William R. Silveira, M.D., Ph.D.

Department of Radiation OncologyOncology Care ProvidersCommunity Medical Centers

CyberKnife: A New Option In the Treatment of Lung Cancer

Conventional radiation therapyDevelopment of radiosurgery • Stereotactic body radiosurgery (SBRT)

SBRT for inoperable patients• Early results & Phase II data• Cases/Examples

SBRT for operable patients

Early stage non-small cell lung cancer (NSCLC)

The Gold Standard for Early Stage Lung Cancer: Surgery

Peripheral T1N0 NSCLC247 patientsLobectomy vs. Limited resection3 year OS ~75-80%Limited resection tripledLocoregional recurrence: 6% → 18%

Ginsberg et al. Annals of Thoracic Surgery (1995) 60:615-623

LCSG 821

Does conventional radiation therapy help?

The Other End of the Spectrum: The Inoperable Patient

Does conventional radiation therapy help?

The Other End of the Spectrum: The Inoperable Patient

Linear Accelerator (Linac)

Timmerman JCO 32: 2847-2854

2D/3D Conventional Radiation

60 Gy in 30 treatments

Author Dose 5-year OS 5-year LC Intercurrent death

Dosoretz et al.

60-69 Gy 10% N/A 11%

Krol et al. 60-65 Gy 15% 25% 34%

Kaskowitz et al.

63 Gy 6% 0% 27%

Sibley et al. 55-70 Gy 13% N/A 43%

Graham et al.

60 Gy 13% N/A 28%

Conventional Radiation Therapy for Stage I/II NSCLC

Death: ~30% of distant metastases,~30% of local failure, ~30% intercurrent Sibley GS. Radiotherapy for patients with medically inoperable Stage I nonsmall cell lung carcinoma:

smaller volumes and higher doses--a review. Cancer 1998;82:433-438.

The Richard L. Roudebush VAMC, Indianapolis, IN

RT ObsMedian Survival (mos) 20 14Death (from cancer) 43% 53%

Conventional RT for Early Stage (I/II) NSCLCIs it better than nothing?

CHEST 2002; 121:1155–1158

The Richard L. Roudebush VAMC, Indianapolis, INRT Obs

Median Survival (mos) 20 14Death (from cancer) 43% 53%

Conventional RT for Early Stage (I/II) NSCLCIs it better than nothing?

CHEST 2002; 121:1155–1158

SEER (Chest 2005): 4,300 patientsRT improved MS vs. ObsStage I 14 → 21 monthsStage II 9 → 14 months

Didn’t help 5-year CSSStage I 15%Stage II 10%

An Improvement with Hypofractionation

Slotman et al. (1996)• 31 pts, T1–2N0 tx w/ 4 Gy/day to 48 Gy • Peripheral lesions only, poor PS.• “Postage Stamp Field” – No nodes

• 3-year OS 42%• 3 year DFS 76%• 6% regional failure

Why? Radiobiology

48 Gy in 12 treatments

Challenge: maximize dose, minimize toxicity

It’s more of a problem in the CNS

Intracranial Radiosurgery – Gamma Knife

Gamma Knife

Beautiful plans & excellent outcomes

Cumbersome & limited to the CNS

What is a “CyberKnife?” Linear accelerator + robotic arm • Sub-mm accuracy• 6 degrees of freedom

Treat anywhere in the body• Stereotactic Body Radiation Therapy• SBRT or SABR

Inventor: Dr. John Adler, Stanford

What is a “CyberKnife?” Linear accelerator + robotic arm • Sub-mm accuracy• 6 degrees of freedom

Treat anywhere in the body• Stereotactic Body Radiation Therapy• SBRT or SABR

Inventor: Dr. John Adler, Stanford

CyberKnife by Accuray

Versatile – initially used for CNS disease

Outside the CNS: “There’s plenty of room at the bottom.”

-Richard Feynman

Small beams, highly targeted

Multiple beams converge

Conformal/Steep fall-off

Hypo-fractionated

Account for motion• 6D skull, fiducials, synchrony,

X-sight spine, X-sight lung

SBRT (SABR) via CK: Another Way to give 60 Gy

Team effort: from tumor board to

treatment delivery

Planning: Radiation Oncologist & PhD

physicist

Author Dosing Local control 3-year OS

Onishi et al. Multiple 84% (3 yr) 57%Nyman et al. 15 Gy x3 80% (3.5 yr) 55%Uematsu et al. 50-60 Gy in 5-

1094% (5 yr) 66%

Timmerman et al.

T1: 20 Gy x3T2: 22 Gy x3

88% (3 yr) 43%

Early SBRT Data for Inoperable IA/B NSCLC

BED >/= 100 Gy was superior• 5 year LC 57% vs. 95%• 5 year OS 30% vs. 71%

Dose ResponseOnishi et al. JTO (2007)

And then came toxicity…

Time to Grade 3 to 5 toxicity

Response & Toxicity JCO 24:4833-4839 (2006)

2 year freedom from toxicity: 83% vs. 54%11x higher risk

Phase II: 70 patients, T1-2 NSCLC, inoperable3 month response (PR + CR): 60%, 2-yr LC 95%Median OS 33 months, 2 year OS 55%

(8) Grade 3-4: pericardial effusions, decline in PFTs, pneumonia, effusions, apnea, skin reaction

(6) Grade 5 (death): 4 pneumonia, pericardial effusion, carina w/ hemoptysis

First major phase II trialRTOG 02-36

Dose: 18 Gy x3T1-3N0 NSCLC, <5 cm, peripheral, 55 pt w/ medical conditions precluding surgery

3-year Control Rates• Primary tumor control rate: 98%• Local control: 91%• Local & regional control: 87%

• Rate of disseminated failure: 22%• 15% for T1 vs. 47% for T2• 6% for SCC vs. 31% for non-SCC

JAMA. 2010 March 17; 303(11): 1070–1076.

