Hahn proton talk (cancer ci 2013) stephen m. hahn
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  • This means,an increase in tumour dose necessitates a decrease in toxicity in order to increase tumour control. This is expressed as an increase of the therapeutic ratio.
  • Key points to make: Completely new carriage and leaf design to Other improvements made: Reduced Head Diameter by 10 cm from previous “Standard” MLC
  • View from HUP

Hahn proton talk (cancer ci 2013) stephen m. hahn Hahn proton talk (cancer ci 2013) stephen m. hahn Presentation Transcript

  • Proton TherapyStephen M. Hahn, MDDepartment of Radiation OncologyFebruary 8, 2013
  • Outline The evolution of high technology in Radiation Oncology The principles & rationale for proton therapy Challenges with proton therapy Assessing the ‘value’ of proton therapy Future directions
  • Effect of underdosage and overdosage Tumor control Late normal tissue damageEffect Tumor Dose View slide
  • The Evolution of Radiation Therapy 1980’s 1990’s 1960’s 1970’s Computerized 3D CT 2000’sThe First Clinac Treatment Planning Functional Imaging Cerrobend Blocking Multileaf Collimator Electron Blocking Dynamic MLC High resolution IMRTStandard Collimator and IMRT Blocks were used to IMRT Evolution MLC leads to 3D evolves to smaller and The linac reduced reduce the dose to conformal therapy Computerized IMRT smaller subfields and complications normal tissues which allows the first high resolution IMRT introduced which compared to Co60 dose escalation trials. along with the allowed escalation of introduction of new dose and reduced imaging technologies compilations View slide
  • Principles of Proton TherapyThe Physical characteristics of protons provide the rational for its use Protons have a finite depth of penetration in material depending on their energy and density of the material Protons have a relatively low energy loss per unit path length (ionization density) at the surface that slowly increases to near the end of beam range and create a high ionization density region ( Bragg Peak) with negligible dose beyond Proton beam deposited dose falls off sharply laterally and distally
  • Characteristics of Proton and Heavy Particle Therapy Ar HIGH LET ADVANTAGE Fast Neutron Neutrons IMRT 2002 Si Ne Pions C 250 kVp 4 MV 22 MV MV 60 X-rays Co X-rays X-rays X-ray p IMRT DOSE DISTRIBUTION ADVANTAGE Kohler, A
  • Comparison of dose distributionsGSI/HIT
  • The Evolution of Conformal Radiotherapy 2-D IMRT 3-D Proton
  • Principles of Proton Therapy Accelerated protons are near monoenergetic and form a beam of small lateral dimension and angular divergence There are two approaches to form a desired dose distribution : Passive Scattering and modulation ( referring to the method of spreading the beam laterally and with method of spreading the beam in depth)
  • Principles of Proton Therapyb . Dynamic Scanning of a pencil beam laterally and in depth involves scanning of a PB both laterally and in depth ( by changing its energy) => in a near arbitrary dose distribution laterally and dose sharpening in depth ( Pedroni et al.) - lateral distribution determined by the lateral positions and weights of each pencil beam of a chosen energy - distribution in depth is determined by weighting the pencil beam at each position within the field.Note: Beam Scanning is the only practical technique which enables IMPT to be performed. 10 1
  • Spot scanning - The principleThe dynamic application of scanned and modulated proton pencilbeams AA proton pencil beam full set, with a Some more… beams A few pencil together…. (spot)…... homogenous dose conformed distally and proximally Images courtesy of E Pedroni and T Lomax, PSI 1
  • Cyclotron and Beam Line 1
  • Penn Medicine’s Gantry at the Duro Felguera factory 1
