Introduction to Spine SBRT and
Current Topics
Singapore IAEA IGRT Course 2012
Yoshiya (Josh) Yamada MD FRCPC
Department of Radiation Oncology
Memorial Sloan Kettering Cancer Center
NY NY USA
Disclosures
The Institute for Medical Education, Speakers Bureau
Varian Medical Systems, Consultant
Spinal metastasis
• Bone metastasis the most common reason for palliative
XRT
• 30-58% of patients with bone metastasis will experience
spinal column metastasis
• 20,000 cases of cord/cauda equina compression
annually in the US
• Breast, lung, prostate cancers account for 50% of cord
compression
• 85% of lesions are located anterior to the spinal cord
Conventional XRT: Who Benefits?
• Patchell
• High grade epidural cord compressions do not do well with XRT
alone
• Radioresistant disease does not respond well to conventional
radiation
• XRT will not palliate mechanical instability
• Multilevel spine disease
• KPS/Systemic Disease/Survival
Dose and Fractionation
• High dose per fraction greater likelihood of lethal cell
damage (same for tumor and normal tissue)
• Increasing the dose per fraction has an exponential
biologic effect
• Increasing the number of fractions has a more linear
biologic effect
• Smaller dose per fraction means less injury to normal
tissue (and also tumor)
• Greater volume of irradiated tissue means a greater
risk of serious radiation injury
Radiation Sensitivity for Spinal Metastases
CR
Prostate Breast Lung
Others Totals
90%
65%
42%
50%
62%
100%
87%
42%
60%
79%
0 analgesia score
<2 pain score
CR + PR
1-2 analgesia score
3-4 pain score
G Arcageli et al. Int J Rad Onc Biol Phys 42(5): 1119-1126
Conventional RT Conformal RT
Dose per fraction
Lower
Higher
Treatment Volume
Bigger
Smaller
Normal Tissue
More
Less
Hypofractionation: A Short History
• 1896--First single fraction treatment to depigment a nevis=necrosis
• Further attempts at single fraction radiation: (1916 Friedrich, 1918 Seitz)
• Coutard: Fractionated radiation could cure deep seated tumors of the
head and neck. Coutard H. Roentgen therapy of epitheliomas of the tonsillar
region, hypopraynx and larynx from 1920-1926. Am J Roentgenol 1932; 28:
313-331.
• “...The greatest cellucidal effect is obtained by single -dose
fractionation; however, as a rule, the concomitant damage to normal
tissues...is not well tolerated...and we are forced to fractionate.” Marciel
V. Time-dose fractionation relationships in radiation therapy. Natl Cancer Inst
Monogr 1967; 24: 187-203
Hypo-fractionation’s effect on the
Therapeutic Ratio
TCP
NTCP
Conventional Fractionation
Problem with hypo-fractionation:
•late responding tissues (normal tissues)
have lower α/β than the tumor, thus are
more responsive to higher dose per fraction.
Dose
BED  nd (1 
Hypo fractionation / Single-fraction
d
 /
)
TCP
NTCP
•This pushes the curves closer together
Dose
Effect of PTV Margin Size
Volume of Normal Tissue Exposed
PTV Volume
1400
700
1200
600
3 mm margin
Volume of Normal Tissue (cc)
3 mm margin
1000
PTV Volume (cc)
1 cm Margin
800
1.5 cm Margin
600
400
500
1 cm Margin
400
1.5 cm Margin
300
200
200
100
0
0
0
2
4
6
Diameter of CTV (cm)
8
• For 5 cm diameter CTV, the
corresponding volumes:
10
0
2
4
6
Diameter of CTV (cm)
8
CTV Diameter
Normal Tissue Volume
0.3
27
1.0
114
1.5
203
10
Margins and Normal Tissue Exposure
CTV
CTV
diameter volume Margin (CTV-PTV) mm
(cm)
(cm3)
1mm
2mm
3mm
4mm
5mm
1
0.5
0.4
0.9
1.6
2.5
3.4
2
4.2
1.4
3.1
5.0
7.3
10.0
3
14.1
3.0
6.4
10.3
14.6
19.4
4
33.5
5.3
11.1
17.5
24.4
31.9
5
65.4
8.2
17.0
26.5
37.7
47.7
TCP
NTCP
Geometry
Hypo fractionation / Single-fraction
Solution is often simply one of geometry:
• Improve the accuracy with which the
target is positioned with respect to the
radiation beams
• Reduce the size of the PTV margins
• Reduce the volume of normal tissue in the
high dose region
Dose
TCP
NTCP
Hypo fractionation / Single-fraction
with small margins, dose escalation
Dose
May allow significant
dose escalation leading
to improved outcome
• Conventional XRT
• Lower doses per fraction
• More fractions
• Less complex
• Fast
• High doses per fraction
• Less normal tissue dose
• Smaller margins
• Important for surgical complication
risks!
