Dose Prescription, Tolerances, Side Effects and Safety and Efficacy of SBRT of the Spine

IAEA Singapore SBRT Symposium

Josh Yamada MD FRCPCDepartment of Radiation Oncology

Memorial Sloan Kettering Cancer Center

Spinal Cord Radiation InjuryType Timing

after XRTClinical

Findings Pathogenesis Outcome

Acute During XRT None -- --

Early-Delayed 2-37 Weeks Lhermitte’s Demyelination RecoveryLate Delayed Months-Years

Transverse myelopathy

Para/QuadriplegiaBrown-SequardSpastic paraparesis

Necrosis Irreversible

Motor Neuron Dysfunction

Leg Weakness Ventral roots Irreversible

Hemorrhagic myelopathy

8-30 years Acute paraparesis

Telangectasia Reversible

From: Posner J, Neurologic Complications of Cancer, p 525

Progressive Myelopathy

• Demyelination, necrosis, BBB disruption• 12-50 months post XRT• Slowly progressive symptoms

– Brown Sequard syndrome with paraethesia and weakness in one side and decrease in pain/temp in side, progressing to transverse myelitis

– Progressive weakness, hyperactive reflexes, loss of position and vibration, pain and temp intact

– Decreased motor conduction velocity– CSF usually N, or increased protein.– MRI: Cord swelling and patchy enhancement

Spinal Cord Tolerance

Institution Dose ConstraintMSKCC 14 Gy Dmax

UPMC 10 Gy Dmax

HENRY FORD V10Gy < 10%

MDACC 12 Gy Dmax TO 0.1 CC

PMH 12 Gy Dmax TO THECAL SAC OR CORD + 2mm

CLEVELAND CLINIC 14Gy Dmax AND V10Gy <10%

STANFORD 14 Gy Dmax, V12Gy < 0.3 CC, V10Gy < 0.5 CC V8Gy < 1 CC

DALLAS 14 GY Dmax, V10Gy < 0.35CC, V8Gy < 1.2CC

Background

• Dose-volume tolerances of the spinal cord in spinal stereotactic radiosurgery (SRS) have been difficult to define– Complication rates required to be very low– Published reports of myelopathy do not account

for the total number of patients treated at given dose-volume combinations

Purpose

• Report spinal cord toxicity from single fraction spinal SRS

• Provide a comprehensive atlas of complication incidence to identify dose-volume predictors of spinal cord toxicity

Materials and Methods• Prospective database of all patients treated

with single fraction SRS between 2003-2010• Retrospective review for spinal cord toxicity• No prior radiation to region allowed• Spinal Cord Toxicity

– Clinical Myelitis– MRI spinal signal changes not attributable to

tumor progression or other causes

Materials and Methods• DVH atlases were created• Complication rates with 95% confidence limits • Probabilities that complication rates were <

1% for myelitis and < 10% for signal changes were determined as a function of dose and absolute volume.

Results: Cohort Characteristicsn Percent

Patients 221  100%Total number of lesions

 251  100%

≥ 2 treatment sites 30  15%Signal information p tx

203 92%

GenderFemale 87 40%Male 134 60%

Age (years)Median 60.2Range 20-86

Baseline KPSMedian 90%  Range 50% - 90%

Spinal RegionCervical 46 18%Thoracic 196 79%Lumbar 9 3%

Follow-Up (months)Median 15  Range 3-81

Status at Last Follow-upAlive 98 44%Deceased 123 56%

nPercen

tPrimary Tumor SiteBreast 13 6%Upper GI (esoph, pancreas, gallbladder) 4 2%Lower GI (anal, rectal, colon) 14 7%Hepatocellular 9 4%Sarcoma 30 14%Melanoma 13 6%Lung 22 10%Prostate 24 11%Renal Cell 40 18%Other GU (penile, testicular, bladder) 5 2%Thyroid 15 7%H&N SCC 7 2%CNS 10 4%Other 15 7%

Histological CategoryAdenocarcinoma 33%Carcinoma 37%Melanoma 7%Sarcoma 14%Other 9%

Prescribed Dose1800 cGy 6 2%2100 cGy 21 8%2200 cGy 4 2%2300 cGy 1 < 1%2400 cGy 219 87%Median (cGy) 2400Mean (cGy) 2356  

Spinal Cord Toxicity with Single Fraction Paraspinal SRS

• One case of clinical myelitis (0.4%)• 5 cases of signal changes without clinical signs

or symptoms of myelopathy (2.4%)

