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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:
Are there potentially “proton-specific”
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:
Are there potentially “proton-specific”
toxicities?
CAVEATS (of undetermined clinical significance):
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:
Are there potentially “proton-specific”
toxicities?
CAVEATS (of undetermined clinical significance):
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
a) High Grade, Severe (Grade 3, 4, 5)
Late Late ToxicitiesToxicities
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
a) High Grade, Severe (Grade 3, 4, 5)
Late Late ToxicitiesToxicities
Severe
Optic
Neuropathy:
sudden
loss
of color
vision, amaurosis
fugax, blindness
Tx: steroids, anticoagulants, Vitamin E, Hyberbaric
Therapy
CPT
a) High Grade, Severe (Grade 3, 4, 5)
Late Late ToxicitiesToxicities
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
a) High Grade, Severe (Grade 3, 4, 5)
Late Late ToxicitiesToxicities
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**
* B. Pehlivan, C. Ares, T. Lomax, E. Hug (in preparation)
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
cont. PT Temporal Lobe Temporal Lobe ToxicityToxicity**
* B. Pehlivan, C. Ares, T. Lomax, E. Hug (in preparation)
CPT
Grade Toxicity D3 mean ± SD (Gy(RBE))
D2 mean ± SD (Gy(RBE))
D1 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
Grade Toxicity D3 mean ± SD (Gy(RBE))
D2 mean ± SD (Gy(RBE))
D1 mean ± SD (Gy(RBE))
D0.5 mean ± SD (Gy(RBE))
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
Grade Toxicity D3 mean ± SD (Gy(RBE))
D2 mean ± SD (Gy(RBE))
D1 mean ± SD(Gy(RBE))
D0.5 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
cont. PT Temporal Lobe Temporal Lobe ToxicityToxicity**
* 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≥
2.7 cc…….0.08…….0.001Volume of brainstem receiving ≥
55 CGE1.3≥
5.9 cc…….0.1…….0.001Volume of brainstem receiving ≥
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
CPTConstraintsConstraints
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
CPTConstraintsConstraints
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
1,2) and c) Quality of Life
Late Late ToxicitiesToxicities
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
Oeffinger et al. (MSKCC). NEJM 355(15):1572-82, 2006
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
Oeffinger et al. (MSKCC). NEJM 355(15):1572-82, 2006
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
1,2) and c) Quality of Life
Late Late ToxicitiesToxicities
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
Late Late ToxicitiesToxicities
d) Risk
of Second Malignancy
CPTThe The RiskRisk
of Second of Second MalignancyMalignancy
Inside
„the field“
High-dose
regionTreated Volume
Irradiated VolumeIntegral Dose
Outside
the „field“„far away“
Scattering
Neutrons
Major Dose Contribution-Definitions
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
of Second of Second MalignancyMalignancy
Inside
„the field“
High-dose
regionTreated Volume
Irradiated VolumeIntegral Dose
Outside
the „field“„far away“
Scattering
Neutrons
Major Dose Contribution-Definitions
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……
CPT The The RiskRisk
of Second of Second MalignancyMalignancy
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.
CPT The The RiskRisk
of Second of Second MalignancyMalignancy
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?
CPT The The RiskRisk
of Second of Second MalignancyMalignancy
Inside
„the field“
High-dose
regionTreated Volume
Irradiated VolumeIntegral Dose
Outside
the „field“„far away“
Scattering
Neutrons
Major Dose Contribution-Definitions
Percentage
Risk
Contribution
? Possible
„Rule
of Thumb“:
80% : 20% ?
Please, do not quote
me………..assumes
also RBE (Neutrons) of 10
CPT ReferencesReferences
Emami
B, Lyman
J, et al. Tolerance
of normal tissue
to therapeutic
irradiation.
IJROBP 21:109-122, 1991
Debus J, Hug EB, et al. Brainstem tolerance to conformal radiotherapy of skull
base tumors. IJROBP 39(5):967, 1997
Kim J, Munzenrider J, et al. Optic
neuropathy
following
combined
protonand photon
radiotherapy
for base
of skull tumors. IJROBP 39(suppl2):272,1997
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
Res
154(4):382-388, 2000
CPT ReferencesReferences
Noel G, Habrand J-L, et al. Combination
of photon
and proton
radiation
therapy for chordomas and chondrosarcomas nof
the skull base: the Centre de
Protonthérapie
d‘Orsay
experience. IJROBP 5(2):392-398, 2001
Hug EB, Sweeney RA, et al. Proton radiotherapy
in management
of pediatric base
of skull tumors. IJROBP 52(4):1017-1024, 2002
Miralbell
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
Noel G, Feuvret
L, et al. Chordomas of the base
of skull and upper
cervical
spine.
One hundred
patients irradiated
by a 3D conformal
technique
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
therapy for chordoma
and chondrosarcoma
of the skull base: the Paul Scherrer Institut
experience. IJROBP 63(2):401-409, 2005
Weber DC, Chan AW, et al. Visual outcome
of accelerated
fractionated radiation
for advanced
sinonasal
malignancies
employing
photons/protons.
Radiother
Oncol
81:243-249,
2006
Kozak
KR, Smith BL, et al.
Accelerated partial-breast irradiation using proton
beams: Initial clinical experience. IJROBP 66(3):691-698, 2006
ReferencesReferences
CPT
Taghian
AG, Kozak
KR, et al. Accelerated partial breast irradiation using
proton beams: Initial dosimetric
experience. IJROBP 65(5):1404-1410, 2006
Oeffinger et al. (MSKCC). NEJM 355(15):1572-1582, 2006
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
CPT 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
CPT ReferencesReferences
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