our cohort. Further studies will have validate our results. Only scarce data is available upon alpha-adrenergic signaling and cancer. Some studies show inhibitory effects on cancer cells by alpha-adrenergic blockage [30–32].
Limitation of this study is the fact that comorbidities were defined only by self-medication. Additional comorbidities not reflected by the medication were not analyzed. Furthermore, dosage and duration of the medications were not considered.
Medication characteristics per patient
Number of mediaction systems/patient
Number of medications/patient
Number of medications/patient
Diabetes and beta-blockage are major risk factors for advanced prostate cancer, which should be incorporated into the pretherapeutic staging strategy and into the planning of definite therapy to allow for optimal results for our patients. The usage of electronic patient charts represent a powerful tool to analyze risk structures within patient cohorts. They could also be used to incorporate medication-based risk factors, which will automatically alert the physicians for high-risk patients.
Does not apply.
The study has been funded from the Department of Urology itself.
Availability of data and materials
All data will be available upon request from the authors.
MK and CJ designed the study, analyzed the data, and wrote the manuscript. CH, AS, KS, and LH acquired the medication data. VD and MW performed histologic analysis of the radical prostatectomy specimens. UW, CJ, and WS performed radical prostatectomies. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
The study does not use personalized data, and hence, a consent for publication does not apply.
Ethics approval and consent to participate
All patient gave written consent prior to data collection. The study has been approved by the Ethics Committee of the University of Freiburg (Engelberger Straße 21 79106 Freiburg) under the reference number 416/11.
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- Howlader N NA, Krapcho M, Miller D, Bishop K, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2013, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2013/, based on November 2015 SEER data submission, posted to the SEER web site, April 2016. 2016.
- Shariat SF, Karakiewicz PI, Roehrborn CG, Kattan MW. An updated catalog of prostate cancer predictive tools. Cancer. 2008;113:3075–99.View ArticlePubMedGoogle Scholar
- Hernandez DJ, Nielsen ME, Han M, Partin AW. Contemporary evaluation of the Dʼamico risk classification of prostate cancer. Urology. 2007;70:931–5.View ArticlePubMedGoogle Scholar
- D'Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick GA, Tomaszewski JE, Renshaw AA, Kaplan I, Beard CJ, Wein A. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280:969–74.View ArticlePubMedGoogle Scholar
- Rodrigues G, Warde P, Pickles T, Crook J, Brundage M, Souhami L, Lukka H, Genitourinary Radiation Oncologists of C. Pre-treatment risk stratification of prostate cancer patients: a critical review. Can Urol Assoc J. 2012;6:121–7.View ArticlePubMedPubMed CentralGoogle Scholar
- Cooperberg MR, Broering JM, Carroll PR. Risk assessment for prostate cancer metastasis and mortality at the time of diagnosis. J Natl Cancer Inst. 2009;101:878–87.View ArticlePubMedPubMed CentralGoogle Scholar
- Cooperberg MR, Pasta DJ, Elkin EP, Litwin MS, Latini DM, Du Chane J, Carroll PR. The University of California, San Francisco Cancer of the Prostate Risk Assessment score: a straightforward and reliable preoperative predictor of disease recurrence after radical prostatectomy. J Urol. 2005;173:1938–42.View ArticlePubMedPubMed CentralGoogle Scholar
- Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, Mason M, Matveev V, Wiegel T, Zattoni F, et al. EAU guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent-update 2013. Eur Urol. 2014;65:124–37.View ArticlePubMedGoogle Scholar
- Hall WH, Jani AB, Ryu JK, Narayan S, Vijayakumar S. The impact of age and comorbidity on survival outcomes and treatment patterns in prostate cancer. Prostate Cancer Prostatic Dis. 2005;8:22–30.View ArticlePubMedGoogle Scholar
- Gurney J, Sarfati D, Stanley J. The impact of patient comorbidity on cancer stage at diagnosis. Br J Cancer. 2015;113:1375–80.View ArticlePubMedPubMed CentralGoogle Scholar
- Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee D. Diabetes and cancer: a consensus report. Diabetes Care. 2010;33:1674–85.View ArticlePubMedPubMed CentralGoogle Scholar
- WHO. Anatomic therapeutic chemical code (ATC). 2011.Google Scholar
- Murray NP, Aedo S, Reyes E, Orellana N, Fuentealba C, Jacob O. A prediction model for early biochemical failure after radical prostatectomy based on the CAPRA-S score and the presence of secondary circulating prostate cells. BJU Int. 2015;118:556–62.
