1. New Ways of Managing Prostate Cancer Jahangeer M.Malik Consultant Clinical Oncology 7 th November 2013

2. BASICS PROSTA TE DOSE TUMOUR CONTROL TOXICITIES

3.  Radiotherapy  Chemotherapy

4. RADIOTHERAPY

5. A)Radical Radiotherapy  Prostate external beam radiotherapy (EBRT)  LDR seed brachytherapy  HDR brachytherapy boost B)Palliative prostate radiotherapy  Strontium-89  Radium-223

6. Risk profiles PROGNOSTIC CATEGORIES PROGNOSTIC FEATURES 5 YEAR PSA RELAPSE FREE SURVIVAL GOOD PROGNOSIS T1-2a AND PSA ≤10 ANDGLEASON SCORE ≤6 85% INTERMEDIATE PROGNOSIS ONE OF THE PROGNOSTIC INDICATORS RAISED 65% POOR PROGNOSIS TWO OF THE PROGNOSTIC INDICATORS RAISED 35%

7. PROSTATE EXTERNAL BEAM RADIOTHERAPY RADICAL PROSTAE RADIOTHERAPY

8. EBRT Advantages Suitable for most pts Including locally advanced disease T3 and nodal disease Don’t need GA Acute and late bowel and bladder toxicities Disadvantages Prolonged course of Rx 37# over 7.5 weeks or 19# over 4 weeks Doesn’t help obstructive symptoms (may need TURP first) PSA follow up

10. Conformal radiotherapy plan Sacrum Rectum Collimator leaves positioned to shape of target inserted into beam Open (conventional) rectangular field Pubis Target (prostate + margin)

12. CRT vs IMRT Beam profile #1 Beam profile #2 Beam profile #3 Dose intensity PTV RO PTV RO 3-field RT 3-field IMRT Prescribed dose (typical distribution) With IMRT, dose distribution can be shaped to the target to spare organs at risk Intensity-modulated radiotherapy RO: risk organ PTV: planning target volume

14. IMRT/hypofractionation CHHIP study 57Gy/19f vs 60Gy/20f vs 74Gy/37f Conformal IMRT Toxicity reported at median follow up for 50.5m Await for bPFS and OS outcome David Dearnaley et al Lancet Oncol 2012; 13: 43–54

15. CHHiP ……Acute Toxicity RTOG 18W 74Gy (N=129) 57Gy (N=129) 60Gy (N=132) GI≥23 (2.3%)1 (0.8%)3 (2.3%) GU≥29(7%) 10 (7.6%) David Dearnaley et al Lancet Oncol 2012; 13: 43–54

16. CHHiP ……Late Toxicity Bowel Bladder RTOG 2Y74Gy (N=138) 57Gy (N=143) 60Gy (N=137) UK STANDARD GI≥26 (4.3%)2 (1.4%)5 (3.6%)20% GU≥23(2.2%)0(0%)3 (2.2%)8% RT01 study (64Gy/32f vs 74Gy/37f) RTOG≥2 GU=8% and GI=20% at 2y

18. Progress at ECC Currently treating 80% patients/week with VMAT-IMRT. Plan to treat all with IMRT in 6months time. Plan to treat prostate and pelvis with IMRT for high risk patients in next 2 years time.

19. LDR SEED BRACHYTHERAPY RADICAL PROSTATE RADIOTHERAPY

20. Brachytherapy the ultimate dose escalated IMRT Permanent LDR Iodine 125 seeds Temporary Iridium 192 HDR implant

21. D-LDR brachytherapy Criteria T1-T2b Vol<70cc No TURP Flow >10ml/sec,RV<150ml GS6+PSA≤20 or Gs7+PSA≤15 or GS9-10 and PSA≤10

22. Advantages of Intraoperative D90 = dose to 90% of the prostate Correlates with PSA RFS Day case single visit Can adjust plan on the day and calculate dose D100 = 145Gy- 100% 3mm D150 = 217Gy- 60-70% PTV D60 = 100Gy = 2cc rectum Safely boost biopsy +ve sites Helps avoid excess dose to critical areas

23. ADVANTAGES Very high radiation dose 145Gy to prostate <1% risk of incontinence 70% potency rates DISADVANTAGES/Side effects Main side effect - urethritis up to 9-12 months Proctitis 5% & Stricture 5-10% PSA falls slowly & can bounce causing anxiety for patients

24. Long term outcome data Blasko347 pts15 yr PFS86% Potters1449 pts12 yr PFS89% Stock & Stone 1561 pts10 yr PFS96% Leeds1141pts10 yr PFS95%

25. Progress at ECC  Treated 500 patients over last 7 years  Catheterization rate<5%  LR outcome=95% PSA control rate,  IR=85% and HR(GS8/PSA>20)=75% (CHRISTIE DATA)

26. Final decisionAll PatientsLocalised Radical Radiotherapy5546 AM/AS/WW54 Brachytherapy32 Prostatectomy52 Palliative RadiotherapyNR Hormone therapy5411 Other11 Total248196 Patients Diagnosed in 2011 who had an oncology consultation and treatment chosen

27. All PatientsLocalised Radical Radiotherapy9730 AM/AS/WW4038 Brachytherapy3128 Prostatectomy2825 Palliative Radiotherapy210 Hormone therapy101 Other71 Total234123 2012

28. HDR BRACHYTHERAPY BOOST RADICAL PROSTAE RADIOTHERAPY

30. Started late 1990’s High dose rate HDR Brachytherapy

31. Usual indication for HDR is a boost Where there is a significant predictive risk of extra capsular or seminal vesicle involvement: External beam Brachytherapy

