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Radiation Biology &Future Trends of SBRT
Brian D. Kavanagh, MD, MPHDepartment of Radiation Oncology
University of Colorado Comprehensive Cancer Center
AAPM Annual Meeting, 2009
Radiation Biology &Future Trends of SBRT
• SBRT: radiobiological modeling• University of Colorado SBRT:
snapshot of the program–Future trends
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
On the other hand, if you do a Pubmed search:
SBRT and modelingor 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 #1:Lotan et al. J Urol. 2006;175(5):1932-6.
• 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]
In vivo animal study #2:Walsh et al. Eur Urol. 2006;50(4):795-800.
• Human A498 RCC cells implanted in the flank of nude mice
• Streotactically irradiated when palpable:– control– 3 x 16 Gy
Walsh et al, Eur Urol, 2006In vivo RCC study, continued
• A maturation of the response over time
– Above: at 4 weeks, still viable tumor cells
– Below, at 7 weeks, much more necrotic
The currently trendy and possibly correct explanation:Tumor response to high dose radiotherapy is largely driven by endothelial cell apoptosis
• Fibrosarcoma and melanoma models
• Growth delay after RT influenced by apoptotic capacity
• Dose-dependence of percent apoptosis in endothelial cells
Garcia-Barros et al, Science, 2003 Threshold?
Apoptosis-incompetent
Apoptosis-competent
In vivo large animal and human evidence of apoptosis after high
dose/fraction RTTumor endothelial apoptosis after 3 Gy or 18 Gy dingle fraction. Larue et al, Rad Res Mtg, 2008 (abst)
Serum marker of apoptosisn =14 pts[to be presented at ASTRO
(L-R) control, 3 Gy fraction, 18 Gy fractionGreen = normal endotheliumRed = apoptosis
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
Note: a prior attempt by the IU group to create a rodent model
of proximal airway stenosis was not successful
Conventional wisdom:Extra caution is needed when near the proximal airways
Timmerman et al, J Clin Oncol, 2006
large proximal airwaysserial architecture
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
• 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)
BELOW: from Joyner et al,Acta Oncol 2006; 45: 802-807
LEFT: from Chang et al,IJROBP 2008; 72(4) 967–971
Sample proximal lesion case:treatment plan
Planning scan Dosedistribution
Sample case, proximal tumor
Planning target volume in zone of proximal bronchial tree
Pre- vs. 12 mos post-SBRT
Segmental/Lobar atelectasis
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
One year later: cough, dyspnea
Coronal reconstruction, CT scan
Chest x-ray
Bronchoscopy:mucus plug cleared from RML bronchus
Lateral segment RML bronchus:
Narrow but patent after clearing
This can also happen after hyper-fractionated RTMiller 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
n
tx
vTDvTD
vTDmvTDDt
dxetNTCP
−
∞−
−
•=
•−=
= ∫
)1()(
))(/()((2
1)(
5050
5050
2/2
π
∑+=
−−=N
Mi
Nfiber
ifiber
iNfiber PPBPMNNTCP
1
1)1(),,(
Stavreva et al. Int. J. Radiat. Biol 77(6): 695-702, 2001
• Critical Volume Model– Initially for spinal cord, where there should be no
complication if a minimum number of “fibers” are undamaged
LKB v Critical Volume Models in SBRT
LKB Critical VolumeRationale Robust performance in
conventionally fractionated liver RT
Analogy to surgical experiences
Strengths FamiliarityBuilt into some planning
systems
Simplicitybased on absolute dose, lack of
need for DVH conversion
Weaknesses Relies on converting high dose per fraction volumes into a
biological equivalent; might be outside LQ model range
Initial assumptions based on educated (?) guesses
PMH Phase I Trial of SBRT for HCC
• 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 5-10-20%
– RILD = anicteric hepatomegaly, ascites, elevated alkaline phos
Tse et al, J Clin Oncol 26:657-664, 2008
Definition of Veff[which I could not recite the last time I tried, so I am writing it down!]
