Stereotactic Body Radiation Therapy (SBRT) I:
Radiobiology and Clinical Experience
Brian Kavanagh, M.D., MPH
University of Colorado
Eric Chang, M.D.
UT MD Anderson
Conflict of interest disclosure
I have no conflict of interest to disclose.
Stereotactic Body Radiation Therapy (SBRT) II:
Physics and Dosimetry Considerations
Stanley H. Benedict, Ph.D.
University of Virginia
Kamil Yenice, Ph.D.
University of Chicago
AAPM 2008 50th Annual Meeting, Houston, Texas
Therapy Continuing Education Course: SBRT: I & II
Monday, July 28, 2008: 7:30 – 9:25AM
Outline
Evolution from conventional RT to SRS to SBRT
Epidemiology, Rationale, Indications using SBRT for spinal metastases
Radiobiology of SBRT
MD Anderson clinical pathway for spinal metastases
Summary of Results from Literature
Case presentations
Summary and conclusion
IG-IMSRT Evolution
•Historically fractionated RT required large safety margins
~2cm around tumor for treatment uncertainties
•Associated with unacceptable toxicity at single dose levels
needed for tumor response
•CT-treatment planning, and hi-precision targeting with
stereotaxy has permitted safe delivery of single-dose
RT to intracranial lesions (SRS) with very small to
no margins
1
IG-IMSRT Evolution
Evolution of intracranial SRS to SBRT…
•SRS for brain metastasis yields:
1-, 2-yr FFP 50% for 15--18Gy
and
>80% for 22-24Gy
(Vogelbaum, J Neurosurg 104:907-12, 2006)
•Current SBRT technology includes IG robotic techniques, MLC,
inverse planning software to generate IMRT plans
conforming to tumor with steep dose gradients needed
near OARs such as spinal cord
Intracranial SRS
Extracranial SBRT delivery systems
2
93 pts
18-24 Gy x 1
Spinal cord <12-14 Gy
Cauda max 15.6 Gy
LC 90%
F/U 15mos
OS 15mos
IJROBP 71:484-90, 2008
Background on Spinal Metastases
Epidemiology of Spinal Metastases
A common sequelae of cancer, present in 30 – 70% patients at
post mortem examination, of which 14% will be symptomatic
(pain, neurologic sx’s) at sometime during their illness1
40% of skeletal metastases occur in the spine which is the
most common osseous site of tumor spread
SBRT
Conventional radiation therapy widely used but is inherently
limited by spinal cord tolerance
SBRT?
1Perrin
RG. Metastatic tumors of the axial spine. Curr Opin Oncol 1992:4:545-532
Klimo, P. et al. Oncologist2004;9:188-196
3
RATIONALE
• Many pts develop recurrent or progressive pain, tumor
progression or neurologic deterioration despite
conventional external beam irradiation,
radiopharmaceuticals, surgery, or systemic therapy
• Patients are very interested in noninvasive treatment
options for spinal metastases which are not amenable to or
are refractory to conventional irradiation
GENERAL INDICATIONS
LIMITED DISEASE - Newly diagnosed solitary
or oligo- spinal metastases
PRIMARY - “Radioresistant” subtypes
POST-OP – adjuvant or elective treatment
SALVAGE - surgical or RT recurrences
Spinal instability is a contraindication
Radiosensitive lymphomas, germ cell tumors etc.
“Therapeutic Window” for conventional RT
4
Previously irradiated spinal cord, melanomas
Renal cell cancer, sarcomas etc.
SBRT dosimetrically widens the therapeutic window by
lowering dose to the OAR
OAR
Little or no therapeutic window exists for
conventional irradiation
Limitations in the linear-quadratic model for high doses
DT is transition dose at which final portion of curve become linear
Astrahan M, IJROBP 71:3:963,2008
Astrahan M, IJROBP 71:3:963,2008
5
Single Fraction Equivalent Dose
(SFED) vs BED
For high dose ablative RT
Defined -as dose in a single fx that would have
same biological effect as any large daily dose
fractionation regimen
Park C, Timmerman RD, IJROBP 71:3:963-4,2008.
Park C, Timmerman RD, IJROBP 71:3:963-4,2008.