  • Why Proton Therapy?An advanced form of targeted radiation therapy – reduction in integral dose to normal tissues compared to conventional radiation including IMRT which may translate into reduced toxicities – Dose escalation to tumors – increased local control – Treat tumors close to critical organs –eye, spinal cord – More safely & effectively combine with chemotherapy & surgery 1
  • The potential advantages of Proton TherapyPediatric MalignanciesCombined modality setting – NSCLC – GI cancers – cervical cancerHypofractionationRe-irradiationTumors of the Brain, Spine & CNSTumors of the Mediastinum 1
  • 1
  • Proton = square, RA= triangle 1
  • Challenges in Proton Therapy1. Beam Uncertainties -Why are these uncertainties of concern? Protons STOP Protons scatter differently ( charged particle) – very sensitive to tissue inhomogeneity Range Uncertainty • Affects beam directions & introduces uncertainty about delivered dose • Accentuate the issues related to random & systematic set up errors2.Motion3.Imaging onboard imaging imaging for QA2.Cost & Value 1
  • Range Uncertainty One must account for this uncertainty by delivering dose beyond the target 1
  • Motion and Setup uncertaintiesWhat happens if the beam is nearly tangential to the target? Per ICRU 78 2
  • Challenges in Proton Therapy1. Beam Uncertainties -Why are these uncertainties of concern? Protons STOP Protons scatter differently ( charged particle) – very sensitive to tissue inhomogeneity Range Uncertainty • Affects beam directions & introduces uncertainty about delivered dose • Accentuate the issues related to random & systematic set up errors2.Motion3.Imaging onboard imaging imaging for QA2.Cost & Value 2
  • Passive PET Measuring proton dose immediately after treatment Figure 1- Dose Distribution for treatment Figure 2-PET/CT image with 1cm x 1cm grid of prostate tumor A PET/CT image illustrating radioactivity 20 minutes after treating the patient in figure 1 was divided into aFigure 1 shows the planned dose distribution for the grid such that the divisions on the patient weretreatment of prostate cancer. The target is outlined in approximately 1cm x 1cm. In this image, there are toored near the center of the patient. few decays at the target. An earlier scan showing oxygen decays could more clearly show decays at the region of interest. 2
  • Passive PET 2
  • Challenges in Proton Therapy1. Beam Uncertainties -Why are these uncertainties of concern? Protons STOP Protons scatter differently ( charged particle) – very sensitive to tissue inhomogeneity Range Uncertainty • Affects beam directions & introduces uncertainty about delivered dose • Accentuate the issues related to random & systematic set up errors2.Motion3.Imaging onboard imaging imaging for QA2.Cost & Value 2
  • IMRT Cumulative AdoptionMell et al, Cancer 2005 2
  • IGRT Technologies - Cumulative AdoptionSimpson et al, Cancer 2010 2
  • Proton Therapy Worldwide… • PT center under operation 45 Estimated 40 centers by 2010 40 35 30 25 25 PT centers 20 15 10 5 0 2005 2025 1960 1970 1980 1990 2000 2010 2020 2030 Technology & Protocol Advances in Scanning Government/ Business Standardization/ Development Technology & Increases Private Payor Optimization & Mass Adoption in Computing Power Reimbursement & Efficient Technology 2
  • What are the Clinical Data in Support of Proton Therapy?REVIEW ARTICLEProton Therapy in Clinical Practice:Current Clinical EvidenceMichael Brada, Madelon Pijls-Johannesma, Dirk De RuysscherFrom The Institute of Cancer Research and The Royal Marsden NationalHealth Service Foundation Trust, Sutton, Surrey, United Kingdom; andDepartment of Radiation Oncology, Maastricht Radiation Oncology, ResearchInstitute Growth and Development, University Hospital Maastricht, Maastricht,the NetherlandsJournal of Clinical Oncology, Vol 25, No 8 (March 10), 2007: pp. 965-970© 2007 American Society of Clinical Oncology. 2
