Spine cases - SBRT Singapore

Report
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

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