Correlation Between Testosterone and PSA Kinetics in Metastatic Prostate Cancer Patients Treated With Diverse Chemical Castrations

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1 552468JMHXXX / American Journal of Men s HealthReis et al. research-article2014 Article Correlation Between Testosterone and PSA Kinetics in Metastatic Prostate Cancer Patients Treated With Diverse Chemical Castrations American Journal of Men s Health 2015, Vol. 9(5) The Author(s) 2014 Reprints and permissions: sagepub.com/journalspermissions.nav DOI: / ajmh.sagepub.com Leonardo O. Reis, MD, MSc, PhD 1,2, Fernandes Denardi, MD, PhD 2, Eliney F. Faria, MD, PhD 3, and Elcio Dias Silva, MD, PhD 4 Abstract To assess total testosterone and prostatic-specific antigen (PSA) kinetics among diverse chemical castrations, advanced-stage prostate cancer patients were randomized into three groups of 20: Group 1, Leuprolide 3.75 mg; Group 2, Leuprolide 7.5 mg; and Group 3, Goserelin 3.6 mg. All groups were treated with monthly application of the respective drugs. The patients levels of serum total testosterone and PSA were evaluated at two time periods: before the treatment and 3 months after the treatment. Spearman s rank correlation coefficient was utilized to verify the hypothesis of linear correlation between total testosterone and PSA levels. At the beginning the patients age, stage, grade, PSA, and total testosterone were similar within the three groups, with median age 72, 70, and 70 years in Groups 1, 2, and 3, respectively. Three months after the treatment, patients who received Leuprolide 7.5 mg presented significantly lower median total testosterone levels compared with Goserelin 3.6 mg and Leuprolide 3.75 mg (9.5 ng/dl vs ng/dl vs ng/dl, respectively; p =.0072), while those who received Goserelin 3.6 mg presented significantly lower PSA levels compared with Leuprolide 7.5 mg and Leuprolide 3.75 mg (0.67 vs vs. 2.57, respectively; p =.0067). There was no linear correlation between total testosterone and PSA levels. Overall, regarding castration levels of total testosterone, 28.77% of patients did not obtain levels 50 ng/dl and 47.80% did not obtain levels 20 ng/dl. There was no correlation between total testosterone and PSA kinetics and no equivalence among different pharmacological castrations. Keywords bioavailable testosterone, luteinizing hormone-releasing hormone, LHRH agonists, prostatic specific antigen, pharmacological castration and surgical castration Introduction Androgen suppression is an effective treatment for prostate cancer in advanced stages, controlling the disease in 80% to 90% of men with results in progression-free survival of approximately 12 to 33 months (Denis & Murphy, 1993). The use of luteinizing hormone-releasing hormone (LHRH) agonists and antiandrogenics began in the 1980s and today represents a standard alternative to surgical castration for patients with prostate cancer and metastases. The LHRH agonists, such as Goserelin and Leuprolide, have been reported to be as effective as surgical castration (Hellerstedt & Pienta, 2002; Seidenfeld et al., 2000). However, some studies have identified that the grade of potency of LHRH analog peptides varies according to their modified amino acid structures, and thus the effect on the pituitary gonadal axis may vary with the agent. Several studies suggested that serum testosterone is not always suppressed below the upper limit of the castration range in patients using LHRH agonists, especially Leuprolide acetate (Heyns, Simonin, Grosgurin, Schall, & Porchet, 2003; Oefelein & Cornum, 2000; Smith & McGovern, 2001; Yri, Bjoro, & Fossa, 2006). 1 Pontifical Catholic University of Campinas, Campinas, Brazil 2 University of Campinas Unicamp, Campinas, Brazil 3 Barretos Cancer Hospital, Barretos, Brazil 4 Maternidade de Campinas e Hospital Sírio Libanês, São Paulo, Brazil Corresponding Author: Leonardo O. Reis, Urology Division, Faculty of Medicine, Pontifical Catholic University of Campinas, PUC-Campinas, Av. John Boyd Dunlop s/n, CEP , Campinas, São Paulo, Brazil. reisleo.l@gmail.com

