Dr. med. Dirk Manski



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Prostate Cancer: Hormonal Therapy (Androgen Ablation)

Guidelines and review literature: (EAU Guidelines, Mottet et al, 2015) (S3-Leitlinie Prostatakarzinom der DGU) (Walsh-Campbell Urology 11th Edition).


Hormonal therapy of advanced prostate cancer:
(*) Antiandrogens are given for the first two weeks of GnRH agonist therapy against the flare of LH and testosterone levels [see section pharmacology/hormone therapy]. Check the testosteron level if patients progress under GnRH therapy.
(**) See figure intermittend androgen suppression for details.
(***) No definitive evidence on the optimal CRPC treatment sequence exists.
Flowchart Hormonal therapy of advanced prostate cancer

Hormone-sensitive Prostate Cancer

Therapeutic Options for Androgen Ablation in Hormone-Sensitive Prostate Cancer

The following options exist for androgen ablation in hormone-sensitive prostate cancer:

The therapeutic options are used as a sequence or in combination, depending on severity and progression of the disease [see figure Hormonal therapy of advanced prostate cancer. Please see section pharmacology/androgen ablation.

Indications For Hormonal Therapy in Prostate Cancer:

Timing of Hormone Therapy:

The survival benefit of immediate hormone therapy in asymptomatic metastases compared to hormone therapy of symptomatic metastases is low to moderate (Loblaw et al, 2004). There is no proven benefit for the common practice of starting androgen ablation in patients with asymptomatic PSA progression after curative therapy without visible metastases. The mean survival time for patients with biochemical progress after prostatectomy is 13 years (Pound et al, 1999), this should be considered for the timing of androgen ablation, since serious side effects such as osteoporosis and anemia are time-dependent.

 

Follow-Up for Patients With Hormonal Therapy

Side effects and clinical success (symptoms, PSA) should be determined three and six months after the initiation of hormone therapy. Further follow-up examinations and imaging are indicated individually depending on the risk of progression and symptoms.

  

Prognosis of Metastatic Prostate Carcinoma:

77% of the patients will survive less than 5 years, 16% will survive 5–10 years and 7% more than 10 years (n=1286 with primary metastasized prostate cancer, follow-up 10 years). Predictors for long-term survival are: minimal disease in imaging, low PSA concentration, low Gleason score, good general performance, no bone pain, good PSA response with hormonal therapy and a long PSA doubling time. There are several nomograms for the prediction of the survival time: (Halabi et al, 2003) (Smaletz et al, 2002).

Pharmacology and Side Effects of Hormonal Therapy:

For details of the pharmacology of hormonal therapy, the side effects of androgen ablation and its prophylaxis please see section pharmacology/hormonal therapy, flutamide, bicalutamide, GnRH agonists and GnRH antagonists.

Comparative Studies for Hormonal Therapy:

Compared to scrotal orchiectomy, GnRH agonists are oncologically equivalent, the androgen receptor antagonists are only slightly inferior. The side effects of the androgen receptor antagonists are more favorable.

Intermittent Androgen Deprivation Therapy for Prostate Cancer

The aim of intermittent androgen deprivation therapy (IAD) is to reduce the rate of side-effects by minimizing time under hormone therapy. Several studies demonstrated better libido, erection function, general physical well-being and less hot flashes. Intermittent androgen deprivation therapy is begun until a certain PSA-Nadir is reached, which depends on the initial PSA concentration. A therapy pause follows until a certain PSA progress is reached, which again leads to another cycle of hormone therapy [fig. flow chart of intermittent androgen deprivation therapy (IAD)]. The testosterone concentration reaches normal values again even after several cycles of hormone therapy (Pether and Goldenberg, 2004).

The onocological equivalence of intermittent hormonal therapy compared to continuous hormone therapy is debated. Several randomized studies have demonstrated oncological equivalence (Crook et al., 2012) (Mottet et al., 2012) (Salonen et al., 2012). In the largest randomized study (SWOG 9346, n = 1535), however, a lower life expectancy was observed in the group of intermittent hormonal therapy (5.1 vs. 5.8 years, 7 years survival rate 38% vs. 42%). This was even more pronounced in the patient group with low disease volume (Hussain, 2012).

Intermittent androgen deprivation therapy (IAD) for prostate cancer: therapy is begun until a certain PSA-Nadir is reached, which depends on the initial PSA concentration. A therapy pause follows until a certain PSA progress is reached, which again leads to another cycle of hormone therapy (Pether and Goldenberg, 2004).
flow chart: intermittent androgen deprivation therapy (IAD) for prostate cancer

Maximum Androgen Blockade for Prostate Carcinoma:

Surgical castration or the administration of GnRH agonists lowers the testosterone concentration to the so-called castration level, which is considered to be below 0.2–0.5 ng/ml testosterone. The production of androgens in the adrenal gland remains intact. By adding androgen receptor antagonists, an additional anti-androgenic effect can be achieved. Nonsteroidal androgen receptor antagonists like flutamide or bicalutamide are commonly used.

