SABR FOR LUNG CANCER

Hale Basak CAGLAR, MD

Anadolu Medical Center
Department of Radiation Oncology
Istanbul, TURKEY
OUTLINE
❑ General information
 Screening
 Definitions
 Evidence of SABR in ES-NSCLC
◼ Central / ultra-central locations
◼ Single fraction
 SABR for operable patients
GENERAL INFORMATION
GENERAL INFORMATION

Siegal R et al. CA Cancer J Clin 2019

More people will be diagnosed at early stages –
Screening
 Rates of positive screen: 24% vs. 7% (CT vs. CXR)
 20% relative reduction in lung cancer mortality from low-dose CT
screening (6.7% absolute reduction)

Aberle D and NLST investigators, NEJM 2011

OUR PATIENTS ARE OLD

1/3 pts > 75 yo

2/3 pts > 65 yo

SEER Stat Fact Sheets: Lung and Bronchus Cancer 2016

Surgery is the current standard for ES-
NSCLC… But
 Elderly patients (≥ 65 years) have multiple comorbidities
 Willingness to operate is variable
◼ Higher risks of morbidity and mortality
 Less likely to receive guideline recommended treatments
 Less likely to participate or eligible for clinical trials

Community practice: >1/3 of patients do not have surgery for various reasons
Janssen-Heijnen et al, Eur J Cancer, 2007
Rogers Jr SO et al, Ann Surg Oncol 2010
Senthi S, Senan S. Eur J Cancer, 2014
Haasbeek CJ et al, Ann Oncol, 2012
Wang S et al, JCO 2012
Huthins NF, NEJM, 1999
Asamura J Thorac Oncol 2008;
Cykert JAMA 2010
Historically elderly patients were being treated less

Haasbeek CJ et al, Ann Oncol, 2012

Raz DJ et al, Chest 2007
Shirvani SM, et al Int J Rad Oncol Biol Phys 2012
Varlotto J et al, Cancer 2013
How were they treated if surgery not possible?
 Historical alternative has been conventional radiation therapy
with suboptimal outcomes
◼ 16-57% OS
◼ 22-56% CSS at 3 years
◼ 19-70% local failure

Qiao Lung Canc 2003

Rowell NP, Thorax 2001
DEFINITIONS
SABR – SBRT
 A technology
 High ablative doses
 Small tumor volumes / small margins
 Short treatment fractions 1-5
 High dose / fraction
 Steep dose gradient / inhomogeneous target dose
 Accurate targeting
SABR IS CONVENIENT
 Outpatient
 Treatments finishes in a couple of minutes
 Entire course finishes in 1-2 weeks / even 1 session
 No sedation / anesthesia
 Painless
 Immediate return to activities
Current trends have changed

Palma et al JCO 2010

IS SABR BETTER THAN CONVENTIONAL
TECHNIQUE?

Timmerman J Clin Oncol 32:2847-2854

SABR vs CONVENTIONAL RT
SPACE trial, histology proven
 Stage I peripheral < 5 cm
 3-year PFS and OS similar
 Local control favored SABR (72%
vs 59%)
 •Toxicity profile favored SABR
◼ Any grade pneumonitis SABR vs.
3DCRT: 19% vs. 34%
◼ Any grade esophagitis SABR vs.
3DCRT: 8% vs. 30%
 SABR: Trend to improved control,
Higher QoL values, dyspnea,
cough, and chest pain
Nyman J, 2016
SABR vs CONVENTIONAL RT
CHISEL trial, histology proven

Ball D, Lancet Oncol 2019

What do the Guidelines Say?
What do the Guidelines Say?
 ESMO guidelines, Vansteenkiste J, Ann Oncol 2013
◼ SABR is the guideline-recommended treatment for inoperable tumors
(BED10 >100 Gy)

