Prostate cancer: Update from the BCCA

Prostate cancer: Update from the BCCA Tom Pickles Clinical Professor, UBC Topics 1. Incidence & Utilization rates 2. New developments with External Beam RT IGRT, VMAT and other enhancements Optimizing ADT duration 3. Brachytherapy results 4. Adjuvant & Salvage RT RADICALS 1

2 Provincial incidence 0 500 1000 1500 2000 2500 3000 3500 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 EBRT Provincial incidence 0 500 1000 1500 2000 2500 3000 3500 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Brachy Incidence RRP

Provincial incidence Curative treatments as % of incidence 40% 35% EBRT EBRT 30% 25% 20% 15% 10% RRP RRP Brachy Brachy 5% 0% 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Incidence projections Number of People 3

Prevalence projections 14,000 12,000 Postate Cancer Prevalence 10,000 8,000 6,000 4,000 2,000 2005 Age Distribution 2015 Age Distribution 2025 Age Distribution 2035 Age Distribution - 2. New developments with External RT 4

EBRT is getting better! 2001 1998 1994 Why EBRT is getting better 1980 s Conventional simulation 1990 s CT planning (2d) CT planning (2½d) CT planning (3d conformal RT) 2000 s IMRT (Intensity Modulated RT) Now IGRT (Image Guided RT) VMAT (Volumetric Modulated RT) 5

Conventional simulation (80 s) Plain X-Ray with urethrogram Based on bony landmarks No prostate position verification Max dose 66Gy CT planned treatment (early 90 s) Mid-prostate CT used to determine patient shape Prostate identified on all slices But Radiation planning was not true 3-Dimensions Max dose 70Gy 6

EBRT: Conformal RT Increased dose effects Increased cure Increased toxicity Grade 3-4 - Rectal 10% v 1% - Urinary 4% v 2% ALAN POLLACK, et al Int. J. Radiation Oncology Biol. Phys., Vol. 53, No. 5, pp. 1097 1105, 2002 7

CT planned treatment (late 90 s) True 3-D planning Radiation dose calculated using all CT information to correct for tissue inhomogeneities Max dose ~76Gy Did this lead to better outcomes? Probably! 3D group Late GU toxicity 2D 3D Grade 1 28% 10% Grade 2 20% 11% Grade 3 8% 6% Grade 4 0 0 proportion not failing 0.0 0.2 0.4 0.6 0.8 1.0 2D group Planning group 2 Planning group 3 Agranovich et al. Radiotherapy & Oncology; 2004. p. S56 0 20 40 60 80 100 time (months) 8

IMRT Many beams of radiation Each can be modulated by the MLC leaves in complex patterns High dose region very tight Allows rectal sparing Simple RT technique 9

IMRT technique Volumetric Modulated Arc Inventor: Karl Otto Single 360º source rotation Variable collimation Variable dose 10

Volumetric Modulated Arc Inventor: Karl Otto Single 360º source rotation Variable collimation Variable dose 11

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VMAT Volume Modulated Arc Therapy 3-D Conformal - limits dose to ~76Gy IMRT - limits dose to ~80Gy VMAT -?86Gy 13

Prostate movement Usually <5mm Exceptionally <10mm Worse in the obese Worse with distended rectums Int. J. Radiation Oncology Biol. Phys., Vol. xx, No. x, pp. xxx, 2007 14

Potential downsides Treatment complexity Errors Diverts resources Impact on waiting lists Cost Brachytherapy $10,400 EBRT $6,600 IMRT?$13,000 RRP (open) $7,700 Markov model estimates intermediate risk $22,000 per QALY 3-D $48,000 per QALY IMRT Second malignancy Konski et al USING DECISION ANALYSIS TO DETERMINE THE COST-EFFECTIVENESS OF IMRT Int. J. Radiation Oncology Biol. Phys., 2006 Induced cancers Overall men with prostate cancer have Reduced risk of other cancers Life expectancy greater than general popl n Some cancers are increased with prostate cancer Bladder SIR 1.3 Testis SIR 2.8 Some cancers are increased with RT Colorectal SIR 1.2 Sarcoma SIR 1.7 1/220 overall. 1/70 after 10 years follow-up Pickles et al. Radiotherapy and Oncology 65 (2002) 145 151 15

b. Androgen Deprivation Therapy with radiation therapy Optimizing ADT High risk bned outcomes, BCCA 2000-75% 1998-55% 1994-45% ADT use 93% 87% 12% 16

