Radiosurgery for Lung Cancer

Robert Miller MD

www.aboutcancer.com

0%

20%

40%

60%

Local Regional Distant

Stage Distribution for Lung Cancer

16% 22%

57%

Very few are diagnosed at an early stage

0%

20%

40%

60%

Local Regional Distant

5 Year Survival for Lung Cancer

55%

28%

4%

Cure rate is still poor even in early stages

Age Distribution at Diagnosis

SEER Data 2009-2013

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 1 2 3 4 5

Stage 1

Stage 2

Stage 3

Stage 4

Observed Survival in the US (2003-2009) NSCL

51%31%14%3%

Survival by Stage with SurgeryStage Clinical 5 Year Pathologic 5 Year

IA 60 months 50% 119 month 73%

IB 43 43% 81 58%

IIA 34 36% 49 46

IIB 18 25% 31 36%

IIIA 14 19% 22 24%

IIIB 10 7% 13 9%

IV 6 2% 17 13%

J Thorac Oncol 2007; 2:706

Conventional Radiation for

Stage I and II NSCL

Years Over All Survival Cancer Specific Survival

2 years 22 – 72% 54 – 93%

5 years 0 – 42% 13 - 39%

Cochrane Database Syst Rev. 2001

Stereotactic body radiation therapy (SBRT) is a technique that utilizes precisely targeted radiation to a tumor while minimizing radiation to adjacent normal tissue. This targeting allows treatment of small- or moderate-sized tumors in either a single or limited number of dose fractions.

SBRT has been defined by the American College of Radiology (ACR) and American Society for Radiation Oncology (ASTRO) as the use of very large doses per fraction

SBRT

Stereotactic Ablative Radiotherapy (SABR)

Radiation delivery to a demarcated tumor target using:

optimal immobilizationmotion accountingmany small fieldsaccurate targetingheterogeneous target dosesteep dose gradients outside targetslarge dose per treatment with ablative intent

May use motion control

Upper Threshold

Lower Threshold

Playba

ck

Indicat

or

Breathing Signal

Beam On / Off

Indicator

Conformal High Dose

Techniques for Hitting the Tumor with a High Dose of Radiation

Highly Targeted Conventional (traditional)

Large dose per fraction = greater BED (biologically effective dose)

Assume an alpha/beta ratio of 10 / from RTOG 0915

Tomotherapy

T1 Adenocarcinoma / 10Gy X 5 with Tomotherapy

Original CT Radiation Plan

Original PET 1 Year PET

Squamous Cancer

SBRT with Tomo

PET 8 months later

Contour in the cancer(GTV)

Use the CT and PET to identify the gross tumor volume (GTV)

Or multiple scans to account for movement are combined to create ITV (internal target volume)

Add a margin around the target (PTV)

Need to make the target a little bigger to account for movement or set up problems, but keep the PTV (planning target volume) as small as possible

Add a margin around the target (PTV)

Review the images in all dimensions

Add in the other Organs to Measure the Radiation to Normal Structures

Computer will track doses to ensure the normal structures are protected

PET before SBRT Target PET 2 months Later

80 yo man with adenocarcinoma LUL / Tomo 10Gy X 5

Cyberknife

Cyberknife for Lung Cancer

Complications from CT Needle Biopsy or Fiducial Placement

Cyberknife for Lung Cancer

Radiosurgery or SBRT for Early Stage Lung Cancer

Are the results better than with conventional radiation?

Are the results as good as conventional surgery?

Does it Work?

• It’s better than doing nothing• It’s better than conventional radiation (3D conformal or daily radiation for 6

weeks)• It’s as good if not better that wedge resections or sub-lobar resections• It’s probably better than risking surgery in ‘high risk’ patients (old or poor

medical status)• It may be as good as lobectomy

A Comparison of Stereotactic Body Radiation Therapy (SBRT) Versus No Treatment in Medically Inoperable Patients With Early-Stage Non-Small Cell Lung Cancer (NSCLC)

From August, 2005 to June, 2013, 147 pts were treated with SBRT at a single institution. The thoracic RT consisted of 45-66 Gy/3 F delivered in 9 days. The control group of 43 untreated pts from Funen County, Denmark with early-stage NSCLC, from 2000 to 2012, was extracted from the Danish Lung Cancer Register.

