Douglas Johnson, MD, FACR
Florida Radiation Oncology Group
ACRIN Sept 2010 Annual Meeting

 High ablative dose
 SRS= single Fx SBRT= 2-5 Fx
 Overwhelms repair/repopulation mechanisms
 BED important? (>100)
 Short time (1-5 treatments)
 Tight targets and rapid dose fall-off
 Damages everything in high dose area
 Critical to limit toxicity
 Need target tracking or gating system

10 0 multiple 2 Gy fractions
10 -1 single fraction
10 -2
2 4
Dose (Gy)
6 8

90% tumor control toxicity
10%
DOSE OF RADIATION

-This constitutes the tumor control (place it well)
- Being conformal is easy – especially with many beams or arcs

This is the hardest part of the SBRT process and distinguishes a good plan from a poor plan!
- This accounts for toxicity. All of this dose is in normal tissues
- Infinite possibilities – some much more toxic than others

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Radiosurgery: initially CNS
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Leksell Gamma Knife
>80-90% control for benign and malignant tumors,
AVM’s, trigeminal neuralgia
 Limited tumor motion within skull
Motion definition and compensation critical in body radiosurgery sites
 To limit normal tissue dose
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Cyberknife (CK)—respiratory modeling for tracking
Linac-based (Novalis NTX)—gating compensation

Lung SBRT

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Nyman et al, Sahlgrenka Univ Hosp (Sweden): Stereotactic hypofractionated radiotherapy for stage I non-small cell lung cancer—Mature results for medically inoperable patients
Lung Cancer 51: 97-103 (2006)
SELECTION:
PATIENT MIX:
STAGING:
EQUIPMENT:
Stg IA & IB, tumors < 5cm and noncentral, any PFTs
45 pts, 40% IA, med age 74, med KPS 80%,
20% without histology
CT staging only
Linac-based, body frame, abdominal compression for motion compensation
PTV MARGIN:
DOSE:
5mm axial, 10mm craniocaudal
45Gy in 3 Fx (BED 112.5), Dmax approx 140%,
100% PTV coverage
ACUTE TOXICITY: 40% Grade 1, 9% Grade 2 (skin, cough, LRI)
LATE TOXICITY: 11% (rib fx, Atx/fibrosis)
OUTCOMES: Med F/U 43 mo, LC 80%, FFDM 80%
OS 1/2/3/5 yr = 80/71/55/30%
NOTES:
Med OS 39 mo
RCT underway--SBRT vs standard Fx EBRT

Lagerwaard et al, VU Univ Med Ctr (Amsterdam): Outcomes of risk-adapted fractionated stereotactic radiotherapy for stage I non-small cell lung cancer
IJROBP 70(3): 685-692 (2008)
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SELECTION:
PATIENT MIX:
STAGING:
EQUIPMENT:
PTV MARGIN:
DOSE:
NOTES:
Stg IA & IB, tumors < 6cm, any PFTs
206 pts, 59% IA, med age 73, 69% without histology
PET staging
Linac-based, 4DCT for motion compensation
ITV + 3mm
Risk-adapted: 3 x 20Gy (BED 180), 5 x 12Gy (132) or 8 x 7.5Gy (105) based on potential for toxicity
ACUTE TOXICITY: 49%, most Grade 1 (fatigue, nausea, SOB, cough,
CW pain)
LATE TOXICITY: 7% (symptomatic RP, rib fx, thoracic pain)
OUTCOMES: Med F/U 12 mo , LC 97%, FFDM 85%
OS 1/2 yr = 81/64%, med OS 34 mo
DFS 1/2 yr = 83/68% (signif correl with T stage)
Longer F/U needed

