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CPT

ProtonProton--

Radiotherapy:Radiotherapy:

Treatment Related

Toxicitiesand OAR Constraints

Eugen B. Hug

CPT

Toxicities:Toxicities:

AcuteAcute

LateLate

Second MalignancySecond Malignancy

CPT

Toxicities:

Are there potentially “proton-specific” toxicities?

By-and-large: Toxicities related to dose and not to modality.

Except:………………

CAVEATS

CPTToxicities:

Are there potentially “proton-specific”

toxicities?

CAVEATS (of undetermined clinical significance):

a) Passive Scattering:

Patch combinations

b) Active Scanning:

Highly weighted Spots

c) Both: The issue of “ranging out towards a critical structure”

CPT Toxicities:


toxicities?

CAVEATS:

a) Passive Scattering:

Patch combinations

Patch-line

in normal tissue:

Patchline

in tumor

Rule: use

several

combinations

For „clinical

evidence“

see:Kim

et al, MGH, IJROBP 39(suppl 2):272, 1997

CPT Toxicities:


toxicities?


b) Active Scanning:

Position of high weighted spots

CPTTreatment with 2 vertical fields:

overlapping position of high weighted spots in the Brainstem

F0

F1

PLAN

Dose spots F1

Dose spots F0

CPTTreatment with 3 fields:

Reduction of high weighted dose spots in Brainstem

F0

F1

PLAN

Dose spots F0

Dose spots F2

Dose spots F1

F2

CPT

Question:

Which

is the „better“

plan?

•Given

the unknown

clinical

significance of persistent

irradiation

of the same

area

with high weighted

spots

•Given

the trade-off:

> fields = > integral dose

CPTToxicities:


toxicities?


c) Both: The issue of “ranging out towards a critical structure”

range

uncertainty

high LET component

at end of range

General General recommendationrecommendation: :

••avoidavoid

ranging out ranging out „„intointo““

an an criticalcritical

OAR OAR

••or: or: trytry

to reduce potential to reduce potential consequenceconsequence by increasing by increasing numbernumber

of fields or of fields or

increase field increase field angulationangulation

CPT Toxicities:

Are there “proton-specific”

toxicities?CAVEATS:CAVEATS:

The issue of using a single field approachThe issue of using a single field approach72 CGE for malignant

falcine

meningioma

with postop. residual

Preoperatively. Postop.

Single vertex

field

CPT

12 12 monthsmonths

after PTafter PTBrain

Necrosis:

•Patient required

on-and- off

steroids

for 2 years,

•complete resolution

of symptoms

and regression

of changes

on MRI at 3 years,

•

local

tumor

control throughout

CPT

Tsuboi

et al 2007, PTCOG 47 4/13 clivus

chordoma

patients treated with

combined

photon/proton RT experienced radiation necrosis

Note: Note: ExclusivelyExclusively

opposingopposing

lateral fields lateral fields usedused

!!

CAVEAT: Using a opposing lateral fields onlyCAVEAT: Using a opposing lateral fields only

CPT

Skin dose:

•usually less with active scanning compared to passive scattering

•Clinically relevant difference:

•

partial alopecia

for skull base

treatments

(hair

thinning

or no hair loss

(active

scan.) versus

temporary

hair

loss

(pass. scatt.))

•Subcutaneous

fibrosis, thinning

of skin, teleangiectasia

of paraspinal

cases treated primarily

from

posterior

ACUTE ACUTE ToxicityToxicity

IssuesIssues

1 field

3 fields

Reduced

skin dose with Act.

Scanning

CPT

•

Phase I/II trial. 20 women

with T-1 breast

Ca, neg. margins

after lumpectomy

•PTV: lumpectomy

cavity

plus 1.5-2.0 cm, minimum

5mm distance to surface/skin

•32 Gy(RBE) total dose: 4 Gy (RBE) B.I.D. over

4 days

•1-3 field arrangements

overall, 1 field treated per day

only

•„Skin dose per field approached

maximum

dose“, Single field per day

= full

4 Gy skin

dose. (MGH, passive scatttering

)

•Observation: Median F/U 12 months

(8-22)

increased

acute

toxicity:

