Principles of Radiation Therapy

Joshua Silverman, MD, PhDDepartment of Radiation OncologyNYU Langone Medical CenterAugust 3, 2015

The therapeutic ratio

Dose selection for a future neurosurgeon

Dose selection after a good plan is very satisfying

Concept of dose• Since the invention of x-rays, radiation treatment needed to be

quantified, in a way that was comparable with it’s biological effect

• 1920-40’s The Erythema dose• Roentgen (R) The amount of radiation to create 1 esu in 1 cc• 1953: The Rad: 100 erg per gram• 1970’s: Gray (Gy) - The radiation to deposit 1 Joule in 1 kg of

tissue• Ultimate goal is to translate these “physics” definitions to

biologic effect in target and non-target tissues

The five ‘R’s of Radiobiology• Repair• Repopulation• Redistribution• Radiosensitivity• Reoxygenation

These all modify the clinical effect of the radiation

Brain metastases• How do we select dose?• Size – paradox with big tumor receiving smaller

dose?• Histology – for melanoma, we deliver a bit more• Location, location, location

Brain metastases dose selection:

Margin doses:Small tumors, no prior RT = 20-22 GyLarger: 16-18 Gy-Lower doses feasible in breast cancer.-Melanoma, renal cell, sarcoma – use 18-20Gy

-Isodose: 50% margin allows high central dose-For small tumors, 60-80% isodose line at margin works well and can be efficient.

RTOG Toxicity data: 90-05

Brain metastases• How do we select dose?• Size – paradox with big tumor receiving smaller dose?• Histology – for melanoma, we deliver a bit more• Location, location, location

• Often times, we select dose based on normal tissue tolerances

Cranial neuropathy• We assume that cranial nerves are a quintessential

serial organ in terms of toxicity• Parallel organs, such as lung and kidney, often

have toxicities expressed as dose-volume relations without threshold effects

• Serial organs, such as the spinal cord, have maximum tolerated doses with threshold

Board examination - ABR• “Dr. Silverman, what is your dose tolerance for the

optic nerve and/or the optic chiasm using SRS?”– “8 Gy”

• “Dr. Silverman, what is your dose tolerance to the brainstem using SRS?”– “12 Gy”

Optic Neuropathy: Mayo Clinic

Dose <8 Gy 8-10 Gy 10-12 Gy >12 Gy

Optic neuropathy

1/58 2/58 0/67 2/29

Pollock et al: IJROBP 55: 1177-81, 2003.4/215 pts with optic neuropathy (median dose = 10 Gy)

1 case: after 12.8 Gy with no prior XRT (risk 1/28?)3 cases: prior XRT: 58.8+7 Gy, 45+9 Gy, 50.4+9+12 GyBetter delineation of optic nerves/chiasm dose (MR vs CT)

Optic Neuropathy: Graz

Dose <10 Gy 10-15 Gy >15 Gy

Optic neuropathy

0 % 27 % 78 %

Leber et al: J Neurosurg 88: 43-50, 1998.SRS for 50 pts with benign skull base tumors & FU 24-60 MO

No cavernous sinus neuropathy with doses of 5-20 Gy

Cranial neuropathy• Not quite as much data as we sometimes think• Often learn about dose tolerance by accident

– Initial dose used was too high and late side-effects observed– From varying context (e.g. temporal lobe necrosis in patients

treated for head and neck cancer)• We say 8 Gy, but few toxicities actually observed below

10 Gy and point doses up to 12 Gy may even be tolerated• What is our threshold/tolerance for tolerance?

AVM control rates

AVM control rates

DEVELOPMENT OF A MODEL TO PREDICT PERMANENT SYMPTOMATIC POST-RADIOSURGERY INJURY FOR ARTERIOVENOUS MALFORMATION PATIENTS

.

