Transcript SBRT for Stage I NSCLC: Recently Published Results

Stage I Lung Radiosurgery:
Overview, Results, and
Current RTOG Studies
Douglas Johnson, MD, FACR
Florida Radiation Oncology Group
ACRIN Sept 2010 Annual Meeting
Stereotactic Body Radiotherapy
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High ablative dose
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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
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Damages everything in high dose area
Critical to limit toxicity
Need target tracking or gating system
Disrupts Clonagenicity
100
Survival
multiple 2 Gy
fractions
10-1
single
fraction
10-2
2
4
Dose (Gy)
6
8
Tumor on Plateau,
Toxicity on Transition
PROBABILITY
90%
tumor control
toxicity
10%
DOSE OF RADIATION
Conformal high dose
-This constitutes the tumor control (place it well)
- Being conformal is easy – especially with many beams or arcs
Compact intermediate dose
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
SRS: from BrainBody
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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
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To limit normal tissue dose
Cyberknife (CK)—respiratory modeling for tracking
Linac-based (Novalis NTX)—gating compensation
Evolution of Technological Innovation
CyberKnife
Respiratory Gating
Lung SBRT
LITERATURE
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)
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SELECTION:
PATIENT MIX:
Stg IA & IB, tumors < 5cm and noncentral, any PFTs
45 pts, 40% IA, med age 74, med KPS 80%,
20% without histology
STAGING:
CT staging only
EQUIPMENT:
Linac-based, body frame, abdominal compression
for motion compensation
PTV MARGIN:
5mm axial, 10mm craniocaudal
DOSE:
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%
Med OS 39 mo
NOTES:
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:
Stg IA & IB, tumors < 6cm, any PFTs
206 pts, 59% IA, med age 73, 69% without
histology
STAGING:
PET staging
EQUIPMENT:
Linac-based, 4DCT for motion compensation
PTV MARGIN:
ITV + 3mm
DOSE:
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)
NOTES:
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:
Stg IA & IB, noncentral tumors, any PFTs
70 pts, 56% IA, med age 76, 49% without
histology
STAGING:
PET staging
EQUIPMENT:
CyberKnife (real-time tracking for motion comp.)
PTV MARGIN:
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)
OS 1/2 yr = 83/62%, DSS 94/86%
NOTES:
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:
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PTV MARGIN:
DOSE:
GR 3-5 TOXICITY:
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OUTCOMES:
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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
5mm axial, 10mm craniocaudal
3 x 20Gy (T1), 3 x 22Gy (T2)
20% (pna, effusion, hemoptysis, decr PFTs, resp failure)
Diff in tox for peripheral vs central tumors NS
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:
STAGING:
EQUIPMENT:
PTV MARGIN:
DOSE:
GR 3-5 TOXICITY:
OUTCOMES:
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NOTES:
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Stg I, lesion with increasing CT size or PET +
115 pts, 81% IA, med age 77, none with histology
Either CT alone or PETCT
Linac-based, abdominal compression and/or gating
“Appropriate”
Varies, 30-70 Gy in 2-10 fx
0% for <2cm, 7% for >2cm (RP, CW pain, rib fx)
Med F/U 14 mo
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:
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PATIENT MIX:
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STAGING:
EQUIPMENT:
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DOSE:
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GR 1-2 TOXICITY:
GR 3-5 TOXICITY:
OUTCOMES:
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Stg I, any PFTs, medically inoperable (6 pts refused surgery)
118 pts treated, 74 with at least 6mo F/U and adequate data
Of those 74 pts: 88% IA, med age 74
3 with “suspicious” rather than definitive pathology
PETCT, a few with mediastinoscopy/EBUS
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)
3 x 20Gy (IA), 3 x 22Gy (IB) for parenchymal lesions
5% (fatigue, cough)
4% (sub-acute RP, persistent late CW pain/fibrosis)
Med F/U 15 mo
2yr LC = 93%,
2yr = FFDM 90%
2yr OS = 74%,
2yr = DFS 94% (NS)
Study
Pt #/
% IAs/
Med F/U
Margins BED
(Gy)
LC
OS
Sweden
45
40% IA
43mo
5mm axial
10mm cc
112
80% crude
2yr 71%
3yr 55%
Amsterdam
206
59% IA
12mo
ITV + 3mm
106-180
97% crude
2yr
64%
2yr
68%
Rotterdam
70
56% IA
15mo
5mm
112-180
2yr
96/78%
Hi/lo BED
2yr
62%
2yr
86%
Timmerman
70
49% IA
50mo
5mm axial
10mm cc
180-212
3yr
88%
3yr
43%
3yr
82%
Japan (no
path)
115
81% IA
14mo
“Appropriate”
95-180
FROG CK
74
88% IA
15mo
Custom,
histology
based
106-212
DFS
3yr
90% <2cm
61% >2cm
2yr
93%
2yr
74%
2yr
94% (NS)
Outcomes After Stereotactic Lung
Radiotherapy or Wedge Resection for
Stage I Non-Small Cell Lung Cancer
Grills, Mangona, et al
William Beaumont Hospital, Detroit
JCO Feb 2010
Study characteristics
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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)
Surgery
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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
SBRT
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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
Conclusions
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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
Current SBRT Issues
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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…
CURRENT RTOG LUNG
SBRT TRIALS
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
 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
RTOG 0813
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
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MTD = 20% chance of designated adverse event
Secondary endpoint: see if circulating molecular marker levels
before and after treatment predict control and adverse events
Lung SBRT Summary
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Excellent local control rates (85-97%) seen in
single institution series
Already replacing open surgery in Europe
Questions remain:
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Can results be duplicated in multi-institution
settings
Ideal dose and fractionation
How best to measure response
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Difficulties with follow-up studies
Doug Johnson, MD, FACR
904-202-7020
[email protected]
QUESTIONS?
www.frogdocs.com