Spinal Cord Toxicity with Single Fraction Paraspinal SRS

• All myelitis or signal changes:– Maximum cord dose > 13.33 Gy– Minimum doses to the hottest:

• 0.1 cc > 10.66 Gy• 0.2 cc > 10 Gy• 0.5 cc > 9 Gy• 1 cc > 8 Gy

Myelitis Signal Changes

Vol v(cc)

Dose

d(Gy)

#

comp

#

tot

99% conf

lim on r

prob

r < 1%

#

comp

#

tot

99% conf

lim on r

prob

r < 10% 0 13.33 0 64 0.068 0.49 0 55 0.079 1.00

0.1 10.66 0 60 0.073 0.47 0 51 0.085 1.000.2 10 0 56 0.078 0.45 0 46 0.093 0.990.5 9 0 45 0.095 0.38 0 36 0.117 0.98

1 8 0 26 0.157 0.25 0 30 0.138 0.96

Statistics for treatments with DVHs passing below the locations (v,d), chosen just below the Myelitis DVH.

95% confidence limit on signal changes ratefor DVHs passing above plot point

Dose (Gy)0 2 4 6 8 10 12 14

Volu

me

(cc)

0

2

4

6

8

10

12

14

160.05 0.10

0.15 0.20

0.25 0.30

0.35 0.40

0.45 0.50

0.55 0.60

0.65 0.70

0.75 0.80

0.85 0.90

0.95

signal changesmyelitis case

95% confidence limit on signal changes rate for DVHs passing above plot point

myelitisprobability that true complication rate > 2%

dose (Gy)0 2 4 6 8 10 12 14

cord

vol

ume

(cc)

0

2

4

6

8

10

12

14

160.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0.90 0.95 1.00

myelitis case

Myelitis:Probability that True Complication

Rate > 2%

signal changesprobability that true complication rate > 5%

dose (Gy)0 2 4 6 8 10 12 14

cord

vol

ume

(cc)

0

2

4

6

8

10

12

14

160.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0.90 0.95

signal changesmyelitis case

Cord Signal Changes:Probability that True Complication

Rate > 5%

Conclusions• High dose paraspinal SRS has a low rate of

clinical apparent myelopathy (<1%)• Asymptomatic spinal cord signal changes are

more common (2%)• The following dose limits minimize the

potential for spinal cord toxicity after SRS– Maximum cord dose < 13.3 Gy– Minimum doses to the hottest 0.1, 0.2, 0.5, and 1

cc < 10.66, 10, 9, and 8 Gy respectively

Future Directions

• Pooled multi-institutional effort to overcome limitations– Single institution cohort with homogeneously

treated population– Limited events

Cord Myelopathy DosimetryCase 1 Case 2 Case 3 Case 4 MSKCC

Total Dose (Gy) 25 24 16 16 NA

Prescription Line 80% 70% 90% 90% NA

Fraction Number 2 3 1 1 NA

PTV Volume (cc) 14.6 7.6 66 10.8 NA

V100% 96 98 95 99 NA

D100 (Gy) 22 21 11 15 NA

D90 (Gy) 26 25 16 15 NA

Level T Spine C Spine Clivus Clivus NA

Time to Sx (Mon) 9 9 13 ? NA

Cord Dmax BED Gy2 190 190 122 136 112

Cord Dmax BED Gy2(1) 18.5 18.5 14.6 15.6 14.0

Yucatan Mini Pig ReirradiationMedin et al. IJROBP 2010

• 23 mature mini pigs received 3000cGy/10• Single Fraction Spine SRS one year later

Dose N Deficit

FU

14 Gy 2 0 40 weeks16 Gy 3 0 52 weeks18 Gy 5 2 48-52 weeks20 Gy 5 4 52 weeks22 Gy 5 5 20 weeks24 Gy 3 3 14-19 weeks

Pig Cord Reirradiation Histopathology

• No changes at 14-16 Gy• 18-20 Gy changes limited to small foci of

demyelination• 22-24 Gy extensive tissue damage including

grey matter infarction• Pigs reirradiated with SRS one year after

3000cGy/10 no different that pigs receiving de novo SRS.

Pig Cord ED50

• 96% calculated recovery after 3000cGy/10 after one year.