80% moderate to severe

skin

color

changes

22% severe

moist

desquamation

Accelerated

Partial-Breast

Proton Therapy: Initial MGH Experience

KozakKozak, , TaghianTaghian

et al. IJROBP 66(3):691, 2006et al. IJROBP 66(3):691, 2006

ACUTE ACUTE ToxicityToxicity: : SKINSKIN

CPT

„Despite

significant

resolution

of acute

skin

toxicities

by 6 months, concerns

persist“

Authors

suggest:

•Multiple field arrangements,

•fields should not overlap

at skin,

•all fields treated per fraction

Accelerated

Partial-Breast

Proton Radiotherapy: Initial MGH Experience

KozakKozak, , TaghianTaghian

et al. IJROBP 66(3):691, 2006et al. IJROBP 66(3):691, 2006

Note: acute toxicity did not translate into early-late toxicity

CPT

Cavities lined by Mucosa: Oral mucosa, pharynx, rectum etc.

•Clinical

advantage

of „partial organ

irradiation“

evident (3D versus

IMRT, Phase III photon

trial

–

even

more

sparing

with IMPT)

•Less

than

circumferential

mucositis

significantly

decreases

pain

and discomfort

thereby

increasing patient

tolerance

in Head

& Neck

treatments. (less

Tx-induced

breaks, less

weight

loss, less, medication)

•Rectum:

•partial rectal

wall tolerance

established

(Hartford et al., IJROBP)

•Importance of increasing distance anterior

to posterior

wall (balloon, water, probe, etc.

ACUTE ACUTE ToxicityToxicity

IssuesIssues

CPT

IntestineIntestine

> 50% Intestine Intestine, posterior

portion

only

CPT ConstraintsConstraints

BowelBowel

DeLaney et al. (MGH)DeLaney et al. (MGH)

IJROBP 2009 in press (50 patients):

SmallSmall--bowelbowel

dosedose:

50.4 Gy RBE or less

RectalRectal

dosedose: no limit to posterior

wall, but„every

effort

was made

to spare the lateral and anterior

wall“,

„where

possible, omentum

was placed

posterior

to the rectum at surgery

to limit rectal

dose“

PSI:PSI:Small Small bowelbowel

64 Gy RBE (D2)

60 Gy RBE „posterior

surface“

( i.e. not circumferential)

RectumRectum

70 Gy RBE (D2) (posterior

surface, possibly

74 Gy)

CPT

a) High Grade, Severe (Grade 3, 4, 5)

b) Low Grade (Grade

1,2) and c) Quality of Life

d) Second Malignancy

Late Late ToxicitiesToxicities

CPT



Proton Radiotherapy can only reduce the risks, it will not eliminate

the risks

Any

high-dose

RT modality

carries risks

of OAR injury

CPT

Long-term Side Effects of high-dose Skull Base Irradiation –

including Protons

The risks of severe side effects following high dose,precision RT depend on several variables:

Tumor size, tumor compression of normal brain, critical structure involvement, dose to normal tissues, number of prior surgeries, general medical risk factors (diabetes, HTN, smoking,), KPS

Low-risk group:

< 5%

High-risk group:

> 10 % -

?? *

* RT as last modality after multiple failures

RuleRule

of of ThumbThumb

for Proton RT for Skull Base requiring > 70 Gy:for Proton RT for Skull Base requiring > 70 Gy:

CPT



Severe

Optic

Neuropathy:

sudden

loss

of color

vision, amaurosis

fugax, blindness

Tx: steroids, anticoagulants, Vitamin E, Hyberbaric

Therapy

CPT



Severe

Optic

Neuropathy:

Sooner

or later

you

will likely

encounter

optic neuropathy: example: 54 Gy(RBE) for cavernous

sinus

meningioma

Tx: start high dose Tx: start high dose steroidssteroids

IfIf

patientpatient

has still has still visionvision

or or visionvision

lossloss

only only recentlyrecently

((i.ei.e. . withinwithin

daysdays): immediate ): immediate referralreferral

to to HyperbaricHyperbaric

CenterCenter

CPT



Severe

Optic

Neuropathy:

Evidence

for effectiveness

of Hyperbaric

Tx:

•No large series

•Convincing

case

studies

of reversibility

of symptoms, i.e. salvage

of vision

•Agreement in literature

–

supported

by personal experience: Need

to start hyperbaric

Tx while

pathophysiologic

ischemic

process

is still reversible.

