Radiosurgery

Radiosurgery: Past, Present, and

Future

Iris C. Gibbs, M.D.,

Associate Professor, Radiation Oncology

Co-Director, Cyberknife Radiosurgery Program

Residency Program Director

Stanford University

?

Disclosures

• Accuray, Inc. (Clinical Advisory Board)

• Accuray, Inc. (honoraria for lectures)

“Rich only in hope, possessing only

incomplete information, incapable of

offering precise techniques, adapted to

diverse forms of cancer, radiotherapy

has, however, obtained definite cures in

cases incurable by surgery.”

– Henri Coutard (1937)

Stereotactic Radiosurgery

• “Stereo” (Greek: “solid” or “3-dimensional”)

“tact” (Latin: “to touch” )

• Thus the literal meaning: “3-dimensional

arrangement to touch”

• Stereotactic Radiosurgery

Technique of delivering high dose radiation

to a specific target while delivering minimal

dose to surrounding tissues

Hallmarks of Radiosurgery

• High Precisionhigh degree of reproducible spatial correlation of the target and the radiation source

• High Accuracy (<1mm)delivering the intended dose within 1 mm of the planned position

• Rapid fall off of radiation dose at the periphery of the targetMinimizes dose to normal tissues in proximity to the target

• High dose conformityMinimizes dose to normal tissues

Radiosurgery & Radiotherapy

Radiosurgery Radiotherapy

Average Dose Per Fraction

High dose

(~ 6 to 25 Gy per fraction)

Low dose

(~ 2 Gy per fraction)

Typical # of Fractions

1 – 5 fractions 30 – 45 fractions

Typical # of Unique Beams Per

Fraction150 – 200 5 – 10

Typical Targeting Accuracy

< 1 millimeter 3 – 20 millimeters

Clinical Intent Tumor ablationCumulative dose tumor

control

500215.B

The Past

Historical Landmarks in Radiosurgery

1951- 1980

Refining radiation sources, and techniques for radiosurgery

Year Author Location Event

1951 Leksell Stockholm

(Karolinksa)

Invention of “Stereotactic Radiosurgery” using

rotating orthovoltage unit

1954 Lawrence Berkeley

(Lawrence/Donner

Labs)

Use of heavy particle treatment for pituitary for

cancer pain

1962 Kjellberg Boston

(Harvard

Cyclotron)

Use of proton beam for intracranial

radiosurgery

1967 Leksell Stockholm Invention of Gammaknife using cobalt-60

sources

1970 Steiner Stockholm Use of Gammknife for AVM’s

1980 Fabrikant Berkeley

(Donner Labs)

Use of Helium ions for AVM’s

The Past of Radiosurgery

Lars Leksell –

- Coined the term “radiosurgery”

-First procedures done with orthovoltage Xray tube

- After initially experimenting with particle beam,

designed Gammknife with 179 cobalt-60 sources in a

hemisphere array

Orthovoltage Xray tube Particle beam


1951- 1980




(Karolinksa)




(Lawrence/Donner

Labs)


cancer pain


(Harvard

Cyclotron)


radiosurgery


sources



(Donner Labs)



John H. Lawrence-- Joined His brother, Ernest Lawrence (1939 Nobel Prize for

developing cyclotron)

-explore the potential use of cyclotron-produced radioisotopes

and nuclear radiation in the treatment of cancer

-- By 1954 Lawrence was using heavy particles for pituitary

treatments for cancer pain

Raymond Kjellberg-

pioneered the first treatment of pituitary

tumors using proton beam radiosurgery at the

Harvard cyclotron.


