Stereotactic Body Radiation Therapy for Non-small Cell Lung Cancer

John H. SuhProfessor and Chairman, Dept. of Radiation Oncology

Taussig Cancer InstituteRose Ella Burkhardt Brain Tumor and Neuro-oncology Center

Conflicts of interest

• Abbott Oncology Consultant

• Varian Travel stipend

Outline

• Define lung stereotactic body radiation therapy

• Review the historic outcomes with radiation therapy for early stage lung cancer

• Discuss the advantages of lung SBRT compared to surgery

• Highlight ongoing and completed prospective studies

• Review the toxicities associated with lung SBRT

Sample case of lung SBRT

• 77 year old female with left upper lobe lung adenocarcinoma, T1aN0M0, stage IA; medically inoperable due to impaired PFTs

• Representative axial CT image at simulation

• Representative axial CT image one year post SRS

What is lung SBRT?

• Form of high precision radiotherapy delivery (1-8 fx)–Needs to account for tumor motion

–Needs to be accurate

–Needs to have reproducible setup prior to treatment

–Has good patient compliance

–Has good resource utilization

• Represents one of the significant advances in the curative therapy of lung cancer

• Also known as SABR (stereotactic ablative body radiotherapy)

Stereotactic Ablative Radiotherapy

for Lung Cancer

Treatment Planning

Assessment of tumor motion

Complex beam arrangement

Advanced planning algorithms

Treatment Delivery

Large doses per fraction

Monitoring of breathing

Image-guided targeting

Senan et al. 2012

SBRT can accomplish more than conventional XRT

• Local ControlHistoric comparisons

– SBRT 54 Gy in 3 fx, 98% (local), 91% (lobe) (RTOG 0236)

– EBRT 60-66 Gy / 30-33 fx, ~50% (Qiao, Lung Cancer 2003)

Beaumont experience (Lanni, Am J Clin Oncol 2011)

– SBRT (48-60 Gy in 4-5 fx, n=45) vs. EBRT (70 Gy/ 35 fx, n=41)

– 3y LC, 88% vs. 66% (p=0.10)

• Meta-analysis (Grutters, Radiother Oncol 2010)

SBRT (n=895) vs. EBRT (n=1326)

– 2-year OS, 70% vs. 53% (p=<0.001)

– 2-year DFS, 83.4% vs. 67.4% (p=0.006)

Stephans et al. l SBRT for Central Lung Tumors l 10/4/11 l 9

Stereotactic Radiation for Stage I NSCLC

• Lung SBRT is gaining a track record of efficacy, now reaching the intermediate term, in more robust patients.

–Japanese data with 10 year survivors

–Long term IU and VUmc data

–Multi-institutional RTOG 0236 data

–Many single institutional series

–Japanese, VUmc data for operable patients

–Need larger, cooperative databases

–Intermodality data, better matching

Peripheral Tumors• Dealing primarily with “parallel” tissues, therefore there may be no

point dose limit (if really only parallel).

• Where does the dose-response curve plateau?

Wulf et al., Radiother Oncol. 2005

Peripheral Tumors

Medically Inoperable: Peripheral Tumors

• 55 evaluable patients, 34 month med follow-up.

• Only 1 local failure (3-year LC 97.6%)

• 3 same-lobe failures (3-year lobar control 90.6%)

• 2 nodal failures (3-year loco-regional control 87.2%)

• 11 distant failures (3-year distant failure rate 22.1%)

Timmerman R, et al. JAMA 303:1070-1076, 2010

CCF early retrospective data

(Stephans et al., JTO 2009)

Peripheral Tumors: The “Right” Dose

Wash U, Olsen et al., IJROBP 2011

Wulf et al., Radiother Oncol. 2005

Randomized Phase II Study Comparing Two SBRT Schedules for Medically Inoperable Patients with Stage I Peripheral NSCLC

RTOG 0915

Primary endpoint: rate of 1-year grade 3 or higher AE

Secondary endpoint: 1-year tumor control

1-year OS and DFS

PET SUV changes

PFT test

34 Gy/1 fraction

48 Gy/ 4 fractions

RAND

RAND

T1, T2 (< 5 cm)

Clinically node negative by PET

Peripherally located

StratifyT stageZubrod

Central Tumors

JTO, Dec 2011

3 year local control 92%

Central Tumors• Now dealing with both parallel (target, normal lung), and some serial tissue (trachea, bronchial tree, esophagus), as well as imperfectly categorized heart/great vessels.

• Can we reach plateau without concerns of unreasonable normal tissue toxicity? (yes)

Wulf et al., Radiother Oncol. 2005

Central Tumors

Notes of Caution (Central Tumors)

• 6 possibly treatment related deaths - 4 bacterial pneumonia- 1 pericardial effusion- 1 hemoptysis* (ascribed to carinal recurrence)

Central Tumors – Treated Safely with SBRT

• Early Japanese data didn’t report significant toxicity.– Used smaller fraction sizes (typically 10-12 Gy/fx)

– (Onishi et al., Onimaru et al, Uematsu et al., and Nagata et al).