•Hyperbaric

Tx likely

not successful

if

actual

cell

death

has occurred.

CPTOpticOptic

Nerve / Nerve / ChiasmChiasm

DVH shape: avoid

steep

gradients

close

to max. dose!

Chiasm: small

volume,

difficult

to defineno pixel dose! Mean dose counts!

Chiasm

r. Optic

Nerve / Chiasm

l. Optic

Nerve / Chiasm

CPT OpticOptic

NervesNerves

/ / ChiasmChiasm

ConstraintsConstraints at at VariousVarious

Proton CentersProton Centers

Emami

et al. IJROBP 1991;21:109-122 (blindness, no partial volume):

TD 5/5: 50 Gy TD 50/5: 65 Gy (?)

Facility

Dose Gy RBE

MGH Loma Linda

Orsay PSI

Mean(1.8-2.0)

54 <58Chiasm

Max. (1.8-2.0)

60 60 55-56 60(D2)

CPT

SummarySummary

OpticOptic

Nerve / Nerve / ChiasmChiasm

Constraints

at PSI:

The maximum dose to the optic chiasm and both optic nerves shall not exceed 60 Gy RBE (D2).

However, if the tumor immediately abuts one optic nerve with distance from Chiasm, OAR constraints may be raised for this optic nerve up to 64 Gy RBE, but only after specific approval, and after special informed consent has been obtained addressing the likelihood of unilateral blindness.In this situation the chiasm shall receive ≤

58 Gy RBE and the

contralateral optic nerve ≤

54 Gy RBE.

CPT

Sensorineural

hearing loss (SNHL):

CochleaCochlea

ToleranceTolerance

Significant cognitive impairment, depression, and reduction in functional status (Cacciatore F, et al. Gerontology

1999;45:323-28)

Risks beyond irradiation: age, hypertension, diabetes mellitus

Risk of clinically overt SNHL for Dmean cochlea:

Bhandare

N, et al. IJROBP

2007;67:469-79Probability and Radiation dose (325 patients):

3%

≤

60.5 Gy 37% > 60.5 Gy

Chan SH, et al. IJROBP 2008,1-8, in press170 eligible ears: RT (n = 30), chemoradiotherapy

(n=140)

47 Gy mean dose cochlea: <15% of patients developing severe (≥

30 dB) high frequency hearing loss

CPT

••

Normal hearing bilateral, one side part of GTV.Normal hearing bilateral, one side part of GTV.

No contraint ipsilateral, keep contralateral dose <

54 Gy RBE

••

Ipsilateral Ipsilateral anacousisanacousis

or significant or significant preexistingpreexisting

hearing deficit:hearing deficit: No constraint affected side, keep contralateral cochlea

dose <

45-50 Gy RBE

Large tumor with GTV close to both Large tumor with GTV close to both cochleascochleas..

Hearing bilaterally. Keep at least one cochlea ≤

60 Gy RBE

Cochlea OAR dose is not an absolute OAR. Carefully weigh risk of deafness versus GTV underdosage.

OrsayOrsay::

mean dose 50 Gy CGE, max. dose 55 Gy CGE)

MGH:MGH:

??

PSI:PSI:

Guidelines for Constraints to Dmean CochleaGuidelines for Constraints to Dmean Cochlea

CPT

G3 G3 --

Brain toxicityBrain toxicity exampleexample

T1Gd 26.02.07

T2 26.09.07T1Gd 26.09.07

Flair 26.02.07

Brain

Parenchyma

Toxicity

CPT G1G1

--

Brain toxicityBrain toxicity

exampleexample

Pre-PT

10/05

T1Gd

05/07

T1Gd

08/07

CPT

PSI:PSI:

64 Skull Base Patients treated at (40 Chordoma, 22 Chondrosarc.)

7 pts. censored: 2 pts Grade 3, 5 pts. Grade 1

4 pts. bilat.. 3 pts. unilateral

High-Dose

Proton Therapy

to the Base of Skull: Temporal Lobe Temporal Lobe ToxicityToxicity**

* B. Pehlivan, C. Ares, T. Lomax, E. Hug (in preparation)

