Disclosures. The Challenges Facing Proton Beam Therapy and Opportunities. Minesh P Mehta, MBChB, FASTRO

Transcription

1 Minesh P Mehta, MBChB, FASTRO The Challenges Facing Proton Beam Therapy and Opportunities Disclosures Consultant: Varian, IBA, Agenus, Remedy, Insys DSMB: Monteris Current as of October

2 The Challenges Facing Proton Therapy Introduction An uneven playing field: shifting the goalposts Do we have equipoise for randomized trials? Benefits are delayed far too delayed The cost debate: payors, legislators Opportunities Major Ways of Treating Cancer Surgery, Chemotherapy and Radiation Therapy Radiation Therapy: Photons ( X-rays ) or PROTONS 2

3 Protons Stop, Unlike Photons Maximize Tumor Dose and Spare Healthy Tissue Therapeutic Index Radiotherapy outcomes are a function of Maximal tumor control through delivery of highest safe and necessary dose to the tumor, and Minimal normal tissue complications by reducing dose to normal tissues Proton therapy affords the best dosimetric advantages in this context Primarily due to their physical characteristics of essentially having no to minimal exit dose 3

4 Our Daily Job: A or B? A B The Challenges Facing Proton Beam Therapy An uneven playing field: Shifting the goalposts 4

5 Historic Evolution of RT 1895: X-rays first used to Rx Ca 1950 s: Co-60 radiators 1960s: Early Linac development : level? Blocking techniques for beam contouring 1980s: CT in RT planning: level? 1990s: MLCs, 3D CRT: level? 2000: IMRT, 4D RT, SBRT: level? 2000+: IGRT, Adaptive RT: level? None of these advances are based on randomized trials We accept dosimetric superiority every day 5

6 The Challenges Facing Proton Beam Therapy Do we have equipoise for a randomized trial? Chordoma: Results Mayo (Krishnan, Neurosurg, 2005): 32% 5Y LC with surgery + 3D CRT + GK SRS (n = 25); 10% symptomatic temporal lobe injury PSI, Switzerland (Ares, IJROBP, 2009): 81% 5Y LC with surgery + scanning PBT (n = 42); 6% symptomatic temporal lobe injury MGH (Munzenrider, StrahlentherOnkol, 1999): 73% 5 Y LC with surgery + PBT; 8% symptomatic temporal lobe injury With such large differences for a tumor that kills, would you want to be randomized? 6

7 Equipoise: The Parachute Story Hazardous Journeys Hazardous Journeys: Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials: BMJ 2003;327:1459 As with many interventions intended to prevent ill health, the effectiveness of parachutes has not been subjected to rigorous evaluation by using randomised controlled trials. Advocates of evidence based medicine have criticisedthe adoption of interventions evaluated by using only observational data. We think that everyone might benefit if the most radical protagonists of evidence based medicine organisedand participated in a double blind, randomised, placebo controlled, crossover trial of the parachute. 7

8 The Challenges Facing Proton Beam Therapy Benefits are delayed far too delayed Protons Lower Risk of 2 nd Cancer: SEER Matched Comparison MGH 2 nd cancer study (Chung, IJROBP,2008): 503 patients treated with protons matched with 1,591 SEER registry photon patients 2 nd cancers: 12.8% with photons, 6.4% with protons (adjusted HR = 2.73; 95% CI = , p<.0001) Absolute reduction of 50% The timeline on this is of course years to decades 8

9 Growth Hormone after conformal radiation therapy for Brain Tumors Merchant et al JCO 2011 IQ Craniopharyngioma (ages 5 9) 9

10 Cardiac Toxicity - Myocardial infarction - Coronary revascularization tx - Death from ischemic heart disease - Cardiac morbidity increases 7.4% with each extra Gy. - There is no safe cardiac dose Darby et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. NEJM 2013 Protons for Breast Cancer PMRT Photons/Electrons Photons Protons Courtesy of Shannon MacDonald, MD - MGH Phase III Randomized Breast Ca Trial >1700 patients, protons vs photons, funded by PCORI 10

11 The Challenges Facing Proton Beam Therapy The Cost Debate, Payors, Legislators Protons in the News: $ One news focus is cost. Reality check: Proton facility construction is more expensive in the short run, estimated at $17m per room in a 5 room center. Lifespan of 30 years Long term: High-end Linaccost per room is estimated at $3-4m with a lifespan of 6-7 years, resulting in similar cost outlay over 30 years 11

