Disclosures. Proton therapy advantages. Why are comparing therapies difficult? Proton Therapy for Low Risk Prostate Cancer

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1 Proton Therapy for Low Risk Prostate Cancer Disclosures No relevant financial disclosures This presentation will not discuss off-label or investigational treatments Andrew K. Lee, MD, MPH Associate Professor Director, Proton Therapy Center M.D. Anderson Cancer Center Why are comparing therapies difficult? No good randomized data (known and unknown confounding factors) Retrospective comparisons prone to selection bias Lack of matched-pair analysis Treatment used 20 years ago may have little significance now (e.g. planning, technique, dose) Proton therapy advantages It s actual treatment Outpatient Learning curve Non-invasive No anesthesia Less dependent upon patient anatomy Fast daily fraction (decrease impact of organ motion) Less total radiation exposure Most of the current proton centers do a good job for prostate cancer patients 1

2 a surgeon needs to conduct at least 250 radical prostatectomies to maximize cancer control IMRT utilization is up but don t just blame the radiation oncologists 25 years to maximize outcomes! For robotic prostatectomy it s 1000!! Approximately 80% of surgeons performed fewer than 10 procedures per year Savage et al. J Urol 182, 2009 Twenty proton centers treating nothing but prostate cancer would account for <2% of all EBRT patients in Patient selection for brachytherapy ct1c-2a Gleason < 7 PSA 10 Prostate volume < cc Pubic arch interference AUA score < 15 Post-implant obstruction No TURP Urethral necrosis, post-implant incontinence, dosimetry Hypertrophic median lobe Post-implant obstruction, dosimetry 2

3 Men who came off active surveillance had higher failure rates after surgery or RT Most of these men were initially low risk! Klotz et al. JCO 2010 Competing risk of death Types of proton therapy Passive scattered (most common) Spot-scanning (aka pencil-beam scanning) Cancer J Clin 2009;59 Intensity modulated proton therapy (IMPT) 3

4 New therapy Would I adopt a new therapy that: Costs more? Requires hardware and software changes? Yes, I did. IMRT More difficult to plan, deliver and QA? Unproven efficacy and advantage over standard Rx? Theoretical advantages but no randomized evidence? Let s clear some things up IMRT is not backed by mature prospective data but I still use it Proton therapy at least has some published prospective data Protons yields much fewer neutrons than Hall proposed Proton therapy is not twice the cost of IMRT Want to save money in prostate RT? Start using 3D-CRT At least use 2Gy x (<8 wks) instead of 1.8Gy x (9 wks) Using $50,000/QALY is obsolete and would be >$150,000/QALY in 2009 dollars Prostate cancer therapy has and always will be about patient choice Radiation treatment options Brachytherapy (seeds) $9-10K 3D-CRT $16K HDR $18.5K IMRT $27.5K IMRT + IGRT $32K IMRT + CBCT $35K Proton therapy $38K Rounded estimates based on 2009 Medicare fee schedules & adapted from Konski,

5 X-rays don t stop in tissue protons STOP How are protons different than x-rays? X-RAYS Tumor Exit dose Single proton beam: Beam on time <1 minute High dose No dose Yellow 100% dose Blue 40% dose PROTONS No exit dose 5

6 2 Lateral Opposed Beams New advance Proton therapy is actually is not new Used clinically for over 20 years to treat tens of thousands of patients worldwide 1954 first used clinically in lab setting 1964 Harvard cyclotron used clinically 1990 LLUMC began treating in hospital setting Used much longer than IMRT What is new? Protons have benefited in technologic advances (just like x-ray therapy) Patient alignment at MDACC PTC-H X-ray tubes Image receptors Imaging Treatment planning (software) Treatment delivery systems Intensity modulation Immobilization Positioning Image Analysis System, PIAS Hitachi 6

