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Professor Suresh Senan
VU University Medical Center
SABR for central tumors:
Is treatment outside clinical trials justified?
Disclosures
• Speakers honoraria from Varian Medical Systems
• Research agreement between Varian Medical
Systems and Department of Radiation Oncology at
VUMC, Amsterdam
SABR for peripheral early-stage NSCLC
• ESMO Guidelines [Vansteenkiste J, 2014]
• SABR is the preferred treatment in patients with a peripheral
early-stage NSCLC who are unfit for surgery, or who refuse it
• For SABR, the tumor dose should be biologically equivalent to
≥100 Gy, prescribed to the encompassing isodose
• NCCN Guidelines [version 7.2015]
• SABR is recommended for patients who are medically inoperable
or who refuse to have surgery after thoracic surgery evaluation
SABR for ‘central’ tumors
Haasbeeck CJ, JTO 2011
“For tumors with a size >5 cm and/or central location, far less data are available for SABR. These patients are preferentially treated with radical radiotherapy using more conventional or accelerated schedules [III, A].”
ESMO Guidelines [Vansteenkiste J, Ann Oncol 2013]
SABR for ‘central’ tumors
Systematic review of SABR
for central tumors Senthi S, Radioth Oncol 2013
Haasbeeck CJ, JTO 2011
20 papers: 563 central tumors
(315 were early-stage NSCLC)
Local control ≥85% when dose
(BED10) was ≥100 Gy
Treatment-related mortality 2.7%
overall, versus 1.0% when normal
tissue dose (BED3) was ≤210 Gy
Grades 3-4 toxicities seen in less
than 9% of patients
SABR for ‘central’ tumors
• Why the reason for concern?
• What are ‘central tumors’?
Location: Risk of fatal hemorrhage
• Huber RM, IJROBP 1997: Randomized trial in patients with endobronchial tumor in
trachea, mainstem or lobar bronchus reported grade 5 hemoptysis in 14% of patients
in the conventional radiotherapy arm to a max. dose of 60 Gy
• Langendijk JA, Radioth Oncology 1998: Retrospective study reported grade 5
hemoptysis in 13% of patients with endobronchial tumor (‘brachytherapy-eligible’)
after conventional radiotherapy
• Cannon DM, JCO 2013: Phase I trial in 79 patients treated in 25 fractions (max
85Gy). The 5 cases of grade 5 toxicity (including 3 hemoptysis) seen in tumors
encasing or abutting main or proximal lobar bronchus. Time: 8-55 months
• Fatal hemoptysis linked to central tumor location, squamous histology, baseline
cavitation, and endobronchial involvement [Ito M, BMC Cancer 2012; Kim Y-H,
Chonnam Med J 2010; Reck M, Ann Oncol 2012 ]
Timmerman et al, JCO 2006
• Phase II trial of SABR (60-66Gy in 3 fractions) for inoperable patients
• T1/T2N0M0 NSCLC (n=70, 22 central, T1 = 34, T2 = 36)
• Median FU: 17.5 months; Median OS: 32.6 months
• Severe toxicity: n = 14 (20%)
– 8 with G3/G4 toxicities (11.4%), median time to toxicity: 7.6 months
– 6 treatment-related deaths (8.6%), of which 4 in central tumors
– Location (hilar/central vs peripheral) is a predictor for severe toxicity
(p=0.004)
Central lung SABR
“This regimen should not be used for patients with tumors near the central airways due to excessive toxicity.”
