Evolution of Radiation

Techniques to Reduce

Mean Heart DosePaul L Nguyen, MD

Associate Professor of Radiation Oncology

Harvard Medical School

Disclosures

• Consulting: Ferring, Medivation, Genome Dx,

Dendreon, Nanobiotix, Bayer, Blue Earth,

Janssen, Augmenix, Boston Scientific, Cota

• Research Funding: Astellas, Janssen

• Equity: Augmenix

Conclusions

• Radiation-induced CV Complications are

Directly Linked with Mean Heart Dose

• Several techniques have been developed to

reduce MHD substantially for breast and

lymphoma patients compared to the 1980s

and 1990s

XRT Uses Ionizing Radiation

• Non-ionizing: Does not produce ions in matter

– Microwaves, ultrasound, radio waves

• Ionizing: Ejects orbital electrons from atoms or molecules, and produce ions

– Photons, electrons, protons, neutrons

Effects of Ionizing Radiation

Radiation

Ionizations

Free Radicals

DNA Damage

Biologic Effects

Radiation and DNA

• Radiation creates free radicals in tissue Radiation creates free radicals in tissue Radiation creates free radicals in tissue Radiation creates free radicals in tissue

• These produce DNA DoubleThese produce DNA DoubleThese produce DNA DoubleThese produce DNA Double----strand breaksstrand breaksstrand breaksstrand breaks

– Tumor cells generally can’t repair these, and dieTumor cells generally can’t repair these, and dieTumor cells generally can’t repair these, and dieTumor cells generally can’t repair these, and die

– Normal cells can repair, if given enough time (6 hours)Normal cells can repair, if given enough time (6 hours)Normal cells can repair, if given enough time (6 hours)Normal cells can repair, if given enough time (6 hours)

• This is why we give a little dose each day for This is why we give a little dose each day for This is why we give a little dose each day for This is why we give a little dose each day for several weeksseveral weeksseveral weeksseveral weeks

Early vs Late Complications

• Early complicationsEarly complicationsEarly complicationsEarly complications

– Occur after days or weeksOccur after days or weeksOccur after days or weeksOccur after days or weeks

– Lasts for days to weeks after RTLasts for days to weeks after RTLasts for days to weeks after RTLasts for days to weeks after RT

– Occur in rapidly proliferating tissues, Occur in rapidly proliferating tissues, Occur in rapidly proliferating tissues, Occur in rapidly proliferating tissues, eg. skin, GI epithelium, eg. skin, GI epithelium, eg. skin, GI epithelium, eg. skin, GI epithelium, hematopoietic systemhematopoietic systemhematopoietic systemhematopoietic system

– Damage may be completely Damage may be completely Damage may be completely Damage may be completely reversiblereversiblereversiblereversible

Early Complications Examples• Skin: Erythema, desquamation, Skin: Erythema, desquamation, Skin: Erythema, desquamation, Skin: Erythema, desquamation,

hair losshair losshair losshair loss

• CNS: Edema CNS: Edema CNS: Edema CNS: Edema ----HeadachesHeadachesHeadachesHeadaches

• Head and Neck: MucositisHead and Neck: MucositisHead and Neck: MucositisHead and Neck: Mucositis

• Lung: esophagitis, pneumonitisLung: esophagitis, pneumonitisLung: esophagitis, pneumonitisLung: esophagitis, pneumonitis

• Upper GI: Nausea, esophagitisUpper GI: Nausea, esophagitisUpper GI: Nausea, esophagitisUpper GI: Nausea, esophagitis

• Lower GI: Diarrhea, proctitisLower GI: Diarrhea, proctitisLower GI: Diarrhea, proctitisLower GI: Diarrhea, proctitis

• GU: Cystitis, urethritis, GU: Cystitis, urethritis, GU: Cystitis, urethritis, GU: Cystitis, urethritis, azospermiaazospermiaazospermiaazospermia

• FatigueFatigueFatigueFatigue

Late Complications

– Occur months or years after RT completeOccur months or years after RT completeOccur months or years after RT completeOccur months or years after RT complete

– Occur in slowly proliferating tissues, Occur in slowly proliferating tissues, Occur in slowly proliferating tissues, Occur in slowly proliferating tissues, eg.eg.eg.eg. lung, lung, lung, lung, kidney, heart, liver, CNSkidney, heart, liver, CNSkidney, heart, liver, CNSkidney, heart, liver, CNS

– Often related to Often related to Often related to Often related to microvesselmicrovesselmicrovesselmicrovessel occlusionocclusionocclusionocclusion

– Damage often not completely reparableDamage often not completely reparableDamage often not completely reparableDamage often not completely reparable