Spinal Cord Radiation Exposure
10%
20%
50%
80%
20%
B
90%
50%
C
A
80%
90%
(a)
(b)
Henry Ford group proposes 10 Gy to 10% spinal cord as tolerance
Park C, Timmerman RD, IJROBP 71:3:963-4,2008
Ryu S et al. Cancer 109: 628-36, 2007
6
White Matter Necrosis of Rat spinal cord
•Major cause of paralysis
•Occurs within 120 - 210 days after irradiation 20 Gy x 1
•Pathogenesis focused on either primary glial or vascular
origin
Characterized by demyelination, loss of axons, focal
necrosis, liquefactive necrosis after > 20 Gy x 1
Vascular edema is usually associated with development
of white matter necrosis
Isoeffect Dose (ED50) according to irradiated length of rat cord
20mm
8mm
4mm
2mm
Single
Bijl HP et al. Van Der Kogel AJ, IJROBP 52:205-11,2002
Bijl HP et al. Van Der Kogel AJ, IJROBP 52:205-11,2002
High precision proton irradiation of rat spinal cord
Grazing
Lateral
Beams
(constant
depth dose
profile)
Central
Beam
Bijl HP et al. Van Der Kogel AJ, IJROBP 52:205-11,2002
Bijl HP et al, IJROBP 61:543-551, 2005
7
Regional Differences in Radiosensitivity in Rat Spinal Cord
White matter
necrosis in left lat
column after
grazing irradiation
Dose-response Curves for Paralysis
Full width
And
Lateral
beam
Central
Beam
Extensive white
Matter necrosis in
Dorsal column
Bijl HP et al, IJROBP 61:543-551, 2005
No lesions in gray
Matter or lateral
columns
Bath/Shower Dose-response of Paralysis of Limbs to
Unmodulated Protons in Rat Cervical Spinal Cord
Bijl HP et al, IJROBP 61:543-551, 2005
Clinical Pathway for Stereotactic Body Radiotherapy program
Referral from
neurosurgery
medical oncology
radiation oncology
self referral
Joint consultation
pain, QOL assessment,
Neurological exam,
informed consent,video,
Protocol registration
IMRT treatment planning
Q/A dosimetry
-film
-ion chamber
Spinal cord tolerance of relatively small volumes (shower) strongly
affected by low dose irradiation (bath)
Bijl HP et al. IJROBP 64:1204-10, 2006
Multi-disciplinary
Tumor board
• Patient selection
•Discussion of complex cases
•Triaging candidates
SBRT simulation
1. immobilization
2. intrathecal contrast
3. CT acquisition
Treatment setup
CT acquisition
image fusion, DRR,
port film, delivery
Protocol follow-up q3 months
pain,QOL,neuro exam, MRI
Spine recurrence
Or new disease
8
Selected stereotactic spine radiation therapy series (FRACTIONATED)
Series
N
Pathology
Dose
F/U
Outcome
cxs
Selected stereotactic spine radation series (SINGLE SESSION)
Milker-zabel
2003
18
Mets
39.6
12mo
13/15
Pain relief
0
Series
N
Path
Dose
(Gy)
F/u
(mos)
Outcome
cxs
Mets
8-18
6.4 (0.5-49)
63
Mets
30/5 or
27/3
9mo
85%
control
0
Ryu
2007
177
Chang
2007
85% pain
relief
1 radiation
injury
Yamada
2008
93
Mets
18-24
15 (2-45)
90%
0
Bilsky
2004
16
Primary and
metastases
59.4-70.2/3338fxs
20 (20-55.8)
/4-31fxs
12mo
2 progression
0
Gerszten
2007
336
Mets
20(12-25)
21(3-53)
LTC
90%
0
Yamada
2005
35
Primary and
metastases
70/33
20/5
11mo
0
Dodd
2006
19
Benign
16-30/1-5fxs
23
3worse
0
Dodd
2006
32
Benign
16-30
/1-5fx
23mo
3 increased
symptoms
1 (3%)
Benzil
2004
31
26mets
9prim
25/10 +68x1
NA
Pain relief
32/34
tumors
2radiculit
1 rad
necrosis
Gibbs
2007
74
Mets
16-25/
1-5
9mo
84%
Symptomatic
improvement
3 severe
mypthy
Total
656
8-25
2-45mos
~90%
4/656
(0.6%)
Total
222
>80%
4/222
cases
(1.8%)
M81% LC
9-23mo
M.D. ANDERSON PHASE I AND II DATA
Patient Positioning Accuracy and Safety Data
