Hormone therapy works best when combined with radiation for locally advanced prostate cancer

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1 Hormone therapy works best when combined with radiation for locally advanced prostate cancer Phichai Chansriwong, MD Ramathibodi Hospital, Mahidol University

2 Introduction

6 Introduction 1/3 of patients with localized disease will present with treatment failure within 5 years of treatment. Huggins and Hodges in 1941 demonstrated the benefit of androgen dependence of PC. For M1 disease, hormone therapy is the mainstay of treatment. In an attempt to improve results for localized cancer

8 Risk Categories Defined in various ways Commonest categorization: Low: PSA < 10, GS < 6, and < T2a Intermediate: PSA 10-20, GS 7, or T2b T2c High: PSA >20, GS > 8, or T3 Very High T3b, T4 Metastases stage M1 Very Low Risk : Added in 2010 PSA <10, GS 6, T1C, PSA density < 0.15 ng/ml/g, < 3 cores positive with 50% cancer in each core

10 Not free margin, seminal invade, extracapsular extend, detectable PSA

11 Diagnostic Pathology (2016) 11:25

12 Prostate cancer is an androgen-dependent malignant disease. Drs. Huggins and Hodges (Nobel prize) demonstrated that orchiectomy or estrogen dramatically affected prostate cancer regression and palliation of symptoms in 1941.

2013 1 ; Denmeade, 2010 2 1. Lamb AD, et al. Trends Urol Mens Health. 2013;4(3):26-30. 2. Denmeade SR.

13 Androgen Regulation of Prostate Hypothalamus-pituitary-gonadal axis 1,2 Adapted from Fast Facts: Prostate Cancer by Roger S Kirby and Manish I Patel Eighth edition Adapted from Lamb, ; Denmeade, Lamb AD, et al. Trends Urol Mens Health. 2013;4(3): Denmeade SR. Holland-Frei Cancer Medicine. 8th ed. Philadelphia, PA: AACR Publications; 2010:

14 Androgens Testosterone is the primary circulating androgen, with approximately 90% produced by Leydig cells in the testes and 10% produced by the adrenal cortex. Only 3% of circulating testosterone is unbound and functionally active the remainder is bound and sequestered by sex-hormone binding globulin and albumin. Following diffusion into the cytoplasm, testosterone is converted by the enzyme 5α-reductase to DHT, which has a five-fold higher affinity for the LBD of AR

15 Hormone Therapies for Prostate Cancer LHRH agonists. leuprolide (Enantone,Lupron, Eligard), goserelin (Zoladex), Triptorerin LHRH antagonists eg Degarelix Androgen Receptor targeted.. eg Casodex, Flutamide, Enzalutamide Steroids.. eg Prednisone, Dexa Estrogens eg Stilboestrol Cyp 17 inhibitors. eg Abiraterone

16 Efficacy of GnRH agonist to suppress testosterone

17 In long-term studies, leuprorelin effectively maintained testosterone below castration levels Leuprorelin effectively maintains testosterone below castration levels in patients with advanced cancer 1 Adapted from Kienle, Key results The median baseline testosterone level before treatment was 350 ng/dl and level decreased to 21 ng/dl after 1 month, staying within the castration range for the entire observation period (45 months). 1 Long-term follow-up (63 months) of serum testosterone levels confirmed no decline in efficacy of leuprorelin monthly injections Kienle E, et al. Urol Int. 1996;56(Suppl 1):S23-S30.

18 In long-term studies, 3mo vs 6 mo effectively maintained testosterone below castration levels In long-term studies, leuprorelin effectively maintains testosterone below castration levels 1 Key results Median testosterone levels ranged from ng/dl for the 3M and 6M arms. Median PSA 3M arm: ng/ml 6M arm: ng/ml Testosterone response rates ( 50 ng/dl) at 12 months 3M arm: 100% 6M arm: 98% Testosterone response rates ( 20 ng/dl) at 12 months 3M arm: 81% 6M arm: 90% 3M, 3 months; 6M, 6 months. Adapted from Tunn, Tunn UW, et al. Prostate Cancer Prostatic Dis. 2009;12(1):83-87.

19 Metastatic group : ANDROGEN ABLATION LHRH Agonists T Surge vs Orchiectomy Leuprolide vs Orchiectomy Impact on Mean Serum T Levels Level MIU/mL Leuprolide Orchiectomy Day Time from First Dose Week Smith JA. Urology. 1985;25:106. With permission from Elsevier Science.

20 GnRh antagonist: no flare up However, practical shortcomings have limited clinical studies.

28 1: AA alone is inferior to RT + AA

29 1205 patients locally advanced (T3 or T4) n=1057; or (T2) with either PSA > 40 ng/ml (n=119) PSA > 20 ng/ml + Gleason score >/= 8 (n=25) median follow-up was 6 0 years ADT = bilateral orchiectomy or LHRH agonist (initially given with 2 weeks of AA)

30 Primary outcome: overall survival HR 0 77, 95% CI

31 disease-specific survival

32 Cumulative incidence of disease-specific survival

33 quality-of-life scores over time for symptom measures

34 High risk group AA alone is inferior to RT + AA Intergroup Study (NCIC, MRC, SWOG, ECOG) (Lancet, 2011, JCO 2015) Phase III: AA vs. AA + RT T3-T4, T2 + PSA > 40, or T2 + PSA > 20 + GS > 8 RT: 45 Gy to pelvic nodes; Gy to prostate/sem. ves. Accrued 1205 patients between 1995 and 2005 Follow-up: 6 years At 7 years AA AA +RT Overall survival 66% 74% (p<0.001) (HR =0.77) Prostate cancer-specific survival 81% 91% (p<0.001) (HR=0.46) Tumor progression 42% 16%