ADT with radiation: survival benefits Bolla I: 0 v 3 years RTOG 8531: 0 v 5+ years D Amico: 0 v 6 months Bolla II: 0.5 v 3 years RTOG 8610: 0 v 4mo Something special is going on 9% absolute survival improvement 1.4 years median survival benefit From 4 months ADT a decade earlier! Roach. JCO VOLUME 26 NUMBER 4 FEBRUARY 1 2008 17

Why does ADT work with RT? 1. Reduces tumour volume 2. Decreases tumour hypoxia Post-treatment versus pretreatment marginal mean prostate cancer po2 levels in 22 patients. Dark points, significant (P V 0.001) changes in oxygenation with androgen withdrawal; bars, SEs. The line of unity is also shown. Milosevic et al., Cancer Res 2007; 67: (13). July 1, 2007 Why does ADT work with RT? 1. Shinogi Tumour Model RT & castration before RT & castration after RTalone % Local Control 100 90 80 70 60 50 40 30 20 10 0 0 10 20 30 40 50 60 70 80 90 100 Radiation Dose (Gy) Zietman 18

Why does ADT work with RT? 1. Reduces tumour volume 2. Decreases tumour hypoxia 3. Increases apoptosis 4. Affects dendritic cells increasing immunologic recognition of prostate cancer Timing of ADT neoadjuvant or adjuvant? 893 men with ADT/EBRT median ADT dur n 33% pure neoadjuvant 5mo 16% neoadjuvant-concurrent 8mo 50% NA-C-Adjuvant 17mo In multivariate analysis No effect of timing Reanalyzed 2008 BCCA Prostate Cohort Outcomes Initiative (unpublished) Pickles T, Prostate Cohort Outcomes Initiative. Duration, Not Timing Is Important When Androgen Ablation Is Combined With External Beam RT. CUA Annual Meeting; 2004; Whistler, BC: Canadian Journal of Urology; 2004. p. 2232 19

Timing of ADT - 9413 study 4 month NA v 4mo Adjuvant Lawton 9413 update. Int. J. Radiation Oncology Biol. Phys., Vol. -, No. -, pp. 1 10, 2007 Timing: Before or after? Most survival benefit was shown in studies using adjuvant bned benefits from neoadjuvant Overall duration most important 20

& it s not permanent castration Testosterone recovery following ADT 1.0 Proportion recovering TTT to 5nmol/l.8.6.4.2 0.0 0 1 2 3 4 Years post cessation of AA EBRT - Cancer. 2002;94(2):362-7 Brachytherapy - unpublished But ADT has potential toxicity Nuisance Weight gain Hot flashes ED Memory change Osteopenia/porosis Arthritis Muscle weakness Serious Metabolic syndrome Weight gain Diabetes risk HR 1.44 1 MI risk HR 1.16 1 Death rate MI inc ~x2fold 2 1: Keating et al, J Clin Oncol 24:4448-4456.2006 2: Tsai et al., J Natl Cancer Inst 2007;99: 1516 24 21

So how much adjuvant ADT do men really need? Life long? 3 years? 2 years? 6 months? None? So how much adjuvant ADT do men really need? 3941 cases with intermediate or high risk cancer 4 centres proportional hazards model of bned outcome bootstrap resampling to derive non-parametric confidence intervals (CI) Work in progress Scott Williams, Tom Pickles, Larry Kestin, Mark Buyyounouski, Gill Duchesne 22

Hazard Ratio 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 So how much adjuvant ADT do men really need? 0 6 12 18 24 30 36 Work in progress Months Scott Williams, of Androgen Tom Pickles, Deprivation Larry Kestin, Mark Buyyounouski, Gill Duchesne So how much adjuvant ADT do men really need? No ADT 0% of the benefit c/w 3 yrs 6 mo 54% 1yr 83% Hazard Ratio 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2yr 96% 0 6 12 18 24 30 36 Months of Androgen Deprivation Work in progress Scott Williams, Tom Pickles, Larry Kestin, Mark Buyyounouski, Gill Duchesne 23