Most commonly, the maximum androgen blockade is considered for disease progression after surgical or medical castration. Some authors advocate the start of hormone therapy with the maximum androgen blockade. The higher the tumor burden, the greater the oncological benefits of the immediate maximum androgen blockade.

Chemotherapy of Advanced Hormone-Sensitive Prostate Carcinoma

Until recently, there have been no established concepts to use chemotherapy alone or in combination with hormonal therapy to treat hormone-sensitive prostate carcinoma. This has changed with the publication of the results of the STAMPEDE and CHAARTED trials. The majority of the experts now recommend six cycles of docetaxel with the onset of hormone therapy for the treatment of primary metastatic prostate carcinoma with a high tumor load (Gillessen et al, 2015). Chemotherapy should be started within the first few months after initiation of hormone therapy.

In CHAARTED trial, 790 patients were randomized: one group received standard hormone therapy with GnRH antagonists or analogues; the second group received 6 cycles of docetaxel chemotherapy in addition to hormone therapy. In the group with high disease volume, there was a clear survival advantage of 17 months for docetaxel in addition to hormone therapy (mean survival time 49 vs. 32 months). A high disease volume was defined with at least four bone metastases or the presence of visceral metastases (Sweeney et al, 2015). In the STAMPEDE study, 2962 patients were randomized: hormone therapy versus additional docetaxel (6 cycles) versus additional zolendronic acid versus additional doxetaxel and zolendronic acid. The combination of hormone therapy with docetaxel extended survival by 10 months (71 versus 81 months). No survival advantage could be demonstrated for zoledronic acid (James et al, 2016). In contrast to the STAMPEDE and CHAARTED trial, no advantage in overall survival could be demonstrated in the GETUG 15 trial (Gravis et al., 2013).







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References

Akduman und Crawford 2003 AKDUMAN, B. ; CRAWFORD, E. D.:
The management of high risk prostate cancer.
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Halabi u.a. 2003 HALABI, S. ; SMALL, E. J. ; KANTOFF, et a.:
Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer.
In: J Clin Oncol
21 (2003), Nr. 7, S. 1232–7

Hussain, M.
Intermittent (IAD) versus continuous androgen deprivation (CAD) in hormone sensitive metastatic prostate cancer (HSM1PC) patients (pts): Results of S9346 (INT-0162), an international phase III trial.
J Clin Oncol, 2012, 30 (suppl; abstr 4).


Loblaw u.a. 2004 LOBLAW, D. A. ; MENDELSON, D. S. ; TALCOTT, J. A. ; VIRGO, K. S. ; SOMERFIELD, M. R. ; BEN-JOSEF, E. ; MIDDLETON, R. ; PORTERFIELD, H. ; SHARP, S. A. ; SMITH, T. J. ; TAPLIN, M. E. ; VOGELZANG, N. J. ; WADE, Jr. ; BENNETT, C. L. ; SCHER, H. I.:
American Society of Clinical Oncology recommendations for the initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer.
In: J Clin Oncol
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Mottet, Nicolas; Damme, Jean Van; Loulidi, Salim; Russel, Christoph; Leitenberger, Armin; Wolff, Johannes M & the TAP22 Investigators Group
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M. Pether and S. L. Goldenberg.
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Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF):
Interdisziplinäre Leitlinie der Qualität S3 zur Früherkennung, Diagnose und Therapie der verschiedenen Stadien des Prostatakarzinoms, Langversion 3.1, 2014 AWMF Registernummer: 034/022OL, http://www.awmf.org/leitlinien/detail/ll/043-022OL.html (Zugriff am: 07.02.2016)


Wein, A. J.; Kavoussi, L. R.; Partin, A. P. & Peters, C. A.
Campbell-Walsh Urology
. Elsevier, 2015. ISBN 978-1455775675.


Wein, A. J.; Kavoussi, L. R.; Partin, A. P. & Peters, C. A.
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. Elsevier, 2015. ISBN 978-1455775675.


Salonen, A. J.; Taari, K.; Ala-Opas, M.; Viitanen, J.; Lundstedt, S.; Tammela, T. L. J. & Group, F.
The FinnProstate Study VII: intermittent versus continuous androgen deprivation in patients with advanced prostate cancer.
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Smaletz u.a. 2002 SMALETZ, O. ; SCHER, H. I. ; SMALL, E. J. ; VERBEL, D. A. ; MCMILLAN, A. ; REGAN, K. ; KELLY, W. K. ; KATTAN, M. W.:
Nomogram for overall survival of patients with progressive metastatic prostate cancer after castration.
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