Radiation Biology &
Future Trends of SBRT
Radiation Biology &
Future Trends of SBRT
Brian D. Kavanagh, MD, MPH
Department of Radiation Oncology
University of Colorado
Comprehensive Cancer Center
• SBRT: radiobiological modeling
• University of Colorado SBRT:
snapshot of the program
–Future trends
AAPM Annual Meeting, 2009
Radiation Biology &
Future Trends of SBRT
• SBRT: radiobiological modeling
• University of Colorado SBRT:
snapshot of the program
–Future trends
www.Bing.com image search:
SBRT and modeling
• “Sporty Beauty Reversible
Black Leather And Mink Coat”
– Aspenfashions.com
– [not sure about the T]
• Apt metaphor?
– Radiobiological modeling for
SBRT is…
• A sport, or at least a parlor game
• Sometimes beautiful
• Something that can be reversed
at any time
• Often politically incorrect
In vivo animal study #1:
Lotan et al. J Urol. 2006;175(5):1932-6.
On the other hand, if you do a Pubmed search:
SBRT and modeling
or something similar, you will retrieve…
• Dozens of theoretical papers
– The vast majority purely mathematical, with dependence on a
variety of assumptions
– Some respiratory motion models (different topic)
•
•
• Exactly 2 in vivo animal studies of tumor response
–
–
–
–
– and an in vivo normal lung model
• A few protocols structured in a prospective manner with
a particular model in mind
• A few post hoc analyses of actual clinical results
In vivo animal study #2:
Walsh et al. Eur Urol. 2006;50(4):795-800.
Human C4-2 prostate cells
implanted in the flank of nude
mice
Stereotactically irradiated
when palpable:
control
3 x 5 Gy
3 x 7.5 Gy
3 x 15 Gy
•
A very straightforward pattern
of dose-response tumor
volume (figure)
•
[note—our group have had trouble giving >6
Gy or so per fraction, but maybe technical]
Walsh et al, Eur Urol, 2006
In vivo RCC study, continued
• A maturation of the
response over time
– Above: at 4 weeks, still
viable tumor cells
•
•
Human A498 RCC cells implanted in the flank of nude mice
Streotactically irradiated when palpable:
– control
– 3 x 16 Gy
– Below, at 7 weeks,
much more necrotic
In vivo large animal and human
evidence of apoptosis after high
dose/fraction RT
The currently trendy and possibly correct explanation:
Tumor response to high dose radiotherapy is
largely driven by endothelial cell apoptosis
Apoptosisincompetent
• Fibrosarcoma and
melanoma models
Apoptosiscompetent
Tumor endothelial apoptosis
after 3 Gy or 18 Gy dingle
fraction. Larue et al, Rad Res
Mtg, 2008 (abst)
Serum marker of apoptosis
n =14 pts
[to be presented at ASTRO
• Growth delay after RT
influenced by
apoptotic capacity
• Dose-dependence of
percent apoptosis in
endothelial cells
Garcia-Barros et al, Science, 2003
Threshold?
(L-R) control, 3 Gy fraction, 18 Gy fraction
Green = normal endothelium
Red = apoptosis
Conventional wisdom:
Extra caution is needed when
near the proximal airways
Cai et al, A rabbit irradiation platform for outcome
assessment of lung sterotactic radiosurgery, IJROBP 2009
• 3 New Zealand rabbits, 3x20 Gy to 1.6cc lung
• Interesting results:
– No change ventilation
– perfusion 2+ months later
large proximal airways
serial architecture
Note: a prior attempt by the IU
group to create a rodent model
of proximal airway stenosis
was not successful
Timmerman et al, J Clin Oncol, 2006
Caveats about the IU proximal
lesion caveats
• Doses calculated without heterogeneity correction
• Tumor volume was also a significant predictor of toxicity
(p = 0.017)
• Grade 5 toxicities:
– 4 cases of pneumonia
• Note that pts with medically inoperable NSCLC are
susceptible to this event, regardless
– 1 pericardial effusion after treatment of a tumor
adjacent to the mediastinum superior to the hilum.
– 1 “Toxic” death from a local recurrence
2 responses to the IU proximal
airway report
BELOW: from Joyner et al,
Acta Oncol 2006; 45: 802807
• UT-SA experience (above)
– n=9; dose = 3x12 Gy
– No serious toxicity
• Median f/u 11 mos (range, 3-42)
• MD Anderson experience
– N = 27; dose = 4x10-12.5 Gy
– No serious lung toxicity
• Median f/u 17 mos (range, 6-40)
• 1 brachial plexopathy (>40 Gy/4 fxns)
LEFT: from Chang et al,
IJROBP 2008; 72(4) 967–971
Sample proximal lesion case:
treatment plan
Planning scan
Dose
distribution
Sample case, proximal tumor
Planning target volume
in zone of proximal
bronchial tree
Pre- vs. 12 mos post-SBRT
Another example case
• Aug, 2008:
– 59yo F with h/o
metastatic NSCLC s/p
surgery/WBRT 1 year
ago
– only current site of
disease = 5cm mass in
rt mid lung.