Necrosis after AVM Radiosurgery• Gamma knife: 425 patients • Marginal doses (Dmin)

– Range: 10-35 Gy, median = 20 Gy• Maximum dose (Dmax)

– Range: 20-60 Gy, median = 36 Gy• Median isodose = 50% (23-90%), MMDR: 1.11-4.43

• Treatment volume– Range: 0.26-143 cc, median = 7.3 cc

• Isocenters: median=2 (range: 1-21)

Limitations of the PIE location score

• Previous scale for location effects (PIE score) wasn’t a true multivariate comparison of all locations at one time (because of limited data)

• PIE score was based on all symptomatic sequelae as an endpoint (including temporary and minimal symptoms)– The AVM Radiosurgery Study Group analysis of

complication outcome found that seizures and headaches were almost always temporary

Patients: AVM SRS Complications• 85 patients with symptomatic neurological sequelae

following radiosurgery– 30 out of 332 Pittsburgh patients (9%)– +55 patients from other centers with no controls– 85 total with sequelae: 38 were permanent

• 337 control patients from Pittsburgh with no symptomatic sequelae and >2 yr follow-up– 519 duplicate controls were added to maintain a 9% rate

of symptomatic sequelae in the database

Location: multivariate modelingVariable Regression coeff. SPIE score PIE score

Frontal 2.35 0.00 1

Temporal 3.48 1.89 2

Intraventricular 4.57 3.72 4

Parietal 5.24 4.83 2

Cerebellaral 5.26 4.87 2

Corpus Callosum 5.93 5.99 4

Location: multivariate modelingVariable Regression coeff. SPIE score PIE score

Occipital 5.96 6.04 3

Medulla 6.51 6.96 4

Thalamus 6.96 7.71 4

Basal Ganglia 7.14 8.01 3

Pons/Midbrain 8.33 10.00 4

12-Gy-Volume 0.0747

Then you can use the risk-location curves to predict the complication risk from the 12-Gy volume

You can use this curve before treatment to estimate 12 Gy volume from AVM diameter

0.5 1 2 5 10 20 50 1000.5

1

2

3

5

Volume (cc) receiving 12 Gy or more

Equi

vale

nt a

vera

ge d

iam

eter

(cm

)

5 10 15 20 25 30 35 400

102030405060708090

100

Volume (cc) receiving 12 Gy or more

% AVM with Symptomatic Radiation Necrosis

pons/midbrain

thalamus

medulla

cerebellar

intaventricular

frontal

5 10 15 20 25 30 35 400

102030405060708090

100

Volume (cc) receiving 12 Gy or more

% AVM with Symptomatic Radiation Necrosis

basal ganglia

corpus callosum

occipital

parietal

temporal

SPIE score: multivariate modeling

Variable P value RegressionCoefficient

Risk ratio

(95% c.i.)

SPIE score <0.00001 0.7506+0.1243 2.12 (1.67-2.70)

12-Gy-Volume 0.00001 0.0734 +0.0191 1.08 (1.04-1.12)

Constant <0.00001 -7.8713 +0.8570

Marginal-12Gy-

volume

0.4691 Not in model Not significant

Maximum dose 0.5871 Not in model Not significant

SPIE score: multivariate modeling

Variable P value Regression Coeff.

Prior hemorrhage 0.3879 Not significant

Treatment volume 0.6795 Not significant

Marginal dose (Dmin) 0.6150 Not significant

Number of isocenters 0.6614 Not significant

Max. /Min. Dose Ratio 0.8722 Not significant

PIE score 0.8780 Not significant

AVM obliteration

AVM obliteration

• Obliteration by angiography in 193/264 (73 %) • Obliteration by MR alone in 75/87 (86%) • 75% corrected obliteration rate (MR 96% accurate) • P(obliteration)=[1-P(miss)] x P(in-field obliteration)• Persistent out-of-field nidus in 29/281 (8.3%)

– Persistent out-of-field nidus in 18 % of embolized patients Vs. 6 % of non-embolized patients (p = 0.006).

Persistent out-of-field nidus

Variable P(out-of-field nidus)

Prior embolization *0.0181

Spetzler grade 0.1741

Prior hemorrhage 0.2118

Nidus volume 0.2122

Stereotactic MR and angiography 0.5481

Prior Surgery 0.8628

MutivariateAnalysis:In-field AVM

obliteration

Variable P(angiographic) P(mr or angiography)

Marginal dose *0.0093 *0.0029

Marginal dose squared *0.0190 *0.0072

Sex (male vs. female) *0.0025 *0.0273

Patient age 0.7698 0.3530

Cobalt-60 source age 0.9661 0.6558

Prior hemorrhage 0.2208 0.2170

Prior embolization 0.8350 0.8588

Treatment isodose 0.1582 0.0546

Spetzler AVM grade 0.6988 0.3067

Prior surgery 0.6394 0.1597

Treatment volume 0.4244 0.6967

MR plus angiography 0.9468 0.9488

Probit linear-quadratic

8 10 12 14 16 18 20 22 24 26 280

20

40

60

80

100

0

20

40

60

80

100

Marginal Dose (Gy)

