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4/9/2019
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Marcio Fagundes, MDMedical Director – Radiation Oncology
Proton Therapy in Breast Cancer: Rationale, Applications and Challenges
MCI - Inaugural Women’s Cancer Symposium 4/5/2019Disclosures: none
Marcio Fagundes, MD MCI – Miami Cancer Institute
Pencil Beam Scanning Proton Therapy
High Dose Rate Brachytherapy
CyberKnife® M6™ GammaKnife® Icon™Varian® TrueBeam™
Viewray® MRIdian™Linac
Radixact
We can create proton backup plans for the best suited equipmentfor any given disease
Miami Cancer Institute = Comprehensive TechnologyA True Multimodality Approach (multiple platforms)
Prostate Brachytherapy
Accelerating Protons
In order for protons to be clinically useful for radiotherapy, they must be accelerated to high energy.
Radiotherapy is performed with protons of energy up to 250 MeV (mega-electron volts).
A 200 MeV proton travels at ~1/2 the speed of light.
Hydrogen atoms are separated into electrons and protons. Protons accelerated in a cyclotron.
Beam line
As acceleration increases so does energy and penetration in tissue
Particles extracted from cyclotron travel down a beam line to the treatment room
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Protons
Gantry CyclotronBeam line
Why Protons?
Dr. Herman Suit - Harvard / MGH Proton Center (1)
(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.
“Direct Radiation Complications Never Occur In Unirradiated Tissues”
“There is no advantage whatsoever to irradiating uninvolved healthy tissue”
Therapeutic ratio is increased by:
– More radiation in the tumor = increased disease control
– Less radiation in the healthy tissues = lower side-effect
Primary Goal of Radiation Therapy Technology Evolutionis aimed at Increasing Therapeutic Ratio
=Therapeutic RatioTumor Control
Normal Tissue Complications
Majority of advancements in the field have been based on this principle:
• IMRT, IGRT, respiratory gating, PET fusion• Deep inspiration breath hold technique• Prone breast treatment
Why Protons are Superior to Photons
ProtonsProtons are clinically superior to X-rays:
X – Rays do not stop
Excess radiation to healthy tissue results in costly side effects and secondary tumors
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The Value of Protons
Protons avoid unnecessary radiation
to heart, lungs, intestines delivered by X-rays
Protons avoid unnecessary radiation
to heart, lungs, intestines delivered by X-rays
Protons are physically superior to X-rays:
Protons
X-Rays do not stopContinue to travel into normal tissuesbeyond the target
Conventional Radiotherapy
Spare heartand coronaries
Use Protons
Unfavorableanatomy
Radiation therapy is an integral component of curative breast cancer treatment for many women
Majority of women with breast cancer are cured and will live long enough to suffer long term consequences of radiation
Increasing trend of treating regional nodes including IMN nodes
The breast and regional nodes lie in close proximity to the heart and lungs
Numerous publications have demonstrated that exposure to the heart and lungs can lead to serious morbidity and mortality
By reducing the exposure to the heart and lung, proton therapy may reduce radiation-related toxicity
Why protons for breast cancer ?
Sweden and Denmark: 2168 pts post-radiotherapy for Breast Cancer
Correlation between mean radiation dose to the heart and risk of major coronary events: Myocardial infarction
Coronary revascularizationDeath from ischemic heart disease
Risk of major coronary event increases by 7.4% per Gray of exposure to the heart1
1 Darby et al., “Risk of Ischemic Heart Disease in Women after Radiotherapy for Breast Cancer,” New England Journal of Medicine 368(2013)
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Nilsson, et al. JCO 30(4) 380-386; 2012
Coronary Exposure to Radiation in Conventional Radiotherapy for Breast Cancer
Stenosis of the main coronary artery left anterior descending (LAD)
Exposure of the main coronary artery
Darby et al. NEJM 2013
- Cardiac morbidity increases by 7.4% with each extra Gy.
- Cardiac events also happen early in first 5 to 10 years of follow up
- There is no “safe” cardiac dose
Increased Heart Dose = Higher Cardiac Toxicity
HEART DOSE
Patients at higher risk for cardiac injury
• Patients not eligible for prone or DIBH treatment • IMN involvement (R or L sided)• Cardiotoxic chemo• Young age• Bilateral disease requiring bilateral XRT• Poor cardiac anatomy• Left medial tumors• Pre-existing cardiac disease• Prior thoracic radiation (lymphoma, breast cancer)
Ares et al., IJROBP 2009
For early stage breast cancer, “Prone Breast Photon XRT”: good option to lower
heart dose
Most patients treated to breast only are suitable for prone setupand will not require Protons
Left Breast Right Breast
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Evolving Radiotherapy Options when Lymph node treatment is required
Whole breast or chestwall + regional LN XRT
3D-Conformal XRT IMRT - Tomotherapy
Highest potential exposure of LAD
Can lower LAD dose but at the expense of extensive moderate dose levels to heart and lungs Intensity Modulated Radiotherapy (IMRT) with
Deep Inspiration Breath Hold (DIBH) can decrease heart exposure.