12 Medulloblastoma Swedish CER Lundkvist, Cancer, 2005 found the lowest lifetime costs for medulloblastoma with protons CRT PBT Fold difference Initial cost $5,622 $13,552 X 2.5 Cost of treating adverse events $44,905 $5,613 X 8 Total costs $50,527 $19,165 X 2.6 What would you choose for your child, irrespective of cost or level of evidence? 100 Pediatric Example: Proton High dose to target, no exit dose Pediatric Example: Photon Dose outside target, could damage normal tissue 12

13 Oregon: Death with Dignity 2/25/15: Oregon Health Evidence Review Commission issues guidance for PBT. Propose an extremely restrictive position: coverage should NOT be provided for pediatric malignancies. Guidances/Proton-Beam-Draft pdf Oregon: Death without Dignity Oklahoma: Leveling the Playing Field 2/19/15: OK house of Representatives passes HB A health benefit plan that. provides coverage for Ca therapy shall be prohibited from holding PBT to a higher standard of clinical evidence for medical policy benefit coverage decisions than the health plan requires for coverage of any other radiation therapy treatment. _id=1602 The entire Insurance Committee of the House of Representatives was treated to a nice lunch by BlueCross/BlueShield just before the vote on whether the Committee would pass the bill onto the full House for consideration. 13

14 Opportunities Exploit Biology Decrease long-term toxicities Decrease acute toxicities NRG BN001: Phase IIR Trial of Hypofractionated Dose-escalated Proton Beam Vs. Std Photon Irradiation With Concomitant and Adjuvant Temozolomide in Newly Diagnosed GBM 28 14

15 Protons Lower the Irradiated Volume IMXT -SIB IMPT -SIB Isodosecomparison of simultaneous integrated boost (SIB) and dose escalation using IMXT and IMPT. The proton approach allows better tumor tissue coverage while sparing more uninvolved structures, and possibly causing less lymphopenia. Images: Anita Mahajan 29 CD4 Counts vs. Survival in GBM Data from Johns Hopkins: Survival in GBM patients by CD4 count 15

16 Cardiac Toxicity - Myocardial infarction - Coronary revascularization tx - Death from ischemic heart disease - Cardiac morbidity increases 7.4% with each extra Gy. - There is no safe cardiac dose Darby et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. NEJM 2013 Protons for Breast Cancer PMRT Photons/Electrons Photons Protons Courtesy of Shannon MacDonald, MD - MGH Phase III Randomized Breast Ca Trial >1700 patients, protons vs photons, funded by PCORI 16

17 Gastrostomy Tubes by >50% With IMPT Case-control study, matched on based on unilateral vsbilateral therapy, tonsil vsbot primary, T-category, N-category, concurrent chemo, induction chemo, smoking status, sex and age. 26 IMPT cases precisely matched to 26 IMRT. Gastrostomy tubes needed in 5 (19%) IMPT vs. 12 (46%) IMRT cases (P <0.039). IMPT = less G3 dysphagia vs. IMRT. Phase 3 randomized trial is ongoing. S.J. Frank, et al: ASTRO How many extra intra-oral x-ray equivalents is IMRT over IMPT? Courtesy of Steven Frank 17

18 Slide 33 1 change "LET (1.1)" to "RBE (>1.1)" Vinai Gondi, 1/27/ removed the pubmed website link and included reference below also would consider changing text of "DSBs" to "double-strand breaks" if it fits Vinai Gondi, 1/27/2013

19 How many intra-oral x-rays is 25 Gy? ,000,000 Courtesy of Steven Frank H-N Phase II/III Randomized Trial Oropharyngeal Cancer - IMPT vs IMRT Eligibility 1) Stage III-IV oropharyngeal cancer 2) Squamous cell carcinoma 3) ECOG<2 4) Target volume delineation R A N D O M I Z A T I O N IMPT (70 Gy(RBE)) Chemotherapy (locally advanced disease) Treatment 33 days PROs Recovery 10 wks IMRT (70 Gy) Chemotherapy (locally advanced disease) Restaging No Surgery Surgery Follow-up PROs Q3 mo Follow-up PROs Q3 mo Frank PI Trial Activated Sept

20 You Can Only Go Home After the Sun Sets Spot Scanning 19