Testosterone therapy and cancer risk

Sexual Medicine Testosterone therapy and cancer risk Michael L. Eisenberg*, Shufeng Li*, Paul Betts, Danielle Herder, Dolores J. Lamb and Larry I. Lipshultz Departments of *Urology, Obstetrics/Gynecology and Dermatology, Stanford University School of Medicine, Stanford, CA, Cancer Epidemiology and Surveillance Branch, Texas Cancer Registry, Texas Department of State Health Services, Austin, TX, and Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA Objective To determine if testosterone therapy (TT) status modifies a man s risk of cancer. Patients and Methods The Urology clinic hormone database was queried for all men with a serum testosterone level and charts examined to determine TT status. Patient records were linked to the Texas Cancer Registry to determine the incidence of cancer. Men accrued time at risk from the date of initiating TT or the first office visit for men not on TT. Standardised incidence rates and time to event analysis were performed. Results In all, 247 men were on TT and 211 did not use testosterone. In all, 47 men developed cancer, 27 (12.8%) were not on TT and 20 (8.1%) on TT. There was no significant difference in the risk of cancer incidence based on TT (hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.57 1.9; P = 1.8). There was no difference in prostate cancer risk based on TT status (HR 1.2, 95% CI 0.54 2.50). Conclusion There was no change in cancer risk overall, or prostate cancer risk specifically, for men aged >40 years using long-term TT. Keywords testosterone, hypogonadism, neoplasms Introduction As the population ages, the numbers of hypogonadal men are increasing. Treatment of hypogonadism with testosterone therapy (TT) has been shown to improve muscle mass and strength, sexual function and desire, mood, and bone mineral density [1 5]. However, there remains concern about possible negative health effects of TT. Since the recognition of the link between castration and prostate cancer regression by Huggins and Hodges [6] in 1941, there has been a concern that TT would increase a man s risk of prostate cancer. However, recent studies have cast doubt on the association between testosterone and prostate cancer. A compilation of several longitudinal studies analysed 3886 men and found no association between baseline testosterone levels and prostate carcinogenesis [7]. While endogenous androgen levels do not appear to impact prostate cancer risk, investigators have explored whether TT alters a man s risk of prostate cancer. Several trials on men on TT found no higher risk of prostate cancer than the general population with up to 3.5 years follow-up [8,9]. A meta-analysis of 19 placebo-controlled trials also failed to show a higher risk of prostate cancer in men on TT [10]. However, short follow-up from the trials included in the meta-analysis may preclude adequate detection of risk if exposure to exogenous testosterone supplementation alters the prostate s chemical milieu to favour cancer development, which may take several years to manifest. A recent retrospective study from the UK with up to 20 years follow-up suggested no increased risk of prostate cancer in men on TT [11]. While reassuring, poor follow-up make definitive conclusions difficult. In addition, other cancers have also been linked to hormone manipulation. A higher incidence of colorectal cancer was identified in men on androgen-deprivation therapy [12]. Data also suggests that breast cancer incidence may be impacted by androgens [13]. In the absence of placebo-controlled trials with long-term follow-up, retrospective observational studies may prove useful. By linking men treated with TT over the past 20 years with the Texas Cancer Registry, we examined the association between cancer incidence (prostate and others) and TT. Patients and Methods After Institutional Review Board approval, an initial study cohort was identified with available data from 1989 to 2009 contained in the andrology database at the Baylor College BJU International 2014 BJU International doi:1111/bju.12756 BJU Int 20; 1: 317 321 Published by John Wiley & Sons Ltd. www.bjui.org wileyonlinelibrary.com

