Fri Hall 135 - Baptist Health South...

11/27/2017

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Proton Therapy for Brain Tumors: Hope or Hype?

• None

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Financial Disclosures

• Discuss the rationale and evidence for proton therapy in

children and adults

• Discuss the late effects that can be significantly reduced with

proton therapy

• Demonstrate how proton therapy can help cancer patients

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Objectives

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• “There is no advantage whatsoever to irradiating uninvolved

healthy tissue.”

• “Direct radiation complications never occur in unirradiated

tissues.”

– Dr. Herman Suit

Why Protons?

Suit H, “The Grey Lecture 2001: Coming Technological Advances in Radiation Oncology”

IJROBP, 2002

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Protons Stop, Photons Do Not

15MV X-ray Protons

10 cm

10 cm

30 cm

30 cm

R

A

L

P

With protons:

• Lower entrance

dose

• No exit dose

• Fewer toxicities

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18 y.o. with a Paraspinal Ewing Sarcoma

Proton Therapy MRI six weeks after RT

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Protons have Lower Total Integral Dose

4 fields

With protons,

• There is lower

total integral dose

10 cm

10 cm

30 cm

30 cm

R

A

L

P

Protons 15MV X-ray

70‘s 80‘s 90‘s

1990s: Prostate

2000s: Lung, Liver

2010s

Breast

Pancreas, Esophagus

Lymphoma, Reirradiation

Head and Neck and More

1970s: “Rare Cancers””””

Skull base, Paraspinal, Sarcomas, Uveal Melanomas, Pediatrics

Proton Therapy Growth

• >1 million patients treated

with proton therapy

• >40% of US children

treated with RT received

proton therapy in 2015

• Cancer is the second most

common cause of death in US

children (#1 is Accidents)

• 5-year overall survival in 1975: 58%

• 5-year overall survival in 2010: 85%

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Progress in Pediatric Cancer Treatment

Siegel R, CA: A Cancer Journal for Clinicians, 2013 and 2017

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Progress in Pediatric Cancer Treatment

Five Leading Causes of Cancer Death

Male (Age<20) Female (Age<20)

CNS Tumors 314 245

Leukemia 272 184

Bone Tumors 100 81

Soft Tissue Tumors 78 65

NHL 46 23

Siegel R, CA: A Cancer Journal for Clinicians, 2017

• Pediatric cancers

– ~50% receive RT

• 65% of long-term survivors develop

serious chronic health conditions

– Neurocognitive deficits, endocrine

deficiencies, heart disease, stroke,

infertility, and secondary cancers

– QOL is compromised by late effects

• 20% mortality from treatment-related

complications and secondary cancers

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Applications of Proton Therapy

Oeffinger, NEJM, 2006

Armstrong, JCO, 2014

1. Escalate dose

• Example: Cure more skull base chordomas without causing blindness

2. Reduce collateral radiation damage

• Example: Cure the same number of medulloblastomas but reduce

damage to heart and lungs

• Protons significantly reduce the amount of normal tissue

exposed to radiation

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How can Protons improve RT delivery?

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Applications of Proton Therapy

Armstrong, JCO, 2014

• Risk of serious (Grade 3-5) chronic toxicities were

significantly increased in long-term childhood cancer

survivors compared to siblings, across all disease sites

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Trends in the Use of RT in Pediatric Cancers

Jairam V, IJROBP, 2012

• Deliver therapeutic tumor dose and spare normal tissues

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Protons Have No Exit Dose

Conventional RT

Proton Therapy

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• Hearing/Vision

• Neurocognitive

Development and IQ

• Endocrine

• Second Cancers

• Vascular

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Proton Therapy for CNS Tumors

Radiation Sensitive

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Lower Normal Tissue Doses with Protons

St. Clair, IJROBP 2004

Miralbell, IJROBP 2002

Mu, Acta Oncol 2005

RT Technique Dose to Cochlea Dose to 50% of Heart

Conventional RT 101.2% 72.2%

IMRT 33.4% 29.5%

Proton Therapy 2.4% 0.5%

RT Technique Risk of Secondary Cancer

IMRT 30%

Electron Beam 21%

Conventional RT 20%

Proton Therapy 4%

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Proton Therapy Reduces Decline in IQ

Merchant TE, Pediatr Blood Cancer, 2008

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1. Age matters

2. Protons may mitigate the age effect

3. Protons & older child �� IQ preservation

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5 y.o. with Craniopharyngioma

IMRT Proton Therapy

• Reduction in dose to the temporal lobes preserves task

efficiency, processing speed, and memory

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• GH deficiency after RT is a serious complication that leads to:

