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Proton Therapy
February 8, 2013
Stephen M. Hahn, MD
Department of Radiation Oncology
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OutlineOutline
The evolution of high technology in The evolution of high technology in Radiation Oncology Radiation Oncology
The principles & rationale for proton The principles & rationale for proton therapytherapy
Challenges with proton therapyChallenges with proton therapy Assessing the Assessing the ‘‘valuevalue’’ of proton of proton
therapytherapy Future directionsFuture directions
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Eff
ect
Tumor Dose
Tumor control
Effect of underdosage and overdosage
Late normal tissue damage
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The Evolution of Radiation TherapyThe Evolution of Radiation Therapy
High resolution IMRTMultileaf Collimator
Dynamic MLCand IMRT
19601960’’ss 19701970’’ss 19801980’’ss 19901990’’ss20002000’’ss
Cerrobend BlockingElectron Blocking
Blocks were used to Blocks were used to reduce the dose to reduce the dose to normal tissuesnormal tissues
MLC leads to 3D MLC leads to 3D conformal therapy conformal therapy which allows the first which allows the first dose escalation trials.dose escalation trials.
Computerized IMRT Computerized IMRT introduced which introduced which allowed escalation of allowed escalation of dose and reduced dose and reduced compilationscompilations
Functional Functional ImagingImaging
IMRT Evolution IMRT Evolution evolves to smaller and evolves to smaller and smaller subfields and smaller subfields and high resolution IMRT high resolution IMRT along with the along with the introduction of new introduction of new imaging technologiesimaging technologies
The First ClinacComputerized 3D CT Treatment Planning
Standard Collimator
The linac reduced The linac reduced complications complications compared to Co60compared to Co60
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Principles of Proton Therapy
The 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
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Characteristics of Proton and Heavy Particle Therapy
p
C
Ne
Si
Ar
Co
4 MV
X-rays
22 MV
X-rays
250 kVpX-rays
Neutrons IMRTNeutron
Pions
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IMRT
MVX-ray
DOSE DISTRIBUTION ADVANTAGE
HIG
H L
ET
AD
VA
NTA
GE
Fast
2002
Kohler, A
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Comparison of dose distributions
GSI/HIT
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The Evolution of Conformal Radiotherapy
2-D
3-D
IMRT
Proton
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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)
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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.
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A proton pencil beam(spot)…...A few pencil beamstogether….
Some more…A full set, with ahomogenous dose conformed distally and proximally
Spot scanning - The principle
The dynamic application of scanned and modulated proton pencil beams
Images courtesy of E Pedroni and T Lomax, PSI
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Cyclotron and Beam Line
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Penn Medicine’s Gantry at the Duro Felguera factory
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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
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The potential advantages of Proton Therapy
Pediatric MalignanciesCombined modality setting
– NSCLC– GI cancers– cervical cancer
HypofractionationRe-irradiationTumors of the Brain, Spine & CNSTumors of the Mediastinum
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Proton = square, RA= triangle
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Challenges in Proton Therapy
1. 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 errors
2.Motion
3.Imagingonboard imaging
imaging for QA
2.Cost & Value
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Range Uncertainty
One must account for this uncertainty by delivering dose beyond the target
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Motion and Setup uncertainties
What happens if the beam is nearly tangential to the target?
Per ICRU 78
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Challenges in Proton Therapy
1. 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 errors
2.Motion
3.Imagingonboard imaging
imaging for QA
2.Cost & Value
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Passive PET
Figure 2-PET/CT image with 1cm x 1cm grid
A PET/CT image illustrating radioactivity 20 minutes after treating the patient in figure 1 was divided into a grid such that the divisions on the patient were approximately 1cm x 1cm. In this image, there are too few decays at the target. An earlier scan showing oxygen decays could more clearly show decays at the region of interest.
Figure 1- Dose Distribution for treatment of prostate tumor
Figure 1 shows the planned dose distribution for the treatment of prostate cancer. The target is outlined in red near the center of the patient.