Patient characteristics with G1 or G3 temporal adverse events

1 3 74 22 yes 12 Bilateral

2 3 74 23 yes 19 Bilateral

3 1 68 50 yes 35 Bilateral N/A stable on MRI

4 1 74 21 yes 10 Bilateral N/A resolution

5 1 74 61 yes 38 Left N/A no change

6 1 74 35 yes 31 Left N/A no change

7 1 74 21 yes 18 Right N/A increase

#: number; PT:proton-radiotherapy; F/U:follow-up; LC: local control; Dx: diagnosis; N/A: not applicable

Overall F/U time (months)

Dx of adverse event

(months after PT)

Location temporal lobe

change

Patient #

PT dose (Gy(RBE))

LCToxicity Grade

Status MRI at last F/U

Impaired short term memory, desorientation

Impaired short term memory, desorientation

Stable with edema reduction

Stable with edema reduction

Symptoms

CPT

Brain parenchyma toxicity

0

10

20

30

40

50

60

70

80

90

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 1 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 3 1 0 0 0 0 0 3 0 0 0 0 0 0 0 0 0 1

Grade toxicity

Dos

e (G

y(RB

E)

D3D2D1D 0.5

cont. PT Temporal Lobe Temporal Lobe ToxicityToxicity**


Threshold High Grade

Local

Failure

Low Grade

High Grade

Threshold Low Grade

CPTRight temporal lobe toxicity

0

10

20

30

40

50

60

70

80

90

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3 0 0 0 0 0 0 0 0 0 1 0 0 3 0 0 1

Grade toxicity

Dose

(Gy(

RBE) D3

D2D1D0.5

Left temporal lobe toxicity

0

10

20

30

40

50

60

70

80

90

0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 1 0 0 0 0 0 3 0 3 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

Grade toxicity

Dose

(Gy(

RBE

)

D3D2D1D0.5



CPT

Grade Toxicity D3 mean ± SD (Gy(RBE))

D2 mean ± SD (Gy(RBE))


D0.5 mean ± SD (Gy(RBE))

0 70 ± 5 71 ± 5 72 ± 5 73 ± 51 73 ± 5 74 ± 5 75 ± 4 76 ± 43 75 ± 1 76 ± 2 76 ± 2 77 ± 2





0 50 ± 23 52 ± 23 56 ± 22 58 ± 221 67 ± 15 69 ± 12 73 ± 9 75 ± 73 71 ± 4 73 ± 3 75 ± 2 76 ± 2



D1 mean ± SD(Gy(RBE))


0 53 ± 21 56 ± 21 59 ± 20 62 ± 191 57 ± 18 62 ± 15 67 ± 12 70 ± 93 68 ± 1 71 ± 0 74 ± 1 75 ± 1

Table 3. Dose-volume values to 3 different neurological structures in relation with grade of CNS toxicity

Brain parenchyma

Right temporal lobe

Left temporal lobe


* B. Pehlivan, C. Ares, T. Lomax, E. Hug (submitted)

CPT55

6065

7075

80D

2cc

[Gy]

0 1 3

Brain D 2cc

Grade Toxicity

5560

6570

7580

D 2

cc [G

y]

0 1 3

Brain D 2cc

Grade Toxicity

cont: PT Temporal Lobe Temporal Lobe ToxicityToxicity**

* B. Pehlivan, C. Ares, T. Lomax, E. Hug (submitted)

Q: What

is a „reasonable“

temp. lobe max. Dose Constraint, i.e. balancing

toxicity

risk

with risk

of failure

?

••D 2 = D 2 = <<

70 or 72 Gy (RBE)?70 or 72 Gy (RBE)?

••„„absoluteabsolute““

or or „„relativerelative““

Maximum Dose?Maximum Dose?

EUD's

for all lobes

0

10

20

30

40

50

60

70

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20a parameter

EUD

(Gy)

Grade 0Grade 1Grade 3

Figure 3.