7 IGRT carbon-coated Zr0 2 PROTON THERAPY FOR PROSTATE CANCER: LOMA LINDA UNIVERSITY EXPERIENCE 1255 men with prostate cancer treated between Combination protons + X-rays (731) Protons only (524) JD Slater, CJ Rossi, LT Yonemoto, et al. Int J Radiat Oncol Biol Phys 59:348-52, 2004 Low morbidity w/ protons <2% RTOG toxicity Acute GI/GU Grade 3-4 < 2% Late GI Grade 3-4 < 2% Late GU Grade 3-4 < 2% 5y and 10y actuarial rate of being free of Grade 3-4 GI/GU ~99% Prior report 3-y RTOG Grade 2 GI/GU incidence of ~5% (Urology 53, 1999) Where to look Focus on data from prospective studies Not just single institution retrospective experiences or anecdotal reports 7

8 PROG PROTON-photon randomized trial MGH Perineal boost Limited beam energy 4x per week T1-2b, PSA<15 N= GyE 79.2 GyE Protons 19.8 GyE 4F X-rays 50.4 Gy Protons 28.8 GyE 4F X-rays 50.4 Gy JAMA 294, 2005 Journal of Urology 167:123, 2002 LLUMC- one field a day Proton-photon trial: PSA-Failure free survival 79.2 CGE 70.2 CGE [JAMA 294: , 2005] 8

9 Proton-photon trial: PSA-Failure free survival CORRECTED calculation (JAMA 299, 2008) 92% PSA-FFS PROG 9509-UPDATE J Clin Oncol 2010 Difference in bned survival between arms persists with median follow-up of 9 years No difference in Gr>3 GI/GU morbidity between arms using data from validated patient questionnaire Fewer patients in high dose arm required salvage hormones C. Rossi-LLUMC. PROG update: Low risk PSA control ~95% w/ median FU 9 years J Clin Oncol March 2010 Comments PROG study has the best PSA control from any prospective external beam trial Proton technique was not optimal and used simple beam arrangement (one beam a day) If this were a drug 9

10 No difference in patient-reported QOL between high and standard dose arms Post-hoc survey of participants 280 responses (141 high dose, 139 standard) Median FU 9.4 years (range ) Median age 76 yo (range ) Mean QOL scores: Standard vs. High Scale (none max) Urinary obstruction/irritation Standard High P-value Incontinence Bowel problems Talcott et al. JAMA 303, 2010 Sexual dysfunction Talcott et al. JAMA 303, % Grade 2 rectal 7.8% Grade 2 bladder No Grade 3 Prospective study of 151 men treated GyE (2GyE/fxn) Median FU 43.4 months CTC v2.0 Nihei et al. IJROBP, in press 10

11 94% PSA failure free survival Grade 2+ side effects from prospective studies Study Grade 2 GI Grade 3 GI Grade 3 GU Nihei et al. IJROBP, in press MDACC X-rays 70 vs. 78Gy Dutch X-rays 68 vs. 78Gy PROG Protons 70.2 vs. 79.2Gy Japanese Protons 74GyE 13 vs. 26% 1 vs. 7% 5 vs. 4% 27 vs. 37% 5 vs. 4% 13 vs. 12% 9 vs. 18% 1 vs. 1% 2 vs. 1% 4% 0% 0% Randomized studies showing benefit continued Dutch multicenter trial 68 vs 78 Gy 664 men 3D-CRT/IMRT 22% hormone therapy Median FU 51 mos 5-y FFF 64 vs 54% Grade 2+ GI toxicity 32% vs. 27% [Peeters et al. J Clin Oncol 2006;24] Is IMRT better than 3D-CRT? Subset of patients in Dutch trial received IMRT compared to 3D-CRT at same institution to 78Gy No statistical difference between two groups for PSA control (nadir+2), grade 2 GU/GI toxicity IJROBP 73:685,

12 Only 78 patients Comments No statistical difference does not equate to equivalence IMRT had shorter FU 56 months (vs 76 mo) IMRT 5-field however, 3D-CRT was 3- field!! IJROBP 73:685, 2009 IMRT Protons IMRT or Protons? Red is prescription isodose. Beige is 20 Gy 12

13 100% 90% Mean DVHs for 27 pairs of plans Protons expose less rectum and bladder 80% 70% IMRT Plan Proton Plan Percent 60% 50% 40% Rectal Wall Prostate 30% 20% 10% 0% Body Dose (Gy) Rectum Bladder Vargas et al. IJRBOP Protons also significantly decrease the integral whole pelvic dose Prostate Ca Second Solid Tumors After XRT SEER Second Cancer 5 years 10 years 6% RR 15% RR 34% RR Brenner et al, Cancer

