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

Aberle D and NLST investigators, NEJM 2011

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)

OUR PATIENTS ARE OLD

SEER Stat Fact Sheets: Lung and Bronchus Cancer 2016

1/3 pts > 75 yo2/3 pts > 65 yo

Surgery is the current standard for ES-

NSCLC… But

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

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

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?

Qiao Lung Canc 2003

Rowell NP, Thorax 2001

Historical alternative has been conventional radiation therapy

with suboptimal outcomes

◼ 16-57% OS

◼ 22-56% CSS at 3 years

◼ 19-70% local failure

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 painNyman 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

◼ Anemia

◼ Neutrophil to lymphocyte ratio (NLR) and the platelet to lymphocyte ratio (PLR)

◼ FDG-PET information

Shirata et al, 2012

Wulf et al, 2005

Baine et al, 2018

Timmerman et al, 2012

Pathak et al, 2019

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-centimeter27% 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

Eligibility criteria Operable non-central stage IA

Operable stage IA, IB (≤ 4 cm)

‘Borderline’operable, stage I <3cm

Primary end-point

Local & regional control, QoL treatment costs at 2-and 5-years

OS at 3 years

OS at 3 years

Secondary end-points

OS, pulmonary functions, QALYs, total costs

DSS at 3 yearsLocal PFS at 3 years; toxicities

LRR, DFS, toxicities, pulmonary function

Total enrolled 22 (of 920) 36 (of 1030)

10 (of 420)

ROSEL STARS Z4099

Eligibility criteria Operable non-central stage IA

Operable stage IA, IB (≤ 4 cm)

‘Borderline’operable, stage I <3cm

Primary end-point

Local & regional control, QoL treatment costs at 2-and 5-years

OS at 3 years

OS at 3 years

Secondary end-points

OS, pulmonary functions, QALYs, total costs

DSS at 3 yearsLocal PFS at 3 years; toxicities

LRR, DFS, toxicities, pulmonary function

Total enrolled 22 (of 920) 36 (of 1030)

10 (of 420)

CLOSED CLOSED CLOSED

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

3 y OS 76.2%Median: 67 yo

• 102 surgeons

• 63 institutions

• 100% general thoracic

• 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…