1951- 1980




(Karolinksa)




(Lawrence/Donner

Labs)


cancer pain


(Harvard

Cyclotron)


radiosurgery


sources



(Donner Labs)


Gamma Knife


1951- 1980




(Karolinksa)




(Lawrence/Donner

Labs)


cancer pain


(Harvard

Cyclotron)


radiosurgery


sources



(Donner Labs)



Ladislau Steiner –

Worked at Karolinska for over 25 years before

spending the remaining career at University of

Virginia at Charlottesville since 1987. Pioneer

in radiosurgery for AVM’s

Féderico Colombo-developed a system for radiosurgery using

LINAC for treatment of AVM’s

Winston/ Lutz– Medical physicist

Wendell Lutz and his physician colleagues at the

Joint Center for Radiation Therapy, Boston,

published the first systematic study on radiosurgery

system performance tests that established the

localization and treatment delivery accuracies

LINAC radiosurgery treatments


1982 -1993


1982 Betti

Colombo

Buenos Aires

Vicenza

Independent development of a system

adapting LINACs for radiosurgery

1986 Lutz/

Winston

JCRT Development of LINAC based SRS based

on common stereotactic frame

1987 Lundsford Pittsburgh First Gammaknife installed in the US

1991 Friedman/

Bova

Florida Development of a more reliable technique

for highly conformal radiosurgery

1991 Lax

Blomgren

Karolinska First to propose extending SRS outside of

the skull

1992 Loeffler/

Alexander

Boston First commercially built dedicated SRS

LINAC (Varian-SRS)

1993 Laing Boston Gill-Thomas-Cosman relocatable frame

University of Pittsburgh leads the

way in Gammaknife Radiosurgery

Kondziolka D, Lunsford LD, Flickinger JC. Neurosurgery. 2008 Feb;62 Suppl 2:707-19.


1983 -1993


1982 Betti

Colombo

Buenos Aires

Vicenza

Independent development of a system

adapting LINACs for radiosurgery

1986 Lutz/

Winston

JCRT Development of LINAC based SRS based

on common stereotactic frame

1987 Lundsford Pittsburgh First Gammaknife installed in the US

1991 Friedman/

Bova

Florida Development of a more reliable technique

for highly conformal radiosurgery

1991 Lax

Blomgren


the skull

1992 Loeffler/

Alexander

Boston First commercially built dedicated SRS

LINAC (Varian-SRS)

1993 Laing Boston Gill-Thomas-Cosman relocatable frame

Refining Radiosurgery for

Flexibility

with Optical Tracking

Bova, Buatti, Friedman et al Int. J. Radiation Oncology Biol. Phys., Vol. 38, No. 4, pp. 875-882, 1997

Relocatable Frames for Fractionated

Stereotactic Radiotherapy

GTC frame

Frame with biteblock and head stabilizer

Frames, frames, and more

frames!!

Talon RelocatableFrame

Salter, Fuss, Volmer etal. Int. J. Radiation Oncology Biol. Phys., Vol. 51, No. 2, pp. 555–562, 2001


1994 -2009

Towards improved conformality, image-guidance, frameless radiosurgery, and SBRT


1994 Lax

Blomgren

Karolinska Stereotactic treatments of abdominal

tumors (1994)

1994 Adler Stanford First clinical use of prototype of

Cyberknife

1995 Hamilton

Lulu

Arizona First report of SBRT case in North America

2000 Murphy Stanford Introduces image-guided radiotherapy

2003 Le/Whyte

Timmerman

Stanford

Indiana

Lung tumor SBRT

2004 Fuss

Salter

San Antonio SBRT with tomotherapy

“The greatest difficulty in the world is

not for people to accept new ideas,

but to make them forget about old

ideas.”

- John Maynard Keynes

Prototype CYBERKNIFE CIRCA 1991

Robotic SRS at Stanford 1994


1994 -2009 SBRT


1991 Lax

Blomgren


the skull

1994 Lax

Blomgren

Karolinska Stereotactic treatments of abdominal

tumors (1994)