 ASTRO guidelines, Videtic GM, PRO 2017

◼ SABR delivers ablative doses in 1-5 fractions
◼ Schedules using 6-10 fractions with a biologically effective dose (BED) of
≥100 Gy10 with stereotactic techniques are used outside the United
States
Determination of Medical Inoperability
 Not one globally accepted definition
 Standard risk (anticipated operative mortality of <1.5%)
 High risk
◼ Performance status
◼ Presence of medical comorbidities
◼ Pulmonary function tests

 RTOG 0236: FEV-1<40% predicted, postop FEV-1 <30% predicted, DLCO

<40% predicted, baseline hypoxemia or hypercapnia, severe pulmonary
hypertension, diabetes mellitus with end organ damage, severe cerebral,
cardiovascular, or peripheral vascular disease, or severe chronic heart
disease
Choi JI, Transl Lung Cancer Res 2019
EVIDENCE OF SABR IN
LUNG CANCER
RAD ONCS LIKE EVIDENCE
 Single center data
◼ Japan
◼ USA
◼ Europe
◼ Good local controls
◼ Dose matters (BED)
 Multicenter / cooperative group trials
◼ Dose constraints
◼ Centrally located tumors
FACTORS EFFECTING TUMOR CONTROL
 Patient related
◼ Co-morbidities
◼ Age
 Tumor related
◼ Tumor size
◼ Tumor location
◼ Histology
◼ Pleural contact
 Treatment related
◼ BED
◼ Technique
 Other factors Shirata et al, 2012
Wulf et al, 2005
◼ Anemia Baine et al, 2018
◼ Neutrophil to lymphocyte ratio (NLR) and the platelet to lymphocyte ratio (PLR) Timmerman et al, 2012
Pathak et al, 2019
◼ FDG-PET information
Sit at al, 2019
Eriguchi et al, 2019
Oikonomou et al, 2018
DOSE MATTERS
TCP - HYTEC
WHAT IS THE BEST FRACTIONATION SCHEME?
 Depends on the location of the tumor
 More fractions when close to critical structures

Central airway
Brachial Plexus
Esophagus
Major vessels
Heart
Diafragm
RTOG
Centrally Located Tumors
DEFINITION FOR ULTRA-CENTRAL TUMORS
 GTV directly abutting the central airway
 PTV overlaps the trachea or main bronchi
 GTV close to/abutting the proximal bronchial tree

Chaudhuri et al, 2015

Tekatli et al, 2016
Haseltine et al 2016
SABR FOR ULTRA-CENTRAL TUMORS
SABR FOR CENTRAL
ULTRACENTRAL
SABR FOR CENTRAL TUMORS –
NON-CANCER DEATH

Risk adapted SABR 55% first-centimeter

27% second-centimeter
SINGLE FRACTION SABR – LESS IS MORE?
 Still no on standard prescription / fractionation
 Current guidelines offer several fractionation options
RTOG 0915
MEDICALLY OPERABLE PATIENTS
OPERABLE NSCLC – SABR OUTCOMES

Siva S, 2019
SABR vs SURGERY
 Multiple retrospective analyses studies comparing survival after
surgery vs. SBRT
◼ No difference between SBRT and surgery
◼ Surgery superior to SBRT
◼ Most of them have no statistical adjustment for baseline factors
◼ Comparative Effectiveness Studies (CER)
 Propensity-score matching