2 Reis et al. 431 Studies correlating testosterone and prostatic-specific antigen (PSA) kinetics among diverse chemical castrations are lacking and total testosterone may not represent the real exposure to bioavailable and active free testosterone. This study assessed the equivalence of Leuprolide 3.75 mg, Leuprolide 7.5 mg, and Goserelin 3.6 mg in terms of correlation between serum total testosterone (TT) and PSA variations. Method Prospectively, this study included 60 patients with advanced prostate carcinoma, with indication for hormone blockade. The patients were randomized into three groups of 20 based on the order of arrival and urologic oncology reference center: Group 1 received Leuprolide 3.75 mg, Group 2 received Leuprolide 7.5 mg, and Group 3 received Goserelin 3.6 mg. All groups were treated with monthly application of the respective drugs. Group 1 had one patient excluded because of a testosterone level of castration before randomization. The subjects were selected from two reference urologic oncology centers. The patients from the first center received Leuprolide 3.75 mg or Goserelin 3.6 mg, and the patients from the second center received Leuprolide 7.5 mg. After written consent, the selected patients were submitted to total testosterone and PSA tests and initiated the treatment with one of the three drugs. Patients who had previously undergone hormone blockade treatments and patients who already presented castration testosterone levels were not included in the study. The drugs were administered once a month during 3 months. After the conclusion of the proposed treatment, the patients were followed in the respective services, with the drugs that were appointed to the respective groups and under the same rules of procedure for patients with advanced prostate cancer. The patients levels of serum total testosterone and PSA were evaluated at two time periods: before the treatment and 3 months after the treatment. The testosterone concentration was taken with microparticle enzyme immunoassay (MEIA) in the patients of Groups 1 and 3 and with eletrochemiluminescence-testosterone II (cobas) Elecys and cobas analyzers (Roche Diagnostics GmbH) in Group 2. The proportion of chemically castrated patients for cutoffs, defined as 50 ng/dl and 20 ng/dl of testosterone, was compared in the three groups. Statistics Kruskal Wallis test compared pretreatment variables. Spearman s rank correlation coefficient was utilized to verify the hypothesis of linear correlation between total testosterone and PSA levels. Spearman s coefficient varies from 1 (negative correlation) to 1 (positive correlation). Values close to zero denote no correlation. ANOVA test compared the three groups in the follow-up, and Tukey test confirmed differences between groups. Significance level was considered 5% (p <.05). Results At the beginning of study, the patients age, disease stage, grade and volume (presence of visceral metastases), total testosterone, and PSA were not significantly different within the three groups (p >.05). Range, median, and average age for group 1 were 58-88, 72, and 71.4 years for Group 1; 56-81, 70, and 69.6 years for Group 2; and 58-86, 70, and 71.3 years for Group 3, respectively. Three months after the treatment, there was no linear correlation between total testosterone and PSA levels, overall (n = 59) and in each group (see Figure 1). Spearman s coefficient (p value): Goserelin 3.6 mg = (.6934), Leuprolide 3.75 mg = (.6524), Leuprolide 7.5 mg = (.4031), overall = (.6757). Patients who received Leuprolide 7.5 mg presented significantly lower median total testosterone levels compared with Goserelin 3.6 mg and Leuprolide 3.75 mg (9.5 ng/dl vs ng/dl vs ng/dl, respectively; p =.0072), while those who received Goserelin 3.6 mg presented significantly lower PSA levels compared with Leuprolide 7.5 mg and Leuprolide 3.75 mg (0.67 vs vs. 2.57, respectively; p =.0067; see Figure 2). Regarding castration levels of total testosterone, 28.77% of patients did not obtain levels 50 ng/dl (26.3%, 25%, and 35% of patients in Leuprolide 3.75 mg, Leuprolide 7.5 mg, and Goserelin 3.6 mg groups, respectively; p =.751 for the difference of proportions). Furthermore, 47.8% of patients did not obtain levels 20 ng/dl (68.4%, 30%, and 45% of patients in Leuprolide 3.75 mg, Leuprolide 7.5 mg, and Goserelin 3.6 mg groups, respectively; p =.054). There were no differences in terms of tumor grade, stage, and volume of disease (presence of visceral metastases) when comparing those that reached or did not reach castration levels. Discussion This preliminary study dissects the connection between testosterone and PSA kinetics in metastatic prostate cancer patients treated with diverse chemical castrations and for the first time identifies no linear correlation between total testosterone and PSA variations, supporting the hypothesis that efficacy in terms of TT and PSA variations independently varies among LHRH analogs. Though PSA is routinely measured to provide an indication of disease control, results from a meta-analysis,

