Marcio Fagundes, MD

Radiation Oncology

ProCure Oklahoma City Proton Center

Proton Therapy

• Why Protons Matter– Differences between conventional x-ray (photon)

radiotherapy and proton therapy– How protons can provide a radiation dose advantage– Clinical applications– Case illustrations

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Agenda

A Very Experienced Team in Proton Therapy: Development, Delivery and Operations

M.D. Anderson

Loma Linda

UFPTI

MGH MPRI

ProCure OKC Center

• Protons are physically superior to X-rays• Protons behave differently than x-rays:

– Protons – X-Rays do not

• Protons improve the “therapeutic ratio”– maximizing tumor control while minimizing side effects

• At a given radiation dose to a tumor protons deliver, on average, less than half the radiation dose to normal tissues than do x-rays 1

The Value of Protons

4(1) Jay Loeffler, Massachusetts General Hospital, “Proton Therapy 2009”

Clinical applications for Proton Therapy

Source : National Cancer Institute

Neurologic• Brain• Spinal Cord

Other Solid Tumors• Breast Cancer• Lung Cancer• Colorectal Cancer• Prostate – select

Head / Neck • Eye• Sinus/nasal• Throat• Ear

Pediatric• Brain• Spinal Cord• Bone

Indications for Proton Therapy

“Classic”• Pediatric tumors• Brain tumors • Base of skull tumors• Spinal tumors• Paraspinal tumors• Prostate cancers• Uveal melanomas• Intracranial radiosurgery

“Emerging”• Lung• Esophagus• Whole pelvic RT

– Examples: Rectal & Anal Canal• Large sarcomas• Liver• Mediastinal tumors

– Example: Lymphoma & Thymoma

• Extracranial radiosurgery– Prostate and Lung SBRT

A different way to think about it• Tumors with:

– curative intent or life expectancy beyond 2 years– in which anatomic motion is either minimal or can be accounted

for – and there is something to avoid

• Example: Pediatrics– Yes: Medulloblastoma

• CSI avoids heart• Boost RT eliminates dose to supratentorial brain

– No: Wilm’s Tumor• Target is often the entire peritoneal surface

• The goal of radiation oncology for 100 years has been to get:– More radiation in the tumor– Less radiation in the healthy tissue

surrounding the tumor

The Goal of Radiation Therapy:Increase the Therapeutic Ratio

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Tumor ControlNormal Tissue Complications=Therapeutic Ratio

External-Beam Radiation Therapy

• “EBRT is radiation from the outside-in”

• This can be done in 2 ways:– X-Ray therapy (IMRT)– Proton therapy

X-ray (photon) radiotherapyIMRT (intensity modulated radiotherapy)

Linear AccelaratorsTomotherapy Cyber-knife

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3D 5 fields6x Parallel

opposed fields

tumor

Improvements in radiation dose distribution

Protons 4 field

IMRT 9 fields

EVOLUTION, NOT REVOLUTION

x-rays x-raysx-rays protons

What is Proton Radiation?

How is it different from X-rays and IMRT?

The Physics of Protons

Depth dose curves for protons and x-rays

150

100

50

00 50 100 150 250200

Rela

tive

Dose

(%)

Depth in Body (mm)

300 350 400

200

250

300

Additional dose outside the target delivered with x-rays

X-rays

TumorProtons

In order to deliver the same dose to the tumor, x-rays must deliver a greater dose outside the target than protons do

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Protons Are More Precise and Spare Healthy Tissue

6 Field IMRT PLAN 3 Field Proton PLAN

Exit dose unnecessarily radiates healthy tissues that may cause harmful side effects or secondary malignancies

Zero exit dose and high degree of conformity eliminates excess radiation

Tumor Tumor

Protons are as advertised,…

Evidence of Distal Range Stopping

Before treatment Treatment plan After treatment

Base of skull clival chordoma-dose shown as percentages in the treatment plans-for physicians use

Protons IMRTIMRT-Protons: showing extra dose for IMRT

Dose volume histogram shown as actual doses

Base of skull clival chordoma (Head)-anatomy

Jaw

Area to be treatedSpinal cord

Muscle Neck bone/vertebra

Why Protons for Paraspinal Sites?

• Increased TCP– Increased dose

• No reductions

• Decreased NTCP– Decreased dose to critical structures

• Kidneys• Lungs• Heart• Blood vessels• GI tract

More dose and better tolerance of therapy

Paraspinal Ewing’s Sarcoma:A Case Comparison

• A teenage football player ignoring a “right back bruise” for 4 months

• Diagnosis: Paraspinal Ewing’s Sarcoma• Treatment per COG protocol:

– 42 weeks of 5 drug chemotherapy– RT to primary site for local control

Diagnosis

Nearly Identical

Location and GTV

These are 2 different patients!