• 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
PMH Phase I HCC SBRT, methods
• 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
JCO 26:657-664, 2008
PMH Phase I HCC SBRT, results
• Toxicity– No cases of RILD
• Though 7 pts progressed to Child-Pugh B
– 2 IHC pts with transient obstruction
• preSBRT steroids recommended
• Patterns of failure (figure)• Median OS:
– HCC, 23 mos
– IHC, 15 mos
JCO 26:657-664, 2008
• Eligibility– 1-3 liver metastases– Solid tumors
– No tumor diameter >6cm– Liver and kidney function OK
• 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
• SBRT Dose– Phase I escalation to 20 Gy x 3
– 20 Gy x 3 fractions for Phase II
J Clin Oncol. 2009
U. Colorado/Multi-center Phase I/II Liver SBRT TrialMethods
• 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
Figure 2a: Actuarial Local Control
0 6 12 18 24 30 36 42 480
20
40
60
80
100
49 49 30 17 7 5 3 2 1Lesionsat risk :
Months
Loca
l Con
trol
Figure 2b: Actuarial Local Control by Size
0 6 12 18 24 30 36 42 480
20
40
60
80
100
£3cm>3cm
£3cm :
3cm :
30 30 20 10 3 1
19 19 12 8 6 3 3 3
Months
Loca
l Con
trol
1 grade 3 skin toxicity due to inadvertent subcutaneous hotspot
Phase II Results, ToxicityNo RILD, no Gr 4-5 toxicity of any kind1 case of grade III soft tissue toxicity
Photo taken 8 mos after SBRTAt last followup 17 post-SBRT,
lesion controlled.Necrosis is slowly healing.
Insufficient number of fields
Non-protocol patient:max pt to stomach >10
Gy/fxn
Pale, denuded mucosa; progressed to ulceration but eventually healed in
approx 3 mos
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
Typical post-SBRT normal liver image a few mos after SBRT
Schefter et al. IJROBP 62(5) 1371-8, 2005
Macroscipiceffect:transient normal liver volume reduction
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.
Liver V30 and Mean dose versus percent volume change
r2= 0.72r2= 0.56
Olsen et al, 73(5):1414-24, 2009
Findings consistent with parallel architecture
Comparison of the 2 lung SBRT chest/rib toxicity studies
Dunlap, IJROBP 2009U Virginia & U Colorado
• 60 patients, minimum point dose 20 Gy in 3-5 fractions to chest wall
• Endpoint: severe pain (narcotics) or rib fracture
• DVHs analyzed:– Chest wall = all tissue
(bone and soft tissue) peripheral to lung
Pettersson, Radiother Oncol 2009Sahlgrenska U, Sweden
• 81 ribs in 26 patients,minimum point dose 21 Gy/3 fractions received
• Endpoint: rib fracture on CT
• DVHs analyzed– Ribs receiving >21 Gy
contoured without margin for setup errors
Dunlap study definition of chest wallnote: 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
Petterssen et al:Keep D2cc as low as possible
Timmerman’s suggested normal tissue constraintsSem Rad Onc. 18(4) :215-222, 2008
THERE IS NO SHAME IN STARTING WITH THESE!!!!
Radiation Biology &Future Trends of SBRT
• SBRT: radiobiological modeling• University of Colorado SBRT:
snapshot of the program–Future trends
Relative measure of interest in SBRT within the field over the past 5 years
*2009 data projected based on published and in press
Papers published in IJROBP, 2004-present
National data not yet available,so a snapshot of UC data
July-Dec, 2008 % external beam treatments
Estimated % of patients treated
IMRT 45 33Non-IMRT 52 46
Cranial /spinal SRS
1 8SBRT 2 13
A wild guess about how many patients mighteventually get SBRT or hypofractionated
RT*note: everything is a rounded estimate
Cancer type RT Patients per year, US
Suitable for sbrt or hypofraction?
Prostate 100,000 25,000
Breast 100,000 50,000Lung 100,000 25,000
Head & Neck 40,000 0
Rectal 20,000 ?Everything else -- 25,000
*10 or fewer fractions in a “curative” setting
?
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