radiation biology & future trends of sbrt - aapm hqapprox 3 mos a few post hoc analyses of...

Radiation Biology &Future Trends of SBRT

Brian D. Kavanagh, MD, MPHDepartment of Radiation Oncology

University of Colorado Comprehensive Cancer Center

AAPM Annual Meeting, 2009


• 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

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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!!!!




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

radiation biology & future trends of sbrt - aapm hqapprox 3 mos a few post hoc analyses of...

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