Jeppesen. IJROBP 2014;90:S642

SBRT No Rx

Survival 40 months 9.9 months

Survival/5y 37% 6%

Lung Cancercause of death

39% 77%

Conventional Radiation versus SBRT

Therapy Local Control Survival/3 Y

Conventional 30 – 40% 20 – 35%

SBRT 97.6% 56%

Timmerman RTOG 0236 / JAMA 2010;303:1070

Improved Local Control is Related to Improved Survival

Cause specific Survival

Radiosurgery Results

Robert Timmerman IJROBP 2009;75:677

Months

Years

Radiosurgery Results – Stage I

Cause Specific Survival

Onishi IJROBP 2011;81:1352

0236 A Phase II Trial of Stereotactic Body Radiation Therapy (SBRT) in the Treatment of Patients with Medically Inoperable Stage I/II Non-Small Cell Lung Cancer0618 A Phase II Trial of Stereotactic Body Radiation Therapy (SBRT) in the Treatment of Patients with Operable Stage I/II Non-Small Cell Lung Cancer0813 Seamless Phase I/II Study of Stereotactic Lung Radiotherapy (SBRT) for Early Stage, Centrally Located, Non-Small Cell Lung Cancer (NSCLC) in Medically Inoperable Patients0915 A Randomized Phase II Study Comparing 2 Stereotactic Body Radiation Therapy (SBRT) Schedules for Medically Inoperable Patients with Stage I Peripheral Non-Small Cell Lung Cancer

Long-term Results of RTOG 0236: A Phase II Trial of Stereotactic Body Radiation Therapy (SBRT) in the Treatment of Patients with Medically Inoperable Stage I Non-Small Cell Lung Cancer Timmerman IJROBP 2014;90:S30

n = 55 / 18 Gy per fraction X 3 fractions (54 Gy total)

5-year primary tumor failure rate was 7%

5 year survival 40% / median of 4 years

Grade 3 side effects in 27% . Grade 4 in 4% / no Grade 5

Timmerman JAMA 2010;303:1070

Stereotactic Body Radiation Therapy for Inoperable Early Stage Lung Cancer RTOG 0236

18Gy X 3

OS 55.8%DFS 48%

RTOG 0618: Stereotactic body radiation therapy (SBRT) to treat operable early-stage lung cancer patients. The study opened December 2007 and closed May 2010 after accruing a total of 33 pts. Of 26 evaluable pts, 23 had T1, and 3 had T2 tumors. Median age was 72 years / dose 20Gy X 3

tumor failure rate of 7.7% / 2 years

2-year survival 84.4%

J Clin Oncol 31, 2013 (suppl; abstr 7523)

34Gy X1 12Gy X 4

Local Control/1y 97% 93%

Survival/2y 61% 78%

Side Effects 10% 13%

RTOG 0915

IJROBP 2015;93:757

A Randomized Phase 2 Study Comparing 2 Stereotactic Body Radiation Therapy Schedules for Medically Inoperable Patients With Stage I Peripheral Non-Small Cell Lung Cancer

CyberKnife with tumor tracking: an effective treatment for high-risk surgical patients with stage I non-small cell lung cancerChen Front. Onc. Feb 2012

N = 45 / 42-60Gy in 3 fx

Local regional control at 3 years: 91%Overall survival at 3 years: 75%

Overall Survival

Years

Outcomes After Stereotactic Lung Radiotherapy or Wedge Resection for Stage I Non–Small-Cell Lung Cancer

Grills Journal of Clinical Oncology 28, no. 6 (February 2010) 928-935.

One hundred twenty-four patients with T1-2N0 NSCLC underwent wedge resection (n = 69) or image-guided lung SBRT (n = 58) from February 2003 through August 2008. SBRT was volumetrically prescribed as 48 (T1) or 60 (T2) Gy in four to five fractions.

SBRT reduced the risk of local recurrence (LR), 4% versus 20% for wedge (P = .07). Overall survival (OS) was higher with wedge but cause-specific survival (CSS) was identical.

Local Regional Control

Years

SBRT

Wedge Resection

Grills Journal of Clinical Oncology 28, no. 6 (February 2010) 928-935.

Cause Specific Survival

Years

Grills Journal of Clinical Oncology 28, no. 6 (February 2010) 928-935.

SBRT

Wedge Resection

Lobectomy, Wedge Resection, or Stereotactic Radiotherapy (SBRT) for Stage I Non-small Cell Lung Cancer: Which Treatment Yields the Best Outcome?