  • Clinical Studies of Proton Therapy With at Least 20 Patientsand With a Follow-Up Period of at Least 2 Years Tumor Site No. of Studies No of Patients Head and neck tumors15,75 2 62 Prostate cancer14,16,17 3 1,642 Ocular tumors18-26 9 9,522 Gastrointestinal cancer27-31 5 375 Lung cancer32-34 3 125 CNS tumors28-35,54,55 10 753 Sarcomas43 1 47 Other sites44-46 3 80 Total 36 12,606 2
  • ChallengesHow do we demonstrate the benefit of proton therapy and other high technology (HT) treatments?The dose distributions are undeniably better in many patientsYet, cost containment pressures are realTechnological changes are rapid and proton therapy tomorrow is likely to look different from proton therapy todayThe difficulties in assessing cost effectiveness 3
  • Comparative Effectiveness The essence of comparative effectiveness research (CER) is to understand what health interventions work, for which patients, and under what conditions In the US, attention has focused on radiotherapy technological advances, including IMRT, proton therapy, and SBRT, that have been quickly adopted with few studies investigating whether they represent an incremental improvement in patient outcomes, the defining evaluation threshold of CER.Bekelman, Shah & Hahn. PRO 2011 3
  • When Should We Use Protons?Serious AE with x-raysImportance of surrounding normal tissueImprovements in local control are neededLate morbidity is an important issueComplex geometryTarget volume large relative to normal tissue compartment – Zietman, Goiten, Tepper JCO 2010 3
  • Possible Clinical Situations for Particle Therapy  Pediatric Malignancies  Combined modality setting – dose avoidance – NSCLC – GI cancers – cervical cancer  Hypofractionation  Re-irradiation  Tumors of the Brain, Spine & CNS  Tumors of the Mediastinum  Low grade or benign tumors  Hypoxic & radio-’unresponsive’ Tumors 3
  • What are the Data For the Clinical Use of Protons? Pediatric Malignancies – Protons based not on the existence of Level 1 data but the unarguable necessity for reducing integral dose Ocular Melanoma Skull Base and Spine Tumors Emerging proton data in the combined modality setting Current randomized trials in protons – locally advanced NSCLC & low/intermediate risk prostate cancer 3
  • Pediatric CancersSerious AE are a problemSparing surrounding normal tissues related to growth and future function is an important goalLate morbidity is a serious issueThere is a significant rationale for the use of proton therapy in pediatric cancers- prospective studies, registries are needed, RCT probably not 3
  • Second Malignancies MGH-Harvard Cyclotron Laboratory Matched retrospective cohort study of 1,450 HCL proton pts and photon cohort in SEER cancer registry. Matched 503 HCL proton patients with 1591 SEER patients Median f/u: 7.7 years (protons) and 6.1 years (photon) Median age 56 (protons) and 59 (photons) Second malignancy rates • 6.4% of proton patients (32 patients) • 12.8% of photon patients (203 patients) Photons are associated with a higher second malignancy risk • Hazard Ratio 2.73, 95% CI 1.87 to 3.98, p< 0.0001 Courtesy of H. Shih, MD Chung et al. ASTRO 2008 3
  • Ocular MelanomaUveal Melanoma70 GyRBE, 5 fractionsLC 95% at 15 yearsHarvard CyclotronLab Slide Courtesy of H. Shih JM Collier 3
  • Skull Base Sarcoma Skull base chondrosarcoma (MGH)• 69.6 Gy(RBE), 37 fx• LC 95% at 10 years Skull base chordoma (MGH)• 70-78 Gy(RBE)• LC 42-65% at 10 years J Adams Slide Courtesy of H. Shih 3
  • Lung CancerSerious AE are a problemSparing surrounding normal tissues is an important goalImprovements in local control are neededComplex geometryThere appears to be a reasonable rationale for protons in lung cancer & some preliminary data suggesting a benefit 3