Eisenberg et al. of Medicine Special Procedures Laboratory in the Scott Department of Urology. The laboratory performs a high volume of hormone analyses for the treatment and management of sexual dysfunction, hypogonadism, and male infertility. Within this group, we reviewed available charts of men. We included men in whom we could discern whether TT was used or was not used in their treatment. Dates and type (transdermal vs injection) of TT were recorded. Men who had used both injection and transdermal therapy were counted in the injection group. All men in the andrology database were linked to the Texas Cancer Registry (TCR). The TCR is a State-wide population-based registry that serves as the foundation for measuring the Texas cancer burden and comprehensive cancer control efforts. The TCR contains information on all cases of histologically confirmed cancer from 1 January 1995 to 31 December 2009 (the last year with complete data available when linkage was performed in October 2011). The TCR provides data on date of diagnosis, age at diagnosis, site of cancer (International Statistical Classification of Diseases for Oncology, Third Edition [ICDO-3] codes), tumour behaviour (ICDO-3 coding), and histological type (ICDO-3 coding). Automated, probabilistic matching was performed using social security number, first name, middle name, last name, date of birth, and address. All matches were reviewed by P.B. Only the first cancer diagnosis was included in the analysis. Men with a cancer diagnosis before the initiation of TT or a non-texas address were excluded from analysis. We limited our analysis to men aged >40 years, given the lower rates of TT and cancer in younger men. A sensitivity analysis using all men in the cohort did not meaningfully change our conclusions. Statistical Analysis As cancer cases before 1995 could not be identified, due to confines of the TCR, our analysis was truncated to begin on 1 January 1995 for the men with a prior hormone analysis. Men accrued at-risk-time from the date TT was initiated or the date of first hormone analysis (for men not on TT) until cancer diagnosis or 31 December 2009 (the final year that complete cancer data was available). The rate of cancer in our cohort was compared with the general Texas population. We calculated the expected number of cases by multiplying the number of years at risk by the 5-year age strata cancer rates from the TCR for the study period. Standardised incidence rates (SIRs) were calculated by dividing the observed number of cancer cases by the expected number of cases. Analyses were performed on the entire cohort, as well as subgroups. We also analysed the risk of cancer in our cohort after stratifying based on TT status using a Cox proportional hazards regression model while adjusting for age and year of evaluation. Comparison between Kaplan Meier curves was performed using the log-rank function. All P values were two sided with P < 5 considered to indicate statistical significance. Analyses were performed using SAS (version 9.3, SAS Institute, Inc, Cary, NC, USA). Results In all, 458 men met inclusion criteria; 247 men were on TT and 211 were not. There was no significant difference between men on and not on TT for age, date of evaluation, or age at last follow-up (Table 1). Of the men on TT, 70 were on injectable and 177 men were on transdermal TT. Transdermal TT was more common in the patients treated Table 1 Characteristics of cohort. Characteristic TT No TT P N 247 211 Mean (SD) age at evaluation, years 54.38 (8.9) 55.21 (11.3) 0.88 Age at evaluation in years, n (%) 1 40 49 88 (35.6) 81 (38.4) 50 59 95 (38.5) 65 (30.8) 60 64 (25.9) 65 (30.8) Mean (SD) age at last follow-up or diagnosis, years 63.4 (9.2) 64.04 (11.4) 0.94 Mean (SD) follow-up, years 6.39 (3.5) 8.75 (3.2) <1 Year of evaluation, n (%) 0.35 1991 1995 21 (8.5) 11 (5.2) 1996 2000 87 (35.2) 84 (39.8) 2001 2005 134 (54.3) 109 (51.7) 2006 present 5 (2.0) 7 (3.3) Type of TT, n (%) Injectable 70 (28.3) Transdermal 177 (71.7) Mean (SD) baseline testosterone, ng/dl 314.25 (187.3) 354.9 (141.2) <1 Mean (SD) average testosterone after TT, ng/dl) 508.69 (243.12) 318 BJU International 2014 BJU International