32. Very high dose per fraction Single 15Gy Reduced irradiated volume Shortened number of XRT visits (15fractions rather 37) Disadvantages Inpatient treatment Catheter discomfort Relatively medically labour intensive Advantages of HDR

33. UK Standard Christie Martinez EBRT Dose (Gy) 7437.546 Number of Fractions 371523 HDR Dose (Gy) 1523 Number of Fractions 12 2 Gy Equivalence74113.6131.4 HDR----Best Dose-escalation

34. HDR is the future? Combine with functional imaging to boost, alter RT ECC will start HDR prostate from next year

35. STRONTIUM-89 RADIUM-223 PALLIATIVE PROSTATE RADIOTHERAPY

36. 4)Strontium-89 Bone seeking beta rays emitter(electron) Single IV for bone pains Maximum range in tissues=8mm RR=80% Time to response=7-20days Duration of response=2months Toxicity=pain flare, bone marrow suppression EurJ Cancer, Vol. 27, No. 8, pp. 954-958, 1991

37. 4)AlphaRadin (Radium 223) Bone seeking α emitter IV T1/2 11.4 days <100µm range

38. Phase 3 trial closed early due to significant survival benefit in favour of Ra 223 reported at ECCO Stockholm sep 2011 46 vs 65w P=0.017

39. ECCO 2011 P3 Interim analysis (ALSYMPCA) 922 cases with CRPC and bone mets 2:1 randomisation with placebo. 4weekly×6 OS 14 m vs 11.2m (P=0.022, HR 0.69) Well tolerated ( G3-4 neutropenia 1.8% vs 0.8%)

40. Future.. you can see! IMRT/VMAT HDR prostate boost Radium -223 radio-isotope treatment

41. CHEMOTHERAPY

42. PROSTATE CANCER TRIALS FOR MORE ADVANCED DISEASE CRPC 3 rd Line estrogens e.g. Diethylstiboestrol 2 nd line AA e.g. Bicalutamide 1 st line LHRHa e.g. Zoladex DOCETAXEL Chemotherapy Trials Low dose Steroids Dexamethasone Or Prednisolone New reported trials After Docetaxel in CRPC DOCETAXEL

43. After DOCETAXEL PROSTATE CANCER TRIALS FOR MORE ADVANCED DISEASE CRPC RR=85%, Median duration of response=18-24m 3 rd Line estrogens e.g. Diethylstiboestrol 2 nd line AA e.g. Bicalutamide 1 st line LHRHa e.g. Zoladex DOCETAXEL Chemotherapy Trials Low dose Steroids Dexamethasone Or Prednisolone New reported trials After Docetaxel in CRPC RR=30-40% Median duration of response=3-6m RR=30% Median duration of response=3-6m Dex 0.5mg OD,RR 50%,MDR=7m Pred 10mgOD,RR30%,MDR=2-3m Abiraterone

44. Newer Drugs 2) Abiraterone (Hormone therapy) 3)Denosumab (Bone) Enzalutamide (Hormone therapy) Sipuleucel-T 5) Sipuleucel-T(Vaccine) 1)Cabazitaxel (ChemoTherapy)

45. 1)Cabazitaxel Tried in patients after Docetaxel. Diarrhoea, Neutropenia and sepsis. Survival benefit=2.4m Available in England Rejected by SMC

46. 2)Abiraterone AA7977366575202826820 Placebo3983553062101053030 21 HR = 0.646 (0.54-0.77) p < 0.0001 Placebo 10.9 months (95% CI: 10.2-12.0) AA 14.8 months (95% CI: 14.1-15.4) 100 80 60 40 20 Survival (%) 0 0369121518 Time to Death (Months) de Bono et al. Ann Oncol 2010; 21 (10 suppl 8): Abstract LBA5 (oral presentation) Scher et al. J Clin Oncol 2011; 25 (suppl 7): Abstract 4 (oral presentation)

47. 3)Denosumab Adapted from Roodman D. N Engl J Med. 2004;350:1655. PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT Osteoblasts Inactivate Osteoclast PDGF, BMPs TGF-β, IGFs FGFs Tumor Cell CA +2 RANKL RANK Denosumab Bone Resorption Inhibited RANK ligand (RANKL) key mediator for osteoclast formation, function, survival Potential target for treating bone metastasis

48. 4)Sipuleucel-T (Vaccine) Immature monocytes thought to mature to fully competent antigen presenting cells (APC), presenting PAP peptides in the patient activates CD4 + and CD8 + T cells Drake et al. Nature Immunol Rev 2010; 10(8): 580-593

49. 5)Enzalutamide Oral hormone tablet Trial in post-docetaxel chemo patients 4.8m survival benefit Awaiting SMC approval, likely to be approved.

50. After DOCETAXEL PROSTATE CANCER TRIALS FOR MORE ADVANCED DISEASE CRPC RR=85%, Median duration of response=18-24m 3 rd Line estrogens e.g. Diethylstiboestrol 2 nd line AA e.g. Bicalutamide 1 st line LHRHa e.g. Zoladex DOCETAXEL Chemotherapy Trials Low dose Steroids Dexamethasone Or Prednisolone New reported trials After Docetaxel in CRPC RR=30-40% Median duration of response=3-6m RR=30% Median duration of response=3-6m Dex 0.5mg OD,RR 50%,MDR=7m Pred 10mgOD,RR30%,MDR=2-3m Abiraterone 12m+

51. Thank you all