– These studies did not use any particular avoidance criteria for organs at risk.

• VUmc experience in 63 patients (37 central, 26 “cardiac”) also demonstrates excellent safety profile.– 60 Gy in 8 fractions

– Haasbeek et al. JTO 2011

Stage I NSCLC:Spectrum of Health

MedicallyOperable

“High risk”Operable

MedicallyInoperable

Lobectomy SBRT

Potential Advantages of Surgical Resection

• Confirmation of cancer diagnosis

• Pathological staging

• Nodal dissection

• Information for adjuvant therapy

• Clear measures of outcome to allow salvage

Pathological Staging and Node Dissection

• ACOSOG study demonstrates no difference in OS between nodal sampling and dissection for early stage NSCLC (Darling et al. JTCVS)

– This is different than no sampling, but improved radiographic staging and EBUS while not the same as surgical sampling allow improved non-invasive sampling

• Even if nodal upstaging is 10% with dissection (2-17%), benefit of adjuvant chemo (provided the patient can tolerate) is only 5%. – ie. 10% * 5% = potential 0.5% OS benefit for population

discovering occult node + disease.

(Okada 2005, Miller 2002, Meyers 2006, Crabtree 2010)

Lack of biopsy in some SBRT series

• Wash U data also suggests no difference by radiographic v pathological diagnosis– Robinson, IJROBP 2012

Stephans, CCF, JTO 2010

• Two separate Netherlands reports suggest same (Laagerward et al, ASTRO 2011), and worse (Palma JCO 2010) outcome in non-biopsied patients.

Caveats for comparisons of SBRT and Surgery

• Overall– What medical “risk” patient population?

– Tumor stage / size?

– Type of staging?

• Surgery– Lobar? Sublobar? Both?

– Open vs. VATS?

– Skill set of surgeon/institution?

• SBRT . . .rapidly learning. . .heterogeneity of data. . .

– Dose / fractionation?

–BED = Biologically Effective Dose

–< 100 Gy10 results in worse LC and OS!

– Dose / location relative to organs at risk?

–Central tumors, Chest wall, Lung

Comparisons of SBRT and Surgery

• Lowest level evidence

–Raw comparisons of surgery and SBRT (i.e., my paper vs. your paper)

–Easily confounded by imbalances in patient, tumor, and treatment factors.

–As it turns out, also confounded by practices for coding failures.

–The individual data itself is great, but comparisons are for now, nearly worthless, (it’s a start).

Comparisons of SBRT and Surgery

• Reports of SBRT for “medically operable” pts?

– Retrospective

–Uematsu, et al (IJROBP 2001)

–Onishi, et al (JTO 2007; IJROBP 2010)

–Amsterdam (Senan et al, ASCO 2011)

– Prospective (final results pending)

–JCOG 0403

–Stage IA NSCLC. Phase II (n=65), 48 Gy /4 fx.

–RTOG 0618

–Stage I/II NSCLC. Phase II (n=33), 60 Gy/ 3 fx.

Comparisons of SBRT and Surgery

Uematsu, IJROBP 2001

– 50 pts w/T1 (n=24) or T2 (n=26) N0 NSCLC tx’d w/SBRT (10/94-06/99)

–29 pts were medically operable but refused surgery

– Mix of SBRT doses, prior radiation, etc.

All 50 29 medically operable

3y LC 94% CSS 88% OS 66%

3y OS 86%

Comparisons of SBRT and Surgery

• Lagerwaard, IJROBP in-press– 177 pts w/medically operable, T1 (n=60%) or T2 (n=40%) N0 NSCLC tx’d w/SBRT

from 2003-2010 in the Netherlands.

– SBRT delivered using “risk adapted” scheme (60 Gy in 3, 5, or 8 fractions)

– Median age 76

– Median F/U 32 mo

– 3-year LC 93%

– 3-year OS 84.7%, median OS 61.5 mo

Comparisons of SBRT and Surgery (source bias)

Study Clinical Stage/Group OS

Sugi (World J Surg 2000) IA; 52 open, 48 VATS 5y 85%/90%

LCSG (Ginsberg, Ann Thorac Surg 1995)

IA; 122 wedge, 125 lobe 5y ~60%/~70%

AJCC 6th IA/IB 5y 61% (T1), 38% (T2)

AJCC 7th IA/IB 5y 47-52% (T1), 36-43% (T2)

Uematsu IA/IB (3y) 86%

Onishi IA/IB 5y 76 (T1)%, 64% (T2)

Amsterdam IA/IB (3y) 85%

Comparisons of SBRT and SurgeryCrabtree, JTCVS 2010

Crabtree et al., Wash Univ, JTCVS 2010

Crabtree et al., Wash Univ, JTCVS 2010

All were not significant

• Analysis of patients with Gold’s III/IV COPD, or predicted post-op FEV1 <40%

• 176 VUmc SBRT patients

• Meta-analysis identified 75 additional SBRT patients, and 121 surgical patients from 4 studies meeting search and review criteria

