SBRT for Stage I NSCLC: Recently Published Results
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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
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
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 BrainBody
Radiosurgery: initially CNS
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
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)
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)
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)
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)
SELECTION:
PATIENT MIX:
STAGING:
EQUIPMENT:
PTV MARGIN:
DOSE:
GR 3-5 TOXICITY:
OUTCOMES:
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)
SELECTION:
PATIENT MIX:
STAGING:
EQUIPMENT:
PTV MARGIN:
DOSE:
GR 3-5 TOXICITY:
OUTCOMES:
NOTES:
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
SELECTION:
PATIENT MIX:
STAGING:
EQUIPMENT:
DOSE:
GR 1-2 TOXICITY:
GR 3-5 TOXICITY:
OUTCOMES:
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
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
69 pts, all judged ineligible for lobectomy
preoperatively
30% had mediastinoscopy prior to surgery
20% open thoracotomy, 52% VATS, 28%
VATSconvert to open
71% had either preop mediastinoscopy, intraop
LND, or both
Pathologic T4 lesions/synchronous primaries
excluded from analysis
SBRT
58 pts, 95% medically inoperable but technically
resectable
Treated prospectively on Phase II trial
Staging
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
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
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
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
Lung SBRT Summary
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
[email protected]
QUESTIONS?
www.frogdocs.com