1. Karcinóm prostaty Ročné 500 000 nových prípadov CaP na celom svete
pacientov zomiera ročne s CaP
2004 – 33 % všetkých karcinómov (CaP) a 10 % všetkých úmrtí na karcinóm v dôsledku CaP (USA)
Kostné komplikácie ohrozujú pacientov s CaP (kostné metastázy a úbytok kostnej masy pri endokrínnej manipulácii)
1: Ferlay J in: Accessed
2: American Cancer Sciety. Cancer facts & figures Atlanta GA, 2004, 3: Crawford DE: Eur.Urol. Suppl, 2004; 3: 10-15

2. Karcinóm prostaty 20 % pacientov má v čase diagnózy kostné metastázy
65-75 % pacientov s pokročilým ochorenie má alebo v priebehu liečby sa objavia kostné metastázy
Postihujú predovšetkým axiálny skelet (lumbálne stavce, panva, rebra, femury)
97 pts /16 (16,5 %) Mts a u 5 (6%) sa vytvorili Mts počas liečby.

3. Karcinóm prostaty Endokrinná manipulácia
Lokálne pokročilý karcinóm (vysokorizikoví pacienti- PSA≥20 ng/ml, gleasonov skóre ≥ 7, viac ako 50 % biopsií pozitívne)
40 % pacientov liečených s úmyslom vyliečenia má pokročilé ochorenia alebo recidivuje do 3-5 rokov
Potlačenie tvorby androgénov –dlhodobá – zníženie kostnej denzity (osteoporóza, patologické fraktúry, bolesti a zníženie kvality života).

4. Priebeh karcinómu prostaty pri „skorom“ záchyte
RP, RTX, BT
Ličba:
GnRH Agonisti
Záchranná
Smrť
SRE
Iniciálna diagnóza a liečba
PSA / masa tumoru
Kostné mts
This slide shows some of the key issues in the natural history of early fatal prostate cancer.
Because of earlier diagnosis and more intensive use of salvage therapy, the natural history of prostate cancer has changed dramatically over the past 2 decades.
Most men with prostate cancer in the United States and other Western countries are diagnosed based on screening. The screening procedures used are the digital rectal examination (DRE) and blood levels of prostate-specific antigen (PSA). If the results of either of these tests are abnormal, the patient will usually undergo further testing. Microscopic analysis of the prostate tissue is necessary for a definite diagnosis.
Positive diagnosis in early stages often prompts definitive local treatment, as shown in this example, with a radical prostatectomy (RP).
Patients with disease progression despite definitive local treatment are initially identified by a rising PSA level before the onset of detectable metastatic disease.
This PSA-only failure typically prompts salvage androgen-deprivation therapy with a gonadotropin-releasing hormone (GnRH) agonist.
Therapy with GnRH is effective, because at this stage, the cancer is hormone sensitive.
Nevertheless, patients inevitably progress to hormone refractory disease (HRPC), which often persists for several years before the development of detectable metastatic disease.
This is a new disease state made possible by earlier diagnosis and more intensive use of salvage therapy.
However, there are no established standards of care for the management of progressive, hormone refractory, non-metastatic prostate cancer; this represents an ideal setting to explore metastasis prevention.
The results of an aborted study of zoledronic acid to prevent metastases have helped to define the natural history of this disease state and have guided the design of successor trials to prevent metastases.
Abbreviations
GnRH, Gonadotropin-releasing hormone; RP, Radical prostatectomy; PSA, Prostate-specific antigen; ADT,
Androgen-deprivation therapy; HRPC, Hormone refractory prostate cancer; SRE, Skeletal-related events.
HRPC
Time
GnRH, gonadotropin-releasing hormone; RP, radical prostatectomy; PSA, prostate-specific antigen; ADT, androgen deprivation therapy; HRPC, hormone refractory prostate cancer; SRE, skeletal-related events. 3