% with In-field Angiographic or MR Obliteration

/= -49.3 +5.3

47

39 103

18

116

27

19

8 10 12 14 16 18 20 22 24 26 280

20

40

60

80

100

0

20

40

60

80

100

Marginal Dose (Gy)

% with In-field Angiographic or MR Obliteration

Male(n=165)

Female

34

41

18 50

18

53

63

7220

(n=186) p = 0.0273

maximum obliteration rate model with / = 0

6 8 10 12 14 16 18 20 22 24 26 280

20

40

60

80

100

0

20

40

60

80

100

Marginal Dose (Gy)

% with Overall Angiographic or MR Obliteration

Not embolized(n=297)

Embolized(n=54)

51

30

94122

71.5 %maximum

87.9 %maximum

Optimal dose for AVM obliteration• Maximum obliteration for dose-response curves

– logistic: 21.75 Gy LQ-Poisson: 24.75 Gy– MaxOblit model: 80,86,87,88 % at 20,23,25,30 Gy

• In-field obliteration Vs marginal dose:– 20-24 Gy: 126/135 (93.3 %)– 25 Gy: 85/100 (85 %) p = 0.049

• Overall obliteration Vs marginal dose:– 20-24 Gy: 113/135 (83.7 %)– 25 Gy: 81/100 (81 %) p = 0.589

Recommendations: AVM dose-selection• Small AVM in low to medium risk locations should be treated

to marginal doses of 23 Gy– Higher doses may increase risk without higher obliteration

• Doses of 16-18 Gy seem prudent for risky locations– Lowering the dose only lowers complication risks slightly

• Marginal doses less than 15 Gy seem relatively ineffective• If possible, avoid embolization since targeting error increases

with embolization (from 6% to 18%)– Large AVMs may be better treated with volume-staged radiosurgery

treating half or one-third of the nidus every 6 months to marginal doses of 15-16 Gy

Dose Selection: vestibular schwannoma

Sweden before 1988: 18, 20 Gy and above1987-1990: 16-18 Gy1990-1993: 14-16 Gy1993-2000: 13-14 Gy2000-present: 12-13 Gy

Common margin dose at NYU = 12 GyEuropean centers = 11 Gy

Dose-selection Acoustic tumors• Marginal doses of 12-13 Gy seem optimal from

the experience of many centers– Marginal doses of 13 Gy for all acoustics <3cm in

diameter, usually to the 50% isodose volume– 11, 11.5, 12 Gy for larger tumors or tumors where

hearing preservation is critical• The lowest dose for tumor control has not been defined

– Some intracanalicular tumors can be treated with higher isodoses and lower maximum dose

Pituitary tumor GK dose-selection• Functional pituitary adenomas (usually small) give as

high a dose as possible without exceeding a maximum of 10 Gy to the optic chiasm or optic nerves, up to a maximum marginal tumor dose of 30 Gy

• Usual marginal doses are 16-25 Gy. Higher doses should give faster responses and greater chances of normalization

• Try custom beam blocking to reduce optic chiasm dose.

• Nonfunctional pituitary adenomas (usually larger) marginal doses of 12-14 Gy seem adequate

• Lower doses can be used for growth control (Vs hormone effects)• Dose depends on keeping optic chiasm/nerves < 8 Gy

Parasagittal meningiomas

Meningiomas: no dose response for benign tumorsGrade 2/3: better response > 16 Gy

Unbiopsied meningiomas• 219 pt.s with meningioma diagnosed by imaging• Marginal dose: 14 Gy median, range: 9-20 Gy• Actuarial local control 93.2 +2.7 % at 10 yrs

– No correlation with dose, volume or other factors in multivariate analysis

• Actuarial complication rate 8.8 +3.0 % • some correlation with volume & V12 Gy (p=0.06)

• Actuarial rate of misdiagnosis: 2.3 +1.4 %

Meningioma radiosurgery dose-selection• Marginal doses of 12-15 Gy seem reasonable for

benign meningioma depending on size and location– Dose for parasellar/cavernous sinus tumors often depends

on keeping the optic chiasm/nerves to < 8-10 Gy – Try custom beam/sector blocking to reduce optic chiasm

dose. • Consider adding additional external beam radiotherapy

for atypical meningiomas to 50-55 Gy (particularly with prior surgery and uncertain dural margins) and all malignant meningiomas to 55-60 Gy