3-year Survival Rates•Disease-free survival 48.3%•Overall survival 55.8%(18% died of lung cancer)

•Median DFS 34 months31 months if T2

•Median OS 48 months34 months if T2

JAMA. 2010 March 17; 303(11): 1070–1076.

Toxicity•Grade 3 toxicity: 13%• Severe cough not responsive to

intervention, dyspnea at rest, intermittent O2/steroids needed

•Grade 4 toxicity: 4%• Continuous oxygen or assisted ventilation

•Grade 5 toxicity: No deaths from toxicity

JAMA. 2010 March 17; 303(11): 1070–1076.

Author Dose Local control 3-year OS

Timmerman et al. 2010

18 Gy x3 98% 56%

Baumann et al.

2009

15 Gy x 3 92% 60%

Ricardi et al. 2010

15 Gy x3 88% 57%

Nagata et al. 12 Gy x 3 98% 83%

Additional Phase II Data for Unresectable IA/B NSCLC

Comparative Effectiveness of 5 Treatment Strategies for Early-Stage NSCLC in the Elderly (SEER)

IJROBP; 84 (5) 1060-1070

100%

80%

50%

40%

20%

Years

10,923 patients aged ≥66 years Stage IA-IB NSCLC

In the propensity-score matched analysis, survival after SBRT was similar to that after lobectomy

Lobectomy

SBRT

Increased use of SBRT and a

decline (12%) in the proportion of

untreated elderly patients

Palma et al. JCO 2010

Overall Survival is increasing (16%) for this

population with historically poor

outcomesPalma et al. JCO 2010

RTOG 08-13: Phase II• Question: How to treat central tumors

safely?• Dose escalation trial• 9, 10, 11, 12 Gy x5

RTOG 09-15, Phase II• Question: Single session safety?• T1-2 inoperable, peripheral• Randomize: 34 Gy vs. 12 Gy x4• Winning arm to face 20 Gy x3

Pending Data For Inoperable Patients

A few cases…

53 M, COPD, cT1aN0M0 (1.3 cm), Stage IA, moderately differentiated adenocarcinoma of the RUL, FEV1 1.45 L, DLCO 23%.

6 months post treatment

67 F, COPD, pulmonary HTN, cT2aN0M0 (4.5 cm), Stage IB, poorly diff SCC of the LUL, 2L NC at baseline, wheelchair bound, FEV1 0.6 L, DLCO 11%

2 months post treatment

66 F, cT2aN0M0 (4.7 cm), Stage IB, poorly differentiated SCC of the LUL, FEV1 1.3 L, DLCO 50%.

66 F, cT2aN0M0 (4.7 cm), Stage IB, poorly differentiated SCC of the LUL, FEV1 1.3 L, DLCO 50%.

6 months post treatment

12 months post treatment

Metastatic disease (briefly)

2 months post treatment

Operable Early Stage NSCLC

Retrospective Data: SBRT can approach limited resection & lobectomy

RTOG 06-18 Phase II, operable I/II NSCLC, 18 Gy x3• PRELIMINARY: 2 year LF (primary lobe) 19.2%, OS 84.4%

PHASE III Studies• ROSEL (Dutch): SBRT vs. Surgery, CLOSED EARLY• STARS (Accuray/MDACC): CK vs. Surgery CLOSED EARLY• ACOSOG 4099/RTOG 1021: Sublobar resection +/- brachy vs.

SBRT: CLOSED

Operable Patients

Retrospective Data: SBRT can approach limited resection & lobectomy

RTOG 06-18 Phase II, operable I/II NSCLC, 18 Gy x3• PRELIMINARY: 2 year LF (primary lobe) 19.2%, OS 84.4%

PHASE III Studies• ROSEL (Dutch): SBRT vs. Surgery, CLOSED EARLY• STARS (Accuray/MDACC): CK vs. Surgery CLOSED EARLY• ACOSOG 4099/RTOG 1021: Sublobar resection +/- brachy vs.

SBRT: CLOSED

Operable Patients

cT1-2aN0M0, operable NSCLC, 58 pts , SBRT vs. Lobectomy

SABR versus lobectomy for operable stage I NSCLC: A pooled analysis of 2 randomized trials

SBRT Lobectomy

Deaths 1 6 (1 of surgical comp)

3-year OS 95% 86%Local recurrence 1 N/A

Regional recurrence 4 (13%) 1 (4%)Distant metastases 1 2Grade 3/4 toxicity 10% 44%

Inoperable patients: it’s an easy choice

Operable: Choose wisely – more data is needed• Low risk upfront, likely higher risk of regional recurrence• Consider: tumor size, pathology, full staging

Question remains: What is the role for systemic therapy?

Thoughts on SBRT for Early Stage NSCLC

Surgery is the standard of care for early stage NSCLC

Conventional radiotherapy fairs poorly for early NSCLC

SBRT/SABR has proven to help tremendously• Higher effective doses to be delivered safely• Increased LC and OS for inoperable early stage NSCLC • Promising for operable early stage NSCLC

We have a lot to learn: Surgery vs. SBRT for operable pts.

Summary

Oncology Care Providers, Drs. Brent Kane and Uma SwamyPhysics: Dr. Georg Weidlich, Ph.D.CCC Radiation Therapists & NursingLung Nodule ProgramCommunity Medical CentersAll of our referring physicians

Acknowledgements