– plan: SBRT to rt lung
mass
Segmental/Lobar atelectasis
One year later: cough, dyspnea
Bronchoscopy:
mucus plug cleared from RML bronchus
Lateral segment
RML bronchus:
Narrow but patent
after clearing
Coronal reconstruction, CT scan
Chest x-ray
This can also happen after hyper-fractionated RT
Miller et al, IJROBP 61: 64-69, 2005
Pre- and post-bronch to clear
mucus plug
Models of Radiation Injury Applied
Prospectively in SBRT
Lyman-Kutcher-Burman v Critical Volume
• LKB Model
– Converts whole organ
tolerance dose into
estimate of complication
based on partial volume
irradiation
1 t − x2 / 2
e
dx
2π −∞
t = ( D − TD50 (v ) /( m • TD50 ( v ))
NTCP(t ) =
TD50 ( v ) = TD50 (1) • v −n
• Critical Volume Model
– Initially for spinal cord, where there should be no
complication if a minimum number of “fibers” are
undamaged
N
NTCP ( N , M , Pfiber ) =
i
BNi Pfiber
(1 − Pfiber ) N −1
i = M +1
Stavreva et al. Int. J. Radiat. Biol 77(6): 695-702, 2001
LKB v Critical Volume Models in SBRT
PMH Phase I Trial of SBRT for HCC
Tse et al, J Clin Oncol 26:657-664, 2008
LKB
Critical Volume
Rationale
Robust performance in
conventionally fractionated liver
RT
Analogy to surgical experiences
Strengths
Familiarity
Built into some planning
systems
Simplicity
based on absolute dose, lack of
need for DVH conversion
Relies on converting high dose
per fraction volumes into a
biological equivalent; might be
outside LQ model range
Initial assumptions based on
educated (?) guesses
Weaknesses
Definition of Veff
[which I could not recite the last time I tried, so I am writing it down!]
• LKB model based dose
escalation
– Veff-based stratification
– Eg, planned to go from 9 to
9.5 to 10 Gy/fxn for low Veff
group, increasing projected
rate of RILD from 5-1020%
– RILD = anicteric
hepatomegaly, ascites,
elevated alkaline phos
PMH Phase I HCC SBRT, methods
JCO 26:657-664, 2008
• The effective liver volume (Veff) irradiated
is defined as the normal liver volume,
minus all GTVs, which if irradiated
uniformly to the treatment dose would be
associated with the same risk of toxicity as
the non-uniform dose distribution delivered
• Technique
– 3-10 beams 6-18MV, breath hold
• Max to GI tract, 30 Gy to 0.5cc; max cord 27 Gy; max heart
40 Gy
– CTV = GTV+8mm, PTV = CTV+5mm or more
– IGRT with MV images of diaphragm as surrogate or
CBCT
• Patient population
– 31 HCC, 10 IHC
– All Child-Pugh A
– Median PTV, 173 cc
• Median dose 36 Gy (24 -54 Gy) /6 fractions/ 2 wk
PMH Phase I HCC SBRT, results
JCO 26:657-664, 2008
•
• Toxicity
Eligibility
–
–
–
–
– No cases of RILD
• Though 7 pts progressed to
Child-Pugh B
1-3 liver metastases
Solid tumors
No tumor diameter >6cm
Liver and kidney function OK
•
•
•
– 2 IHC pts with transient
obstruction
t bili <3 mg/dL, alb > 2.5 g/dL
Liver enzymes <3xULN
No ascites
– No systemic therapy within 14
days pre- or post-SBRT
• preSBRT steroids
recommended
• Patterns of failure (figure)
• Median OS:
•
SBRT Dose
– Phase I escalation to 20 Gy x 3
– 20 Gy x 3 fractions for Phase II
– HCC, 23 mos
– IHC, 15 mos
J Clin Oncol. 2009
U. Colorado/Multi-center Phase I/II Liver SBRT Trial
Methods
• Breathing motion control via breath hold or abdominal
compression
– Generally frameless setup
• Target delineation:
– GTV based on CT +/or MRI fused to planning scan
• CTV = GTV
– PTV = GTV+ 5-7mm radial, 10-15mm sup-inf
• Arcs or multiple non-coplanar static beams
– Prescription 70-90% isodose line
• Image guidance with stereo kV images augmented by
verification CT scan on d1
Liver and Non-liver Protocol
Dose Volume Constraints
• Non-liver:
– Total kidney volume > 15 Gy to be < 35%
– Max spinal cord dose 18 Gy
– Max dose to stomach or intestine 30 Gy
– Later, max point to skin <21 Gy
• Modified critical volume method for liver:
– At least 700 cc had to receive < 15 Gy
Results: (1) no severe liver toxicity
(2) tumor volume effect
Insufficient number of fields
1 grade 3 skin toxicity due to inadvertent subcutaneous hotspot
Figure 2b: Actuarial Local Control by Size
100
100
80
80
Local Control
Local Control
Figure 2a: Actuarial Local Control
Phase II Results, Toxicity
No RILD, no Gr 4-5 toxicity of any kind
1 case of grade III soft tissue toxicity
60
40
60
£3cm
>3cm
40
20
20
0
0
0
0
6
12
18
24
30
36
42
48
5
3
2
1
6
12
18
24
30
36
42
3
3
48
Months
Months
Lesions
at risk :
49
49
30
17
7
£3cm : 30
30
20
10
3
1
3cm : 19
19
12
8
6
3
Non-protocol patient:
max pt to stomach >10
Gy/fxn
Photo taken 8 mos after SBRT
At last followup 17 post-SBRT,
lesion controlled.