CPT

•

9/96 patients have white matter changes within the irradiation field on follow-up MRI with clinical symptoms

RTOG grading

G2 1pt., G3 8 patients•

The cumulative TL damaged rates–

2y 7.6% 5y 13.2%

•

Only gender -

male patients have higher risk

(p= 0.0155)

MGH:MGH:

Temporal lobe necrosis for skull base tumors Santoni et al (IJROBP 1998;41(1):59)

OrsayOrsay::

Noel G, et al. Acta Oncol

44(7):700-708, 2005•100 chordoma

patients, median follow-up

31 months

(range

0-87)

•

One patient

with asymptomatic

bilateral necrosis, diagnosed

on imaging

CPT

Miyawaki

et al. Hyogo

Ion Beam Medical

Center, Hyogo, Japan IJROBP 75(2), 2009

CPT

Demizu

et al. Hyogo

Ion Beam Medical

Center, Hyogo, Japan IJROBP 75(5), 2009

CPTConstraintsConstraints

Temporal LobeTemporal Lobe

FacilityVolumeTemporal lobe

MGH Loma Linda

Orsay PSI

Relativemax. doseGy RBE(1.8-2.0)

2 cc ≤

70 („soft“

OAR)

AvoidPlanning

Hot spots2cc <72

(?) Absolute max. dose Gy RBE (1.8-2.0)

?

CPT

•

n = 367–

195 chordomas,172 chondrosarcomas

•

Prescribed target dose –

63 to 79.2 Gy(RBE) (mean 67.8 Gy(RBE))

•

Photons + protons•

Brainstem dose constraints–

Surface

≤

64 CGE

–

Center

≤

53 CGE•

Mean follow-up –

42.5 months (6 m -21.4y)

Brain Stem Toxicity

MGHMGH: Debus et al. IJROBP 1997;39(5):967

CPT

cont. Debus et al. IJROBP 1997;39(5):967

•

17/367 patients were considered to have radiation-induced brainstem toxicity (brainstem symptoms with contrast enhancement of the brainstem within the irradiation field on follow-up MRI)

RTOG gradingG1 3G2

3

G3 4G4

4

G5

3

•

actuarial rate toxicity free survival–

5y 94%

–

10y 88%

CPT

2.6≥

2…….0.001…….0.0006Surgical Procedures at the base of skull1.4yes/no…….0.3…….0.1High blood pressure5.7yes/no…….0.01…….0.04Diabetes1.4yes/no…….0.2…….0.08History of smoking

……11.4≥

0.9 cc…….0.001…….0.0001Volume of brainstem receiving ≥

60 CGE1.5≥


55 CGE1.3≥


50 CGE1.364 CGE…….0.09…….0.001Maximum dose at brainstem1.170 CGE…….0.5…….0.3Prescribed tumor dose

Actuarial risk ratioThreshold

Significance in multivariate

analysis

Significance in univariate

analysis

Variable

Multivariate analysis: risk factors for brainstem toxicity

Brain Stem Toxicity at MGHBrain Stem Toxicity at MGH cont.

Debus et al. IJROBP 1997;39(5):967

CPT Brain Stem Toxicity at MGHBrain Stem Toxicity at MGH Debus et al. IJROBP 1997;39(5):967


BrainstemBrainstem

Emami

et al. IJROBP 1991;21:109-122:

TD 5/5: 1/3 > 60 Gy, 2/3 > 53 Gy, 3/3 > 50 Gy TD 50/5: 3/3 > 65 Gy

FacilityLocationBrainstem

MGH Loma Linda

Orsay PSI

SurfaceGy RBE(1.8-2.0)

64 64 64 (anterior)

64

Center Gy RBE(1.8-2.0)

53 53 53-56(48 posterior)

53


Spinal CordSpinal Cord

Emami

et al. IJROBP 1991;21:109-122:

TD 5/5: 5 cm/55 Gy, 10 cm/50 Gy, 20 cm/47 Gy TD 50/5: 5 cm/73 Gy, 10 cm/70 Gy, 20 cm/65 Gy

FacilityLocationSpinal cord

MGH Loma Linda

Orsay PSI

SurfaceGy RBE(1.8-2.0)

63max. 5 cm

64 55(anterior)