1994 Adler Stanford First clinical use of prototype of

Cyberknife

1995 Hamilton

Lulu

Arizona First report of SBRT case in North America

2000 Murphy Stanford Introduces image-guided radiotherapy

2003 Le/Whyte

Timmerman

Stanford

Indiana

Lung tumor SBRT

2004 Fuss

Salter

San Antonio SBRT with tomotherapy

Hamilton Rigid Stereotactic Spine

Frame

Hamilton et al Stereo Funct NS, 1995

Hamilton et al Neurosurgery 36(2):311-19, 1995

The Present

Exquisite Accuracy Required

for Spinal Radiosurgery

• The spine moves during treatment

– Vertebrae can move independent of one

another

– Rigid transformation may be of limited

value in many cases

• Adjacent structures necessitate exquisite

precision and accuracy (preferably <1mm)

Solution for Need for Accuracy:

Image-guidance

Cyberknife

Synchrony™

camera Linear

accelerator

Robotic

Manipulator

Image

detectors

Imaging X-ray sourcesTargeting System

Cyberknife™

Robotic Delivery

System

Radiosurgery Treatment

Planning: Cyberknife

Gibbs et al Rad & Onc, 2007

• Treatment planning

– 100-200 non- isocentric beams

– Optimize tumor coverage; fractionation

– Spinal cord constraints:

Limit multi-fraction volume of spinal cord receiving BED

equivalent of 8 GY to <1ml

Radiosurgery Treatment

Planning: Novalis

• Treatment planning

– 7-9 coplanar, isocentric IMRT fields

– Spinal cord/cauda contoured 6 mm above and

below target

– Spinal cord constraints:

10 % spinal volume limited to 10 Gy

Ryu et al Cancer 109:628-36, 2007

Ryu et al Cancer 97:2013-18, 2003

Current Techniques in

Radiosurgery

• Image-guidance

• Extracranial Radiosurgery (SBRT)

- Spinal Tumors

- Lung Tumors

- Liver/Pancreas Tumors

- Prostate Tumors

• 4-D planning & treatment delivery

Current Spinal Radiosurgery Devices

System Immobilization Image-guidance Error Analysis

Cyberknife

(Accuray, Inc)

Head mask,

cradle,

vacuum bag

Xsight skeletal

tracking or

Fiducial tracking

Phantom- 0.61± 0.27mm

Patient- 0.49 ± 0.22 mm

Novalis

(BrainLAb,

Inc.)

Head mask,

cradle,

vacuum bag

Orthogonal images

to set-up

Optical tracking

Measure iso dose 2-4%

Patient- 1.36 ± 0.11 mm

TomoTherapy

(Tomotherapy

Inc.)

Head mask,

vacuum bag

CT Phantom- ± 0.6 -1.2 mm

Patient- ± 4-4.3 mm

Synergy S

(Elekta, Inc.)

BodyFix (Elekta) Conebeam CT

HexaPOD robotic

couch

Patient (w/o image guidance)-

5.2 ± 2.2 mm

Patient (with image guidance)-

0.9 -1.8 mm (translational)

0.8 – 1.6 o (rotational)

In-house

systems

Stereotactic body frame

or body cast

CT Patient- varies from 1-3.6 mm

Adapted from Sahgal et al IJROBP 71(3): 652–665, 2008

Kim et al IJROBP 73 ( 5),:1574–1579, 2009

Selected Spinal Radiosurgery Series

Author (Institution)

Lesion type/ Treatment system

# Fraction

#pts/ #lesions

Total dose(Gy) (presc. Isodose)

Length FU

Prior RT Pain relief(%)/Comments

Ryu, Rock

(Henry Ford, 2003, 2005)

Mets/ Novalis

1 49/ 61

18

Post op

10-16(90%)

36

36

-- 65% dose escal study

92%(neuro improv/stable

Chang(MDACC, 2007)

Mixed/

In-house

3 or 5 63/74 30 Gy in 5

27 Gy in 3

50 -- 77% 1-yr FFP84% LC

Yamada

(MSKCC, 2008)

LINAC/ IMRT

1 103 18-24 51 none 90% LC/ pain relief

Henderson(Georgetown, 2009)