3 432 American Journal of Men s Health 9(5) Figure 1. Spearman s rank correlation coefficient (p value) between total testosterone and PSA. Figure 2. Median PSA and testosterone variations among groups. utilizing data from three randomized clinical trials, suggested that PSA could not be statistically validated as a surrogate for overall survival. However, patients in such study were not treated uniformly and PSA was not monitored in a similar way (Collette et al., 2005). Sustaining the controversy, subsequent studies reported that effective PSA control (Hussain et al., 2009) and a shorter PSA half-life (faster PSA reduction) are associated with improved prostate cancer progression and overall survival (Hanninen, Venner, & North, 2009; Lin et al., 2009). The main purpose of any type of hormonal blockade is to reach testosterone levels less than 50 ng/dl, which is, historically, considered castration level (Oefelein & Cornum, 2000; Perez-Marreno et al., 2002). Nevertheless, there are controversies regarding this level, because it derives from the older measurement method used in the 1960s and 1970s, which was known as isotope derivative dilution technique, that considered 50 ng/dl as the lower limit for detection (Novara, Galfano, Secco, Ficarra, & Artibani, 2009; Tombal, 2005). In this context, the equivalence of surgical and different pharmacological castrations has been contested (Dias Silva et al., 2012). Besides that, there is a cluster of evidence supporting the hypothesis that the lower the better when achieving castration levels of testosterone, based on the data from second-line hormonal manipulation and its molecular basis (Reis, 2011, 2012), and on better oncological results reported for patients with castration levels <32 ng/dl (Morote et al., 2007). There is rapidly growing evidence that the depth of the testosterone nadir is associated with a survival advantage in men with metastatic prostate cancer (Perachino, Cavalli, & Bravi, 2010), yet without PSA/testosterone correlation analysis, the original scope of the present study. In terms of PSA variations among different LHRH analogs, recent data suggest that about 70% of patients experienced decreased PSA after the LHRH switch, and this decrease appeared more pronounced when switching from Leuprolide to Goserelin rather than vice versa (Lawrentschuk, Fernandes, Bell, Barkin, & Fleshner, 2001). These data suggest that the pharmacodynamics of these agents may be different and are in line with our results that confirm that the lowest levels of PSA occurred in patients under Goserelin 3.6 mg, even though starting from not significantly different levels. Another interesting fact is that Goserelin is the only LHRH agonist that has been described to improve overall survival when used as an adjuvant to radiotherapy in locally advanced disease (Bolla et al., 2002; Pilepich et al., 2005) and to radical prostatectomy in patients with nodepositive disease (Messing et al., 1999). This may be related to lowest PSA levels and might occur independent of total testosterone variations, once the lowest TT levels occurred in patients under Leuprolide 7.5 mg treatment when comparing LHRH analogs. There are few studies directly comparing the different LHRH analogs, and most include a small number of patients, are not randomized and limited to TT levels, and are lacking PSA and survival analysis (Fujii et al., 2008; Kuhn et al., 1997; Smith, 2007; Tanaka et al., 2007). Adding to the LHRH disparities, there appears to be a correlation between a greater body mass index (BMI) and greater concentrations of free testosterone in patients under chemical castration (Smith, 2007; van der

4 Reis et al. 433 Sluis et al., 2013). A potential relationship between BMI and the development and/or progression of prostate cancer might be caused by elevated free testosterone levels and by a potential difference in pharmacodynamics among normal weight, overweight, and obese patients receiving LHRH agonist therapy for prostate cancer (van der Sluis et al., 2013). One robust hypothesis explaining no correlation between TT and PSA kinetics is that free (bioavailable) testosterone may be the main factor driving PSA and disease control, but not total testosterone, and different medicines may present different efficiency in lowering the bioavailable testosterone. In fact, the role of free testosterone in prostate cancer remains unclear, supporting the bioavailable testosterone hypothesis. The best marker of hormonal deprivation efficacy is to be defined, and free (bioavailable) testosterone concentrations could be an interesting topic for future research, especially with the increased possibilities of testosterone measurement in the castrate range using ultrasensitive technique of serum testosterone measurement and considering that no correlation between TT and PSA variations was achieved in the setting of diverse chemical castrations in this study. Free testosterone deserves more research regarding its relation to clinical outcomes once it may better reflect prostate cancer tissue androgen levels than serum total testosterone concentration (Rove et al., 2014). In this scenario, a recent study is in line with our results, recognizing the clinical utility of these new data. The authors report that while Leuprolide was more efficient in lowering TT, an oral selective estrogen receptor alpha agonist (GTx-758) lowered free testosterone and PSA more than Leuprolide (Yu et al., 2014). These findings add to the current study to underscore the importance of other markers over TT as a more accurate measure of available circulating testosterone, supporting the free hormone hypothesis where free testosterone levels better correlate with PSA kinetics and androgen action. It is important to highlight that while original, our study is not devoid of limitations, including a relatively small number of patients with short follow-up. Additionally, BMI and tumor neuroendocrine differentiation were not assessed and might affect PSA and TT levels. Confirmatory trials will need stronger methodology with patients stratification, analyzing disease progression and survival to add to this hypothesis generating study. Besides, LHRH antagonists should also be compared with agonists, considering different times to achieve castration level with potential different clinical outcomes between them. Conclusions This prospective randomized study complements recent data contesting the equivalence of different pharmacological castrations regarding TT and PSA levels. Also, there was no correlation between TT and PSA kinetics in the setting of chemical castration. While Goserelin 3.6 mg reported the lowest PSA levels, the lowest TT levels occurred in the Leuprolide 7.5 mg treatment, even starting from not significantly different groups in terms of TT, PSA, age, and disease stage, grade, and volume. Labeling and classifying LHRH agonists from a regulatory perspective in different classes according to their efficacy in terms of TT and PSA variations appears warranted. 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Goserelin versus leuprolide in the chemical castration of patients with prostate cancer

Int Urol Nephrol (2012) 44:1039 1044 DOI 10.1007/s11255-012-0134-z UROLOGY ORIGINAL PAPER Goserelin versus leuprolide in the chemical castration of patients with prostate cancer Élcio Dias Silva Ubirajara