63-64

Center Gy RBE(1.8-2.0)

54max. 5 cm

53 50(45 posterior)

53-54

CPT ConstraintsConstraints

Spinal CordSpinal CordPSI: Rutz et al. IJROBP 2007;67:512-520 (26 patients)

Update: 54 patients MGH: DeLaney et al. IJROBP 2009

(50 patients)

--No No high-grade

spinal cord

injury

observed

at either

institution

SacralSacral

Nerve Nerve ToxicityToxicityMGH:MGH:

DeLaney et al., IJROBP 2009

29 chordomas, 14 chondrosarcomas, 7 others

(n=50)

Prescribed

target

dose:50.4 / 70.2 / 77.4 Gy RBE at 1.8 Gy RBE qd

(Photons + protons); no

constraints

to nerve roots, effort

to spare contralateral NR3/50 patients with sacral

neuropathies

after 77.12-77.4 Gy RBE

PSI:PSI:

no constraints

to sacral

nerves70 Gy RBE (D2) preferable

limit. Selective

decrease

if

contralateral

sacral

nerve

damaged

CPT CaudaCauda

EquinaEquina

ToleranceTolerance

Pieters et al. IJROBP 2006;64(1):251-257

53 patients, median caudal

dose 65.8 Gy RBE (31.9-85.1), median follow-up

87 months

13 patients with neurologic

toxicity

40 patients without neurologic

toxicity> median dose 73.7 Gy RBE > median dose 55.6 Gy RBE

TD 5/5 and TD 50/5 male: 55 Gy RBE and 72 Gy RBE(2 Gy RBE /fraction) female: 67 Gy RBE and 84 Gy RBE

Below

65.8 Gy RBE significantly

less

likely

to experience neurologic

toxicity

CAVEAT: tumor

control

rate!Tolerance

doses

were 8 Gy RBE lower

when

estimated

at 10 years from

treatment…Neurologic

toxicity

continued

to appear

long

after 5 years!

However: often

difficult

to differentiate

RT-related

Sx

from

local

recurrence!

CPT CaudaCauda

EquinaEquina

ToleranceTolerance

MGH MGH constraintsconstraints:

70.2 Gy RBE, except

direct

contact

to tumor

PSI PSI constraintsconstraints:

70 Gy RBE (D2)

{64 Gy RBE to center

(Rutz et al. IJROBP 2007;67(2):512-520)}

Emami

et al. IJROBP 1991;21:109-122: TD 5/5: 60 Gy, TD 50/5: 75 Gy

> no differentiation

between

male and female

tolerances

CPT CategoriesCategories

OAROAR‘‘ss

Category

1 (absolute constraints): Contains

the list of organs

at risk

where

the maximum

tolerable dose is set

„in stone“

and may

not be

exceeded…

spinal cord, brainstem, chiasm, optic nerve

Category

2 (soft constraints):Contains

the organs

at risk, where

we

feel

we

would

have a

preference

of significant

sparing

but

our

dose constraint

is more

relative, not as absolute and should not significantly

change

the GTV coverage

> temporal lobes?, cochlea, nerve roots, (cranial) nerves, parotid

glands, eye, lens, lacrimal

glands, skin

CPT

b) Low Grade (Grade



Chronically

underreported

in trials, unless specifically

included

in design

Quality of Life studies

basically

absent in Adult Rad. Oncology

QoL

studies

conducted

in Pediatric Oncology

CPT

Chronic Health Conditions in Adult Survivors of Childhood Cancer: The Childhood Cancer Survivor Study

Oeffinger et al. (MSKCC). NEJM 355(15):1572-82, 2006

•

Method:•

Pooled data from 25 Pediatric Oncolgy

Centers

•

Diagnosis and Treatment of Childhood Cancer between 1970-1986

•

10,397 Survivors, > 3000 matched siblings•

Minimal survival time 5 years (up to 31 years):

Adult

Life after Radiation Therapy

in Childhood

CPT


CPTChronic Health Conditions in Adult

Survivors of Childhood Cancer: The Childhood Cancer Survivor Study Oeffinger et al. (MSKCC). NEJM 355(15):1572-82, 2006