 Match-pair analysis

 Markov modeling

 Cost-effectiveness

 Meta-analytic methodologies

WLC, 2015
Louie et al, 2015
PROPENSITY SCORE META-ANALYSIS
 OS:
◼ statistically significant differences favouring surgery, both after lobectomy
and sublobar resection
 DSS
◼ no statistically significant differences (neither lobectomy nor sublobar
resection)
THE BEST WAY IS TO RANDOMIZE
ROSEL STARS Z4099
ROSEL STARS Z4099
Eligibility criteria Operable Operable ‘Borderline’
Eligibility criteria non-central
Operable stage IA, IB
Operable ‘Borderline’
operable,
stage IA
non-central (≤ 4 cm)
stage IA, IB stage I <3cm
operable,
stage IA (≤ 4 cm) stage I <3cm
Primary end- Local & OS at 3 OS at 3
point
Primary end- regional
Local & years
OS at 3 years
OS at 3
point control,
regionalQoL years years
treatment
control, QoL
costs at 2-
treatment
and
costs5-years
at 2-
and 5-years
Secondary end- OS, DSS at 3 LRR, DFS,
points
Secondary end- pulmonary
OS, years
DSS at 3 toxicities,
LRR, DFS,
points functions,
pulmonary Local
years PFS pulmonary
toxicities,
QALYs, total
functions, at 3 years;
Local PFS function
pulmonary
costs
QALYs, total toxicities
at 3 years; function
costs
CLOSED toxicities
CLOSED CLOSED
Total enrolled 22 (of 920) 36 (of 10 (of 420)
Total enrolled 22 (of 920) 1030)
36 (of 10 (of 420)
1030)
STARS – ROSEL POOLED ANALYSIS

Immunogenic effects of
SABR?
ONGOING RANDOMIZED TRIALS OF SABR vs
SURGERY
Randomization Process is Important!

Courtesy of D. Moghanaki
MAJOR CRITICISMS BY SURGEONS
 Treatment without pathology
 Lack of nodal staging
 No randomized trials
 Lack of long-term follow-up
 Depriving patients of the only curative option
 Detection of recurrences
TREATMENT WITHOUT PATHOLOGY

 Decision analysis and Markov model

assessing QALYs achieved,
comparing 3 approaches to a nodule
≥1 cc
◼ Surveillance
◼ PET then biopsy if PET+
◼ PET, then treat if PET+
 Sensitivity analysis to determine
factors influencing outcome

Louie et al Chest, 2014; 146(4):1021-1028

TREATMENT WITHOUT PATHOLOGY – WHAT
DO THE GUIDELINES SAY?
PATHOLOGICAL DIAGNOSIS IS IMPORTANT
MEDIASTINAL STAGING BEFORE SABR?
 Patients should be stages minimum with PET-CT
◼ 82% accuracy
◼ False (+) rates can be as high as 25%
◼ Invasive mediastinal staging
◼ Larger, centrally located and multiple tumors tend to have occult
mediastinal metastases despite PET negativity
 Patients who are borderline resectable and will be treated with
SABR should undergo pathological mediastinal staging
 Despite this the outcomes are similar with and without invasive
mediastinal staging after SABR
SURGERY HAS COMPLICATIONS – EARLY MORTALITY

Surgical outcomes ACOSOG Z0030

• 102 surgeons
• 63 institutions
3 y OS 76.2% • 100% general thoracic
Median: 67 yo • 98% R0 resections (4%
segment, 74% lobe, 5%
pneumonectomy)
• 0% N2 by initial MLNS
(13.1 upstaged to st II,
4.4% upstaged to st III)
• 38% perioperative
complications
(45% for age 70+)
• 1.4% mortality
(2.3% for age 70+)

Darling J Thorac Cardiovasc Surg 2011;

Allen Ann Thorac Surg 2006
30 AND 90 DAY MORTALITY FROM SURGERY vs SABR - POOL
ANALYSIS
SALVAGE TREATMENTS ARE POSSIBLE AFTER SABR
SALVAGE TREATMENTS ARE POSSIBLE AFTER SABR
 Chen F, J Thoracic Oncology, 2010
 Neri S, J Thoracic Oncology, 2010
 Hamamoto Y, Japan J Radiology 2012
 Allibhai Z, Eur Resp Journal, 2012
 Hamaji M, J Thoracic Oncology, 2015
 Verstegen N, Radioth Oncol 2016
 Antonoff MB, JTCVS 2017
IMAGING FOR
SURVEILLENCE

Ronden M, J Thoracic Oncol 2018

SUMMARY…
 Effective
 In-expensive
 Convenient
 Outpatient
 Technology has evolved
 Continue to evolve…