Sage Journals: Discover world-class research

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. 20.0 ng/dL vs. 30.0 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. 1.86 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).

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 = −.09402 (.6934), Leuprolide 3.75 mg = .11053 (.6524), Leuprolide 7.5 mg = .19782 (.4031), overall = −.05561 (.6757).

Figure 1.

Spearman’s rank correlation coefficient (p value) between total testosterone and PSA.

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. 20.0 ng/dL vs. 30.0 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. 1.86 vs. 2.57, respectively; p = .0067; see Figure 2).

Figure 2.

Median PSA and testosterone variations among groups.

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, 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 node-positive 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 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 pharmaco-logical 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.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Bolla

Collette

Blank

Warde

Dubois

J. B.

Mirimanoff

R. O.

. . . Pierart

(2002). Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): A phase III randomised trial. Lancet, 360, 103-106.

Collette

Burzykowski

Carroll

K. J.

Newling

Morris

Schröder

F. H.

(2005). Is prostate-specific antigen a valid surrogate end point for survival in hormonally treated patients with metastatic prostate cancer? Joint research of the European Organisation for Research and Treatment of Cancer, the Limburgs Universitair Centrum, and Astra Zeneca Pharmaceuticals. Journal of Clinical Oncology, 23, 6139-6148.

Denis

Murphy

G. P.

(1993). Overview of Phase III trials on combined androgen treatment in patients with metastatic prostate cancer. Cancer, 72(12 Suppl.), 3888-3895.

Dias Silva

Ferreira

Matheus

Faria

E. F.

Silva

G. D.

Saito

. . . Reis

L. O.

(2012). Goserelin versus Leuprolide in the chemical castration of patients with prostate cancer. International Urology and Nephrology, 44, 1039-1044.

Fujii

Yonese

Kawakami

Yamamoto

Okubo

Fukui

(2008). Equivalent and sufficient effects of Leuprolide acetate and Goserelin acetate to suppress serum testosterone levels in patients with prostate cancer. BJU International, 101, 1096-1100.

Hanninen

Venner

North

(2009). A rapid PSA half-life following docetaxel chemotherapy is associated with improved survival in hormone refractory prostate cancer. Canadian Urological Association Journal, 3, 369-374.

Hellerstedt

B. A.

Pienta

K. J.

(2002). The current state of hormonal therapy for prostate cancer. CA: A Cancer Journal for Clinicians, 52, 154-179.

Heyns

C. F.

Simonin

M. P.

Grosgurin

Schall

Porchet

H. C.

(2003). Comparative efficacy of triptorelin pamoate and Leuprolide acetate in men with advanced prostate cancer. BJU International, 92, 226-231.

Hussain

Goldman

Tangen

Higano

C. S.

Petrylak

D. P.

Wilding

. . . Crawford

E. D.

(2009). Prostate-specific antigen progression predicts overall survival in patients with metastatic prostate cancer: Data from Southwest Oncology Group Trials 9346 (Intergroup Study 0162) and 9916. Journal of Clinical Oncology, 27, 2450-2456.

10.

Kuhn

J. M.

Abourachid

Brucher

Doutres

J. C.

Fretin

Jaupitre

. . .Dufour-Esquerré

. (1997). A randomized comparison of the clinical and hormonal effects of two GnRH agonists in patients with prostate cancer. European Urology, 32, 397-403.

11.

Lawrentschuk

Fernandes

Bell

Barkin

Fleshner

(2001). Efficacy of a second line luteinizing hormone-releasing hormone agonist after advanced prostate cancer biochemical recurrence. Journal of Urology, 185, 848-854.

12.

Lin

G. W.

Yao

X. D.

Zhang

S. L.

Dai

C. G.

Zhang

H. L.

. . . Ye

D. W.

(2009). Prostate-specific antigen half-life: A new predictor of progression-free survival and overall survival in Chinese prostate cancer patients. Asian Journal of Andrology, 11, 443-450.

13.

Messing

E. M.

Manola

Sarosdy

Wilding

Crawford

E. D.

Trump

(1999). Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. New England Journal of Medicine, 341, 1781-1788.

14.

Morote

Orsola

Planas

Trilla

Raventos

C. X.

Cecchini

Catalán

(2007). Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy. Journal of Urology, 178(4 Pt 1), 1290-1295.

