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New Ways of Managing Prostate Cancer Jahangeer M.Malik Consultant Clinical Oncology

New Ways of Managing Prostate Cancer Jahangeer M.Malik Consultant Clinical Oncology 7 th November 2013. BASICS. TUMOUR CONTROL. TOXICITIES. PROSTATE. DOSE. Radiotherapy Chemotherapy. RADIOTHERAPY. A)Radical Radiotherapy Prostate external beam radiotherapy (EBRT)

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New Ways of Managing Prostate Cancer Jahangeer M.Malik Consultant Clinical Oncology

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

  2. BASICS TUMOUR CONTROL TOXICITIES PROSTATE DOSE

  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

  7. RADICAL PROSTAE RADIOTHERAPY ProstaTeExternal beam radiotherapy

  8. EBRT Advantages Disadvantages Suitable for most pts Including locally advanced disease T3 and nodal disease Don’t need GA Acute and late bowel and bladder toxicities 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

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

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

  11. 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 Oncol2012; 13: 43–54

  12. CHHiP ……Acute Toxicity David Dearnaley et al Lancet Oncol2012; 13: 43–54

  13. CHHiP ……Late Toxicity Bowel Bladder RT01 study (64Gy/32f vs 74Gy/37f) RTOG≥2 GU=8% and GI=20% at 2y

  14. 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.

  15. RADICAL PROSTATE RADIOTHERAPY Ldr SEED BRACHYTHERAPY

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

  17. 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

  18. Advantages of Intraoperative 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 D90 = dose to 90% of the prostate Correlates with PSA RFS

  19. 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

  20. Long term outcome data

  21. 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)

  22. 2012

  23. RADICAL PROSTAE RADIOTHERAPY HDR BRACHYTHERAPY BOOST

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

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

  26. Advantages of HDR • 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

  27. HDR----Best Dose-escalation

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

  29. PALLIATIVE PROSTATE RADIOTHERAPY STRONTIUM-89RADIUM-223

  30. 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 EurJCancer, Vol. 27, No. 8, pp. 954-958, 1991

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

  32. 46 vs 65w P=0.017 Phase 3 trial closed early due to significant survival benefit in favour of Ra 223 reported at ECCO Stockholm sep 2011

  33. 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%)

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

  35. CHEMOTHERAPY

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

  37. PROSTATE CANCER TRIALS FOR MORE ADVANCED DISEASE 1st line LHRHa e.g. Zoladex RR=85%, Median duration of response=18-24m RR=30-40% Median duration of response=3-6m 2nd line AA e.g. Bicalutamide DOCETAXEL Chemotherapy Trials CRPC 3rd Line estrogens e.g. Diethylstiboestrol RR=30% Median duration of response=3-6m After DOCETAXEL Abiraterone Low dose Steroids Dexamethasone Or Prednisolone Dex0.5mg OD,RR 50%,MDR=7m Pred 10mgOD,RR30%,MDR=2-3m New reported trials After Docetaxel in CRPC

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

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

  40. 2)Abiraterone 100 AA 14.8 months (95% CI: 14.1-15.4) 80 60 Survival (%) 40 Placebo 10.9 months (95% CI: 10.2-12.0) 20 HR = 0.646 (0.54-0.77) p < 0.0001 0 0 3 6 9 12 15 18 21 Timeto Death (Months) AA 797 736 657 520 282 68 2 0 Placebo 398 355 306 210 105 30 3 0 de Bono et al. Ann Oncol 2010; 21 (10 suppl 8): Abstract LBA5 (oral presentation) Scher et al. J ClinOncol 2011; 25 (suppl 7): Abstract 4 (oral presentation)

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

  42. 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

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

  44. PROSTATE CANCER TRIALS FOR MORE ADVANCED DISEASE 1st line LHRHa e.g. Zoladex RR=85%, Median duration of response=18-24m RR=30-40% Median duration of response=3-6m 2nd line AA e.g. Bicalutamide DOCETAXEL Chemotherapy Trials CRPC 3rd Line estrogens e.g. Diethylstiboestrol RR=30% Median duration of response=3-6m After DOCETAXEL Abiraterone Low dose Steroids Dexamethasone Or Prednisolone 12m+ Dex0.5mg OD,RR 50%,MDR=7m Pred 10mgOD,RR30%,MDR=2-3m New reported trials After Docetaxel in CRPC

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