• Higher dose to tumor
Image Guided Radiotherapy
• Near real time 3D
imaging for position
verification
• Positional
corrections in X, Y,Z
planes
• Accuracy within +/1mm
Spine RT: Systematic Literature Review
Gerzsten et al. Spine 2009
• Conventional (standard fractionation, 1-2 fields)
• Radiosurgery (hypofractionation, 1-5 fractions, conformal
techniques)
• Pubmed/Embase/Cochrane Reviews
• 479 relevant articles
• 62 for in depth review
• 49 included
• 9 prospective papers
• 3 RCT
Conventional XRT: Pain
• 2 RCT reported improvement in pain
• 46-57% with 4-5 month median survival
• 3 prospective non-randomized results
• 73-82% improved pain (6 months median follow up)
• Retrospective data
• 70% report improvement in pain
Conventional Spine XRT: Local Control
• Local control = lack of cord compression/return of symptoms
• 885 patients in 7 retrospective studies
• 61-89% (mean 77%) local control
• Histology a significant predictor of outcome
• “Radioresistant” vs “radiosensitive”
Introduction
Basic principles of “conventionally” fractionated radiotherapy for
metastases
Complete depletion of tumor stem cells is required for cure
The main mechanism is clonogenic/reproductive stem cell death
Cells/tumors exhibit a heterogenous response to radiation
Response may depend upon a number of factors:
•
Dose and fraction size (limited by spinal cord/irradiated volume) impact
upon tumor control probabilities
•
•
The 4 R’s
Radiation response broadly categorized by tumor phenotype (ie.
histology)
•
Linear Quadratic formalism-α/β ratio
Histologic Classification
• Radiosensitive:
• Prostate, H & N (SCC), Ovarian, Endometrial, Cervical, Breast
• Radioresistant:
• GI, NSCLC, RCC, Melanoma, Sarcoma, NSGCT, Hurthle Cell,
Thyroid, Adnoid Cystic, Unknown Primary
Lymphoma
Seminoma
Myeloma
Breast
Prostate
Sarcoma
Melanoma
GI
NSCLC
Renal
Gilbert
F
F
U
U
U
U
U
U
Maranzano
F
F
F
U
U
U
U
U
Rades
F
I
I
I
U
I
U
I
Rades
F
F
F
U
U
U
U
U
Katagiri
F
F
F
U
U
U
U
U
Maranzano
F
F
F
U
U
U
U
U
Rades
F
I
I
I
U
I
U
I
Ambulatory Status After Conventional XRT
N
Breast
Prostate
Maranzano
35
60%
Rades
81
Rades
87
Smith
35
66%
Rades
281
33%
Rades
335
Bach
59
22%
Rades
252
14%
Merminsky
19
Rades
142
TOTALS
512
493
363
81
87
Renal
Sarcoma
29%
31%
27%
33%
40%
52
44
GI
14%
133
Maranzano
NSCLC
29%
46%
34%
36%
17%
14%
29%
Histologic Classification
Radiosensitivity to cEBRT (30 Gy in 10)
Lymphoma
Seminoma
Myeloma
Breast Prostate
Sarcoma
Melanoma
GI
NSCL
C
Renal
Gilbert
F
F
U
U
U
U
U
U
Maranzano
F
F
F
U
U
U
U
U
Rades
F
I
I
I
U
I
U
I
80%
F
F
U
U
U
U
U
Katagiri
F
F
F
U
U
U
U
U
response
Maranzano
F
F
F
U
U
U
U
U
@ 16
Rades
F
I
I
I
U
I
U
I
months
Responses: F-Favorable, I-Intermediate, U-Unfavorable
Rades
F
Gerszten PC, Mendel E, Yamada Y. Radiotherapy and radiosurgery
for metastatic spine disease: What are the options, indications, and
outcomes. Spine 34(22S):S78-92, 2009
Histologic Classification
Radiosensitivity to cEBRT (30 Gy in 10)
Lymphoma
Seminoma
Myeloma
Breast Prostate
Sarcoma
Melanoma
GI
NSCL
C
Renal
Gilbert
F
F
U
U
U
U
U
U
Maranzano
F
F
F
U
U
U
U
U
Rades
F
I
I
I
U
I
U
I
Rades
F
F
F
Katagiri
F
F
F
Maranzano
F
F