15.

Novara

Galfano

Secco

Ficarra

Artibani

(2009). Impact of surgical and medical castration on serum testosterone level in prostate cancer patients. Urologia Internationalis, 82, 249-255.

16.

Oefelein

M. G.

Cornum

(2000). Failure to achieve castrate levels of testosterone during luteinizing hormone releasing hormone agonist therapy: The case for monitoring serum testosterone and a treatment decision algorithm. Journal of Urology, 164(3 Pt 1), 726-729.

17.

Perachino

Cavalli

Bravi

(2010). Testosterone levels in patients with metastatic prostate cancer treated with luteinizing hormone-releasing hormone therapy: Prognostic significance? BJU International, 105, 648-651.

18.

Perez-Marreno

Chu

F. M.

Gleason

Loizides

Wachs

Tyler

R. C.

(2002). A six-month, open-label study assessing a new formulation of Leuprolide 7.5 mg for suppression of testosterone in patients with prostate cancer. Clinical Therapeutics, 24, 1902-1914.

19.

Pilepich

M. V.

Winter

Lawton

C. A.

Krisch

R. E.

Wolkov

H. B.

Movsas

. . . Grignon

(2005). Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma: Long-term results of phase III RTOG 85-31. International Journal of Radiation Oncology, Biology, and Physics, 61, 1285-1290.

20.

Reis

L. O.

(2011). Old issues and new perspectives on prostate cancer hormonal therapy: The molecular substratum. Medical Oncology, 29, 1948-1955.

21.

Reis

L. O.

(2012). Variations of serum testosterone levels in prostate cancer patients under LH-releasing hormone therapy: An open question. Endocrine Related Cancer, 19(3), R93-R98.

22.

Rove

K. O.

Crawford

E. D.

Perachino

Morote

Klotz

Lange

P. H.

. . . Reis

L.O.

(2014). Maximal testosterone suppression in prostate cancer: Free vs total testosterone. Urology, 83, 1217-1222.

23.

Seidenfeld

Samson

D. J.

Hasselblad

Aronson

Albertsen

P. C.

Bennett

C. L.

Wilt

T. J.

(2000). Single-therapy androgen suppression in men with advanced prostate cancer: A systematic review and meta-analysis. Annals of Internal Medicine, 132, 566-577.

24.

Smith

M. R.

(2007). Obesity and sex steroids during gonadotropin-releasing hormone agonist treatment for prostate cancer. Clinical Cancer Research, 13, 241-245.

25.

Smith

M. R.

McGovern

F. J.

(2001). Gonadotropin-releasing hormone agonist failure in a man with prostate cancer. Journal of Urology, 166, 211.

26.

Tanaka

Fujimoto

Hirao

Shimizu

Tsujimoto

Samma

(2007). Endocrine response to a single injection of Goserelin 3.6 mg or Leuprolide 3.75 mg in men with prostate cancer. Archives of Andrology, 53(2), 87-90.

27.

Tombal

(2005). Appropriate castration with luteinizing hormone releasing hormone (LHRH) agonists: What is the optimal level of testosterone? European Urology, 4(1), 14-19.

28.

van der Sluis

T. M.

van Moorselaar

R. J.

Meuleman

E. J.

Ter Haar

R. W.

Bui

H. N.

Heijboer

A. C.

Vis

A. N.

(2013). Relationship between body mass index and serum testosterone concentration in patients receiving luteinizing hormone-releasing hormone agonist therapy for prostate cancer. Urology, 81, 1005-1009.

29.

Yri

O. E.

Bjoro

Fossa

S. D.

(2006). Failure to achieve castration levels in patients using Leuprolide acetate in locally advanced prostate cancer. European Urology, 49(1), 54-58.

30.

E. Y.

Getzenberg

R. H.

Coss

C. C.

Gittelman

M. M.

Keane

Tutrone

. . . Steiner

M. C.

(2014). Selective estrogen receptor alpha agonist GTx-758 decreases testosterone with reduced side effects of androgen deprivation therapy in men with advanced prostate cancer. European Urology. Advance online publication. doi:10.1016/j.eururo.2014.06.011

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

Abstract

Keywords

Introduction

Method

Statistics

Results

Discussion

Conclusions

Footnotes

Declaration of Conflicting Interests

Funding

References