– Decreased growth and bone maturation

– Decreased metabolism, hypersecretion of insulin and leptin

– Disturbance in the autonomic nervous system and neurocognitive

deficits

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Endocrinopathies

Probability of GH Deficiency (peak GH <7ng/ml) by Mean Hypothalamus Dose and Time

Time 5Gy 10Gy 15Gy 20Gy 25Gy 30Gy 35Gy 40Gy 45Gy 50Gy 55Gy 60Gy

12 mo 12% 14% 17% 19% 22% 25% 28% 31% 34% 38% 42% 45%

36 mo 11% 18% 26% 37% 48% 59% 70% 79% 86% 91% 95% 97%

60 mo 11% 22% 39% 57% 75% 87% 95% 98% 99% 100% 100% 100%

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Proton Therapy IMRT

Mean Hypothalamus Dose: 27 Gy Mean Hypothalamus Dose: 0.8 Gy

Proton Therapy Reduces Hormone Deficiencies

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4 y.o. with Posterior Fossa Ependymoma

Proton Therapy IMRT

Mean Hypothalamus Dose: 18 Gy Mean Hypothalamus Dose: 0.2 Gy

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• Cost of growth hormone replacement:

– $10,000-25,000 per year

• Cost of hormone assisted fertility (female):

– >$10,000 per treatment course

• Cost of DDAVP, levothyroxine, and hydrocortisone:

– Thousands of dollars per lifetime

• Cost of treating heart disease, hearing loss, second

malignancies, etc.

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Endocrine Replacement Therapy

Lundkvist J, Acta Oncol, 2005

Mailhot Vega R, IJROBP, 2015

Yock TI, Radiother Oncol, 2014

Kuhlthau KA, JCO, 2012

• Health-Related Quality of Life (HRQoL) compared in pediatric

patients treated at MGH (Proton) and Stanford Lucille

Packard Children’s Hospital (Conventional RT)

• Prospective data collected using the PedsQL scale (n=120)

• Children who received proton therapy reported significantly:

• Better overall HRQoL scores (mean 75.9 vs. 65.4, p=0.002)

• Higher HRQoL was significantly associated with higher IQ scores

• Better physical health scores (mean 78.4 vs. 68.1, p=0.01)

• Better psychosocial health scores (mean 74.5 vs. 64.0, p=0.001)

Quality of Life


• Compared to healthy controls, QOL scores were 5.0 points lower in

the proton population (p=0.024) and 13.3 points lower in the photon

population (p<0.001)

• QOL scores in the proton cohort were similar/better than children

with chronic diseases: Diabetes 76.0, Obesity 75.0, and Asthma 68.8

Better Health-Related Quality of Life

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• Differences were most notable in children with Medulloblastoma,

Ependymoma/High-Grade Glioma, and Low Grade Glioma

Quality of Life

• Modeled cost-effectiveness of proton therapy for medulloblastoma

– Considered risk of heart disease, IQ loss, hearing loss, hypothyroidism,

GH deficiency, osteoporosis, and secondary cancers

• Proton therapy reduced total cost by €23,600/patient and

significantly increased quality-adjusted life years (QALY)

• Proton therapy dominated (had both lower cost and better

outcomes than) conventional RT

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But Proton Therapy is too Expensive…

Lundkvist J, Acta Oncol, 2005

• Proton therapy cost <$5,000/QALY gained in children

• Proton therapy had both lower costs/higher QALYs than conventional RT

• Biggest reasons that proton were better

– Reduced risk of heart failure

– Reduced risk of hearing loss

– Reduced risk of secondary cancer

– Reduced risk of GH deficiency

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But Proton Therapy is too Expensive…


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• What is the cost of proton therapy in a pediatric

medulloblastoma?

– <$5,000/QALY

• Cost of an airbag in your car?

– $61,000/QALY

• Cost of adding bevacizumab to FOLFOX in metastatic

colorectal cancer (for which there is Level I Evidence)?

– $935,000/QALY

– Benefit 0.21 QALY at a cost of $98,570/patient

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Pop Quiz!