14 The longer you wait the more 2 nd cancers you get Doses >5Gy associated w/ increased risk of 2 nd cancers for pelvic RT 10-14y RR 1.6, >15y RR 1.91 de Gonzalez et al. Lancet Oncol, Mar 2011 de Gonzalez et al. Lancet Oncol, Mar 2011 for sites such as the prostate, where the age at treatment is decreasing, while long-term survival rates are increasing, the issue of radiotherapy-related second cancers will be become increasingly pertinent It is unquestionably the responsibility of the radiation oncology profession as a whole to ensure that these risks are made as low as is practical. [Brenner D. Induced Second Cancers after Prostate-Cancer Radiotherapy: No Cause for Concern? Int J Radiat Oncol Biol Phys. 65: , 2006.] 14

15 Results: Proton therapy reduced the risk of SMN by 26 to 39% compared to IMRT. Protons decreased the ratio of relative risk of 2 nd radiationassociated cancers by 26-39% compared to IMRT Clinical data does not support the neutron issue Risk w/ IMRT MGH report of 647 pts treated w/ protons or mixed photons-protons w/ median FU 107 months. Risk w/ protons Overall 2 nd ca rate 7.3% (6,893 person-yrs of FU) No 2 nd ca in pts treated w/ protons alone Significantly lower than XRT pts from population Fontenot et al. IJROPB 74;

16 What is spot scanning? Conventional proton therapy (Right side view) Passively scattered beam Prostate 1 st scatterer = scattering foil in a linac 2 nd scatterer = flattening filter in a linac 16

17 The Pencil Beam Scanning Mode of Proton Beam Delivery Spot Scanning Multiple spots are used to cover the target Prostate = 1800 spots and 24 layers Delivered in 68 seconds Some A few proton more pencil pencil beams together. (spot)... A Smith. Med. Phys Pedroni, PSI SINGLE right scanning beam Spot-scanning SFUO (80 CGE) Right lat field only Bilateral fields Purple is 80 CGE 17

18 Scanning pencil beam is needed for Intensity Modulated Proton Therapy Rectal V70 Gy (light green) and anterior rectal wall V70 Gy (dark green) reduced by ~10% Conventional protons IMPT Conventional IMPT Advantages of Pencil Beam Scanning Improved conformality especially concave structures Esophagus (Single field) Fewer patient specific devices (less hardware) Improves feasibility of more beam angles Sparing of healthy tissues proximal to the target Intensity modulated proton therapy (IMPT) Fewer neutrons 18

19 Scanning proton therapy for chordoma (2 fields) Snapshot of daily PTC patient mix 122 patients per day (including 12 anesthesia cases) Pedi 14% GI 3% CNS 8% GU 47% Thoracic 28% It s not magic it s still radiation Is technology enough? + No kv-igrt and half the rectum is getting 74Gy!! 19

20 Patient satisfaction w/ protons Overall, how satisfied were you with the treatment you received for prostate cancer? Survey of nearly 2000 men w/ prostate cancer treated with protons Over 95% of respondents (n=1921) were satisfied or extremely satisfied with treatment Full analysis is pending Do you feel you made the best treatment decision for yourself? Thank you Physicians Physicists Engineers Therapists Dosimetrists Nurses Pt Services Coordinators Pt Access Specialists Pt Access Coordinators Billing Administrative 20

21 Translational shifts < 6mm and rotational shifts <5º do not significantly impact CTV coverage UF-Vargas et al. IJROBP 71, 2008 NCC Korea-Yoon et al. IJROBP 71, 2008 MDACC- Sejpal et al. IJROBP (in press) Vargas et al. IJROBP 71, 2008 Virtual shifts Yoon et al. IJROBP 71,

22 Yoon et al. IJROBP 71, 2008 Coverage maintained well for shift up to 6mm How important is rotation? 0º 0º LR shifts >5mm occur <2.5% 3º +3º 5º -3º Worst case scenario is underdosing by 0.06 GyE (<0.08%) [Sejpal et al. IJROBP (in press)] If you make systematic error every fraction, change in normal tissue dose <5% 22