Vertebral Body Fracture RiskVertebral body involvement is a significant risk for fracture (p=0.02)

• Not found to be significant risk factors:

• Obesity, posterior element involvement, local kyphosis, pre-exisiting endplate infraction or fracture,

• XRT dose

• N = 114 patients

• FU = 10.9 months (median)

• Grade 2 N= 5, Grade 3 N= 1, grade 4 N= 1

Esophagus Constraints Level 1 < 15 Gy/2cc

Level 2 < 20 Gy/2cc

Progressive risk of vertebral body fractures post high dose IGRT

10-O6 3-O7 3-O7

63 year old female with NSCLC acute onset of back pain post 2400cGy to T5

Methods

• 71 treated sites in 62 consecutive patients with solid tumor spine metastases

• 1800-2400 cGy single fraction IGRT• Serial MRI every 3-4 months• All images reviewed by same 3 spine surgeons and

neuroradiologist• Primary outcome: New fracture or progression of exisiting

fracture• Secondary outcomes:

– ASIA score– VAS pain score, narcotic use

Results

• Fracture/progression noted in 27 sites (39%) • 65% lytic, 17% mixed, 18% sclerotic• Lytic lesions were 6.8 times more likely to fracture vs.

mixed/sclerotic lesions (p<0.001)

Lytic vs. Non Lytic

Function and Symptoms

• Fracture/progression not correlated with – BMI– XRT dose

• ASIA score not impacted• Median VAS score in fracture patients 5 vs 2 in non

fracture patients (p=0.051)• Fracture patients more likely to use narcotics (70% vs.

41% p = 0.005)

Conclusions

• A high risk of radiographic vertebral body fracture was found after high dose single fraction radiation – Dose not a significant predictor– Lytic lesions and greater tumor involvement were found to be

risk factors– ASIA score not affected– Patients with fracture were found to report more pain and

require more narcotics• High dose radiation may contribute to the development of

vertebral body fracture• Currently investigating the role of prophylactic

kyphoplasty in highest risk patients

Materials & Methods

• 204 consecutive spinal metastases abutting the esophagus in 182 patients were treated with single fraction paraspinal SRS at MSKCC between 2003-2010

• Esophageal toxicity scored with NCI CTCAE 4.0

• Atlases of complication incidences were generated

• Clinical factors were correlated with toxicity

Cohort Characteristicsn Percen

tPatients 182  100%Lesions  204  100%Patients ≥ 2 treatment sites

28  15%

GenderFemale 73 40%Male 109 60%

Age (years)Median 61Age 21-88

Baseline KPSMedian 90%  Range 50% -

90%

Spinal RegionCervical 26 13%Thoracic 178 87%

Follow-Up (months)Median 12  Range 3-81

Status at Last Follow-upAlive 102 56%Deceased 80 44%

nPercen

tPrimary Tumor SiteBreast 11 6%Upper GI (esoph, pancreas, gallbladder) 4 2%Lower GI (anal, rectal, colon) 13 7%Hepatocellular 8 4%Sarcoma 25 14%Melanoma 12 6%Lung 18 10%Prostate 20 11%Renal Cell 33 18%Other GU (penile, testicular, bladder) 3 2%Thyroid 13 7%H&N SCC 3 2%CNS 7 4%Other 12 7%

Prescribed Dose1600 cGy 1 < 1%1800 cGy 24 12%2100 cGy 10 5%2200 cGy 3 1%2300 cGy 1 < 1%2400 cGy 165 81%Median cGy 240

0

Esophageal Toxicity with Single Fraction Paraspinal SRS

n Percent

Acute Toxicities

Overall 31 15 %

Grade 1-2 28 14%Grade 3 1 < 1%Grade 4 2 1%Grade 5 0 0%

Esophagitis/Pain 28 90%Esophageal ulcer 2 7%Esophageal edema 1 3%

n Percent

Late Toxicities

Overall 24 12%

Grade 1-2 13 6%Grade 3 6 3%Grade 4 4 2%Grade 5 1 < 1%

Esophagitis/Pain 12 50%Esophageal stenosis

4 17%

Esophageal fistula

4 17%

Esophageal ulcer 4 17%

Patients with Grade ≥ 3 Toxicityn Time Grad

eSite Dose

(cGy)Toxicity Class

Time to Maximum Toxicity (days)

