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