Late Complications Examples• CNS: subtle neurocognitive decline,

• Head and Neck: Dry mouth (dental issues)

• Lung: Cardiac, Cardiac, Cardiac, Cardiac, Pneumonitis, esophageal stricture,

• Lower GI: Small bowel obstruction (rare)

• Prostate: Rectal bleeding (rare), erectile dysfunction, sterility

Dose

1 Gray = Standard Radiation Unit of Dose

Older unit: 1 rad = 1 centiGray (cGy)

– 1 Gray = 100 rad

Typical doses

• Prostate cancer- 78 Gy (Solid Tumor)– 8.5 weeks

• Breast cancer- 60 Gy (Microscopic disease)– 6 weeks

• Hodgkin’s Disease- 30 Gy (Very Radiosensitive)– 3 weeks

The First Cobalt Unit - 1951

CV Events are Linked to Mean

Heart Dose (MHD) in Hodgkins

van Nimwegen FA et al J Clin Oncol. 2016

• 2,617 Hodgkin’s 2,617 Hodgkin’s 2,617 Hodgkin’s 2,617 Hodgkin’s

survivors treated survivors treated survivors treated survivors treated

1965 1965 1965 1965 ----1995199519951995

CV Events are Linked to Mean

Heart Dose (MHD) in Hodgkins

van Nimwegen FA et al J Clin Oncol. 2016

• 7.4% Excess CHD 7.4% Excess CHD 7.4% Excess CHD 7.4% Excess CHD

risk per 1 risk per 1 risk per 1 risk per 1 GyGyGyGy MHDMHDMHDMHD

CV Events are Linked to Mean

Heart Dose (MHD) in Breast

Darby S, et al NEJM 2013

• >2000 breast cancer >2000 breast cancer >2000 breast cancer >2000 breast cancer

survivorssurvivorssurvivorssurvivors

• 7.4% Excess CHD risk 7.4% Excess CHD risk 7.4% Excess CHD risk 7.4% Excess CHD risk

per 1 per 1 per 1 per 1 GyGyGyGy MHDMHDMHDMHD

• Same excess risk Same excess risk Same excess risk Same excess risk

ratio as in Hodgkin’sratio as in Hodgkin’sratio as in Hodgkin’sratio as in Hodgkin’s

Evolution in XRT-CV Awareness

1980s/1990s 2019

Heart Receiving Heart Receiving Heart Receiving Heart Receiving

High Doses from High Doses from High Doses from High Doses from

XRTXRTXRTXRT

Multiple Multiple Multiple Multiple

Techniques to Techniques to Techniques to Techniques to

Minimize Mean Minimize Mean Minimize Mean Minimize Mean

Heart DoseHeart DoseHeart DoseHeart DoseHodgkin’sHodgkin’sHodgkin’sHodgkin’s

CV EventsCV EventsCV EventsCV Events

DataDataDataData

Darby NEJMDarby NEJMDarby NEJMDarby NEJM

BreastBreastBreastBreast----CVCVCVCV

PaperPaperPaperPaper

2013201320132013

PET-CT Aided Huge Reduction in RT Field for Lymphomas

Specht & Yahalom Int J Clin Onc 2015

Involved Field RT

1990s-2000sMantle Field

1970s/1980s

Involved Node RT

Today

Modeling Data on Reduced CVD Risk with Modern RT

Blue: Mantle

Red: INRT

MeanMeanMeanMean 25 y AER (%)25 y AER (%)25 y AER (%)25 y AER (%)

Involved Node RT Mantle

Typical Typical Typical Typical

MHDMHDMHDMHD

<5Gy<5Gy<5Gy<5Gy 25Gy25Gy25Gy25Gy

Any CDAny CDAny CDAny CD 1.4 (0.41.4 (0.41.4 (0.41.4 (0.4----5.1)5.1)5.1)5.1) 9.19.19.19.1 (5.5(5.5(5.5(5.5----16.6)16.6)16.6)16.6)

AV 0.6 (0-4.2) 9.2 (2.5-30.3)

PV 0.2 (0-1.3) 1.9 (0.4-4.5)

MV 0 (0-0.2) 3.1 (1.1-6.7)

TV 0 (0-0.2) 2.2 (0.4-8.4)

Any V 0.8 (0-4.8) 16.4 (4.7-49.8)

Maraldo IJROBP 2012

Breast Cancer Technique EvolutionA woman in her 30s had a left-sided mastectomy and then received post-operative

radiation to the chest wall in 1984 due to positive lymph nodes. Ten years later, she

developed a myocardial infarction. What was the most likely technique used to What was the most likely technique used to What was the most likely technique used to What was the most likely technique used to

deliver her radiation?deliver her radiation?deliver her radiation?deliver her radiation?