Do all risk groups benefit? - Effect of ADT on bned by risk group 110% 100% 100% 100% 90% 90% 80% 70% 60% 50% ADT No ADT 80% 70% 60% 50% ADT 80% 60% ADT 40% 40% 40% bned (Phoenix) 30% 20% 10% 0% 0 2 3 5 7 8 10 bned (Phoenix) 30% 20% 10% 0% 0 2 3 5 No ADT 7 8 10 bned (Phoenix) 20% 0% 0 2 3 5 No ADT 7 8 10 Years post - radiation Low risk n.s. Months post - radiation Intermediate p=0.01 Years post - radiation High p<0.0001 BCCA GURO data Beasley M, Williams SG, Pickles T. In Press BMC Radiation Oncology Dec 2007 Effect of ADT on bned intermediate risk 100% 90% 80% 70% ADT 60% 50% 40% bned (Phoenix) 30% 20% 10% 0% No ADT 0 2 3 5 7 8 10 Months post - radiation Beasley M, Williams SG, Pickles T. In Press BMC Radiation Oncology Dec 2007 24

Effect of ADT on bned intermediate risk 100% 90% 80% 70% ADT 60% 50% 40% bned (Phoenix) 30% 20% 10% 0% No ADT 0 2 3 5 7 8 10 100% Months post - radiation 100% PSA <10, Gleason 7 PSA 15-20, Gleason 6 80% 80% ADT bned (Houston) 60% 40% PSA 7.5-15 Gleason 6 bned (Houston) 60% 40% 20% No ADT 20% 0% 0 2 4 6 8 10 0% 0 2 3 5 7 8 10 Years Years Low-intermediate p= n.s. High-intermediate P=0.003 HR 1.7 Contemporary BCCA radiation results by risk group Low Intermediate High Unpublished PCOI data. Patients treated 2000-2001 25

Optimizing ADT High risk bned outcomes By number of risk factors BCCA: EBRT & ADT (99%) Median ADT dur n 17 months Median f/up 4.1 yrs VGH: RRP & ADT (83%) Median ADT dur n 18 months Median f/up 3.3 yrs BCCA PCOI outcomes & Rod Studd 2007 Urology Rounds 3. Brachytherapy 26

Why might brachytherapy give better outcomes? Very high radiation doses Equivalent to ~90Gy EBRT (maybe) Very focal Low toxicity except for urinary Margin ~5mm Enough for extracapsular spread Low radiation dose rate Radiobiological advantages (?) How does brachy shape up? No randomized data available Institutional data very suggestive that results with brachy are superior to EBRT 1. Meta comparison (adjusted) 2. BCCA results & comparison 27

Meta comparison bned rates low risk 1 % Progression Free 0.9 0.8 0.7 0.6 11 12 14 20 4 16 12 21 12 24 1 27 7 13 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Years 9 6 19 23 +wd 18 16 3 Brachy Surg EBRT Cryo HIFU *Hypofractionated ** HDR *** D 90 > 130 Gy wd= well Diff Courtesy Peter Grimm Meta comparison bned rates low risk 1 % Progression Free 0.9 0.8 0.7 0.6 11 12 14 20 4 16 12 21 12 24 1 27 7 13 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Years 9 6 19 23 +wd 18 16 3 Brachy Surg adjusted EBRT Cryo HIFU *Hypofractionated ** HDR *** D 90 > 130 Gy wd= well Diff Courtesy Peter Grimm 28

Meta comparison bned rates low risk 1 2 10 16*** % Progression Free 0.9 0.8 0.7 0.6 11 15 17 12 14 20 4 16 12 21 12 5 24 1 27 7 13 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Years 9 6 19 23 +wd 18 16 3 Brachy Surg adjusted EBRT Cryo HIFU *Hypofractionated ** HDR *** D 90 > 130 Gy wd= well Diff Courtesy Peter Grimm Meta comparison bned rates intermediate risk % Progression Free 1 0.9 0.8 0.7 0.6 0.5 0.4 21 20 14 27 19 12 12 12 11 13 8 8 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Years 26 Brachy Surg EBRT Cryo EBRT & Seeds Courtesy Peter Grimm 29