F
U
U
U
U
U
Rades
F
I
I
I
U
I
U
I
20%Uresponse
U
U
U
U @ 3
U months
U
U
U
U
Responses: F-Favorable, I-Intermediate, U-Unfavorable
Gerszten PC, Mendel E, Yamada Y. Radiotherapy and radiosurgery
for metastatic spine disease: What are the options, indications, and
outcomes. Spine 34(22S):S78-92, 2009
Common Observations of Bone Metastases Palliation:
Low Dose Single Fraction vs Multi Fraction
• 2 Meta Analysis of 12 (Sze et al) and 6 (Wu et al) RCT (N=3508 and 3260)
of single fraction vs multifraction regimens for palliation of bone pain:
• 800cGyx1 - 4000cGy/20
• No difference in initial palliation (60%)
• No difference in complete response (30%)
• Short fractionation schedules results in a greater need for retreatment
(7% vs 20%)
Conventional RT: Durability of Response
• UK/NZ Bone Mets RCT
Trial
• N=761
• 800cGyx1 vs 2000cGy/5 or
3000cGy/10
• 30% available for FU at 12
months
8 Gy single fraction radiotherapy for the treatment of metastatic skeletal
pain:
randomised
within
a multifraction schedule over 12 months
• Nearly
50%comparison
increase
of
patient follow-up.
Bone Pain Trial
Party.“ Radiother Oncol.
relapse
at 12 months
vs Working
3
1999 Aug;52(2):111-21.)
months
Conventional Spine XRT: Local Control
Gerszten et al. Spine 2009
• 1-2 beams, 800cGy-4000cGy/1-20 fractions
• Local control = lack of cord compression/return of symptoms
• 885 patients in 7 retrospective studies
• 61-89% (mean 77%) local control
• Histology a significant predictor of outcome
• “Radioresistant” vs “radiosensitive”
Local Control of Oligometastatic Tumors by Histology
The MSKCC Series of SD-IGRT: Greco & Zelefsky, 2009 Unpublished
100
Prostate (n=42; 83%)
Local Relapse-free Survival
Local Relapse-free Survival
100
80
Other (n=32; 62%)
60
Renal cell (n=37; 60%)
Colorectal (n=10; 50%)
40
20
18-24 Gy
0
80
60
Prostate (n=19; 86%)
40
Renal cell (n=24; 81%)
20
12
24
Time (months)
36
Other (n=16; 83%)
24 Gy only
p=0.16
48
0
10
20
30
Time (months)
40
Spine IGRT: Radiobiologic Observations Unique to High
Dose Single Fraction Radiation
Tumors appear to respond with similar sensitivities to single-dose
radiotherapy regardless of tumor type, stage or other phenotypic
features
Local control is dose-dependent within a narrow dose range (15-25
Gy)
Local cures of ~90% appear achievable within the range of 24 Gy
The uniformity of tumor response to single dose radiotherapy
regardless of tumor type support a mechanism of response different
from that regulating fractionated radiotherapy
High Dose/IGRT Hypothesis
High dose/single fraction radiation provides excellent tumor control
• Intracranial stereotactic radiosurgery experience
High dose radiation can be given safely if normal tissue dose and
volume can be minimized
Sophisticated image guided technologies are able to provide high
precision radiation
Image guidance + IMRT is able to deliver tumorcidal radiation safely near
critical structures such as the spinal cord and esophagus.
Local control is an important and meaningful clinical goal
MSKCC Update: Where We Are Now
• 413 lesions in 372 consecutive patients were treated with SRS 2003-2010
at MSKCC.