Testosterone therapy and cancer risk Table 2 Incidence of cancer stratified by TT status examining all cancers, prostate cancer, and all cancers excluding prostate cancer. Multivariable model adjusted for patient age and year of evaluation. Cancers TT status N Observed, n Expected, n SIR (95% CI) Adjusted HR (95% CI) P All cancers All men 458 47 31.8 1.48 (1.09,1.97) TT yes 247 20 14.1 1.42 (0.86,2.19) Reference 0.94 TT no 211 27 17.7 1.53 (1.01,2.22) 1.02 (0.57 1.84) Prostate cancer All men 458 28 9.4 2.99 (1.98,4.32) TT yes 247 11 4.2 2.62 (1.30,4.68) Reference 0.70 TT no 211 17 5.2 3.29 (1.91,5.26) 1.16 (0.54 2.50) All cancers excluding prostate cancer All men 458 19 22.4 0.85 (0.51,1.32) TT yes 247 9 9.9 0.91 (0.41,1.72) Reference 0.73 TT no 211 10 12.5 0.80 (0.38,1.47) 0.85 (0.34 2.14) Table 3 Incidence of prostate cancer stratified by baseline PSA level (< vs median of 1.1 ng/ml) level. TT status N Observed, n Expected, n SIR (95% CI) PSA level <1.1 ng/ml All men 138 2 2.8 0.72 (8, 2.61) TT yes 82 1 1.5 0.68 (1, 3.80) TT no 56 1 1.3 0.77 (1, 4.28) PSA level 1.1 ng/ml All men 147 16 4.6 3.51 (2.01, 5.70) TT yes 76 6 1.8 3.34 (1.22, 7.27) TT no 71 10 2.8 3.62 (1.73, 6.66) more recently, with 77% of patients on transdermal TT after 2001 compared with 65% on transdermal TT before this date (P = 4). In all, 47 men developed cancer in the cohort, 8.1% of men on TT and 12.8% of men not on TT (P = ). Compared with the general Texas population, the men in our cohort had a higher risk of overall cancer with 47 cases observed with only 32 expected (SIR 1.5, 95% CI 1.1 2.0; Table 2). The rates did not differ based on TT status. The sites of cancers included prostate (28), lung (four), bladder (four), thyroid (two), colon (one), biliary (one), kidney (one), larynx (one), leukaemia (one), liver (one), lymphoma (one), oral (one), and pancreas (one). The excess cancer risk seemed to be entirely explained by increased prostate cancer cases. While the risk of prostate cancer for the cohort was three-fold higher than that expected in the general population (SIR 2.99, 95% CI 2.0 4.3), the risk of all other cancers was not different from the expected rate (SIR 0.9, 95% CI 0.5 1.3). Importantly, there was an elevated prostate cancer rate seen for both men on TT and not on TT (Fig. 1a c). Prostate biopsy rates were similar between the groups with 64 of 247 (25.9%) men on TT and 67 of 211 (31.8%) not on TT receiving a prostate biopsy during follow-up (P = 7). We then stratified men based on our baseline median PSA level of 1.1 ng/ml (Table 3). Men below the threshold had no altered risk of prostate cancer regardless of TT status (SIR 0.72, 95% CI 8 2.61). In contrast, men above the median had an elevated prostate cancer risk (SIR 3.51, 95% CI 2.01 5.70). The elevated risk was similar regardless of TT status (P = 0.8). Other PSA thresholds (2.5 or 4 ng/ml) yielded similar conclusions with no difference in prostate cancer incidence based on TT status. No meaningful changes in the conclusions occurred when stratifying men by type of TT (i.e. injection vs transdermal) or baseline testosterone levels with similar cancer rates identified between the groups (data not shown). Discussion The present study found no increased risk of any cancer, or prostate cancer specifically, for men on TT for up to years. Moreover, on subgroup analysis, there was no difference in risk based on the type of TT or baseline testosterone levels. However, men with a baseline PSA level of >1.1 ng/ml, had an elevated risk of prostate cancer, which was independent of TT status. TT benefits men in quality of life measures, such as sexual function and desire and mood [5,14,]. In addition, health benefits have also been shown including increased muscle mass and strength, bone mineral density, and even overall mortality [1 3,16]. Despite benefits, there are concerns about the risk of TT for prostate health. Testosterone product warning labels include possible risks of prostate carcinogenesis. The relationship between serum androgen levels and prostate cancer risk remains unclear. A compilation of several longitudinal studies found no association between baseline testosterone levels and prostate carcinogenesis [7]. In BJU International 2014 BJU International 319