CPT

Chronic Health Conditions in Adult Survivors of Childhood Cancer: The Childhood Cancer Survivor

Study Oeffinger et al. (MSKCC). NEJM 355(15):1572-82, 2006

•

Results:•

62% at least one chronic condition

•

1/4 severe or life-threatening condition•

1/4 had 3 or more chronic health problems

CPT

Chronic Health Conditions in Adult Survivors of Childhood Cancer: The Childhood

Cancer Survivor Study


Cumulative

Incidence

of Chronic

Health Conditions

among

10,397 Adult

Survivors

of Pediatric Cancer, Severity

of subsequent

health

conditions

was scored

according to the Common Terminology

Criteria

for Adverse Events (version

3) as:mild (grade 1), moderate (grade 2), severe

(grade 3), life-threatening

or disabling

(grade 4),or fatal (grade 5).

CPT

b) Low Grade (Grade



IfIf

wewe

believebelieve

that:that:

•Reduction

in Integral Dose = one

of the central, long

term advantages

of protons over

photons

andand……

•that low-moderate-dose-irradiated

volumes

are

an important

factor

determining

low-grade, long

term

toxicities, performance

function

and quality

of life (which

is what

our

patients believe

already)

ThenThen

……....

We

need

to focus

our

attention

on prospective

evaluation

/ trials

of QoL

and Functional Performance Studies

in ADULT

patients.

CPT

Inside

„the field“

High-dose

regionTreated Volume

Irradiated VolumeIntegral Dose

Outside

the „field“„far away“

Scattering

Neutrons

Major Dose Contribution-Definitions

„Irradiated Volume: ICRU #62 (suppl. to # 50): = …tissue

volume that receives

a dose that is considered

significant

in relation

normal tissue

tolerance…“

(?????)

Integral Dose = vast

majority is result

of volumes

within

the path

of irradiation

= within

entrance-

and exit

path

= primary

dose within

the

beam arrangement


d) Risk

of Second Malignancy

CPTThe The RiskRisk

of Second of Second MalignancyMalignancy

Inside

„the field“

High-dose



Outside


Scattering

Neutrons


Integral Dose:

Generally

reduced

by Protons

(example: factor

2 for volume receiving

> 30% dose (Lomax, 1999))

Potential gain: risk

reduction

by factors

2-15 (Miralbell, Lomax

2002; Schneider, Lomax

2000)

CPT The The RiskRisk


Inside

„the field“

High-dose



Outside


Scattering

Neutrons


Neutron Contamination:

Produced

in major

parts

by beam-modifying

material in the treatment head

/nozzle

(example: double scattering

system, modulator

wheels,

aperture

etc.)

Therefore: applies

more

to passive scattering

than

active

scanning.

Additional component

produced

inside

the patient

CPTThe Risk

of Second Malignancy

by

Neutron Contamination

•Eric Hall,2006*:

*Hall EJ. IJROBP 65:1-7,2006

** Gottschalk, IJROBP 66:1594, 2006

***Hall EJ. Technol

Cancer Res Treat. 6, suppl. 31-34, 2007

•Publication

prompted

major

criticism

from

data

sources:B. Gottschalk (HCL)**: doses

for passive scattering

are

too

high by factor

of 9

•Eric Hall, 2007***: ….adjusted

doses

(by factor

9) for passive scattering still comparable

to, or slightly

higher

than

for IMRT……



Paganetti* (MGH): Even revised

data

from

E. Hall misleading

since extrapolation

based

on small

aperture

measurements. Neutron dose

highly

facility

dependent

and even

case-

dependent

within

same facility. Variables can cause differences

in order of one

order of

magnitude. For specific

tx-situation

neutron

doses

can even

be

one order of magnitude

below

scattered

dose from

IMRT.

*Paganetti H. Letter to the Editor re. E. Hall‘s

article

2007. Technol

Cancer Res Treat. 6(6):661-2, 2007

** Wroe

et al. Med

Phys. 34(9):3449, 2007

Wroe

(U. Wollongong, NSW), Schulte (LLUMC)**: Out-of-field

equivalents

delivered

by

proton

therapy

of prostate

cancer.