• 1800-2400cGy in a single fraction with LINAC based IGRT
• Dose escalation 2003-2005 (1800-2400cGy)
• Extensive disease (ie circumferential) received reduced doses
<2400cGy
• All patients followed with serial imaging until death
• Local failure = radiographic progression
Competing Risks Analysis N = 413
3 Year Recurrence
Rates
1800-2300cGy
= 0.104
2400cGy
= 0.024
All Patients
= 0.040
Local Control By Histology
Histology
3 Yr
Local
Control
Breast
98%
GI
98%
H&N
93%
Lung
98%
Melanoma
90%
Unknown
91%
Prostate
98%
Renal
89%
Sarcoma
96%
Thyroid
92%
Summary
• In contrast to conventionally fractionated radiotherapy, traditional
phenotypical factors such as histology and volume are not significant
prognostic factors with high dose single fraction therapy
• The dose of radiation is the only predictive factor for durable treatment
success when utilizing high dose single fraction therapy
• Local tumor “cures” can be achieved at 2400cGy x 1
• Radioresistant histologies in particular should be considered for high
dose single fraction therapy
Non surgical tx for spinal mets
Tumor
Neurologic
Pain
Function
Breast
93%
87%
93%
Prostate
91%
64%
82%
Myeloma
90%
100%
90%
SCLC
86%
86%
86%
Ovarian
100%
100%
100%
RESPONSIVE
87%
83%
85%
NSCLC
47%
65%
53%
Hepatocellular
33%
44%
33%
Gastric
50%
50%
25%
Colon
50%
50%
75%
Cholangio
50%
0
50%
Renal
67%
67%
67%
Sarcoma
50%
100%
50%
0
0
0
RESISTANT
49%
55%
47%
Total
67%
67%
64%
Thyroid
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%
Importance of dose
Tumor Control Outcomes after hypo-fractionated and single – dose stereotactic
image-guided intensity modulated RT for extra-cranial metastases from renal cell
carcinoma
Dose
/fractionation
N patients
PFS*
High dose
1 frac 24 Gy
45
88%
Low dose
1 frac <24 Gy
14
21%
Hypo fraction
3 frac, 20-30 Gy
46
17%
Actuarial local control (Kaplan-Meir method) as a function of prescription regimen for renal cell cancer (p
= 0.001). Y axis represents local relapse-free survival (%). PFS = progression-free survival.
Tumor control outcomes after hypofractionated and single-dose stereotactic image-guided intensity-modulated radiotherapy for
extracranial metastases from renal cell carcinoma. Zelefsky MJ, Greco C, Motzer R, Magsanoc JM, Pei X, Lovelock M, Mechalakos
J, Zatcky J, Fuks Z, Yamada Y. Int J Radiat Oncol Biol Phys. 2012 Apr 1;82(5):1744-8.
Spine Radiosurgery: Proof of Principle of the
IGRT Hypothesis
• Hypothesis: IGRT will improve outcomes
by:
↓Uncertainties and
• ↓ Toxicity
}
Systematic Errors
• ↑ Tumor control
• Spine Radiosurgery a test of the IGRT paradigm
• Proximity of spinal cord:
• Demands high precision
• Rapid dose fall off to limit dose to spinal cord
• Many spine tumors are “resistant” to conventional
fractionation
• Significant experience with high dose single fraction
radiation for intracranial brain metastases of radioresistant
Spine IGRT: Radiobiologic Observations Unique to High
Dose Single Fraction Radiation
Tumors appear to respond with similar sensitivities to singledose radiotherapy regardless of tumor type, stage or other
phenotypic features
Local control is dose-dependent within a narrow dose range (1525 Gy)
Local cures of ~90% appear achievable within the range of 24 Gy
The uniformity of tumor response to single dose radiotherapy
regardless of tumor type support a mechanism of response
different from that regulating fractionated radiotherapy
IGRT Hypothesis: Improving Tumor Control
to Improve the Therapeutic Ratio
particularly with lower α/β
“radioresistant” tumors
-Dose remains the only
predictive factor for tumor
control
• Not at the expense of
toxicity
-Limiting normal tissue
volume and dose
Tumor control
• Higher tumor control
Dose
Summary: Hypofractionation Paradigm
Dose is an important predictor of tumor control
Hypofractionation appears to be superior to conventional
fractionation
• Dose is an important predictor of local control
• Histology is an important factor in tumor control
Single fraction appears to be superior to conventional
fractionation
• Single fraction local control is dose dependent but independent of
histology
• Single fraction radiation is superior to all other dose fractionation
schedules for radioresistant disease
• Redefining traditional radiobiologic constructs of radiosensitivity
IGRT is changing the management of metastatic lesions at MSKCC
Improvements in outcome largely
come down to geometry
•
•
Each site has its own, sometimes unique challenges
Many opportunities for therapy physicists to work with physicians to develop new
protocols, treatment procedures
Spine:
• Careful patient immobilization
• Image guidance
Lymph nodes
• Careful patient immobilization
• Soft tissue imaging
Liver, Pancreas, Adrenal
• Motion management
• Image guidance
• Implanted fiducial markers
Lung
• Cone beam soft tissue imaging
Prostate
• Daily setup on implanted markers
• Radio frequency tracking beacons real time prostate
position readout