Necrosis is slowly healing.
A few post hoc analyses of actual
clinical results
• A liver SBRT analysis
– Analyzing transient total liver volume
reduction
• 2 lung SBRT analyses
– Analyzing incidence of chest wall pain and/or
rib fracture
Pale, denuded mucosa; progressed to
ulceration but eventually healed in
approx 3 mos
Macroscipic
effect:
transient normal
liver volume
reduction
Typical post-SBRT
normal liver image a
few mos after SBRT
Figure from Kavanagh et al.
Stereotactic Irradiation of Tumors
outside the Central Nervous System.
In Principles and Practice of Radiation
Oncology, 5th ed., Lippincott, Williams
& Wilkins, 2007.
Schefter et al. IJROBP 62(5) 1371-8, 2005
Liver V30 and Mean dose versus
percent volume change
r2= 0.72
r2= 0.56
Findings consistent with parallel architecture
Olsen et al, 73(5):1414-24, 2009
Comparison of the 2 lung SBRT
chest/rib toxicity studies
Dunlap, IJROBP 2009
U Virginia & U Colorado
Pettersson, Radiother Oncol 2009
Sahlgrenska U, Sweden
• 60 patients, minimum
point dose 20 Gy in 3-5
fractions to chest wall
• Endpoint: severe pain
(narcotics) or rib fracture
• DVHs analyzed:
• 81 ribs in 26
patients,minimum point
dose 21 Gy/3 fractions
received
• Endpoint: rib fracture on
CT
• DVHs analyzed
– Chest wall = all tissue
(bone and soft tissue)
peripheral to lung
– Ribs receiving >21 Gy
contoured without margin
for setup errors
Dunlap study definition of chest wall
note: not all sections relevant here
(suggest not using this entire volume to speed DVH calcs)
Common finding:
absolute volume predictive parameters
Dunlap et al:
Keep absolute V30 < 30 cc
Timmerman’s suggested normal tissue constraints
Sem Rad Onc. 18(4) :215-222, 2008
Petterssen et al:
Keep D2cc as low as possible
Radiation Biology &
Future Trends of SBRT
• SBRT: radiobiological modeling
• University of Colorado SBRT:
snapshot of the program
–Future trends
THERE IS NO SHAME IN STARTING WITH THESE!!!!
Relative measure of interest in SBRT within
the field over the past 5 years
Papers published in
IJROBP, 2004-present
July-Dec, 2008
*2009 data projected based on
published and in press
A wild guess about how many patients might
eventually get SBRT or hypofractionated
RT*
note: everything is a rounded estimate
Cancer type
Prostate
Breast
Lung
Head & Neck
Rectal
Everything else
National data not yet available,
so a snapshot of UC data
RT Patients
per year, US
100,000
100,000
100,000
40,000
20,000
--
Suitable for
sbrt or
hypofraction?
25,000
50,000 ?
25,000
0
?
25,000
*10 or fewer fractions in a “curative” setting
IMRT
Non-IMRT
Cranial /spinal
SRS
SBRT
% external
beam
treatments
45
52
1
2
Estimated % of
patients
treated
33
46
8
13
Hmmm…am I
forgetting anything
that will have a lot
more influence than
some of us like to
acknowledge?
• Maybe you have heard:
Medicare is revising
radiation oncology
reimbursement rates…stay
tuned on that one
Thanks for your
attention!
And thanks to the UCD physics
and dosimetry team:
Francis, Kelly, Moyed, Wayne