Van Zyp et al, Erasmus Med Ctr (Rotterdam): Stereotactic radiotherapy with real-time tumor tracking for non-small cell lung cancer: Clinical outcome
Radiother and Oncol 91: 296-300 (2009)
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SELECTION:
PATIENT MIX:
STAGING:
EQUIPMENT:
PTV MARGIN:
Stg IA & IB, noncentral tumors, any PFTs
70 pts, 56% IA, med age 76, 49% without histology
PET staging
CyberKnife (real-time tracking for motion comp.)
5mm
DOSE: Most 3 x 20Gy (BED 180), early pts 3 x 15Gy (112.5)
ACUTE TOXICITY: 46% Grade 1-2 (fatigue, SOB, cough)
LATE TOXICITY: 10% Grade 3 (symptomatic RP, CW pain)
OUTCOMES: Med F/U 15 mo, crude FFDM 90%
2yr LC 96% (60Gy) vs. 78% (45Gy)
NOTES:
OS 1/2 yr = 83/62%, DSS 94/86%
Confirms dose response; no diff in outcomes with/without pathology

Fakiris et al (Timmerman group): Stereotactic body radiation therapy for early-stage non-small cell lung carcinoma:
Four-year results of a prospective phase II study
IJROBP 75(3): 677-682 (2009)
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SELECTION:
PATIENT MIX:
STAGING:
EQUIPMENT:
Stg IA & IB, <7cm, any location, medically inoperable
70 pts, 49% IA, med age 76, all with histology
PET staging
Linac-based, body frame immobilization, abdominal compression for motion compensation
PTV MARGIN:
DOSE:
GR 3-5 TOXICITY: 20% (pna, effusion, hemoptysis, decr PFTs, resp failure)
Diff in tox for peripheral vs central tumors NS
OUTCOMES:
5mm axial, 10mm craniocaudal
3 x 20Gy (T1), 3 x 22Gy (T2)
Med F/U 50 mo, median OS 32 mo (signif correl to T stg)
3yr LC 88%, FFDM 87%
3yr OS = 43%, DSS = 82%

Inoue et al (Japan): Clinical outcomes of stereotactic body radiotherapy for small lung lesions clinically diagnosed as primary lung cancer on radiologic examination
IJROBP 75(3): 683-687 (2009)
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SELECTION:
PATIENT MIX:
Stg I, lesion with increasing CT size or PET +
115 pts, 81% IA , med age 77, none with histology
STAGING:
EQUIPMENT:
PTV MARGIN:
DOSE:
Either CT alone or PETCT
Linac-based, abdominal compression and/or gating
“Appropriate”
Varies, 30-70 Gy in 2-10 fx
GR 3-5 TOXICITY: 0% for <2cm, 7% for >2cm (RP, CW pain, rib fx)
OUTCOMES: Med F/U 14 mo
NOTES:
3/5yr OS = 90/90% for <2cm vs. 61/53% for >2cm
Non-prospective, multi institutions & regimens

Preliminary FROG results for Stg I NSCLC 2009
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SELECTION: Stg I, any PFTs, medically inoperable (6 pts refused surgery)
118 pts treated, 74 with at least 6mo F/U and adequate data
PATIENT MIX: Of those 74 pts: 88% IA, med age 74
3 with “suspicious” rather than definitive pathology
PETCT, a few with mediastinoscopy/EBUS STAGING:
EQUIPMENT: CyberKnife with real-time tracking
32% treated without fiducial markers
With percutaneous marker placement, 10% Ptx rate
4 x 12-12.5Gy (central, some pleural-based) DOSE:
3 x 20Gy (IA), 3 x 22Gy (IB) for parenchymal lesions
GR 1-2 TOXICITY: 5% (fatigue, cough)
GR 3-5 TOXICITY: 4% (sub-acute RP, persistent late CW pain/fibrosis)
OUTCOMES: Med F/U 15 mo
2yr LC = 93%, 2yr = FFDM 90%
2yr OS = 74%, 2yr = DFS 94% (NS)