Central lung SABR
• Song et al, Lung Cancer 2008
• Retrospective study
• SABR (40-60 in 3-4 fractions) for T1/T2N0M0 NSCLC (n=32)
• Median FU: 26.5 months; 1- and 2-year OS: 70.9% and 38.5%
• Severe toxicity:
– 33.3% for central versus 0% in peripheral
– 8 of 9 central tumors developed partial or complete bronchial
stricture (median time to stricture: 20.5 months)
Moderately central tumors: located in the proximal bronchial tree
zone and/or 1 cm from the heart or mediastinum
SABR 8x7.5Gy
– 4D-CT imaging, no cone-beam CT
– 9-11 non-coplanar fixed beams
– Position verifying using orthogonal X-ray imaging
Central SABR at VUmc (2003-08)
Total 63 patients
Median FU 35 months
Median OS 47 months
3-year local control 92.6%
G3 toxicity 6% (2x chest wall pain, 2x dyspnea)
G4/G5 toxicity 0%
Treatment-related death could not be excluded 14.3%
Haasbeek CJ, JTO 2011
COPD and sudden cardiac death
Lahousse L, Eur Heart J 2015
• Population cohort study
• 13 471 persons aged ≥45 years;
up to 24 years follow-up
• Age- and sex-adjusted HR for
sudden cardiac death was 2.12
(95% CI 1.6-2.8) after 5.5 years
of COPD diagnosis
COPD with
exacerbations
• Phase II multi-center RTOG 0813 study [Bejzak A,
WCLC Denver 2015]
• Phase II single-institution study [Bradley JD, WCLC
Denver 2015]
• Single center analysis of plan quality and long-term
clinical outcomes [Tekatli H, Radiother Oncol 2015]
• Literature update [Tekatli H, Radiother Oncol 2015]
SABR for central tumors: New data
RTOG 0813 Trial for central tumors
• Inoperable, biopsy-proven, centrally-located PET-staged
T1-2N0M0 NSCLC, ≤ 5 cm
• 100 evaluable patients from 43 centers (2009-2013)
• Median age 72 years (range 52- 89 years)
• 45% squamous cell carcinoma, 65% T1 tumors
• Median follow-up was 26.6 months
Bezjak A, Oral 19.03, WCLC Denver 2015
RTOG 0813 Trial: Adverse events
• 4% (4/100) fatal hemoptysis potentially attributable to SABR;
mean time to hemoptysis post-SABR was 13 months
Bezjak A, WCLC Denver 2015 (Oral 19.03)
* Gr 5 all due
to hemoptysis
Prospective Phase II Trial of SBRT for
Centrally-Located Lung Cancer
• 42 patients treated with 5 fractions of 11 Gy
• Median follow-up was 13.9 months
• Local Control at 12 months = 100%
• Local Control at 24 months = 83 %
• Nodal control at 24 months = 87%
• OS at 24 month = 34%
• Gr 5 hemoptysis: 1
• Gr 3 pleural effusion (cytology -ve): 1
• Gr 3 atelactasis: 1
Bradley JD, WCLC2015, Mini Oral 33.01
???
Moderately central tumors
Tekatli, H. Radiother Oncol 2015 Tekatli, H. unpublished
Moderately central tumors (Vumc)
• Retrospective cohort:
– 8x7.5Gy RapidArc delivery
– Between 2008-2013
– Single primary, moderately
central NSCLC
– No prior lung surgery
– No prior/simultaneous thoracic,
mediastinal/neck radiotherapy
Tekatli, H. Radiother Oncol 2015
Moderately central lung tumors
Tekatli, H. Radiother Oncol 2015
Moderately central: SABR plan quality
Tekatli, H. Radiother Oncol 2015
Details available on toxicity 78 of total cohort (98%)
≥G3 toxicity 9 (11%)
Grade 3 toxicity 5 (6%)
Radiation Pneumonitis 4 (5%)
Chest Wall Pain 1 (1%)
Bronchial obstruction with atelectasis 1 (1%)
Grade 4 toxicity 0 (0%)
Severe toxicity and mortality
Details available on causes of death 38 of 42 deceased (90%)
Grade 5 toxicity 6 (7.5%)
Likely treatment-related death 3 (4%)
Possible treatment-related death 3 (4%)
Fatal lung hemorrhage 4 (5%)
Patients with interstitial lung disease 4 of the total cohort (4%)
≥G2 Radiation Pneumonitis 3
Tekatli, H. Radiother Oncol 2015
Treatment mortality
Moderately central: Treatment mortality
Tekatli, H. Radiother Oncol 2015
IPF is a chronic, progressive fibrotic
interstitial lung disease of unknown origin
HRCT images: usual interstitial
pneumonia (UIP) pattern
Raghu G, AJRCCM 2011
Interstitial Pulmonary Fibrosis (IPF)
UIP pattern, with extensive
honeycombing: basal
predominant, peripheral
predominant reticular
abnormality, with multiple layers
of honeycombing.