5. ADT predstavuje najčastejsie liečba LHRH agonistami
Účinná látka
Podávanie
LHRH agonisti
Leuprolide1
inj. á 1, 3, 4 alebo 6 mesiacov;
implantát na 12 mesiacov
Goserelin2
inj. á 1 alebo 3 mesiace
Triptorelin3
LHRH antagonisti
Degarelix4
úvodná dávka vo forme bolusu nasledovaná mesačnými udržovacími dávkami
Anti-androgény (ako kombinovaná liečba pri komplentnej androgénnej blokáde)
Flutamide5
perorálne, 3 x denne á 8 hodín
Bicalutamide6
perorálne, 1 x denne
This slide shows the current ADT treatment options in prostate cancer.
Different LHRH agonists are currently approved for use in prostate cancer, and they are administered in different forms.1-3
Leuprolide, or leuprorelin acetate, can be given in different forms, at different time intervals.1
In contrast to the agonists, LHRH antagonists bind immediately and competitively to LHRH receptors in the pituitary gland.4,7
In December 2008, a new LHRH antagonist, degarelix, was approved for use by the FDA to treat advanced prostate cancer.4
Anti-androgens are used together with LHRH agonists to achieve complete androgen blockage, which is commonly applied when PSA levels begin to rise.5,6
References
Eligard® US Product Information. Sanofi-Aventis U.S. LLC; 2008.
Zoladex® US Product Information. AstraZeneca Pharmaceuticals LP; 2007.
Trelstar® US Product Information. Watson Pharma, Inc.; 2006.
Firmagon EPAR 2008 as assessed on August 2009.
Drogenil SmPC Schering-Plough Ltd, as assessed on August 2009.
Bicalutamide Patient Information Leaflet AstraZeneca UK Limited, as assessed on August 2009.
European Association of Urology. Guidelines on Prostate Cancer. 2009;
1Eligard® Product Information. Sanofi-Aventis U.S. LLC; 2008; 2Zoladex® Product Information. AstraZeneca Pharmaceuticals LP; 2007;
3Trelstar® Product Information. Watson Pharma, Inc.; 2006; 4Firmagon EPAR 2008 assessed on August 2009; 5Drogenil SmPC Schering-Plough Ltd,
as assessed on Aug 2009; 6Bicalutamide SmPC AstraZeneca UK Limited, as assessed on August 2009. 4

6. Nie všetky nežiaduce účinky ADT sú zjavné
Viditeľné NÚ
„Skryté“ NÚ
Najčastejšie
Viditeľné známky
„Skryté“
„Pocity“
Strata libida
Erektilná disfunkcia
Návaly
Nárast hmotnosti
Gynekomastia
Strata svalovej sily a hmoty
Zmenšenie penisu a semeníkov
Zmeny ochlpenia
Strata kostnej hmoty
Anémia
Nástup / zhoršenie hypertenzie, diabetu, KVS ochorení
Zmeny lipidového profilu v sére
Únava
Nedostatok energie
Nedostatok iniciatívy
Depresia
Emočné poruchy
Poruchy kognitívnych funkcií
The common side effects of ADT can be divided into physical (visible) and metabolic and physiologic (non-visible) symptoms.
The most frequently recognised side effects, common to all methods of ADT, are loss of libido, erectile dysfunction and hot flashes.
Further visible symptoms (physical changes) include weight gain, gynaecomastia, loss of muscle mass and strength, decreased size of penis and testes and hair changes.
Non-visible symptoms (metabolic and physiological changes) include signs which cannot be assessed visually, such as loss of BMD, anaemia, onset/worsening of lipids, hypertension, diabetes or cardiovascular diseases.
As studies show loss of BMD in patients treated with ADT compared to patients not treated with ADT, BMD should be monitored.
So far, the true incidence of these adverse events is not generally understood and appreciated by physicians, however, all of the above side effects unquestionably affect the patient’s quality of life.
Studies on strategies to manage the toxicities of hormone therapy are required, however, it is known that many of the side effects are reversible and may dissipate on withdrawal of ADT administered in an intermittent regimen.
To minimise or prevent the development of serious consequences from long-term ADT, physicians should recommend a program of diet and exercise.
Such a program is expected to have an added global benefit in reducing fatigue and depression and improving quality of life.
Reference
Higano CS. Side effects of androgen deprivation therapy: monitoring and minimizing toxicity. Urology 2003;61:32-8.
Higano CS. Urology 2003; 61:32-8. 5