Mixed/

Cyberknife

3-5 151/ --mets

21 – 24 Gy in 3 fractions– 37.5 Gy in 5 fractions

18 125 >97%Objective QOL/assessments

Gibbs(Stanford, 2007)

MetsCyberknife

1-5 74/ 102 16 – 25 (80%)

33 50 84%

Gerszten(Pittsburgh, 2005)

Mets/ Cyberknife

1 500 12- 25(80%)

53 344 92%

Literature for Radiosurgery for Benign

Extramedullary Spinal Tumors

Moving targets

• Imaging at treatment planning:

– Localization of tumor and sensitive normal

structures

– Characterization of respiratory motion

– Selection of motion management strategy

• Imaging at treatment delivery:

– Verification of anatomic localization

The Solution for Moving Targets:

Image Guidance

Elekta Body Fix

HexaPOD evo, iBEAM evo, BodyFIX, BlueBAG and iGUIDE

HexaPOD evo and iBEAM couch top are compatible with the entire range of Elekta linear accelerators and, when integrated

with the iGUIDE™ software, enables fast, flexible and automated patient set-up. This makes it a time and cost saving tool for

any modern radiation therapy department.

Synchrony® Respiratory

Tracking System

• Surgical resection is the standard of care: ~70% cure rates – if candidates for lobectomy

• BUT… >20% of patients cannot tolerate surgery because of medical comorbidities

• Standard alternative is conventional radiation therapy (historically 10-30% overall survival, 45-65% local control)

Early lung cancer?

Asamura H, J Thorac Oncol, 2008

Dosoretz D, Semin Radiat Oncol, 1996

Radiotherapy for Lung Cancer

Cancer specific survival, unresected Stage I NSCLC

Median OS 14 → 21 months with conventional RT

Wisnivesky, et al., Chest 2005

Rosenzweig, et al., Cancer 2005

Can we improve radiotherapy?

MSKCC dose escalation study3-D CRT, 1.8-2 Gy fractions

Dose intensification is

critical

Thoracic SBRT

Conventional vs. SBRT dose distribution

Indiana University Phase II (Fakiris, ASTRO 2008):– 70 pts Stage I NSCLC, median f/u 50.2 months

– 3 year local control 88%, OS 43%

MDACC experience (Chang, ASTRO 2007):– 73 pts Stage I & recurrent, median f/u 14 months

– Local control 98%

Kyoto University experience (Nagata, ASTRO 2008):– 126 pts Stage I NSCLC < 4cm, included some operable

– 5 year local control 90% (IA), 88% (IB)

– 3 year OS 69% (IA), 80% (IB)

VUMC Amsterdam (Lagerwaard, 2007):– 206 pts Stage I NSCLC, 19% operable, 31% biopsy

proven, median f/u 12 months

– 1 year local control 98%, OS 81%

Medically inoperable

0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 120

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12

Local control rate

BED>100Gy

5y LC 83.1% (95% C.I. 76.8-89.5%)

BED<100Gy

5y LC 44.2% (95% C.I. 23.6-64.8%)

BED>100Gy

BED<100Gy

P<0.0001

BED>100Gy (n=227)

5y CSS 77% (95% C.I. 70-85%)

BED<100Gy (n=73)

5y CSS 62% (95% C.I. 46-78%)

Results of 300 stage I NSCLC patients

presented at ASCO 2006

Cause-specific survival

BED>100Gy (n=227)

BED<100Gy (n=73)

Time (years)

Survival

P < 0.0001

H Onishi / U Yamanashi / ASTRO 2007

Timmerman, et al., J Clin Oncol 2006

Thoracic SBRTIndiana University Phase II experience – Toxicity

RTOG 0236 (Timmerman, ASTRO 2007):Phase II: 55 pts (44 Stage IA, 11 Stage IB),

medically inoperable, peripheral tumors

Dose: 60 Gy in 3 fractions

6 pts (11%) with Grade 3-4 toxicities, no deaths

1 local failure so far (not formally reported)

JCOG 0403 (Onishi, 2008 prelim results,

unpublished):Phase II: 133 pts (82 operable, 51 med inoperable)

Dose 48 Gy in 4 fractions

RP: 7 Grade 3, 1 Grade 4, no deaths

LC 95%, OS 87% (op) & 65% (inop) at 2 yr

Cooperative group trials

• What about limited resection?