Response Frequency Count

A. Deep inspiration breath hold 31.6% 18

B. Hockey stick 21.1% 12

C. Tangents 22.8% 13

D. Prone position 24.6% 14

Hockey Stick – 1980s – Lots of Heart RTDirect Anterior Field Into Heart (Chest Wall,

Axila, and Internal Mammary Nodes)

3D “Tangents” IMRT TangentsTangential (Rather Than Anterior Beams) Intensity Modulation Can “Bend Beams”

Give less heart Dose (1990s-Present) So 100% Blue Isodose Pulled off Heart

Lee J, Medicine 2016

StandardStandardStandardStandard

Photons Photons Photons Photons ProtonsProtonsProtonsProtons

Protons Have No Exit Dose

Courtesy T. Yock, N. Tarbell, J. Adams

Copyright MGH-NPTC 2003

Courtesy Yock and Delaney

Protons Photons

“Protons Stop on a Dime”

3D “Tangents” ProtonsTangential (Rather Than Anterior Beams) Have no exit dose- can be stopped

Give less heart Dose (1990s-Present) precisely

Florida Proton Center

“Cardiac Block” For Tangents

Prone – Best for Reducing Heart

Dose for Women w/ Large Breasts

Deep Inspiration Breath HoldBeam is gated to only turn on while patient is holding in a deep breath,

Thereby reducing exposure to heart (Lymphoma Example Below)

DIBH PositionRegular Position

Deep Inspiration Breath HoldBeam is gated to only turn on while patient is holding in a deep breath,

Thereby reducing exposure to heart (Breast Example Below)

DIBH Position Normal Breathing

CV Events are Linked to Mean

Heart Dose (MHD) in Breast

Darby S, et al NEJM 2013

• >2000 breast cancer >2000 breast cancer >2000 breast cancer >2000 breast cancer

survivorssurvivorssurvivorssurvivors

• 7.4% Excess CHD risk 7.4% Excess CHD risk 7.4% Excess CHD risk 7.4% Excess CHD risk

per 1 per 1 per 1 per 1 GyGyGyGy MHDMHDMHDMHD

• Same excess risk Same excess risk Same excess risk Same excess risk

ratio as in Hodgkin’sratio as in Hodgkin’sratio as in Hodgkin’sratio as in Hodgkin’s

Current goal is

<2Gy MHD

Old (80s/90s) and New RT

TechniquesOld, High Heart DoseOld, High Heart DoseOld, High Heart DoseOld, High Heart Dose New, Less Heart DoseNew, Less Heart DoseNew, Less Heart DoseNew, Less Heart Dose

LymphomaLymphomaLymphomaLymphoma Mantle Field (80s) Involved Node Field

BreastBreastBreastBreast Hockey Stick (80s) Tangents w/Cardiac Block

Prone Position

Deep Inspiration Breath

Hold

IMRT Tangents

Protons

Conclusions• Radiation-induced CV Complications are

Directly Linked with Mean Heart Dose

• Several techniques have been developed to

reduce MHD substantially for breast and

lymphoma patients compared to the 1980s

and 1990s

ARS Question• A woman in her 30s had a left-sided mastectomy and then

received post-operative radiation to the chest wall in 1984

due to positive lymph nodes. Ten years later, she developed

a myocardial infarction. What was the most likely technique What was the most likely technique What was the most likely technique What was the most likely technique

used to deliver her radiation?used to deliver her radiation?used to deliver her radiation?used to deliver her radiation?

• A. Deep inspiration breath hold

• B. Hockey stick

• C. Tangents

• D. Prone position

Lewiston Tribune, Idaho

Dec 2007, page 1

“Michael Millhouse

giving the windows

some holiday spirit

with a Christmas

greeting”

AcknowledgementsDana Farber Breast Rad Dana Farber Breast Rad Dana Farber Breast Rad Dana Farber Breast Rad OncsOncsOncsOncs::::

Jennifer Bellon

Rinaa Punglia

Julia Wong

Harvard Radiation Oncology:Harvard Radiation Oncology:Harvard Radiation Oncology:Harvard Radiation Oncology:

Danielle Bitterman

MGH Proton CenterMGH Proton CenterMGH Proton CenterMGH Proton Center

Torunn Yock

Thomas Delaney

Dana Farber Lymphoma Rad Onc:Dana Farber Lymphoma Rad Onc:Dana Farber Lymphoma Rad Onc:Dana Farber Lymphoma Rad Onc:

Andrea Ng

Penn Med Onc:Penn Med Onc:Penn Med Onc:Penn Med Onc:

Vivek Narayan