7. Kostné komplikácie Po 3-5 rokoch endokrínnej manipulácie– MTS
Po vzniku kostných MTS – prežívanie od mesiacov ( riziko kostných komplikácii)
30-50 % pts s MTS má minimálne jednu kostnú komplikáciu v priebehu 2 rokov sledovania
Vznik fraktúry kosti koreluje s úmrtnosťou (10-20 % zomiera do 6 mesiacov po fraktúre krčku femuru)

8. Kostné komplikácie indukovane liečbou CaP
Časť pacientov je v čase dg osteopenická alebo osteoporotická
Antiandrogénová liečba znižuje denzitu kostnej masy v priemere o 3-5 %/rok

9. GnRH agonisti znižujú BMD u mužov s karcinómom prostaty
Proximálny femur
p<0.001
Zmena BMD počas 12 mesiacov (%) -4 -3 -2 -5 -1 1 2
Bedrová chrbtica NS
Kontrola
GnRH agonisti
NS=not significant
Androgen deprivation therapy (ADT) using gonadotropin-releasing hormone (GnRH) agonists, the standard of care for the treatment of advanced prostate cancer, results in hypogonadism that may lead to bone loss and osteoporosis.
This study evaluated the effects of GnRH agonist treatment on BMD and markers of bone turnover in 15 men with prostate cancer in comparison to 13 age-matched healthy controls.
BMD was determined at several skeletal sites at baseline and after 6 and 12 months; the graph shows changes in BMD after 12 months for lumbar spine (L1 – L4) and total hip.
No significant bone loss was noted in the healthy controls.
In the men with prostate cancer receiving GnRH agonist therapy, BMD for lumbar spine and total hip decreased 2.8% and 3.3%, respectively at 12 months.
Compared with the controls, the change in BMD for total hip experienced by men on ADT was statistically significant (p<0.001).
Abbreviations
NS, not significant; ADT, androgen deprivation therapy; GnRH, gonadotropin-releasing hormone; BMD, bone
mineral density.
Reference
Mittan D, Lee S, Miller E, Perez RC, Basler JW, Bruder JM. Bone loss following hypogonadism in men with prostate cancer treated with GnRH analogs. J Clin Endocrinol Metab 2002;87:
Adapted from Mittan D, et al. J Clin Endocrinol Metab 2002; 87: © The Endocrine Society. 8

10. Riziko zlomenín rastie s dĺžkou podávania ADT
Prežívanie bez zlomeniny (%)
Roky po diagnóze 20 40 60 80
100 2 4 6 8 10
GnRH agonisti, 1-4 dávky
GnRH agonisti, 5-8 dávok
GnRH agonisti, ≥ 9 dávok
Orchiektómia
Bez ADT
Therapy-induced bone loss may increase fracture risk in prostate cancer patients.
Of men surviving at least five years after diagnosis, 19.4% of those who received ADT had a fracture, compared with 12.6% of those who did not receive ADT (p<0.001).
There was a statistically significant relation between the number of doses of GnRH received during the 12 months after diagnosis and the subsequent risk of fracture.
The relative risk of the occurrence of any fracture or a fracture that resulted in hospitalisation increased steadily with the increasing number of doses of a gonadotropin-releasing hormone agonist received during the first year after diagnosis (p<0.001 for linear trend).
The relative risk of any fracture was 1.45 (95% CI, 1.36 to 1.56) among those receiving nine or more doses of gonadotropin-releasing hormone agonist in the first 12 months after diagnosis and 1.54 (95% CI, 1.42 to 1.68) among those who underwent orchiectomy.
Furthermore, this study provides an estimate of the risk of fracture that is attributable to androgen-deprivation therapy by including patients who were not treated with androgen deprivation and adjusting for confounding variables.
Relative risk of any fracture and fracture resulting in hospitalisation was similar between patients treated with either nine or more doses of GnRH agonist or who had undergone orchiectomy.
Abbreviation
GnRH, gonadotropin-releasing hormone.
Reference
Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005;352:
Shahinian VB, et al. N Engl J Med 2005; 352: 9