Patient on the left – 13 year old who presented in March 2006

Patient on the right – 16 year old who presented in June 2006

R Kidney

10%

50%

Larger PTV needed for

IMRT

18 months post-RT

Patient on the left – 13 year old who presented in March

2006 and was treated with X-Ray IMRT

Patient on the right – 16 year old who presented in June 2006

who was treated with proton therapy

Why Protons for Lung Cancer? X-rays have reached its dose limits

3 trials showing that the maximum tolerated dose is 74 Gy with chemotherapy

RTOG 0117 Phase I North Central Cancer Treatment Group CALGB

• Protons allow dose escalation while reducing toxicity compared to x-rays– Sejpal, M.D. Anderson 2011– Chang, M.D. Anderson 2011

• Dose escalation can be achieved with protons without exceeding known indicators of lung toxicity

– Chang, M.D. Anderson 2006

• For stage III tumors, radiation with chemotherapy holds the most promise• Clinical outcomes suggest better control rates and lower toxicity when using

protons compared to x-rays with chemotherapy for stage III NSCLC• NCCN guidelines consider RT + chemo standard of care1

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11http://www.nccn.com/images/patient-guidelines/pdf/nsclc.pdf

Lung/Mediastinum – IIIA NSCLC

Protons IMRTIMRT-

Protons

Dose volume histogram shown as actual doses with TV to 70 CGE

Dash – IMRTSolid – Proton

Less dose to right (I/L) lungNo dose to left lungLess dose to heartLess dose to spinal cord

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(1) A Allen et al., “Fatal pneumonitis associated with IMRT radiation therapy for mesothelioma,” International Journal Radiation Oncology Biology Physics 65 (2006): 640-645(2) E Yorke et al., “Correlation of dosimetric factors and radiation pneumonitis for non-small-cell lung cancer patients in a recently completed dose escalation study,” International Journal Radiation

Oncology Biology Physics 63 (2005): 672-682(3) Y Seppenwoolde et al., “Comparing different NTCP models that predict incidence of radiation pneumonitis,” International Journal Radiation Oncology Biology Physics 55 (2003): 725-735(4) Liao et al., “Analysis of Clinical Dosimetric Factors Associated with Radiation Pneumonitis in Patients with Non-Small Cell Lung Cancer Treated with Concurrent Chemotherapy and Three Dimensional

Conformal Radiotherapy,” International Journal Radiation Oncology Biology Physics 63 Supplement 1 (2005): S41(5) J Chang et al., “Significant reduction of normal tissue dose by proton radiotherapy compared with three-dimensional conformal or intensity-modulated radiation therapy in stage I or stage III non-

small-cell lung cancer,” International Journal Radiation Oncology Biology Physics 65 (2006): 1087-1096

Lung with tumor (dose to healthy tissue only) Lung without tumor Both lungs

Volume receiving dose Volume receiving Integral dose

Mean Dose 5 Gy 10 Gy 20 Gy 5 Gy

IMRT 24.2 Gy 61.5% 49.0% 37.1% 49.7% 8.1 Gy

Proton 21.2 Gy 44.0% 39.3% 33.3% 27.1% 5.4 Gy

Absolute improvement 3.0 Gy 17% 10% 4% 23% 33%

• Radiation-induced pneumonitis can result from even low doses of excess radiation in the lungs (1,2)

• Compared to IMRT, protons expose less lung tissue at all the critical/threshold doses listed below(5) which have been shown to be predictors of pneumonitis:

• Mean dose to lung(1,2,3,4)

• Volume of lung receiving 5 Gy(1,2,4)

• Volume of lung receiving 10 Gy(2,4)

• Volume of lung receiving 20 Gy(1,2,4)

Excess Radiation Causes Long-Term Side Effects

Comparison of Dose Escalated Proton Therapy and IMRT, both 74 Gy, for Stage III Lung Cancer

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M.D. Anderson lung toxicity data for inoperable locally advanced nsclc

3D CRT IMRT Protons

Dose 63 Gy 63 Gy 74 CGE

% patients stage IIIA-B22 87% 91% 87%

Toxicity

Esophagitis – G3+ 18% 44% 5%

Pneumonitis – G3+ 30% 9% 2%

1 Samir Sejpal et al., “Early findings on toxicity of proton beam therapy with concurrent chemotherapy for nonsmall cell lung cancer,” Cancer e-publication ahead of print (January 24, 2011): 1- 102 Retrospective analysis. In lieu of selection criteria, percentage of patients with Stage IIIA-IIIB were summarized