Study Pt #/
% IAs/
Med F/U
Sweden
Amsterdam
45
40% IA
43mo
206
59% IA
12mo
Rotterdam 70
56% IA
15mo
Timmerman
70
49% IA
50mo
Japan (no path)
115
81% IA
14mo
FROG CK 74
88% IA
15mo
Margins BED
(Gy)
5mm axial
10mm cc
5mm
5mm axial
10mm cc
“Appropriate”
Custom, histology based
112
ITV + 3mm 106-180
112-180
180-212
95-180
106-212
LC OS DFS
80% crude 2yr 71%
3yr 55%
97% crude 2yr
64%
2yr
68%
2yr
96/78%
Hi/lo BED
3yr
88%
2yr
62%
3yr
43%
2yr
93%
2yr
86%
3yr
82%
3yr
90% <2cm
61% >2cm
2yr
74%
2yr
94% (NS)

Grills, Mangona, et al
William Beaumont Hospital, Detroit
JCO Feb 2010

 Nonrandomized, retrospective, singleinstitution experience (SBRT patients treated prospectively on Ph II trial)
 124 pts, all ineligible for anatomic lobectomy, all staged w/contrast CT & PETCT
 First published direct comparison of SBRT to any form of surgery for Stg I NSCLC
 Outcomes examined = recurrence, metastasis, survival, complications
 Median F/U 2.5 yrs (30 mo)

 69 pts, all judged ineligible for lobectomy preoperatively
 30% had mediastinoscopy prior to surgery
 20% open thoracotomy, 52% VATS, 28%
VATS
 convert to open
 71% had either preop mediastinoscopy, intraop
LND, or both
 Pathologic T4 lesions/synchronous primaries excluded from analysis

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58 pts, 95% medically inoperable but technically resectable
Treated prospectively on Phase II trial
Staging
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 contrast CT, PETCT, brain MRI, bone scan
20% had mediastinoscopy
Linac radiosurgery with isocentric planning, daily cone-beam CT target registration
GTV defined on 10 different phases of respiration to form ITV, total of 9mm margin added to ITV
48Gy in 4 fx for T1, 60Gy in 5 fx for T2, given QOD
Conservative normal tissue constraints

Median time to LR = 10.5 mo for SBRT, 25 mo for wedge
Median time to RR or DM = 9 mo for SBRT, 25 mo for wedge

 For medically inoperable/borderline operable pts, SBRT provides outcomes equivalent to limited resection, with shorter recovery time & fewer significant complications.
 Randomized clinical trials comparing SBRT to limited resection are justified and needed

 Appropriate margin
 Appropriate dose for central vs parenchymal vs peripheral lesions
 Interpretation of CT & PET changes following
SBRT
 Can/Should we treat PET-positive apparent
Stg IA disease without pathology?

Location, location, location…

RTOG 0915:
A Randomized Phase II Study Comparing 2 Stereotactic
Body Radiation Therapy (SBRT) Schedules for
Medically Inoperable Patients with Stage I Peripheral
Non-Small Cell Lung Cancer
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Activated September 2009
Intergroup RTOG/NCCTG
N: 88 patients
(32 or 88 enrolled as of 9/13/2010)
Primary endpoint: to compare > grade 3 toxicities at 1 year
Secondary endpoints: compare 1 year control rates, survival, DFS, FDG PET SUV changes, PFT’s, biomarkers

Seamless Phase I/II Study of Stereotactic Lung
Radiotherapy (SBRT) for Early Stage, Centrally Located,
Non-Small Cell Lung Cancer (NSCLC) in Medically
Inoperable Patients
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Activated Feb 2009
N: 94 patients (21 enrolled as of 9/13/2010)
Central caution: Timmerman showed 11 fold increase in G>3 complications with 3 Fx 20Gy
Primary endpoint: Determine Max Tolerated Dose (MTD) with 5 Fx over 2 weeks, and local control at that MTD
 MTD = 20% chance of designated adverse event
Secondary endpoint: see if circulating molecular marker levels before and after treatment predict control and adverse events

 Excellent local control rates (85-97%) seen in single institution series
 Already replacing open surgery in Europe
 Questions remain:
 Can results be duplicated in multi-institution settings
 Ideal dose and fractionation
 How best to measure response
 Difficulties with follow-up studies

Doug Johnson, MD, FACR
904-202-7020 djohnson@frogdocs.com
www.frogdocs.com