sabr for central tumors - biennalecancerologie.org · sabr for ‘central’ tumors systematic...

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]


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


• 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


Moderately central: SABR plan quality


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


Treatment mortality

Moderately central: Treatment mortality


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


Compliance:VUmc & study protocols


• 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)


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 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

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