NSCLC treated with radiation therapy + chemotherapy1

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Summary of toxicity from other studies of x-ray radiation and chemotherapy

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Note: Please see Sejpal paper in Cancer 2011 for literature cited

Lung cancer lung trials

Study name Trial type Modalities DescriptionSelection criteria

(inoperable)

Proton with chemoM.D. Anderson Phase II Protons and

chemo-Primary goal is to improve survival-Chemo and 74 CGE of proton therapy

Stage IIIA and IIIB

Loma Linda Phase I/II Protons and chemo

-Chemo with accelerated proton therapy-5 week RT (first two weeks – daily; final three weeks – twice daily)

Stage II,IIIA or IIIB

University of Florida Phase II Protons and chemo

-Chemo with higher 74 CGE dose delivered by protons Stage IIIA or IIIB

UPENN Phase I/II Protons and chemo

- Chemo with 5.5 – 7.5 weeks of proton radiation (total dose not disclosed)

Stage IIIA that are eligible for surgery

UPENN Phase I Protons and Nelfinavir

-Goal is to test the highest safest dose of proton therapy that can be given concurrently with drug

Stage IIIA or IIIB

RandomizedM.D. Anderson Phase II Protons and x-

rays-Randomize between x-rays and protons Stage II-IIIB

PCG Phase III Protons and x-rays

-Randomize between x-rays and protons Stage IIIA - IIIB

HypofractionationM.D. Anderson Phase I Protons -Hypofractionating starting at 45 Gy in 15 Fx to

60 Gy in 15 Gy -NSLC, small cell lung cancer, thymic or carcinoid tumors

University of Florida Phase II Protons Hypofractionating:-48 CGE in 4 fx (peripherally located)-60 CGE in 10 fx (centrally located)

Stage I

Dose escalation

M.D. Anderson Phase II Protons -Dose escalation to 87.5 CGE in 35 Fx Stage IA, IB, and selected stage II

Summary of lung trials for proton therapy

Source: clinicaltrials.gov search “protons AND lung AND radiation” 31

Invasive Non-Invasive

Definitive Therapy

Surgery

Open Laparoscopic(Da Vinci)

Brachytherapy

Low-Dose Rate

High-Dose Rate

External-Beam Radiation

X-Ray(IMRT)

Proton Beam

external-beamradiation therapy

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Therapy for Prostate Cancer

Radiation Therapy (proton or IMRT)is an option after surgical failure

Salvage Therapy

After Radiation Therapy Failure

Surgery Brachytherapy

Hormones and/or

Chemotherapy

Observation

After Surgical Failure

External Beam

Radiation

Hormones and/or

Chemotherapy

Observation

radiation after surgery is easier to do than surgery after radiation

“Direct Radiation Complications Never Occur In Unirradiated Tissues”

Dr. Herman Suit1

IMRT - 7-field co-planer Proton Therapy - 2-field DS

Radiation Therapy Plans for Prostate Cancer

Less healthy tissue exposed to radiation compared to IMRT

Higher dose bath to healthy tissue with IMRT:

Pelvis, rectum and bladder

Blue – 13%

Green – 51%

Purple – 63%

Yellow – 76%

Red – 95%

(1) Herman Suit, “The Grey Lecture 2001: Coming Technological Advances in Radiation Oncology,” International Journal of Radiation Oncology Biology Physics 53 No. 4 (2002): 798-809.

IMRT immerses more healthy tissue with radiation

Tumor

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University of Florida Dosimetry Data Show Protons Reduce Dose To The Rectum By 59%

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IJROBP 2008Radiation dose to the rectum – proton therapy and IMRT1

Radiation Dose (CGE/Gy)0 10 20 30 40 50 60 70 80 90

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Rect

al V

olum

e Re

ceiv

ing

Radi

ation

(%)

Proton

IMRT

Dose to rectum is more than 2x with IMRT vs.

protons at 32 Gy

Background on study First prostate patients seen at University of Florida

Proton Therapy Institute (“UFPTI”) Both proton and IMRT plans were planned

prospectively for each patient

The results Relative and absolute mean rectal dose savings of

59.2% and 20.1%, respectively, with proton therapy

Why this is important Entire Dose Volume Histogram (“DVH”) does matter,

not just high the dose region

– Rectal wall volume irradiated at 32.4 Gy is biggest predictor of rectal toxicity2