Measuring proton dose immediately after treatment
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Passive PET
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Challenges in Proton Therapy
1. 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 errors
2.Motion
3.Imagingonboard imaging
imaging for QA
2.Cost & Value
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IMRT Cumulative Adoption
Mell et al, Cancer 2005
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IGRT Technologies - Cumulative Adoption
Simpson et al, Cancer 2010
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Proton Therapy Worldwide…
1960 1970 1980 1990 2000 2010 2020 2030
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40
35
30
25
20
15
10
5
0
Technology & ProtocolDevelopment
Advances in Scanning Technology & Increases in Computing Power
Government/Private Payor Reimbursement & Efficient Technology
Business Standardization/Optimization & Mass Adoption
Estimated 40 centersby 2010
2005
• PT center under operation
25 PT centers
2025
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REVIEW ARTICLE
Proton Therapy in Clinical Practice: Current Clinical Evidence
Michael Brada, Madelon Pijls-Johannesma, Dirk De Ruysscher
From The Institute of Cancer Research and The Royal Marsden National Health Service Foundation Trust, Sutton, Surrey, United Kingdom; and Department of Radiation Oncology, Maastricht Radiation Oncology, Research Institute Growth and Development, University Hospital Maastricht, Maastricht, the Netherlands
Journal of Clinical Oncology, Vol 25, No 8 (March 10), 2007: pp. 965-970© 2007 American Society of Clinical Oncology.
What are the Clinical Data in Support of Proton Therapy?
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Clinical Studies of Proton Therapy With at Least 20 Patients and 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
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ChallengesHow 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 realTechnological changes are rapid and
proton therapy tomorrow is likely to look different from proton therapy today
The difficulties in assessing cost effectiveness
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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
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When Should We Use Protons?
Serious AE with x-raysImportance of surrounding normal tissueImprovements in local control are neededLate morbidity is an important issueComplex geometryTarget volume large relative to normal
tissue compartment
– Zietman, Goiten, Tepper JCO 2010
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Possible Clinical Situations for Particle Therapy
Pediatric MalignanciesCombined modality setting – dose avoidance
– NSCLC– GI cancers– cervical cancer
HypofractionationRe-irradiationTumors of the Brain, Spine & CNSTumors of the MediastinumLow grade or benign tumorsHypoxic & radio-’unresponsive’ Tumors
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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
settingCurrent randomized trials in protons – locally
advanced NSCLC & low/intermediate risk prostate cancer
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Pediatric Cancers
Serious AE are a problemSparing 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
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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
Chung et al. ASTRO 2008Courtesy of H. Shih, MD
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Ocular MelanomaOcular Melanoma
JM Collier
Uveal Melanoma
70 GyRBE, 5 fractions
LC 95% at 15 years
Harvard Cyclotron Lab
Slide Courtesy of H. Shih
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Skull Base SarcomaSkull Base Sarcoma
Skull base chondrosarcoma (MGH)
• 69.6 Gy(RBE), 37 fx
• LC 95% at 10 years
Skull base chordoma (MGH)Skull base chordoma (MGH)
• 70-78 Gy(RBE)70-78 Gy(RBE)
• LC 42-65% at 10 yearsLC 42-65% at 10 years
J Adams
Slide Courtesy of H. Shih
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Lung Cancer
Serious AE are a problemSparing surrounding normal tissues is an
important goalImprovements in local control are neededComplex geometryThere appears to be a reasonable
rationale for protons in lung cancer & some preliminary data suggesting a benefit
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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
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Photon Total lung - PTV
Proton Total lung - PTV
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Lung Cancer and Proton TherapyConsecutive 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 mosGrade 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
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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?
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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
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The Near future -Technology Development
Multi-leaf CollimatorsCone Beam CT scanOn-Board PET ImagingIntensity Modulated Proton therapy
(IMPT)Single room proton therapy delivery
systems
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Planning of Proton Therapy Future… ICRU 78
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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
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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
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Penn Radiation Oncology
Thank You
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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 effects
Wilt TJ et al Ann Int Med 2008
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Efficacy & Toxicity of IMRT and PBT
Outcome IMRT PBT FU (yrs) Evidence
OS >80-90% >80-90% 5 Limited
DSS8 >95% >95% 5 Limited
FFBF 74-95% 69-95% 1.5-6
Toxicity Acute vs. Late IMRT(Pooled Rate 95 CI)
PBT(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
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Rationale for PBT in Prostate Cancer
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Study Schema
A parallel registry will be conducted to assess the representativeness and potential generalizability of the RCT.
Bekelman and Efstathiou