Meta comparison bned rates intermediate risk 1 % Progression Free 0.9 0.8 0.7 0.6 0.5 0.4 21 20 14 27 19 12 12 12 12 11 13 26 8 8 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Years Brachy Surg adj EBRT Cryo EBRT & Seeds Courtesy Peter Grimm Meta comparison bned rates intermediate risk % Progression Free 1 0.9 0.8 0.7 0.6 0.5 0.4 15 21 20 14 1 27 19 24 23 12 12 9 12 12 11 13 8 8 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Years 8 22 26 25 Brachy Surg adj EBRT Cryo EBRT & Seeds Courtesy Peter Grimm 30

BCCA results Brachy program is 10 years old this summer >2200 implants Prospective data collection Real time data entry and analysis 1006 consecutive patients from #1 7/1998-10/2003 Data cut off Oct 2007 = minimum 4 yrs f/up No exclusions Patient selection Low risk PSA 10 Gleason 6 ADT for TRUS volumes > 50cc Intermediate (low tier) PSA 10 and Gleason 7 or PSA 10-15 Gleason 6 ADT for 3 months before & 3 months after 31

Outcomes 1. bned (Phoenix = Nadir +2) Low: bned 95.4 % Int: bned 96.3% Outcomes Metastases n=5 (99.1% KM) Deaths 54 non-prostate 1 prostate 1 complication (renal failure/urosepsis) 32

Toxicity GU Prevalence RTOG grades 60% 50% 40% 30% 20% 10% Grade 1 Grade 2 Grade 3 Minor nuisance Medication Minor surgical (excl catheterization) 0% 2 3 4 5 6 7 8 Years Brachytherapy outcomes database 2008 unpublished BCCA Toxicity publications Bucci, J, W J Morris, M Keyes, et al.: Predictive factors of urinary retention following prostate brachytherapy. Int J Radiat Oncol Biol Phys, 53,(1): 91-8, [2002]. Macdonald, A G, M Keyes, A Kruk, et al.: Predictive factors for erectile dysfunction in men with prostate cancer after brachytherapy: is dose to the penile bulb important? Int J Radiat Oncol Biol Phys, 63,(1): 155-63, [2005]. Keyes et al. Urinary toxicity 845 patients. In preparation AUR rates Peak time of AUR in first few weeks ~0.6% long term Learning curve related to Procedure dexterity Needle loading Patient selection 33

Toxicity GI Prevalence RTOG grades 60% 50% 40% 30% Grade 1 Minor nuisance Grade 2 Medication Grade 3 Minor surgical 20% 10% 0% 2 3 4 5 6 7 8 Years Brachytherapy outcomes database 2008 unpublished Potency by age group 1, 2, and 3 years after implant Macdonald, A G, M Keyes, et al Int J Radiat Oncol Biol Phys, 63,(1): 155-63, [2005]. 34

How does Brachy compare with EBRT? 1:1 matched pair analysis with EBRT Same dates (7/98-2/01) Same PSA (within 1ng/ml) Same use ADT (within 2 months) Same Gleason total (exact) Same % positive cores (<>50%) Same T stage (major T category) How does brachy compare with EBRT? Baseline prognostic features Brachy EBRT Patient numbers 139 139 Median follow-up 68mo 66mo NCCN risk group Low 77.7% 77.7% Intermed 22.3% 22.3% p=ns ipsa median 5.6 6.4 p=ns Stage(1997) 1a-c 38.8% 41.7% 2a 54% 50.4% 2b 7.2% 7.9% p=ns %PC <=50% 87.8% 87.85 p=ns Gleason 6 87.8% 87.8% 7 12.2% 12.2% p=ns ADT use Yes 31.7% 30.2% p=ns Duration 6mo 5.8mo p=ns 35

How does brachy compare with EBRT? 7 yr rates: 95% 75% p=0.0008 Brachy EBRT Last PSA (in non-relapsers) 0.04 0.86 PSAdt (relapsers) 6mo 24mo How does brachy compare with surgery? Canadian trial 3 v 8 months Neoadjuvant ADT Courtesy Martin Gleave 36