Possible UIP pattern;
peripheral predominant,
basal predominant
reticular abnormality with
moderate amount of
ground glass abnormality,
but without honeycombing.
Central tumors Peripheral tumors
Median FU 45 months (95% CI: 40-51) 47 months (95% CI: 43-52)
Median OS 38 months (95% CI 26-50) 44 months (95% CI: 38-51)
Overall survival
Tekatli, H. Radiother Oncol 2015
Compliance:VUmc & study protocols
Tekatli, H. Radiother Oncol 2015
• Similar 3-year survivals observed as in peripheral
tumors
• Acceptable toxicity rates; patients with interstitial lung
disease (ILD) had higher risk for serious complications
• Organ at risk tolerance doses needs to be refined
• These outcomes should not be extrapolated to ultra-
central tumors
SABR moderately central (8x7.5Gy)
Tekatli, H. Radiother Oncol 2015
Memorial Sloan Kettering Cancer Center
• 108 patients with 5-fractions of SABR
• Median FU: 23 months
• 18 patients with tumors overlapping the proximal bronchial tree
– 4 treatment-related deaths (22%), incl 2 lung hemorrhages
Significantly higher risk of treatment-related death in ultra-
central (22%) versus moderately central (0%) (p<0.001)
SABR in ultra-central tumors
Haseltine JM, PRO 2015
Examples of ultra-central lung tumors treated at VUmc
(12 fractions of 5 Gy (BED10=90Gy, EQD2=75Gy) )
Tekatli, H. unpublished
Hypo-fractionated RT in ultra-central NSCLC
Is treatment outside clinical trials justified?
Treatment of central tumors:
Huber RM, IJROBP 1997: Randomized trial in patients with endobronchial tumor in the
trachea, mainstem or lobar bronchus reported Grade 5 hemoptysis in 14% of patients in
the conventional radiotherapy arm (max dose 60 Gy)
Langendijk JA, Radioth Oncology 1998: Retrospective study reported Grade 5
hemoptysis in 13% of patients with endobronchial tumor (‘brachytherapy-eligible’) after
conventional radiotherapy
Nichols L, Arch Pathol Lab Med. 2012: Post-mortem analysis of 100 lung cancer deaths
found fatal hemorrhage in 12% (7 patients had vascular invasion, 1 infected abscess
invading artery)
Cannon DM, JCO 2013: Phase I trial in 79 patients treated in 25 fractions (max 85Gy).
The 5 cases of Grade 5 toxicity (including 3 hemoptysis) seen in tumors encasing or
abutting main or proximal lobar bronchus. Time: 8-55 months
Is treatment outside clinical trials justified?
Treatment of central tumors:
Huber RM, IJROBP 1997: Randomized trial in patients with endobronchial tumor in the
trachea, mainstem or lobar bronchus reported Grade 5 hemoptysis in 14% of patients in
the conventional radiotherapy arm (max dose 60 Gy)
Langendijk JA, Radioth Oncology 1998: Retrospective study reported Grade 5
hemoptysis in 13% of patients with endobronchial tumor (‘brachytherapy-eligible’) after
conventional radiotherapy
Nichols L, Arch Pathol Lab Med. 2012: Post-mortem analysis of 100 lung cancer deaths
found fatal hemorrhage in 12% (7 patients had vascular invasion, 1 infected abscess
invading artery)
Cannon DM, JCO 2013: Phase I trial in 79 patients treated in 25 fractions (max 85Gy).
The 5 cases of Grade 5 toxicity (including 3 hemoptysis) seen in tumors encasing or
abutting main or proximal lobar bronchus. Time: 8-55 months
Is SABR for central tumors justified
outside clinical trials?
Tekatli H, Radioth Oncol 2015
• SABR is justified for moderately central
tumors, at centers experienced with SABR
• SABR (BED10 ≥100 Gy) is presently not
indicated for ultracentral tumors
• The optimal radiotherapy scheme for
ultracentral tumors is unknown
ViewRay (MRIdian) research
• Prospective study: Visualise
tumor and surrounding
anatomy during treatment
• On-line adaptive treatment
planning
• Reliable dosimetry
Acknowledgments: VUMC clinicians and physicists in the SABR and
ViewRay teams; PhD’s and collaborators in LRCP, Ontario, Canada