Palma IJROBP, March 2012

Palma et al., VUmc, IJROBP 2012

Markov Modeling Comparisons (Puri et al., JTCVS 2011, and Louie et al., IJROBP 2010)

• Attempt to model a comparison of SBRT and surgery using available data– Demonstrate Surgery to be cost effective…

– … However, outcome highly sensitive to surgical mortality rate

• When surgical mortality exceeds 4% model favors SBRT (Louie)

Low riskLow risk High risk (n=57)High risk (n=57)

Operative Operative MortalityMortality

2.7%2.7% 7%7%

Any Any complicationscomplications

38%38% 43.8%43.8%

ArrhythmiaArrhythmia 22.7%22.7% 21%21%

RespiratoryRespiratory 19.9%19.9% 27%27%Crabtree et al, Wash Univ data

Henderson et al., IJROBP 2010 Mar 1;76(3)

PET scan after lung SBRT

RTOG 0618: Phase II trial of SBRT for patients with operable Stage I/II NSCLC

Quality of Life Comparisons:SBRT

Videtic et al., CCF Data van der Voort van Zyp, IJROBP 2010 (Netherlands)

Comparisons of SBRT and Surgery

• Highest level evidence– Randomized trials

–None completed

– Two trials of SBRT vs. lobectomy for medically operable pts

–ROSEL

–Terminated early

–STARS

–Struggling

–Question asked too early. . .???

– One trial SBRT vs. sublobar resection for “high risk” operable pts

–ACOSOG Z4099/RTOG 1021

Comparisons of SBRT and Surgery – Toxicity?

SBRT

• Skin toxicity?

• Fatigue?

• Chest wall toxicity?

• Pneumonitis?

• Brachial plexopathy?

• Bleeding?

• Fistula or stenosis?

• Esophageal toxicity?

Surgery

• Death?

• Post-op pain?

• Infection?

• Atrial fibrillation?

• Extended hospital stay?

• Decreased pulmonary function?

• Post-thoracotomy pain?

Pulmonary Function

• Studies have been mixed on PFT changes

• IU Phase I protocol described transient decline followed by return to baseline

- Timmerman et al., Chest 2003;124(5)

• IU Phase II protocol showed no change in FEV1 but DLCO ↓ 1.11 mg/min/mm Hg/y

- Henderson et al., IJROBP 2008 Oct 1;72(2)

• RTOG 0236 showed 1 grade 4 (2%) and 8 grade 3 (15%) pulmonary/upper respiratory events (included PFT changes).

- Timmerman et al., JAMA 2010 March 17;303(11)

Toxicity - Pneumonitis

• Most studies report pneumonitis as 0-5%:

• 25 patients treated at U. Tokyo to 48 Gy in 4 fractions prescribed to isocenter. - Grade 2-5 RP 29%, including 3 pt’s w grade 5

- RP correlated with high conformality index

- In general had high conformality, 7 pts > 2.00

Yamashita et al., Rad Oncol 2007;2:21

IJROBP 2012 82:2

ACUTE CT CHANGES (≤ 6 months) LATE CT CHANCES (> 6 months)

Description Description

Patchyconsolidation

Consolidation ≤ 5 cm in largest dimension and/or the involved region contains more consolidation than aerated lung.

Mass-like

Well-circumscribed focal consolidation limited to area surrounding the tumor. The abnormality must be larger than the orginal tumor size

Diffuse GGO> 5 cm of GGO, (without consolidation). The involved region contains more GGO than normal lung

Scar-like Linear opacity in the region of the tumor, associated with loss of volume

Patchy GGO≤ cm of GGO, (without consolidation), and/or the involved region contains less GGO than normal lung

No evidence of increased density

No new abnormalities. Includes patients with tumors that are stable, regressing or resolved, or fibrosis in the position of the original tumor that is not larger than the original tumor

Diffuse consolidation

Consolidation > 5 cm in largest dimension. The involved region contains more consolidation than aerated lung.

Modified conventional pattern

Consolidation, loss of volume, bronchiectasis similar to conventional radiation fibrosis, but usually less extensive. May be associated with GGO.

Senan et al. 2012

Importance of the multi-disciplinary team

• Radiation oncologist

• Radiologists

• Nuclear medicine physicians

• Pulmonologists

• Pathologists

Conclusions

• Lung SBRT is an effective, efficient, and safe radiation technique for patients with early stage NSCLC

• Peripheral lesions may be treated more aggressively compared to centrally located lesions

• Clinical trials are underway to better understand the role of lung SBRT

Title of Presentation Arial Regular 22ptSingle line spacingUp to 3 lines long

Date 20ptsAuthor Name 20ptsAuthor Title 20pts