  • Lung CancerNon-small cell lung cancer (NSCLC) – ~ 200K cases per year in the US – ~35-40% treated with a combination chemotherapy & radiation – 3-D radiation therapy or IMRT is usedSubstantial morbidity and some mortality result from the concurrent use of chemotherapy and radiation in this patient populationWe achieve 80% complete response rates with radiation and chemotherapy 4
  • 4
  • Proton Total lung - PTVPhoton Total lung - PTV 4
  • Lung Cancer and Proton TherapyConsecutive patients enrolled in two IRB approved protocols at MDA Cancer Center 5/06-6/0844 pts with Stage III NSCLC treated with 74 cGy, weekly carbo/paclitaxelMedian F/U 19.7 mos; Median OS 29.4 mosGrade 3 esophagitis 5 pts (11%)Grade 3 pneumonitis 1 pt (2%)Local disease recurrence 4 pts (9%) Chang JY et al Cancer Mar 22 2011 4
  • Cost Effectiveness Analysis We have begun to evaluate the “cost” of morbidities in our NSCLC population when conventional chemoradiotherapy is used If the major toxicities of chemoradiotherapy are reduced or eliminated there appear to be significant cost savings Question: Does reduction in morbidity or improvement in local control (if shown by well designed trials) associated with proton therapy reduce costs in our health care system? 4
  • RCT in NSCLCRandomized trial of protons versus photons • Stage II/III NSCLC • Adaptive randomization of pts to 74 Gy of IMRT or 74 CGE of protons (2 Gy/CGE fractions) • If the dose constraints cannot be met, patient will not be treated on study • The primary outcome will be local control and grade 3 or greater pneumonitis and esophagitis • The study is nearing completion and is jointly by MD Anderson and MGH Cox J, ASTRO Advances in Technology Meeting 2008 4
  • The Near future -Technology DevelopmentMulti-leaf CollimatorsCone Beam CT scanOn-Board PET ImagingIntensity Modulated Proton therapy (IMPT)Single room proton therapy delivery systems 4
  • Planning of Proton Therapy Future… ICRU 78 47 4
  • Protons – the Context There has been a substantial increase in the technological complexity of radiotherapy over the last 20 years Driven by advances in computing power, imaging and more efficient methods for delivering radiation Proton therapy provides theoretical benefit over conventional radiotherapy – does this translate into clinical benefit? Rapid adoption of proton therapy will force us to evaluate the value of this potentially beneficial therapy 4
  • ConclusionsCurrent role for protons in pediatric tumors, ocular melanoma, base of skull tumorsHeavy emphasis on questions related to the role of protons in the combined modality setting, dose escalation, & hypofractionationRethink the approach to clinical trials – RCT, PCT, adaptive strategies and registriesTechnological advances will further improve the delivery, increase the indications for PBT, & decrease the costs 4
  • Penn Radiation Oncology Thank You 5
  • An Example: Prostate Cancer Despite the theoretical advantages of PBT, investigators have yet to demonstrate prospectively a clinical benefit to PBT compared to IMRT A 2008 AHRQ-sponsored systematic review of found little high-quality evidence of either IMRT or PBT Interpreting the sparse evidence available is problematic because of the absence of rigorous, prospective, randomized trials of sufficient size and statistical power to assess key clinical outcomes, failure to control for known confounders, and substantial selection effectsWilt TJ et al Ann Int Med 2008 5
  • Efficacy & Toxicity of IMRT and PBTOutcome IMRT PBT FU (yrs) EvidenceOS >80-90% >80-90% 5 LimitedDSS8 >95% >95% 5 LimitedFFBF 74-95% 69-95% 1.5-6Toxicity Acute vs. Late IMRT PBT (Pooled Rate 95 CI) (Pooled Rate 95 CI)GI Acute 18.4 (8.3, 28.5) 0* Late 6.6 (3.9, 9.4) 16.7 (1.6, 31.8)GU Acute 30.0 (13.2, 46.7) 40.1* Late 13.4 (7.5, 19.2) 5.5 (4.6, 6.5)ED 48-49** Not reported** 2 studies * 1 study 5
  • Rationale for PBT in Prostate Cancer 5
  • Study Schema A parallel registry will be conducted to assess the representativeness and potential generalizability of the RCT.Bekelman and Efstathiou 5