Marcio Fagundes, MD Radiation Oncology ProCure Oklahoma City Proton Center
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Transcript of Marcio Fagundes, MD Radiation Oncology ProCure Oklahoma City Proton Center
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