However, some patients do not tolerate breath hold techniques
Protons for whole breast radiation?Ares et al., IJROBP 2009
Protons for whole breast radiation?Ares et al., IJROBP 2009
Most benefit from protonsseen when comprehensivetarget includes:
chest wall or breast +
axilla, sclav and IMC nodes
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Older Proton Techniques: Double scatter or Uniform Scanning
Protons/SOBP
Compensate accounting for tissue inhomogeneity and distal shape of tumor
Lucite Compensator
Brass aperture shapes the beam
THE PAST: 2011-2012, Before PBS technique we used uniform scanning for breast treatment
Limited field size = requires multiple fields and match lines
Supraclavicular and axilla LN fieldField
edge
Match line
Chest wall and IMC LN field
Chest wall target
Sclav target
• Long treatment time + 45 min• Higher skin dose then PBS• Match lines subject to hot or
cold spots• ….
Marcio Fagundes, MD MCI – Miami Cancer Institute
Miami Cancer Institute: Modern Proton Therapy
Pencil Beam Scanning
Deeper penetrating proton spots fill the deeper portion of the target first
Then shallower spots with lower energy (less penetrating) protons fill the remaining of the target volume.
single spot
Magnets steer protons
Target
ASTRO states that “in patients with breast cancer, it is recommended that the irradiated heart volume be minimized to the greatest possible degree without compromising the target dose” 1
Heart toxicity (cont)Abril 2015
Radiation type:
3-D CRT
VMAT
Tomotherapy
Minus the proton dose =
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3DCRT VMAT Tomo Protons
LAD mean dose 23.7 19.9 10.6 5.8 Gy
Heart mean dose 7.3 8.2 10.5 0.9 Gy
Total Lung V5 Gy 33.6% 54.6% 46.3% 20.6%
Contral. Breast mean 1.5 3.9 6.8 0.2 Gy
Unspecified normal tissue volume > 10 Gy(cc)
2817 3943 3504 353
ASTRO states that “in patients with breast cancer, it is recommended that the irradiated heart volume be minimized to the greatest possible degree without compromising the target dose” 1
1 Gagliardi et al., “Radiation dose-volume effects in the heart,” International Journal Radiation Oncology Biology Physics Supplement 2010: S77-S852 Fagundes, M. et al. “Cardiac Sparing Adjuvant Proton Radiotherapy for Stage IIII Breast Cancer Patients.” ASTRO 2013.
“Protons Maximizes Cardiac Sparing..” Fagundes et al. IJPT April, 2015
Consistent with ASTRO’s Statement:
Heart Dose Comparison between modalities
Marcio Fagundes, MD
IMPT - Chestwall with comprehensive LNSSIB IMC boost
50.4. Gy in 28 fxs of 1.8 Gy to CW, axilla, Sclav and entire IMC
56 Gy in 28 fxs of 2 Gy to upper IMC (+LN excised)
3 Field Composite Dose
Monoisocentric IMPT plan with gradient junction using 3 fields
AP
LAO RAO
Marcio Fagundes, MD MCI – Miami Cancer Institute
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Gradient junction
IMPT plan and gradient junction
AP LAO RAO
Dose per field
Marcio Fagundes, MD MCI – Miami Cancer Institute
IMPT: Coverage and Constraints
CTV
Heart
Total lungV20 = 8%
IMPTTarget coverage: D99 50.4 Gy
Mean heart dose: 0.06 Gy
LAD: D1 0.47 GyMean 0.09 Gy
Total lung: V20 8%V5 21%
Esophagus: D1 29.8 GyMean 4.2 Gy
Marcio Fagundes, MD MCI – Miami Cancer Institute
Patient SetupImaging and Monitoring
C-RADPatient treatment setup and monitoring
Orthogonal X-raysSurface BBs for correlation
- C-RAD- KV/KV imaging with skin surface fiducials- CBCT
Marcio Fagundes, MD MCI – Miami Cancer Institute
C-RADPatient treatment setup and monitoring
Note: the time shown in this figure is consistent with what we quoted in ASTRO abstract: The average treatment time per fraction, which included the pre-treatment imaging for setup, during treatment imaging
for verification and proton beam delivery of all fields, was 29:30 min (range from 17:26 to 69:06)
Monitoring during beam on
Treatment fraction completed in 21 minutes
Highly efficient pre-treatment imaging and delivery
Marcio Fagundes, MD MCI – Miami Cancer Institute
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Tomotherapy Comparative plan
IMPT TomoTarget coverage: D99 50.4 Gy 50.4 Gy
Mean heart dose: 0.06 Gy 7.5 Gy
LAD: D1 0.47 Gy 26.7 GyMean 0.09 Gy 16.2 Gy
Total lung: V20 8% 26%V5 21% 87%
Esophagus: D1 29.8 Gy 33 GyMean 4.2 Gy 11 Gy
Tomotherapy
Patient completed proton treatment uneventfully without any downtime
Marcio Fagundes, MD MCI – Miami Cancer Institute MacDonald, S et al MGH - Harvard
Proton enables Bilateral Breast Treatment with minimal lung and heart exposure:
Yet another indication is patients who cannot raise the arm
Under such conditions, tangent photons or IMRT would result in significant exposure of the arm itself
IMPT – Intensity Modulated Proton Therapy Using split volume technique for Expanders
RAO field dose
Composite dose
+
LAO field dose
Good solution as long as the expander doesn’t rotate in the patient
Challenges: Large shift of metal port position of (5 cm) seen between simulation and treatment day can significantly impact dose distribution
Expander on the day of CT sim
Expander on Tx day of 2/22/2017Expander on Tx day of 2/16/2017
Expander on the day of CT sim
Saline Expanders (Metallic Port)Metal will have more stopping power on protons than
on X-rays radiation like IMRT
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MacDonald et al, RO 2013
Tangent Photons
Anatomy following bilateral implants are frequently not suitable for tangent photons or IMRT because of excessive exposure of:- Contralateral chest wall- Lung- Heart
15 Gy
5 Gy
IMRT
Mean heart dose 6-10 Gy
Protons
Mean heart dose < 1 Gy
Applications of protons post-mastectomy with implant Reconstruction: photons vs protons
(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.
