Future Directions in Prostate Cancer: The Case for Protons. John J. Coen, MD Helen & Harry Gray Cancer Center
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1 Future Directions in Prostate Cancer: The Case for Protons John J. Coen, MD Helen & Harry Gray Cancer Center November 14, 2012
2 Protons and prostate cancer Early proton experience at the MGH The case for higher h doses PSA era randomized trials The means of higher doses Brachytherapy Conformal EBRT Protons, photons and intensity modulation Future directions
3 The first use of proton radiation in prostate cancer Four field photons plus a perineal proton boost (160 Mev) Shipley, JAMA 241: 1912, 1979
4 Dose Escalation in Prostate Cancer Supported by Randomized Data doses n Low dose High dose P-value MDACC 70 vs 78Gy % 78% Dutch trial 68 vs 78Gy % 64% 0.02 UK MRC 64 vs 74Gy % 71% PROG vs 79.2GyE % 91% <0.001
5 PROG 9509 Dose escalation using photons/protons t Trial design No hormonal therapy T1b-2b prostate cancer PSA <15ng/ml randomization a i o n ACR/RTOG Total prostate dose 70.2 GyE Total prostate dose 79.2 GyE
6 Prostate boost with protons - MGH PROG 9509
7 PROG 9509 Prostate boost with protons - LLUMC
8 PROG ASTRO Phoenix Zietman et al JCO 2010
9 PROG Low risk Intermediate risk
10 PSA era dose escalation studies Suggest benefits to higher doses Improved bned survival High dose treatment is tolerable with either 3D conformal treatment IMRT Protons
11 What about brachytherapy?
12 Case Matched Analysis High dose arm of PROG CGE using a proton boost 196 pts accrued from 1/31/96 to 12/31/ with GS 7 used for case matching Brachytherapy by a single brachytherapist (ALZ) from at MGH 203 similar pts treated with brachytherapy alone 145 Gy I-125 or 115 Gy Pd-103 Coen et al IJROBP 2012
13 Case Matched Analysis Matched for Tstage Gleason score PSA Age High Dose EBRT 177pts Brachytherapy Alone 203pts 141 matches
14 Case Matched Analysis Patient Characteristics EBRT Brachytherapy Age (median) PSA Follow-up (yrs)
15 Patient Characteristics EBRT (n=141) Brachytherapy (n=141) Tstage 1c 104 (74%) 104 (74%) 2a 36 (25%) 36 (25%) 2b 1 (1%) 1 (1%) Gleason (89%) 125 (89%) 7 16 (11%) 16 (11%) PSA <=4 17 (12%) 28 (20%) (79%) 107 (76%) (9%) 6 (4%)
16 Biochemical Failure
17 Risk Group Stratification EBRT (n=141) Brachytherapy (n=141) Risk group Low 113 (80%) 118 (84%) Intermediate 28 (20%) 23 (16%)
18 BF by risk group Low risk Intermediate t risk
19 BF Phoenix 8 yr BF EBRT Brachytherapy P-value Overall 7.7% 7% 16.1% 1% P=0.42 Low risk 7.5% 11% P=0.74 Intermediate risk 8.2% 38% P=0.21
20 Nadir PSA EBRT Brachytherapy Nadir (median)* Time to nadir (median) 60 mths 56 mths * Ttest p=
21 PSA at last follow-up failure free patients Last PSA EBRT Brachytherapy (n=129) (n=117) (66%) 109 (93%) (19%) 6 (5%) > (15%) 2 (2%) X-square p<0.0001
22 Case Matched Analysis Conclusions High dose EBRT and brachytherapy appear equivalent in patients with low-intermediate risk prostate cancer Brachytherapy results in lower PSAs in patients free of fdisease QOL assessments may guide treatment decisions in the future
23 QOL assessment of current therapies
24 Longitudinal QOL comparisons using the EPIC instrument Sanda et al NEJM 2008
25 PROG QOL analysis Single survey median 9.4 yrs post-tx No diff in any QOL outcome Talcott et al JAMA 2010
26 Further dose escalation using conformal protons
27 Phase I/II study - ACR 0312 Study of: 85 pts - Low/intermediate risk prostate cancer Further dose increase More convenient fractionation Protons alone Image guidance 82GyE with 2GyE fraction
28 ACR Late Toxicity Coen et al IJROBP 2011
29 Long-term QOL analysis of men receiving 78-82GyE proton RT Long term questionnaires ranged from mths post-txtx Coen et al IJROBP 2012
30 Long-term QOL analysis by baseline function
31 Long-term QOL analysis by baseline function Urinary Incontinence = 0.05 Urinary Obstruction = Long term function nal outcomes % Normal Intermediate Baseline category Poor long term Intermediate t long term Normal long term Long term functiona al outcomes % Normal Intermediate Poor Baseline category Bowel Problems = Sexual Problems < Lo ong term functional outco omes % Normal Intermediate Poor Baseline category Lo ong term functional outco omes % Normal Intermediate Poor Baseline category
32 Refining high dose EBRT The role of protons Dose distribution ib ti comparisons Clinical trials Quality of life endpoints Theoretical risks Secondary malignancies Integral dose Neutron scatter
33 Dosimetric comparisons of protons vs IMRT 3DCPT IMXT 3DCPT IMPT
34 Dose distribution (a) IMRT (b) 3d-conformal proton (c) IMPT (a) Dose [Gy] (b) (c) Dose [CGE] Dose [CGE]
35 Intensity Modulated Proton Therapy (IMPT) Spot Scanning - Principle The dynamic application of scanned and modulated proton pencil beams A Some A full few proton set, more pencil with pencil beams a homogenous together. (spot)... dose conformed distally and proximally Images courtesy of Eros Pedroni
36 Intensity-modulated proton therapy Lateral beams deliver inhomogeneous dose distributions, which combine to a homogeneous dose in the target volume (a) (b)
37 Dose volume histograms, from photon IMRT, 3D-CPT (parallelopposed lateral beam configuration) and IMPT plans
38 DVH data from 6pts With 3D protons (a) (b) IMRT (c) (d)
39 Technical issues with protons Limitations Penumbra at depth End of range uncertainty Smearing (d) Future directions Non-traditional beam arrangements Focal tumor boosting Image guidance is critical Image guidance is critical Daily Target localization Dosimetric recalculation
40 Now Open QOL endpoint T1-2 prostate cancer PSA <15ng/ml r a n d o m i z a t i o n 79 GyE 79 Gy Proton radiation IMRT Quality of Life analysis
41 Risks of highly conformal radiation
42 Integral Dose
43 Neutron production with proton radiation Hall IJROBP 2006
44 Radiation exposure from EBRT Out of field Passive Scattering Crude Correction Hall IJROBP 2006
45 Where do protons fit in? Is the dose distribution superior to IMRT? Technically yes, but clinical implications unclear Are they clinically more efficacious or better tolerated? Not currently Can we afford them? Maybe not y Has treatment delivery been optimized? Definitely not
46 Future directions where protons may be superior Hypofractionation Stereotactic therapy Focal therapy Dependent on improved imaging As opposed to AS Partial prostate boost All of these may create a new opportunity for proton radiation to be an important and cost- effective tool for prostate cancer treatment
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