Eisenberg et al. Fig. 1 Kaplan Meier curves examining incidence of development of all cancers, prostate cancer, and all cancers excluding prostate cancer after stratifying based on TT status. A B C All Cancers p = 0.83 211 247 203 208 195 160 132 89 2.5 5.0 7.5 1 12.5 Prostate Cancers p = 0.59 201 238 196 201 190 5 130 87 70 70 2.5 5.0 7.5 1 12.5 Non Prostate Cancers p = 0.65 194 2 188 200 2.5 182 8 5.0 125 88 7.5 66 35 1 35 12.5 contrast, other investigators have reported higher rates of prostate cancer in men with higher testosterone levels [17]. Adding to the uncertainty, other investigators have suggested a higher risk of prostate cancer incidence and more aggressive disease in hypogonadal men [18 20]. Studies examining the risk of TT on prostate cancer suggest its safety but are limited by short follow-up duration. A recent report by Feneley et al. [11] did have longer follow-up, but poor cohort retention limited interpretability. Moreover, given differences in prostate cancer screening and incidence between the USA and UK, the study s conclusions may not be generalizable to the USA population. The present study suggests that TT does not alter a man s prostate cancer risk or risk for any other cancers. Indeed, all subanalyses that compared TT methods and baseline patient characteristics showed no alteration in prostate cancer risk. Thus, any further increase in serum testosterone levels above saturation levels will not further stimulate or activate the prostate or other androgen-responsive tissues [21]. Consistent with prior work, men with higher baseline PSA levels are more likely to be ultimately diagnosed with prostate cancer [22]. It is important to note that the incidence of prostate cancer was higher in our present cohort compared with the general Texas population. Consistent with other studies, routine prostate cancer screening does increase the incidence of prostate cancer [23,24]. However, no difference in cancer rate or prostate biopsy rate was noted based on TT status suggesting that TT does not meaningfully affect this risk. Several limitations warrant mention. The retrospective, observational study design limits the interpretation of the findings because patients were not randomised to treatment and were, instead, treated based on clinical condition. Moreover available records may have been differentially represented based on treatment and/or outcome, although we have no reason to suspect that. As such, bias may be introduced as we may not be able to adequately control for confounding factors that may have affected both treatment and outcome. While follow-up protocols and PSA monitoring on TT were consistent in our clinic over time, many men did not strictly adhere to recommended monitoring. Moreover, the rationale for prostate biopsy evolved over time and was individually influenced by family history and patient comorbidities. In addition, all men were biopsied for cause. In other words, not all men underwent a prostate biopsy; thus, undiagnosed prostate cancermayhavebeenpresent.whilemenhadbeenseen in the clinic for at least 3 years before TCR linkage, it is conceivable that some men may have left the state. In such cases, cancer diagnoses may not be captured by the TCR. Next, the number of men was relatively small, which may limit our power to detect the impact of TT. Moreover, the population was limited to the state of Texas. While 320 BJU International 2014 BJU International

Testosterone therapy and cancer risk cancer rates in Texas are similar to the national rates, the findings may not apply to other populations. Finally, only the first cancer diagnosis was available for analysis. While the rates of secondary malignancy are low, this may have impacted our findings for the prostate cancer analysis [25,26]. Nevertheless, the present study showed no increased risk of prostate cancer or any other cancer for men aged >40 years on TT. To our knowledge, this represents the longest term data on the safety of TT with respect to prostate carcinogenesis in the USA. While controversy exists about prostate cancer screening and treatment in the USA, the present study is reassuring regarding any added risks with TT [23,24,27]. Conflict of Interest M.L.E. and L.I.L. report a grant from Endo Pharmaceuticals to partially support this work. All other authors have nothing to disclose. References 1 Bhasin S, Storer TW, Berman N et al. 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Evaluation of second cancer induction risk by CT follow-up in oncological long-surviving patients. Health Phys 2013; 104: 1 8 27 Moyer VA. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012; 7: 120 34 Correspondence: Michael L. Eisenberg, Department of Urology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5118, USA. e-mail: eisenberg@stanford.edu Abbreviations: ICDO-3, International Statistical Classification of Diseases for Oncology, Third Edition; SIR, standardised incidence rate; TCR, Texas Cancer Registry; TT, testosterone therapy. BJU International 2014 BJU International 321