Graham JD, JAMA, 1997

Goldstein DA, JCO, 2015

• Real-life case

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Soft tissue sarcoma in the Photon Path

100

60

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• Matched Pairs Analysis

– 558 Proton patients vs. 558 SEER patients treated with Conventional RT

– Incidence of Secondary Cancers: 12.8% Photons vs. 6.4% Protons (HR =

2.73; 95% CI = 1.87-3.98, p<.0001); Absolute reduction of 50%

• Prospective (Retinoblastoma)

– 86 Retinoblastoma patients (55 Proton, 31 Conventional) treated since 1986

– 10-year incidence of RT-induced in-field SMNs: 0% vs. 14% (p=0.015)

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Growing Evidence for Proton Therapy

Chung CS, IJROBP 2013

Sethi RV, Cancer 2014

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• Proton therapy reduces the risk of second cancers

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Growing Evidence for Proton Therapy

Chung CS, IJROBP 2013

Sethi RV, Cancer 2014

Eaton BR, IJROBP 2015

• Prospective clinical studies have demonstrated the benefit of

protons vs. conventional RT in reducing normal tissue doses for:

– Brain Tumors (Prospective)

– Retinoblastoma (Prospective)

– Rhabdomyosarcoma (Prospective)

– Orbital rhabdomyosarcoma (Prospective)

– Hodgkin lymphoma (Prospective)

– Chordoma and Chondrosarcoma (Prospective)

– Ewing sarcoma in the Pelvis/Spine

– Neuroblastoma

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Growing Evidence

Macdonald SM, Neuro Oncol 2013

Yock TI, Lancet Oncol 2015

Merchant T, IJROBP 2011

Hoppe BH, IJROBP 2014

Pubmed accessed on Oct 8, 2017

Proton therapy is not Experimental

• Articles:

– “pediatric cancer proton”: 455

– “pediatric cancer IMRT”: 105

– “pediatric cancer proton outcomes”: 72

– “pediatric cancer IMRT outcomes”: 14

• >1 million patients have been treated with proton therapy

• >40% of US children treated with RT with curative intent

received proton therapy in 2015

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Protons Reduce Dose to Heart during CSI

Conventional RT

Proton Therapy

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Heart Dose = Cardiac Toxicity

Darby (Breast Cancer)– Relative risk of major

coronary events increased by 7.4% per Gy mean heart dose

Darby S, N Engl J Med 2013

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Heart Dose = Cardiac Toxicity

van Nimwegan FA, JCO 2016

van Nimwegan (Hodgkin)– Relative risk of major

coronary events increased by 7.4% per Gy mean heart dose

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106

89

78 77

40 42

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2521

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2421 21 19 18 16

14 14

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57 59

32 33

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2012 2011 2010

Pediatric Proton Therapy in the US: 2010-2012

• The “typical” proton therapy patient is a child <10 years old

with a curable brain tumor or axial sarcoma who requires

anesthesia and/or concurrent chemotherapy

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• Children with brain tumors treated in high volume hospitals

have better survival than at low volume hospitals (Level 1).

– This lower mortality risk is most pronounced in children <2 y.o.

• “It is likely” that children with Ewing sarcoma, osteosarcoma,

leukemia, Neuroblastoma, and Wilms Tumor have better

survival in high volume centers and when treated by high case

volume providers (Level 2).

– The quality of radiotherapy is related to the volume of patients treated

Experience Matters

Knops RRG, Annals Oncol, 2013

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• To care for children with cancer, you need a team

Caring for Children with Cancer

• Pediatric Radiation Oncologist

• Pediatric RNs

• Pediatric Anesthesiologists

• Pediatric Recovery Room RNs

• Child Life Specialist

• Pediatric Social Worker

• Radiation Therapists with

Pediatric Experience

• Pediatric Oncologists

• Pediatric Neurosurgeons

• Pediatric Surgeons

• Pediatric Radiologists…

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• Pediatric Brainstem Radionecrosis

• 313 patients treated with Proton Therapy at UFPTI

• 11/313 patients developed brainstem toxicity

• Seven with Grade 2, Three with Grade 3-4, One Grade 5

• 2-year cumulative incidence

– Any brainstem toxicity: 3.8% ± 1.1%

– Grade 3+ brainstem toxicity: 2.1% ± 0.9%

• Symptoms stabilized/resolved in

9/10 living patients

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Indelicato DJ, Acta Oncol, 2014.

Caution: Unexpected Toxicity -- Brainstem

• 3-year cumulative incidence

• Any Vasculopathy: 7.5%

• Stroke or Revascularization: 2.6%

Caution: Unexpected Toxicity -- Vasculopathy

Hall MD, IJROBP, 2017.