4. Post-op adjuvant radiation Treatment of the positive margin 24% from 3 month arm of 3 v 8 mo study Margin ve or Margin +ve & RT +ve margin No adjuvant RT Van der Kwast. JCO VOLUME 25 NUMBER 27 SEPTEMBER 20 2007 37

Treatment of the positive margin 3 randomized trials EORTC. 1005 men, 5 yr follow-up Relapse HR 0.52 No survival advantage (yet) NCIC-SWOG. 473 men, 10 yr follow-up Relapse HR 0.51 Mets HR 0.8 (ns) No survival advantage (HR 0.76, ns) ARRO. 293 men, 3 yr follow-up Relapse HR 0.4 No survival advantage How about waiting for the PSA to rise? 1.0.9.8 Salvage RT.7 BF Estimate.6.5.4.3 Adjuvant RT.2.1 0.0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 Months Allan Pollack personal communication 38

Or using ADT instead? EPC trial of bicalutamide Increased non-cancer death rate with survival detriment RTOG 9601 trial results soon Also used bicalutamide though Retrospective data conflicting RADICALS Radiotherapy and Androgen Deprivation In Combination After Local Surgery 39

RADICALS randomised comparisons: Flow diagram Radical prostatectomy All Groups Assess need for RT Time RADICALS randomised comparisons: Flow diagram Radical prostatectomy Uncertain Group Assess need for RT Uncertain group RANDOMISE Immediately after surgery Time 40

RADICALS randomised comparisons: Flow diagram Radical prostatectomy Uncertain Group Assess need for RT Uncertain group Immediately after surgery RANDOMISE Immediate RT RANDOMISE Immediately after surgery Monitor on trial RT + no AD RT + short AD RT + long AD Time RADICALS randomised comparisons: Flow diagram Radical prostatectomy Uncertain Group Assess need for RT Uncertain group Immediately after surgery RANDOMISE Immediate RT RANDOMISE Immediately after surgery Monitor on trial RT + no AD RT + short AD RT + long AD Trial follow-up Deferred RT RANDOMISE At rising PSA RT + no AD RT + short AD RT + long AD Time 41

RADICALS randomised comparisons: Flow diagram Radical prostatectomy Immediate Group Assess need for RT Immediate RT group Immediate RT Immediately after surgery RANDOMISE RT + no AD RT + short AD RT + long AD Trial follow-up Time Outcome measures RADICALS randomised comparisons: Flow diagram Radical prostatectomy Deferred Group Assess need for RT Deferred RT group Monitor, not on trial Time 42

RADICALS randomised comparisons: Flow diagram Radical prostatectomy Deferred Group Assess need for RT Deferred RT At rising PSA RANDOMISE Deferred RT group (Monitored off trial, now PSA rising) RT + no AD RT + short AD RT + long AD Trial follow-up Time Outcome measures RADICALS randomised comparisons: Flow diagram Radical prostatectomy All Groups Assess need for RT Immediate RT group Uncertain group Immediately after surgery RANDOMISE Immediate RT RANDOMISE Immediately after surgery Monitor on trial RT + no AD RT + short AD RT + long AD Trial follow-up Note: Patients can be randomised between three AD arms or any two AD arms Deferred RT At rising PSA RANDOMISE Deferred RT group (Monitored off trial, now PSA rising) RT + no AD RT + short AD RT + long AD Trial follow-up Time Outcome measures 43

RADICALS randomised comparisons: Flow diagram Radical prostatectomy All Groups Assess need for RT Immediate RT group Uncertain group Immediately after surgery RANDOMISE Immediate RT RANDOMISE Immediately after surgery Monitor on trial RT + no AD RT + short AD RT + long AD Trial follow-up Deferred RT At rising PSA RANDOMISE Deferred RT group (Monitored off trial, now PSA rising) RT + no AD RT + short AD RT + long AD Trial follow-up Time Outcome measures Outcome measures Primary: Disease-specific survival (death after PCa progression) Secondary: Freedom from treatment failure Clinical progression-free survival Overall survival Duration of androgen deprivation Quality of life 44