11. Výsledky po vstupnom vyšeterení
0,9428
0,8273
1,0622
Kontrolná skup.
0,022
0,965
0,028 p
0,9161
0,8067
1,0217
Sledovaná skup.
BMD celkovo
BMD femur
BMD L1-L4
g/cm2
Sledovaná skupina (CaP): 39 (40,2%) osteopénia, 18 (18,5%) osteoporóza
Kontrolná skupina: 30 (33,7%) osteopénia, 7 (7,9%) osteoporóza
Pacienti v sled. skupine majú signifikantne nižšie vstupné BMD L1- L4 a celkové BMD 10 10

12. Výsledky po 1. kontrole
0,9274
0,8053
1,0382
Kontrolná skup.
<0,001
0,534
0,004 p
0,8717
0,7625
0,9786
Sledovaná skup.
BMD celkovo
BMD femur
BMD L1-L4
g/cm2
Sledovaná skupina: Osteopénia 50 pacientov (51%), Osteoporóza 23 pacientov (23,7%)‏
Kontrolná skupina: Osteopénia 31 pacientov (31,9%), Osteoporóza 7 pacientov (7,8%)
Signifikantný pokles BMD L1-L4 (p=0,004), signifikantný pokles celkového BMD (p<0,001), nevýznamný pokles BMD femuru (p=0,534) v sledovanej skupine oproti kontrole ˇ 11 11

13. Patologické fraktúry po 1. kontrole
Po prvej kontrole sa patologické fraktúry L1 - L4 vyskytli u 4 pacientov sledovanej skupiny (4,1%)
V kontrolnej skupine sa patologické fraktúry L1 - L4 nevyskytli
Patologické fraktúry krčka femuru sa nevyskytli ani v jednej skupine 12 12

14. Výsledky po 2. kontrole
0,8978
0,7506
0,9845
Kontrolná skup.
<0,001
0,03
0,001 p
0,7757
0,6684
0,8860
Sledovaná skup.
BMD celkovo
BMD femur
BMD L1-L4
g/cm2
Sledovaná skupina: Osteopénia 73 pacientov (76,2%), Osteoporóza 30 pacientov (30,9%)‏
Kontrolná skupina: Osteopénia 35 pacientov (39,3%), Osteoporóza 14 pacientov (11,2%)
Signifikantný pokles BMD L1-L4 (p=0,001), signifikantný pokles celkového BMD (p<0,001), významný pokles BMD femuru (p=0,03) v sledovanej skupine oproti kontrole 13 13

15. Patologické fraktúry po 2. kontrole
Po druhej kontrole sa patologické fraktúry L1 - L4 vyskytli u 5 pacientov a u 2 krčka femuru (8,5%)
V kontrolnej skupine sa vyskytla 1 patologická fraktúra L1 - L4 (1,2%)
Rozdiel v incidencií je 7 - násobný 14 14

16. Vplyv fraktúry na QL Fraktúra krčka femuru u osteoporetických mužov
16 % mortalita/mesiac
10-20 %/ 6 mesiacov
32 %/rok
Patologické fraktúry
Štúdia na 195 pts liečených hormonálne
Celkové prežívanie pts s fraktúrami bolo nižšie až o viac ako 3 roky (p<0.04)
Oefelein MG a spol.: J. Urol., 2002; 168:

17. Konzervatívna liečba Analgetiká Rádioterapia
Rádioizotopy (stroncium 89, renium 188 a samarium  žiariče)
Bisfosfonáty
Inhibítor receptoru endotelinu A (
Denosumab (RANKL inhibitor)

18. Dlhodobé účinky ADT
Sarcopenic obesity
Bone loss 17 17 17

19. Závery Ciele komplexnej liečby CaP
Predľženie života, liečba symptómov ochorenia a zlepšenie QL
Liečba kostných komplikácií v dôsledku antiandrogénnej liečby a v dôsledku kostných metastáz je potrebná
Prebiehajúce štúdie – včasné opatrenia a podávanie liekov zamedzujúce vzniku kostných komplikácií redukujú morbiditu a mortalitu pacientov