• More conservative guidelines are needed in pediatric patients

receiving proton therapy than are currently used by COG

• Solutions:

1. Normal tissue guidelines

2. Rigorous QA

3. Expert Team

– Pediatric Fellowship Training

– PENTEC Late Effects Project

– CAYAHL Harmonization Project

– COG Late Effects Working Group

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Spinal Cord Absolute dose at 0.5cc 1.7 Gy28.3 Gy46.4 Gy46.4 Gy

0 Gy0 Gy

13.8 Gy21.6 Gy31 Gy

18.9 Gy0 Gy0 Gy

59.7 %60.8 %41.8 Gy44.9 Gy33.7 Gy36.1 Gy41.8 Gy25.9 Gy11.1 Gy10.3 Gy1.8 Gy0 cc0 %

19.2 Gy14.2 Gy14.8 %41.3 %34.3 %9.6 %

Goals= 55, 60 GyOptic Chiasm Absolute dose at 0.1cc Goals= 55, 60 GyBrainstem Surface Absolute dose at 0.1cc Goals= 59, 64 GyBrainstem Core Absolute dose at 0.1cc Goals= 54, 57 GyRetina Left Absolute dose at 0.1cc Goals= 50, 55 GyRetina Right Absolute dose at 0.1cc Goals= 50, 55 GyOptic Nerve Left Absolute dose at 0.1cc Goals= 55, 60 GyOptic Nerve Right Absolute dose at 0.1cc Goals= 55, 60 GyCochlea Left Mean absolute dose Goals= 30, 36 GyCochlea Right Mean absolute dose Goals= 30, 36 GyLacrimal Gland Left Mean absolute dose Goals= 34, 41 GyLacrimal Gland Right Mean absolute dose Goals= 34, 41 GyTemporal Lobe Left Relative volume at 20Gy Goal= 10 %Temporal Lobe Right Relative volume at 20Gy Goal= 10 %Hippocampus Tail Left Mean absolute dose Goal= 20 GyHippocampus Tail Right Mean absolute dose Goal= 20 GyHippocampus Head Left Mean absolute dose Goal= 5 GyHippocampus Head Right Mean absolute dose Goal= 5 GyHypothalamus Mean absolute dose Goal= 5 GyPituitary Mean absolute dose Goal= 30 GyMastoid Air Cell Left Mean absolute dose Goal= 30 GyMastoid Air Cell Right Mean absolute dose Goal= 30 GyPosterior Nasopharynx Mean absolute dose Goal= 30 GyScalp Absolute volume at 30Gy Goal= 5 ccBrain Relative volume at 115% dose Goal= 0 %Brain Mean absolute dose As low as possibleNon Target Brain Mean absolute dose As low as possibleSupratentorial Brain Rel volume getting 0-1Gy As low as possibleSupratentorial Brain Rel volume getting 1-20Gy As low as possibleSupratentorial Brain Rel volume getting 20-40Gy As low as possibleSupratentorial Brain Rel volume getting >40Gy As low as possible

Make Patient Safety a Priority

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• At pediatric proton therapy centers, up to 50% of patients

may require anesthesia

– 7 fellowship-trained pediatric anesthesiologists

– Pediatric recovery room (3 pediatric nurses/day)

– No current limit on anesthesia case capacity

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Pediatric Anesthesia

• At UFPTI,

– 62.3% of children aged 5-8 required anesthesia in 2006-2011;

– 28.8% of children aged 5-8 required anesthesia in 2012-2014 after a

child life specialist was hired

• An average 6-week course of pediatric anesthesia costs $50,000/patient

• The average annual cost to employ one child life specialist is $50,000/year

• Employing a child life specialist and reducing anesthesia results in an

expected cost savings to the healthcare system exceeds $950,000 in a

program treating 100 pediatric patients per year

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Smith MT. IJROBP. 2016.

The Value of a Certified Child Life Specialist

• A Child Life Specialist

– Reduces the need for anesthesia and makes treatment faster

• Pediatric CNS case: 30 minutes

• Pediatric CNS case with anesthesia: 45 minutes

– Improves patient and family experience

– Represents the standard of care in a pediatric radiation oncology

program

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The Value of a Certified Child Life Specialist

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• Patients derive no benefit from the irradiation of normal

developing tissues– Proton therapy can significantly reduce the volume of normal tissue

receiving collateral radiation

– Clinical data continues to mature, but already verifies the modeled

benefits in children

• Appropriate patient selection maximizes the absolute benefit

achieved in patients receiving proton therapy.

• This benefit is greatest in children.

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Conclusions

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• Thank you!

Matthew D. Hall, M.D., MBA

Radiation Oncology

Baptist Health South Florida

[email protected]

Cell: (618) 910-8157

Miami Cancer Institute

Fri Hall 135 - Baptist Health South...

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