– Lung Cancer Study Group, lobectomy vs. limited

resection

– 247 pts with pathologic stage IA, randomized in

OR

– Local recurrence: lobectomy 6%, limited

resection 17%

• Is SBRT a type of “non-surgical wedge

resection?”

What about surgical candidates?

Ginsberg R, Ann Thorac Surg, 1995

0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12

0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12

Local control rate (LC)

Time (years)

LC rate IA (n=65)

5yLC 92%

IB (n=22)

5yLC 82%

P =0.06

P =NS

Squamous (n=25)

5yLC 95%

Adeno (n=54)

5yLC 85%

Mean diameter

Squamous: 27.3mm

Adeno : 25.3mm

LC rate

IA vs IB Sq vs Adeno


Surgical candidates

Overall survival (OS) rateIA vs IB Sq vs Adeno

P =NS

Squamous (n=25)

5yOS 73%

Adeno (n=54)

5yOS 73%

Time (years)

OS rate

Time (years)

IA (n=65)

5yOS 76%

IB (n=22)

5yOS 64%

OS rate

P =0.10Mean diameter

Squamous : 27.3mm

Adeno : 25.3mm0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12


Surgical candidates

0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12

Stage IA

Stage IB

Comparison of 5-year overall survival by SBRT with that by surgery

1: Mountain CF. Semin. Surg. Oncol. 18:106-115,2000.

2: Naruke T. Ann Thorac Surg. 71:1759-1764, 2001.

3: Shimokata K. Jap. J Lung Cancer 47:299-311, 2007.

Clinical stage

SBRT

76% / 92%

64% / 82%

Surgery

Mountain1

JNCCH2

(Japan)

National survey3

(Japan)

61%

40%

71%

44%

77%

60%

OS / LC

Surgical Candidates

• UPMC/Accuray Phase II

– Medically inoperable stage I, CyberKnife SBRT

– Peripheral: 60 Gy/3 fx, Central: 48 Gy/4 fx

• RTOG 0618 Phase II

– Operable stage I NSCLC, peripheral: 60 Gy/3 fx

• STARS (MDACC/Accuray) Phase III

– Operable stage I NSCLC

– Randomized: CyberKnife SBRT vs. Lobectomy

– Peripheral 60 Gy/3 fx, Central: 60 Gy/4 fx

• ROSEL Phase III

– Operable stage I NSCLC, peripheral: 60 Gy/3-5 fx

– Randomized: SBRT vs. Lobectomy

Current & Future Protocols

Future Directions

Goldfinger (1964)

SBRT using Cyberknife vs. HDR dosimetry comparison:

Courtesy of Don Fuller, Cyberknife San Diego

SBRT for Prostate Cancer

“Conclusions: The early and late toxicity profile and

PSA response for prostate SBRT are highly

encouraging.Continued accrual and follow-up will be

necessary to confirm durable biochemical control rates

and low toxicity

profiles.”

King CR, et al , 2009 IJROBP

Extending Current Endeavors

• Functional Radiosurgery

Uveal Melanoma

Treatment f/u 8 months

“Bridging the time since it took its first

faltering steps, radiation therapy is

today a healthy adult: acclaimed and

acknowledged in all intellectual medical

centers as a highly specialized integral

part of the practice of medicine.”

- Alert Soiland (1944)

“Bridging the time since it took its first

faltering steps, radiation therapy is

today a healthy adult: acclaimed and

acknowledged in all intellectual medical

centers as a highly specialized integral

part of the practice of medicine.”

- Alert Soiland (1944)

Radiosurgery

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Radiosurgery

Health & Medicine