Reirradiation and Primary
Treatment Spine Cases
IAEA Singapore SBRT Symposium
Yoshiya (Josh) Yamada MD FRCPC
Department of Radiation Onology
Memorial Sloan Kettering Cancer Center
Mechanisms of CNS Damage
• Direct injury to normal cells
– Endothelial apoptosis
– Oligodendroglial cells most vulnerable
• 10-20Gy x 1 causes apoptosis within hours
– Schwann cells most resistant
– Poor DS repair of mature neurons and precursors
– Inflammation from activated glial cells and monocyte infiltration
• Vascular injury
– Endothelial apoptosis within hours and BBB disruption
– P53 dependent phenomenon
– Increased VEGF
• Immune hypersensitivity response
– Antigens released by injured glial cells induce hypersensitivity
response.
Spinal Cord Radiation Injury
Type
Timing
after XRT
Clinical
Findings
Pathogenesis
Outcome
Acute
During XRT
None
--
--
Early-Delayed
2-37 Weeks
Lhermitte’s
Demyelination
Recovery
Late Delayed
Months-Years
Para/Quadriple
gia
Brown-Sequard
Spastic
paraparesis
Necrosis
Irreversible
Leg Weakness
Ventral roots
Irreversible
Acute
paraparesis
Telangectasia
Reversible
Transverse
myelopathy
Motor Neuron
Dysfunction
Hemorrhagic 8-30 years
myelopathy
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 Recovery: Rodent Cord
Nieder et al. Semin Rad Oncol 2000
Priming
Dose (Gy)
%ED50
2.15Gy x10
25%
26%
2.15Gy x20
50%
41%
2.15Gy x 30
75%
43%
2.2Gy x20*
58%
2.15Gy x36
90%
35%
4.5Gy x 9
67%
70%
4.5Gy x 12
87%
N/A
9Gy x 2
47%
20%
35%
9Gy x3
71%
16%
33%
10.25Gy x 3
89%
11%
23%
10Gy x1
48%
12Gy x1
50%
83%
15Gy x1
53%
45%
3 Months
5-6 Months
9-12
Months
24 Months
75%
90% (9 mon)
40%
100%
Reirradiation and Myelopathy: BED Modeling
Neider et al IJROBP 2005
• Literature search for myelopathy after reirradiation
• N = 40 with complete dosimetric data available
– 11 cases of myelopathy
• Doses converted to BED equivalents
– (α/β 2 or 4 - 50Gy/25 = 75Gy4 or 100 Gy2)
• No Myelopathy was seen if:
– Total BED < 135.5 Gy2
– Initial XRT <102 Gy2
– >2 months between courses of XRT
• Low risk of myelopathy if:
– Total dose < 135.5Gy2, each course < 98 Gy2
– 6 months between treatments
• Underscores the need for cord sparing techniques
Reirradiation x 3
Patient
Course 1
Site
Dose
(Gy)/Fractions
Site
Course 2
Dose
Time
(Gy)/
Interval
Fractions (months)
Site
Course 3
Dose (Gy)
Time
/
Interval
Fractions (months)
1
2
3
4
5
T9-T11
L5-S3
R Lung
R 4th rib
SCV/
PAB
30/5
37.5/15
30/10
20/5
50.4/28
T8-T10
L5-S1
T1-T3
T3-T4
C3-C5
25/5
30/5
24/4
30/5
25/5
23
121
12
4
14
T9-T11
L4-L5
T1-T3
T3-T4
C6-T1
25/5
30/5
25/5
20/5
27/3
4
20
2
14
21
6*
Left neck
60/50
C3-C6
30/5
9
C7
25/5
31
7
8
9
10
T11-L1
L3
Lt neck
H&N
30/10
24/1
55.8/31
70/35
T11-T12
L4
C7
C2/BOS
30/5
24/3
30/5
30/3
144
3
8
23
T9-T11
T12-L3
C6-7
C2
30/5
20/5
30/5
30/5
52
9
8
5
Reirradiation x 3: MSKCC
1st Course
Dmax(Gy)
2nd Course
Dmax(Gy)
3rd Course
Dmax (Gy)
Max Total
nBED Gy2/2
D05 Total
nBED Gy2/2
PTV D80
(Gy)
1
25
16
7.2
70.7
61.2
19
2
37.5
16
15.9
83.5
75.1
31
3
32.5
23.2
4.2
90.8
NA
24
4
20
14
10.1
56.9