Extremely high correlation between rectal volume irradiation to 70 Gy and 5-year toxicity rates3

(1) Carlos Vargas et al., “Dose-Volume Comparison of Proton Therapy and Intensity-Modulated Radiotherapy for Prostate Cancer,” International Journal of Radiation Oncology Biology Physics 70 No.3 (2008): 744-751.(2) Susan Tucker, Lei Dong, Rex Cheung, et al., “Comparison of Rectal Dose-Wall Histogram Versus Dose-Volume Histogram for Modeling the Incidence of Late Rectal Bleeding After Radiotherapy,” International Journal of Radiation Oncology

Biology Physics 60 (2004): 1589-1601.(3) Mark Storey, Alan Pollack, Gunar Zagars et al., “Complications from Radiotherapy Dose Escalation in Prostate Cancer: Preliminary Results of a Randomized Trial,” International Journal of Radiation Oncology Biology Physics 48 (2000): 635-642.

Dose to rectum is almost 2x with IMRT vs. protons

at 70 Gy

GI (Rectal) Side Effects and Complications

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Inflammation causedby radiation

Chronic Radiation Proctitis in the GI tract

Necrosis and ulcer

The probability of damage to the GI tract is much higherwith x-rays than protons

Dose Escalation Trials Support the Use of Protons for Prostate Cancer

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Randomized Boost Planning High 5-year GI toxicitytrial1-5 Modality Technique dose arm control ≥G2 ≥G3

MD Anderson X-rays 2-D, 3-D 78.0 Gy 75% 26% 7%

CKVO96-10 X-rays 3-D, IMRT 78.0 Gy 64% 32% 5%

MRC RT01 X-rays 3-D 74.0 Gy 71% 33% 10%

GETUG 06 X-rays 3-D 80.0 Gy 72% 20% 6%

PROG 95-09 Protons 3-D 79.2 Gy 91% 17% 1%

(1) Alan Pollock et al., “Prostate cancer radiation dose response: results of M.D. Anderson Phase III randomized trial,” International Journal of Radiation Oncology Biology Physics 53 (2002): 1097-1105. (Note: toxicity updated from Viani et al, ref 6)

(2) ST Peters, WD Heemsbergen, PC Koper et al., “Dose-response in radiotherapy for localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy,” 24 (2006): 1990-1196.

(3) DP Dearnaley, MR Sydes, JD Graham et al, “Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT101 randomized controlled trial,” Lancet Oncology 8 (2007): 475-487.

(4) Anthony L. Zietman, “Correction: Inaccurate analysis and results in a Study of Radiation Therapy in Adenocarcinoma of the Prostate,” JAMA 299 No. 8 (2008): 898-900. Anthony L. Zietman et al., “Comparison of Conventional-Dose vs. High-Dose Conformal Radiation Therapy in Clinically Localized Adenocarcinoma of the Prostate. A Randomized Controlled Trial,” JAMA 299 No. 10 (2008): 899-900.

(5) Veronique Beckendorf et al. “70 Gy vs. 80 Gy in localized prostate cancer: 5 year results of GETUG 06 randomized trial,” Int J Radiat Oncol Biol Phys (2011) epublication(6) Viani GA et al. Higher-than-conventional radiation doses in localized prostate cancer treatment: a meta-analysis of randomized, controlled trials. Int J Radiat Oncol Biol Phys. 2009

Aug 1;74(5):1405-18.Note: Control rates are measured using the ASTRO definition, except for MRC RT01 which uses the Phoenix definition

Protons offer better control and lower toxicity than X-Rays

The best outcome for control AND toxicity was achieved using protons

Fig. 3. Left anterior descending coronary artery in a 16-year-old boy 1 year after receiving 40 Gy mantle radiotherapy for Hodgkin ’s disease. Myointimal proliferation with considerable lumen narrowing. (Fajardo LF et al. Acta Oncologica 44:13,2005)

Intimal fibroblast proliferation

macrophage plaque formation

thrombus formation

Radiation-Related Coronary Artery DiseaseAtherosclerosis process similar to other CAD causes

Ischemic heart disease

“Significantly higher rate of fatal and non-fatal diagnosis of coronary artery disease seen in left-sided patients compared with right-sided XRT”

U PennReview of 961 pts (1977-1994)Median f/u 12 years

Harris, E et al. JCO 24:4100,2006

Survival free fromCoronary Artery Disease (CAD)

90% Right-sided

75% Left-sided

Distal LAD 2nd Diagonal

Coronary Artery CT Scan

Protons and Electron/X-Ray Match

Protons Electron / X-Ray Match

Difference