- Cooperberg MR, Hilton JF, Carroll PR. The CAPRA-S score: a straightforward tool for improved prediction of outcomes after radical prostatectomy. Cancer. 2011;117:5039–46.View ArticlePubMedPubMed CentralGoogle Scholar
- Loeb S, Carvalhal GF, Kan D, Desai A, Catalona WJ. External validation of the cancer of the prostate risk assessment (CAPRA) score in a single-surgeon radical prostatectomy series. Urol Oncol. 2012;30:584–9.View ArticlePubMedGoogle Scholar
- May M, Knoll N, Siegsmund M, Fahlenkamp D, Vogler H, Hoschke B, Gralla O. Validity of the CAPRA score to predict biochemical recurrence-free survival after radical prostatectomy. Results from a european multicenter survey of 1,296 patients. J Urol. 2007;178:1957–62. discussion 1962.View ArticlePubMedGoogle Scholar
- Wojciechowska J, Krajewski W, Bolanowski M, Krecicki T, Zatonski T. Diabetes and cancer: a review of current knowledge. Exp Clin Endocrinol Diabetes. 2016;124:263–75.View ArticlePubMedGoogle Scholar
- Lipscombe LL, Fischer HD, Austin PC, Fu L, Jaakkimainen RL, Ginsburg O, Rochon PA, Narod S, Paszat L. The association between diabetes and breast cancer stage at diagnosis: a population-based study. Breast Cancer Res Treat. 2015;150:613–20.View ArticlePubMedGoogle Scholar
- Briganti A, Karakiewicz PI, Chun FK, Suardi N, Gallina A, Abdollah F, Freschi M, Doglioni C, Rigatti P, Montorsi F. Obesity does not increase the risk of lymph node metastases in patients with clinically localized prostate cancer undergoing radical prostatectomy and extended pelvic lymph node dissection. Int J Urol. 2009;16:676–81.View ArticlePubMedGoogle Scholar
- Margel D, Urbach D, Lipscombe LL, Bell CM, Kulkarni G, Austin PC, Fleshner N. Association between metformin use and risk of prostate cancer and its grade. J Natl Cancer Inst. 2013;105:1123–31.View ArticlePubMedGoogle Scholar
- Preston MA, Riis AH, Ehrenstein V, Breau RH, Batista JL, Olumi AF, Mucci LA, Adami HO, Sorensen HT. Metformin use and prostate cancer risk. Eur Urol. 2014;66:1012–20.View ArticlePubMedGoogle Scholar
- Bansal D, Bhansali A, Kapil G, Undela K, Tiwari P. Type 2 diabetes and risk of prostate cancer: a meta-analysis of observational studies. Prostate Cancer Prostatic Dis. 2013;16:151–8. S151.PubMedGoogle Scholar
- Li Q, Kuriyama S, Kakizaki M, Yan H, Sone T, Nagai M, Sugawara Y, Ohmori-Matsuda K, Hozawa A, Nishino Y, Tsuji I. History of diabetes mellitus and the risk of prostate cancer: the Ohsaki Cohort Study. Cancer Causes Control. 2010;21:1025–32.View ArticlePubMedGoogle Scholar
- Scallan JP, Hill MA, Davis MJ. Lymphatic vascular integrity is disrupted in type 2 diabetes due to impaired nitric oxide signalling. Cardiovasc Res. 2015;107:89–97.View ArticlePubMedPubMed CentralGoogle Scholar
- Braadland PR, Ramberg H, Grytli HH, Tasken KA. β-adrenergic receptor signaling in prostate cancer. Front Oncol. 2014;4:375.PubMedGoogle Scholar
- Goepel M, Wittmann A, Rubben H, Michel MC. Comparison of adrenoceptor subtype expression in porcine and human bladder and prostate. Urol Res. 1997;25:199–206.View ArticlePubMedGoogle Scholar
- Magnon C, Hall SJ, Lin J, Xue X, Gerber L, Freedland SJ, Frenette PS. Autonomic nerve development contributes to prostate cancer progression. Science. 2013;341:1236361.View ArticlePubMedGoogle Scholar
- Andersen S, Richardsen E, Nordby Y, Ness N, Storkersen O, Al-Shibli K, Donnem T, Bertilsson H, Busund LT, Angelsen A, Bremnes RM. Disease-specific outcomes of radical prostatectomies in Northern Norway; a case for the impact of perineural infiltration and postoperative PSA-doubling time. BMC Urol. 2014;14:49.View ArticlePubMedPubMed CentralGoogle Scholar
- Lu H, Liu X, Guo F, Tan S, Wang G, Liu H, Wang J, He X, Mo Y, Shi B. Impact of beta-blockers on prostate cancer mortality: a meta-analysis of 16,825 patients. Onco Targets Ther. 2015;8:985–90.View ArticlePubMedPubMed CentralGoogle Scholar
- Morelli MB, Amantini C, Nabissi M, Liberati S, Cardinali C, Farfariello V, Tomassoni D, Quaglia W, Piergentili A, Bonifazi A, et al. Cross-talk between alpha1D-adrenoceptors and transient receptor potential vanilloid type 1 triggers prostate cancer cell proliferation. BMC Cancer. 2014;14:921.View ArticlePubMedPubMed CentralGoogle Scholar
- Hui H, Fernando MA, Heaney AP. The alpha1-adrenergic receptor antagonist doxazosin inhibits EGFR and NF-kappaB signalling to induce breast cancer cell apoptosis. Eur J Cancer. 2008;44:160–6.View ArticlePubMedGoogle Scholar
- Partin JV, Anglin IE, Kyprianou N. Quinazoline-based alpha 1-adrenoceptor antagonists induce prostate cancer cell apoptosis via TGF-beta signalling and I kappa B alpha induction. Br J Cancer. 2003;88:1615–21.View ArticlePubMedPubMed CentralGoogle Scholar