50
19
5
6
25
11.9
67.8
NA
23.5
6
7.7
13.7
9.8
66.7
57.4
26
7
30
14
9.6
63.7
57.6
30
8
15.9
14.1
7.9
101.7
77.4
19.5
9
50
13.8
10
71.6
64.3
22
10
41.7
3.5
13.5
51.9
NA
31
Patient
Reirradiation x 3: Results
Patient
Primary
Age Sex
1
Leiomyosarcoma
Thyroid
Renal
71
F
T9
23
Alive
65
54
M
M
L5
T2
2
11
Dead
Dead
Renal
Breast
Adenoid
Cystic
Renal
Leiomyosarcoma
Ewings
82
57
56
M
F
M
T4
C6
C6-7
12
6
3
Dead
Dead
Alive
69
45
M
F
T11
L3
3
23
Alive
Alive
Yes
Yes
16
M
C6-7
8
Alive
Yes
2
3
4
5
6
7
8
9
Spine
Level
Follow- Alive/
up
Dead
(months)
Local
Control
Toxicity
Progressed Motor neuropathy
(Grade 1)
Yes
None
Marginal
None
failure
Yes
None
Yes
None
Yes
None
None
Foot drop
(Grade 2)
None
Quantec: Spinal Cord Reirradiation
Kirkpatrick et al IJROBP 2010
• Most data on reirradiation with a minimum
interval of at least 6 months
• Volume effects:
– At 2 Gy equivalents, full circumference cord dose, at least
25% recovery at 6 months
– With SBRT (partial cord) 13Gy/1 or 20Gy/3 < 1% risk of
myelopathy
• Impact of systemic therapy unknown
Yucatan Mini Pig Reirradiation
Medin 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 weeks
16 Gy
3
0
52 weeks
18 Gy
5
2
48-52 weeks
20 Gy
5
4
52 weeks
22 Gy
5
5
20 weeks
24 Gy
3
3
14-19 weeks
Pig Cord ED50
• 96% calculated recovery after 3000cGy/10
after one year.
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.
MSKCC Normal Tissue Constraints for
Reirradiation
Structure
Fractionation
Dmax Limit
Spinal Cord
3.5 Gy x 5
17.5 Gy
4.5 Gy x 3
13.5 Gy
4.4 Gy x 5
22 Gy
5.9 Gy x 3
17.7 Gy
3.5 Gy x 5
17.5 Gy
4.7 Gy x 3
14 Gy
Brachial Plexus
Cauda
Salvage Spine Radiation
• Local control of spine metastases after
conventional radiation is 20-60%
• Durability of symptom control for conventionally
fractionated spine XRT is low (median 2.5 – 3
months-Patchell and Maranzano)
• Systemic therapy is often less effective in treating
spine metastases
• Recurrence is often highly symptomatic
• Surgical salvage can be morbid and recurrence
rates are high without adjuvant therapy
Rationale for Hypofractionation
• By definition, recurrent tumors are resistant to
conventional XRT
• Hypofractionation represents a different
radiobiologic approach to treatment
• IGRT is the best vehicle to deliver high dose
radiation near the spinal cord/esophagus
Salvage XRT for Cord Compression
Rades Red Journal 2005
• N = 62
 ESCC after XRT
failure
 6 months median
time to repeat XRT
 Cumulative BED 80102 Gy2
 40% improved, 45%
stable, 15% worse
 No myelopathy
N
Initial Tx
Salvage Tx
34
8Gyx1 or
4Gyx5
8Gyx1
15
8Gyx1 or
4Gyx5
5Gyx3
13
8Gyx1
4Gyx5
SRS vs Conventional XRT
• Differences in volumes
• Steep dose fall off
• Single fraction or hypofractionation vs.
conventional fraction sizes
Radiation Myelopathy After Spine SRS
• N=6/1075
• Mean of 6.3 months (2-9 months)
• 2 patients had prior RT (39.6Gy/22, 50.4Gy/28
70 and 80 months prior)
• 20-21 Gy/2 fractions, 20Gy/2-14Gy/2 cord
Dmax
– Both had prior chemotx
– Progression to paraplegia, walker dependent.