Lobectomy Wedge SBRT

Local-regional recur/2y 2% 25% 9%

Overall Survival/2y 85% 91% 72%

Cause Specif Surv/2y 97% 96% 92%

Welsh. IJROBP 2010;78:S180

Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomized trials

Eligible patients in the STARS and ROSEL studies were those with clinical T1–2a (<4 cm), N0M0, operable NSCLC. Patients were randomly assigned in a 1:1 ratio to SABR or lobectomy with mediastinal lymph node dissection or sampling

Chang in Lancet Oncology 16:630. June 2015

Outcome SABR Lobectomy

OS/3y (overall survival) 95% 79%DFS/3y (progression free) 86% 80%ToxicityGrade 3 10% 44%Grade 4 0% 4%

Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomized trials

Chang in Lancet Oncology 16:630. June 2015

Outcomes of stereotactic body radiotherapy (SBRT) in 175 patients with stage I NSCLC aged 75 years and older

Since 2003, 175 consecutive patients (67% male; 32% female) were treated with SBRT at a single center. The median age was 79 years, with 47% of patients aged 80 years or older. 56% of patients had T1 lesions and 44% T2 tumors.

Risk-adapted SBRT schemes were used with the same total dose of 60 Gy in 3 (31%), 5 (53%) or 8 fractions (16%) depending upon risk for toxicity.

Senan Journal of Clinical Oncology 27, no. 15S (May 2009) 9545-9545.

All patients completed planned SBRT and survival rates at 1 and 3 years were 85% and 46%.

60% of patients reported no early side effects, and fatigue (31%), cough (6%), dyspnea (5%), local chest wall pain (3%) and chest wall erythema (2%) were observed in others.

Severe late toxicity was uncommon, with RTOG Grade 3 or higher radiation pneumonitis observed in 2%, radiation-induced rib fractures in 2%, chronic chest wall pain in 3%, and non-malignant pleural effusion in 2% of cases

Senan Journal of Clinical Oncology 27, no. 15S (May 2009) 9545-9545.

Outcomes of stereotactic body radiotherapy (SBRT) in 175 patients with stage I NSCLC aged 75 years and older

Survival With Stereotactic Body Radiation Therapy (SBRT) and Conventional Radiation Therapy (CRT) in Stage I Non-Small Cell Lung Cancer Patients in the Veterans Affairs System

2001 to 2010 along with increased SBRT utilization from 15.6% to 47.3%, and PET utilization from 12.0% to 69.4%.

Boyer IJROBP 2016;96:S9

SBRT Conventional

Overall Survival/4y 30% 19.2%

DSS/ Survival / 4 y 54.7% 33.7%

Stereotactic Body Radiotherapy (SBRT) for Lung Lesions > 4 cm: Safety and EfficacyWoody. IJROBP 2011;81:S603 Cleveland Clinic

Between 2005 and 2010, 51 lesions ranging from 4 to 7.2cm (20 > 5 cm) in 51 pts were treated. Forty (78%) were non small cell lung cancer (NSCLC) and 11 (22%) were oligometastatic disease.

Local control at 12 and 24 months was 100 and 80.8% respectively. Loco-regional control at 12 and 24 months was 88% and 71% respectively.

SBRT appears safe for lung lesions >4cm. Local control was excellent, with distant failure the primary form of failure. There appears to be an association between higher doses and tumor control.

3 X 18 or 20 Gy

5 x 10Gy

Side Effects and Toxicity of SBRT for Lung Cancer

Stereotactic body radiation therapy of early-stage non–small-cell lung carcinoma: Phase I studyMcGarry IJROBP 2005;63:1010

8.0 Gy/fraction for 3 fractions (total dose: 24 Gy / Radiation was given once daily with fractions separated by 2–3 days.

The maximum tolerated dose was not achieved in the T1 stratum (maximum dose = 60 Gy), but within the T2 stratum, the maximum tolerated dose was realized at 72 Gy for tumors larger than 5 cm.

Dose-limiting toxicity included predominantly bronchitis, pericardial effusion, hypoxia, and pneumonitis.

Excessive Toxicity When Treating Central Tumors in a Phase II Study of Stereotactic Body Radiation Therapy for Medically Inoperable Early-Stage Lung CancerTimmerman JCO 2006:24:4833

staged T1 or T2 (≤ 7 cm), N0, M0, biopsy-confirmed NSCLC. All patients had comorbid medical problems that precluded lobectomy. SBRT treatment dose was 60 to 66 Gy total in three fractions during 1 to 2 weeks.

Patients treated for tumors in the peripheral lung had 2-year freedom from severe toxicity of 83% compared with only 54% for patients with central tumors.

Timmerman JCO 2006:24:4833

“No Fly Zone” Avoiding High Dose Centrally

What dose is safe for central cancer

Efficacy and Toxicity Analysis of NRG Oncology/RTOG 0813 Trial of Stereotactic Body Radiation Therapy (SBRT) for Centrally Located Non-Small Cell Lung Cancer (NSCLC)Bezjak IJROBP 2016;96:S8

PET staged T1-2 (<5 cm) N0M0 centrally located NSCLC (within or touching the zone of the proximal bronchial tree or adjacent to mediastinal or pericardial pleura) were successively accrued onto a dose-escalating 5 fraction SBRT schedule ranging from 10-12 Gy/fraction (fr) delivered over 1.5-2 weeks.