Reducing radiation dose to normal tissue is not a research question (we already know it is toxic!)
We can only investigate the magnitude of the achievable gain by reducing normal tissue radiation dose.
Dr. Herman SuitHarvard / MGH Proton Center
Medical Vision
Locally Advanced Breast Cancer (Stage IIA‐IIIC) Requiring breast/chest wall and regional nodal RT
(including IMN)
RANDOMIZATION
Arm 2
Proton RT
Arm 1
Photon RT
Co-PIs: Shannon MacDonald (MGH) and Oren Cahlon (MSK)
45 - 50.4 Gy over 5-6 weeks daily treatments
Primary Objective
• To assess the effectiveness of proton vs. photon therapy in reducing major cardiovascular events (MCE)
• Primary hypothesis: For patients with locally advanced breast cancer, proton therapy will reduce the 10-year MCE rate after radiation from 6.3% to 3.8%
• Sample size: 1,716 patients -> 1200
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Participating Institutions
1 MGH-Massachusetts General Hospital (Boston, MA) 17. MCL- Karmanos / McLaren Proton Therapy (Flint, MI)
2. MDACC-University of Texas MD Anderson (Houston, TX) 18. TCPT – Texas Center for Proton Therapy (Dallas, TX)
3. UF-University of Florida (Jacksonville, FL) 19. UFO–Orlando Health (Orlando, FL)
4. OKC-Oklahoma City Procure (Oklahoma City, OK) 20. ACC–Ackerman Proton Center (Jacksonville, FL)
5. PENN-University of Pennsylvania (Philadelphia, PA) 21. OU–Oklahoma University (Oklahoma City, OK)
6. NWCH-Northwestern/Cadence Health (Chicago, IL) 22. HPTC–Hampton (Hampton, VA)
7. NJ-NY Proton/MSKCC Consortium (NYC & Somerset, NJ) 23. MAYO Clinic (Phoenix, AZ)
8. UW-University of Washington (Seattle, WA) 24. EU-Emory University (Atlanta, GA)
9. WUSTL-Washington University (St. Louis, MO) 25. WB-William Beaumont (Royal Oak, MI)
10. PROV-Provision (Knoxville, TN) 26. HOPK-Johns Hopkins (Washington D.C.)
11. UC San Diego (La Jolla, CA) 27. UTSW-UT Southwestern (Dallas, TX)
12. WK-Willis Knighton (Shreveport, LA) 28. GU-Georgetown University (Washington D.C.)
13. CINJ-Cancer Institute of New Jersey (New Brunswick, NJ) 29. CINN – University of Cincinnati (Cincinnati, OH)
14. MAYO Clinic (Rochester, MN) 30. MCI – Miami Cancer Institute (Miami, FL)
15. UM-University of Maryland (Baltimore, MD)
16. UH-Case-Western (Cleveland, OH)
• Proton therapy is most beneficial in breast cancer patients requiring comprehensive lymph node treatment including IMC
• …especially true for those who cannot tolerate DIBH IMRT
• Transient dermatitis during Tx can be enhanced with protons
• Magnitude of the long term benefit in cardiac toxicity reduction is being assessed by RadComp Trial
• Flap or permanent implant reconstruction is preferred if proton therapy is anticipated over saline expander
Conclusions
THANK YOU to our entire staff for the team work and high quality care we offer at MCI
Marcio Fagundes, MDMedical Director – Radiation Oncology
Miami Cancer CenterBaptist Health South Florida
marciof@baptisthealth.net
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