My present

view

(as MD):

•

Active

Scanning technology avoids

the issue

and is the preferred

option

•Passive Scattering

results

in neutron

contamination with nominal scattering

dose likely

somewhat

worse

than

IMRT in most

cases –

but

this

needs

to be facility-

and case-specific

adjusted.

•Actual

dose depends

also largely on assumed

RBE for neutrons

–

which

can potentially

make things

worse.

•Justifiable

question: Should one

use

passively scattered

protons for hereditary

retinoblastoma

with

high propensity

for Second Malignancy

–

given

the alternatives of stereotactic

photons?



Inside

„the field“

High-dose



Outside


Scattering

Neutrons


Percentage

Risk

Contribution

? Possible

„Rule

of Thumb“:

80% : 20% ?

Please, do not quote

me………..assumes

also RBE (Neutrons) of 10

CPT ReferencesReferences

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B, Lyman

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of normal tissue

to therapeutic

irradiation.

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neuropathy

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combined

protonand photon

radiotherapy

for base

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Lomax

A. Intensity modulation methods for proton radiotherapy. Phys Med Biol 44(1):185-205, 1999

Schneider U, Lomax

A et Lombriser N. Comparative risk assessment of

secondary cancer incidence after treatment of Hodgkin's disease with photon and

proton radiation. Radiat

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154(4):382-388, 2000


Noel G, Habrand J-L, et al. Combination

of photon

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radiation

therapy for chordomas and chondrosarcomas nof

the skull base: the Centre de

Protonthérapie

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in management

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R, Lomax

A, et al. Potential reduction of the incidence of radiation- induced second cancers by using proton beams in the treatment of

pediatric

tumors. IJROBP 54(3):824-9,

2002

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L, et al. Chordomas of the base

of skull and upper

cervical

spine.

One hundred

patients irradiated

by a 3D conformal

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combining

photon and proton

beams. Acta Oncol

44(7):700-708, 2005

CPT

Weber DC, Rutz HP, et al. Results of spot scanning proton

radiation

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2006

Kozak

KR, Smith BL, et al.

Accelerated partial-breast irradiation using proton

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ReferencesReferences

CPT

Taghian

AG, Kozak

KR, et al. Accelerated partial breast irradiation using

proton beams: Initial dosimetric



Pieters RS, Niemierko

A, et al. Cauda

equina

toerance

to high-dose fractionated

irradiation. IJROBP 64(1):251-257, 2006

Hall EJ. Intensity-modulated radiation therapy, protons, and the risk of second

cancers. IJROBP 65(1):1-7, 2006

Gottschalk B. Neutron dose in scattered and scanned proton beams: In

regard to Eric J. Hall (Int

J Radiat

Oncol

Biol

Phys

2006;65:1–7) . IJROBP

66(5):1594,

2006

ReferencesReferences


Hall EJ. The impact of protons on the incidence of second malignancies in radiotherapy. Technol

Cancer Res Treat. 6, suppl. 31-34,

2007

Paganetti H. Letter to the Editor re. E. Hall‘s

article: The impact of protons on

the incidence of second malignancies in radiotherapy. Technol

Cancer Res

Treat. 6, suppl. 31-34, 2007. Technol

Cancer Res Treat. 6(6):661-662,

2007

Wroe

A, Rosenfeld A et Schulte R. Out-of-field dose equivalents delivered by

proton therapy of prostate cancer. Med

Phys. 34(9):3449,

2007

Bhandare

N, Antonelli

PJ, et al. Ototoxicity

after radiotherapy for head and

neck.

IJROBP

67(2):469-79, 2007


Rutz HP, Weber DC, et al. Extracranial chordoma: outcome

in patients treated

with function-preserving

surgery

followed

by spot-scanning

proton

beam

irradiation. IJROBP 67(2):512-520, 2007

Chan SH, Ng WT, et al. Sensorineural

hearing

loss

after treatment of

nasopharyngeal

carcinoma: a longitudinal analysis. IJROBP:1-8 in press, 2009

DeLaney TF, Liebsch

NJ, et al. Phase II study of gigh-dose

photon/proton radiotherapy

in the management

of spine

sarcomas. IJROBP :1-8 in press, 2009

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