Phase I data analysis revealed that maximum tolerated dose was the highest dose level allowed on the study, 12 Gy/fr x 5 fractions. Two-year OS rates of 70% in this medically inoperable group of elderly pts with comorbidities were comparable to pts with peripheral early stage tumors.

Author Local Control Rate

Timmerman 95%Chang 57-100%Milano 73%Song 85%Haasbeek 93%Rowe 94-100%Nuyttens 76-85%Chang 97%

Radiosurgery for Central Lesions

Chang. IJROBP 2014;88:1120

Instead of 50Gy in 4 fractions they are using 70Gy in 10 fractions

Results: Local Control (3y) WAS 96.5% and overall survival (3y) was 70.5%

Conclusion: as long as lower dose constraints are used the outcome for central lesions is as good as peripheral

Is it safe to use radiosurgery for central lesions?

Pulmonary VeinBronchus

Esophagus

Cord Skin

Chestwall

Lung

Published dose limits for the normal structures near the target

Normal structures that need to be identified (contoured) so that the computer can keep track of the radiation exposure and ensure it stays in a safe range

Maximum Dose Constraints (to normal structures) for SABR (from Stablemates Trial)

RTOG 0236 Timmerman JAMA 2010:303:1070

Side Effects of SBRT

Rib Fractures After Stereotactic Body Radiation Therapy for Primary Non-small Cell Lung CancerOguir IJROBP 2012;84:S596

Between November 2001 and April 2009, 177 patients who had undergone SBRT were assessed for clinical symptoms and underwent follow-up thin-section computed tomography (CT).

Forty-one patients were found to have rib fractures on follow-up thin-section CT. The frequency of rib fractures was 23.2%, appearing at a mean of 21.2 months (range, 4 -58 months) after completion of SBRT. The frequency of chest wall pain in patients with rib fractures was 34.1% (14/41), and was classified as Grade 1 or 2.

Limiting Chest Wall Toxicity by Adapting the Dose Schedule and Dose Constraints in Stereotactic Body Radiation Therapy for Early-Stage Lung CancerIJROBP 2016:96:E457

60 Gy (range, 54 – 60). SBRT was delivered in 3 fractions for patients with a CW V30 of less than 30cc. If the CW V30 exceeded 30cc, 5 fractions were delivered and the SBRT plan was optimized on the biologically equivalent parameter of CW V30: CW V37 <30cc.

Three hundred and eighty-one lesions were treated in a cohort of 363 patients with a median follow-up of 17 months (range, 1 - 62). Twenty patients (6%) had CW toxicity: 13 patients (4%) developed CW pain and 9 patients (3%) developed rib fractures.

Dose–effect analysis of radiation induced rib fractures after thoracic SBRTBarbara Stam

N = 466 / Dose was 18 Gy X 3Based on Max dose to ribs

37.5Gy = 50%<22.5Gy = < 5%

http://www.thegreenjournal.com/article/S0167-8140(17)30009-9

Side Effects of SBRT

80 yo 2.7 cm adenocarcinoma / 10Gy X 5 with Tomo

Tomo Radiation CT CT 4 months later

Note: mediastinal mass was thyroid goiter

Same patient, PET at 4 months, not hypermetabolic and assumed to be radiation fibrosis

Same patient, PET at 12 months, not hypermetabolic and assumed to be radiation fibrosis

Compare 3-year survival in high risk stage I NSCL between SAbR (18Gy X 3) and Sublobar resection

High-Risk =

Minimum of 1 major or two minor criteria

• SABR/SBRT has achieved primary tumor control rates and survival , comparable to lobectomy and higher than 3D-CRT In non-randomized comparisons in medically inoperableor older patients

• SBRT is an option if they cannot tolerate a lobectomy, with local control and survival comparable to wedge resections

• In partially completed randomized trials found outcome similar to lobectomy with lower toxicity

• Intensive Regimens (BED >100Gy) have better local control and survival

• For central lesions 4-10 fraction risk-adapted regimens appear to be safe and effective (while 54-60Gy/3 should be avoided)

• For central lesions (from RTOG 0813) 50Gy in 5 fx appearssafe

• Most commonly used up to 5cm but larger lesions can be treated safely if the dose constraints are met

Comparable Survival Data for Stage I Lung Cancer