Gibbs et al, Neursurgery, 2009
Salvage SRS After Spine XRT Failure
Gerzsten et al. Spine 2007
•
•
•
•
•
•
N = 393
Prior XRT = 3Gy x10 or 2.5Gy x14
20Gy x1 (12.5-25Gy) mean dose to 80%
Median FU = 21 months (3-53)
88% local control, 86% dural pain palliation
No cases of myelitis
Hypofractionated Salvage Spine IGRT:
400cGyx5 vs 600cGyx5 Local Control
Damast et al. IJROBP 2010
• N = 97
• Median FU= 14.7 months
40%
p=0.04
23%
• 38 LF
• Overall LF = 30%
MD Anderson: Salvage IGRT
Garg et al, Cancer 2011
•
•
•
•
•
•
•
N =63 lesions
16 LF
Median FU 13 months
Prior XRT < 45 Gy
Prior XRT > 3months
600cGyx5 or 900cGyx3
Mean cord dose: 10 Gy
Local Control
Reirradiation Spinal Cord Summary
• Animal data suggests that reirradiation of the
spinal cord is feasible
– Significant repair of radiation does occur
• Dose dependent
• Volume dependent
• Time dependent
• Clinical data is of poor quality
• Repeat radiotherapy is effective palliation
• Risk of myelitis is low
• SRS is safe after conventional radiation failure
Spine Reirradiation Summary
• There is mounting evidence that:
• Spinal cord is likely capable of radiation repair
over time
– Cord recovery occurs after prior XRT
– 6-12 months
– Pig data: Steep complication curve slope!
• Spine reirradiation is safe and an effective salvage
treatment.
– Both single fraction or hypofractionated
– 75% durable successful salvage rates
Recommendations
• Careful and meticulous treatment planning
and delivery is crucial
– Accurate cord deliniation (ie myelogram)
• Minimum of 6 months between initial and
salvage XRT for spinal cord recovery
• Maximum cord doses should be less than 17.5
Gy/3 fractions
• Detailed and well documented discussion with
patients about potential complications
Compression/Burst Fracture
Axial Load Pain
•64 year old male with stage IV thyroid
cancer
•Prior I 131 treatment
•T6 burst fracture
•Systemic disease otherwise well
controlled
•Increased pain with sitting to standing
•No myelopathy
Compression/Burst Fracture
Axial Load Pain
Compression/Burst Fracture
Axial Load Pain
• Axial Load Pain: No gross instability
Percutaneous cement augmentation
Vertebroplasty
Kyphoplasty
18 Reduction of T6-L1 Kyphosis
T6
T6
Post
18 
Pre
36
L1
Melanoma L5 with mechanical
radiculopathy
•54 year old male with long standing melanoma
•4 month history of progressive lower back pain, 3
week history of pain radiating down the right leg,
laterally below the knee to ankle in L5 distribution
•Motor intact
•Pain worse with weight bearing, 8/10
•Visceral metastases to liver and lung, “stable”
•KPS 80, able to tolerate any treatment
•No prior RT
Treatment options?
•
•
•
•
•
•
34 year old right handed female with MPNST
Delivered her first child 8 weeks ago
Neck pain for 12 weeks
Metastatic work up negative
Pain radiates down right neck and shoulder
Progressive weakness right triceps (4/5)
Subaxial Cervical
Treatment Options?
Renal Cell Carcinoma
52 y.o. RCC
Sutent chemotherapy
Prior RT: 30 Gy/10 C8-T1
Visceral Metastases
No other bone lesions
Exam: Right C8 radiculopathy
No myelopathy
Medical Problems:
CASHD
HTN
Diabetes
N: Functional Radiculopathy
O: RT-resistant tumor
M: No instability
S: Tolerate any treatment
Prostate Carcinoma
60 y.o.
Known Hx: Prostate
Hormone refractory, no chemo
Bone metastases
Exam: T6 pin level
Intact Proprioception
Lower Extremities 3/5
Medical Problems:
CASHD: Pacemaker
HTN
Subaxial Cervical
 56 year old with stage IV breast ca
 3 month history of neck pain, able to flex
rotate and extend the neck
 Pain radiates to the right shoulder
 Hand function intact
 No myelopathy
Treatment Options?
Midthoracic
Unknown primary
Myelopathy: Sensory level T9
Babinski reflex
MRI T9-T11 high-grade epidural spinal cord
Compression
No bone involvement
No mechanical instability