1 Acute

3 T2-3 2100 Esophagitis 54

2 Acute

4 T4 2400 Esophagitis 65

3 Acute

4 C7 2400 Ulcer 84

Median 2400 65

4 Late 3 C5 2200 Stenosis 2455 Late 3 T2-T4 2400 Stenosis 1786 Late 3 T2-T3 2400 Ulcer 3507 Late 3 C7-T1 2400 Stenosis 3958 Late 3 C6-T1 2400 Stenosis 3469 Late 3 T6 2400 Ulcer 132

10 Late 4 T3 2400 Fistula 44411 Late 4 T3 2400 Fistula 14912 Late 4 T7 2400 Fistula 38013 Late 4 C4-T2 2400 Ulcer 12814 Late 5 T2 2100 Fistula 584

Median 2400 346

Dosimetric and Volumetric Predictors of Grade ≥ 3

Esophageal ToxicityDosimetric Variable

Median Split

Toxicity Incidence

Below Median

Split

Toxicity Incidence

Above Median

Split

RR Grade ≥ 3 Toxicity

p value

n % n %

D2.5 cc 14.02 Gy 2/102 2% 12/102 12% 12/2 = 6 0.01

V10 Gy 4.77 cc 4/102

4% 10/102 10% 10/4 = 2.5 0.16

V12 Gy 3.78 cc 3/102 3% 11/102 11% 11/3 = 3.7 0.05V15 Gy 1.87 cc 1/102 1% 13/102 13% 13/1 = 13 0.0013V20 Gy 0.11 cc 2/102 2% 12/102 12% 12/2 = 6 0.01V22 Gy 0.0 cc 1/102 1% 13/102 13% 13/1 = 13 0.0013

Atlas of Complication Incidence for Grade ≥ 3 Acute or Late

Esophageal ToxicityProbability the true complication rate > 10%

Dose (Gy)0 5 10 15 20 25 30

Esop

hagu

s Vo

lum

e (c

c)

0

2

4

6

8

10

12

140.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Dose Response Model for Grade ≥ 3 Esophageal Toxicity

Dose Response for >= Grade 3 EsophagitisSingle Fraction Treatments

Dose to hottest 2.5 cc (Gy)

0 5 10 15 20 25 30

Prob

. of >

= gr

ade

3 es

oph.

com

p.

0.0

0.1

0.2

0.3

logistic fit observed rate (quartiles)

p < 0.0006

Clinical Risk Factors for Developing Grade ≥4 Esophageal

Toxicityn Site Dose

(cGy)Time Grad

eToxicity Class

Probable Radiation

Recall Reaction (Agent)

Iatrogenic Manipulatio

n Before Maximum Toxicity

Time to Maximum Toxicity (days)

1 T4 2400 Acute 4 Esophagitis Adriamycin -- 652 C7 2400 Acute 4 Ulcer Liposomal

AdriamycinBiopsy 84

3 T3 2400 Late 4 Fistula -- Dilation 4444 T3 2400 Late 4 Fistula -- Biopsy 1495 T7 2400 Late 4 Fistula Gemcitabin

eStent 380

6 C4-T2 2400 Late 4 Stenosis Adriamycin Dilation 128

7 T2 2100 Late 5 Fistula -- Stent 584

Grade IV Esophageal Fistula• 45 year old male• Oligometastatic RCC• Symptomatic T3 lesion• 2400 cGy• Cord Dmax < 14 Gy• Esophagus 15 Gy / 2 cc

Grade IV Esophageal Fistula• 4 months: Grade 2 esophageal pain

• 4.5 months: EGD• 3 cm non bleeding ulcer @ 22 cm• Cold forceps biopsy

• 6 months: Worsening pain • Increased ulceration with

superinfection• ¾ circumference with moderate

stenosis• Dilation and cold forceps biopsy

• 6.5 months: Acute development of TEF• Multiple repairs and stent procedures

• 11 months: Expired from distant progression

Conclusions• High dose, single fraction paraspinal SRS has a low

rate of grade ≥ 3 esophageal toxicity• Careful attention to esophageal doses minimizes

toxicity

• MSKCC: 2.5 cc of esophagus ≤ 14 Gy• Radiation recall reactions and iatrogenic manipulation

of the irradiated esophagus predispose for development of grade ≥ 4 toxicity

Toxicity Summary

• Spinal cord injury at current dose levels is extremely rare– Poor statistics because of limited events

• Vertebral body injury is common after spine SBRT– Radiographic 40%– Symptomatic 15-20%

• Esophageal injury is most common and very worrisome complication