35 JCO, VOLUME 33, NUMBER 19, JULY

36 RT alone is inferior to RT + AA

37 RT alone is inferior to RT + AA EORTC (Lancet, 2002) (Lancet Oncol, 2010) Phase III: RT vs. RT + 3 years adjuvant AA 415 patients; Median age: 71 years T3-4 or T1-2 with WHO Grade 3 Median follow-up: 9.1 years RT vs. RT + 3 yr adj. AA 10-year overall survival 39.8% 58.1% 10-year cause specific survival 69.6% 89.7% 10-year clinical DFS 22.7% 47.7% 10-year local failure 23.5% 6% 5-year bdfs (Lancet, 2002) 45% 76% * No difference in cardiovascular mortality

38 Lancet Onco, October 7, 2010

39 Long-term AA is superior to shortterm neoadjuvant/concurrent AA

40 RTOG 9202 (JCO, 2008) Phase III: 4 mos neoadj./conc. AA + RT vs. 4 mos neoadj./conc. AA + RT + 24 mos adj. AA 1521 patients; T2c-T4 and PSA <150; 4% had positive node Median follow-up: 11.3 years for alive patients Neoadj/Conc AA + RT vs. RT + Adj AA 10-year overall survival 51.6% 53.9% 10-year cause specific survival 83.9% 88.7% (p=0.004) 10-year disease free survival 13.2% 22.5% 10-year local failure 22.2% 12.3% 10-year distant metastasis 22.8% 14.8%

41 JCO, VOLUME 26 NUMBER 15 MAY

43 Long-term adjuvant AA is superior to short-term adjuvant AA

44 EORTC (NEJM, 2009) Phase III: RT + 6 mos adj. AA vs. RT + 3 yrs adj. AA Non-inferiority design 970 patients; median age: 69 years T2C-T4 any N or T1c-T2b pn1-n2 Median follow-up: 6.4 years RT + 6mos AA vs. RT + 3 yrs AA 5-year overall survival 81% 84.8% (HR=1.42, CI ) 5-year cause specific survival 95.3% 96.8% (HR=1.71, CI )

46 Short ADT vs Long ADT

47 Mean score of QoL A. Insomnia B. hot flush C. Reduced interest in sex D. Reduced sex activity E. Overall QoL

48 5. Single AA is not recommend SPCG-7 study used anti-androgens which would not be considered adequate androgen deprivation therapy

50 SPCG-7 study 875 patients Locally advanced (T3; 78%; PSA<70; N0; M0) randomly :439 endocrine treatment alone (3 months of GnRH agonist +AA followed by flutamide until PD VS endocrine treatment combined with RT 70 Gy. (436 patients). The primary endpoint was PC-specific survival

51 Follow-up of 7 6 years, 79 vs 37 (combined) men died of prostate cancer. 10 years for pc-specific mortality was 23 9% vs 11 9% ( 95% CI %), for a relative risk of 0 44 ( ). At 10 years overall mortality was 39 4% vs 29 6% (CI %), for a relative risk of 0 68 ( ). 10 years for PSA recurrence was substantially higher in men in the endocrine-alone group (74 7% vs 25 9%, p<0 0001; HR 0 16; ). After 5 years, urinary, rectal, and sexual problems were slightly more frequent in the endocrine plus radiotherapy group.

52 Cumulative incidence of (A) PSA recurrence, (B) death from prostate cancer, and (C) death from any cause Vol 373 January 24, 2009

53 GUIDELINE

57 Intermediate risk PC: EAU 2016

59 High Risk PC: EAU guideline

62 Comparing with surgery: no RCT High risk : cat B

63 EAU guidelines

70 760 case post prostatectomy + LN ( T2,3 and node negative) then PSA rising to ng/ml RT + bicalutamide 150 mg/d * 24 months VS Rt + placebo

71 F/U 13 years OS at 12 years: 76.3% vs 71.3 % ( HR0.77, P 0.04) 12 year incidence of death from PC 5.8% vs 13.4% P Distant metastases at 12 year : 14.5% vs 23.0% (P 0.005) AE from RT similar in 2 groups Gynecomastia 69.7 % vs 10.9%

75 National drug list ตามประกาศบ ญช ยาหล กแห งชาต 2560 ยา Leuprorelin 11.25, 22.5 และยา Triptorelin 11.25mg เป นยาบ ญช ง. เป นการร กษา Adjuvant + Rt in intermediate risk ไม เก น 6เด อน(2cycles) เป นการร กษา adjuvant + RT in High risk or very high risk ไม เก น 2ป (8 cycles)

76 Summary Role of RT + ADT well established by RCTs High risk: Long term ADT superior to short term ADT Dose RT escalation improves outcomes Waiting results of new treatment study: IMRT, new drugs Adding 24 months of AA to salvage RT improving OS and reducing cancer death

Initial Hormone Therapy

Initial Hormone Therapy Alan Horwich Institute of Cancer Research and Royal Marsden Hospital, London, UK Alan.Horwich@icr.ac.uk MANAGEMENT OF PROSTATE CANCER Treatment windows Subclinical Localised PSA