Int J Radiat Oncol Biol Phys 59:1288-1294, 2004
9
RESULTS - Patient Characteristics
Dates enrolled
Patients
n
Male
Female
Age (yrs)
Median
Range
Histology
Renal cell
Breast
Sarcoma
Lung
Melanoma
Colon
Unk Primary
Other
KPS score
60
70
80
90
Nov 2002 – Mar 2005
63
38 (60%)
25 (40%)
59
21-82
25 (39.7%)
9 (14.3%)
8 (12.7%)
7 (11.1%)
2 (3.2%)
1 (1.6%)
2 (3.2%)
9 (14.3%)
RESULTS - Tumor Characteristics
Tumor volume (cc)
median
range
Spinal Metastases (n)
One
Two
Lesion Location
Spinal
Paraspinal
Level
cervical
thoracic
lumbar
sacral
37.4
1.6 –357.9
51
12
61
13
5 (6.7%)
43 (57%)
26 (34.7%)
1 (1.3%)
4 (6.3%)
17 (27%)
17 (27%)
25 (39.7%)
RESULTS - Follow-up of Tumor and Vital Status
Vital Status
alive
dead
Tumor status
Stable
Progressed
Follow-up
Median
Range
26 (41%)
37 (59%)
57 (77%)
17 (23%)
21.3 mos
0.5 – 49.6 mos
10
PAIN AND SYMPTOM CONTROL
Pain incidence
Pain severity
25%
6.7%
Narcotic use decreased from 60% (baseline), 44% (3mos), 36% (6mos)
MDASI showed reduction in pain (p<0.001), sleep disturbance(p<0.01),
with no added impairment of daily function, while fatigue severity
unchanged.
11
Neurotoxicity evaluation
Grade 1
headache (1)
numbness (1)*
tingling (4)*
numbness and tingling (1)*
(all reversible)
Grade 3-4 toxicity
Grade 3
Nausea (1)
Fatigue (1)
Non-cardiac chest pain (1)
Pain, severe tongue edema, trismus (1)
Grade 4
None
Grade 2 -4
none
Reported Toxicity in Literature
CLINICAL CASES
Fractionated SBRT
12
Case1: 46 M previously irradiated (40 Gy in 16 fxs)
Lung cancer T12 metastasis progressed (biopsy proven)
July
2004
Case2: 52 M solitary renal cell carcinoma
metastasis centered on cervical vertebrae 2
July
2005
13
Case3: 20 F plasmacytoma causing back pain, failed
conventional RT and surgery
Neuroforaminal and Epidural Disease
-Extradural extension causing cord compression
at T10
-Needle bx revealed plasmacytoma
-45 Gy in 25 fractions to T9-11
-3 mos later, recurred below: Epidural dz T11-12.
RT was not an option at the time
-Laminectomy, facetectomy, resection tumor
-4 mo later recurred above: Rt T7-8 neuroforamen
-Received SBRT to epidural disease
-Attending college and remains disease-free 4
years later
Patterns of Failure
14
All the following are indications for
performing stereotactic body
radiosurgery for spinal metastases
EXCEPT?:
Summary and conclusions
• Literature and phase I/II data support the safety
and effectiveness of stereotactic body radiosurgery
for the spine
• POF data suggest routinely treating the pedicles
and posterior elements using a wide bony margin
posterior to the diseased vertebrae.
• Prospective trials are needed to determine the true
spinal cord tolerance and to compare efficacy of
SBRS against conventional RT
25%
25%
25%
25%
1.
2.
3.
4.
Solitary or oligometastatic disease
Failure of prior XRT or surgery
Spinal instability
Gross residual disease after surgery
10
Based on pooled published data on spinal metastases,
SBRT is associated with a crude local control rate of:
25%
25%
25%
25%
1.
2.
3.
4.
The following statements regarding spinal cord
tolerance to single session steretoactic body
radiosurgery (SBRS) are true EXCEPT:
25%
65-70%
70-75%
75-80%
80% or higher
25%
2. <12 Gy has been reported as safe
25%
3. 10 Gy to 10% of the spinal cord volume
4. Rat spinal cord tolerance can be directly
applied to humans
25%
10
1. Human spinal cord tolerance unknown
10
15