1. Radiosurgery: Past, Present, and
Future
?
Iris C. Gibbs, M.D.,
Associate Professor, Radiation Oncology
Co-Director, Cyberknife Radiosurgery Program
Residency Program Director
Stanford University

2. Disclosures
• Accuray, Inc. (Clinical Advisory Board)
• Accuray, Inc. (honoraria for lectures)

3. “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)

4. 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

5. Hallmarks of Radiosurgery
• High Precision
high 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 target
Minimizes dose to normal tissues in proximity to the
target
• High dose conformity
Minimizes dose to normal tissues

6. Radiosurgery & Radiotherapy
Radiosurgery Radiotherapy
High dose
Average Dose Per Low dose
Fraction (~ 6 to 25 Gy per
(~ 2 Gy per fraction)
fraction)
Typical # of
Fractions
1 – 5 fractions 30 – 45 fractions
Typical # of
Unique Beams Per 150 – 200 5 – 10
Fraction
Typical Targeting
Accuracy
< 1 millimeter 3 – 20 millimeters
Cumulative dose tumor
Clinical Intent Tumor ablation
control
500215.B

7. The Past

8. Historical Landmarks in Radiosurgery
1951- 1980
Refining radiation sources, and techniques for radiosurgery
Year Author Location Event
1951 Leksell Stockholm Invention of “Stereotactic Radiosurgery” using
(Karolinksa) rotating orthovoltage unit
1954 Lawrence Berkeley Use of heavy particle treatment for pituitary for
(Lawrence/Donner cancer pain
Labs)
1962 Kjellberg Boston Use of proton beam for intracranial
(Harvard radiosurgery
Cyclotron)
1967 Leksell Stockholm Invention of Gammaknife using cobalt-60
sources
1970 Steiner Stockholm Use of Gammknife for AVM’s
1980 Fabrikant Berkeley Use of Helium ions for AVM’s
(Donner Labs)

9. 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

10. Historical Landmarks in Radiosurgery
1951- 1980
Refining radiation sources, and techniques for radiosurgery
Year Author Location Event
1951 Leksell Stockholm Invention of “Stereotactic Radiosurgery” using
(Karolinksa) rotating orthovoltage unit
1954 Lawrence Berkeley Use of heavy particle treatment for pituitary for
(Lawrence/Donner cancer pain
Labs)
1962 Kjellberg Boston Use of proton beam for intracranial
(Harvard radiosurgery
Cyclotron)
1967 Leksell Stockholm Invention of Gammaknife using cobalt-60
sources
1970 Steiner Stockholm Use of Gammknife for AVM’s
1980 Fabrikant Berkeley Use of Helium ions for AVM’s
(Donner Labs)

11. The Past of Radiosurgery
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.

12. Historical Landmarks in Radiosurgery
1951- 1980
Refining radiation sources, and techniques for radiosurgery
Year Author Location Event
1951 Leksell Stockholm Invention of “Stereotactic Radiosurgery” using
(Karolinksa) rotating orthovoltage unit
1954 Lawrence Berkeley Use of heavy particle treatment for pituitary for
(Lawrence/Donner cancer pain
Labs)
1962 Kjellberg Boston Use of proton beam for intracranial
(Harvard radiosurgery
Cyclotron)
1967 Leksell Stockholm Invention of Gammaknife using cobalt-60
sources
1970 Steiner Stockholm Use of Gammknife for AVM’s
1980 Fabrikant Berkeley Use of Helium ions for AVM’s
(Donner Labs)

13. Gamma Knife

14. Historical Landmarks in Radiosurgery
1951- 1980
Refining radiation sources, and techniques for radiosurgery
Year Author Location Event
1951 Leksell Stockholm Invention of “Stereotactic Radiosurgery” using
(Karolinksa) rotating orthovoltage unit
1954 Lawrence Berkeley Use of heavy particle treatment for pituitary for
(Lawrence/Donner cancer pain
Labs)
1962 Kjellberg Boston Use of proton beam for intracranial
(Harvard radiosurgery
Cyclotron)
1967 Leksell Stockholm Invention of Gammaknife using cobalt-60
sources
1970 Steiner Stockholm Use of Gammknife for AVM’s
1980 Fabrikant Berkeley Use of Helium ions for AVM’s
(Donner Labs)

15. The Past of Radiosurgery
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

16. Historical Landmarks in Radiosurgery
1982 -1993
Year Author Location Event
1982 Betti Buenos Aires Independent development of a system
Colombo Vicenza adapting LINACs for radiosurgery
1986 Lutz/ JCRT Development of LINAC based SRS based
Winston on common stereotactic frame
1987 Lundsford Pittsburgh First Gammaknife installed in the US
1991 Friedman/ Florida Development of a more reliable technique
Bova for highly conformal radiosurgery
1991 Lax Karolinska First to propose extending SRS outside of
Blomgren the skull
1992 Loeffler/ Boston First commercially built dedicated SRS
Alexander LINAC (Varian-SRS)
1993 Laing Boston Gill-Thomas-Cosman relocatable frame

17. University of Pittsburgh leads the
way in Gammaknife Radiosurgery
Kondziolka D, Lunsford LD, Flickinger JC. Neurosurgery. 2008 Feb;62 Suppl 2:707-19.

18. Historical Landmarks in Radiosurgery
1983 -1993
Year Author Location Event
1982 Betti Buenos Aires Independent development of a system
Colombo Vicenza adapting LINACs for radiosurgery
1986 Lutz/ JCRT Development of LINAC based SRS based
Winston on common stereotactic frame
1987 Lundsford Pittsburgh First Gammaknife installed in the US
1991 Friedman/ Florida Development of a more reliable technique
Bova for highly conformal radiosurgery
1991 Lax Karolinska First to propose extending SRS outside of
Blomgren the skull
1992 Loeffler/ Boston First commercially built dedicated SRS
Alexander LINAC (Varian-SRS)
1993 Laing Boston Gill-Thomas-Cosman relocatable frame

19. 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

20. Relocatable Frames for Fractionated
Stereotactic Radiotherapy
GTC frame
Frame with biteblock and head stabilizer

21. Frames, frames, and more
frames!!

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

23. Historical Landmarks in Radiosurgery
1994 -2009
Towards improved conformality, image-guidance, frameless radiosurgery, and SBRT
Year Author Location Event
1994 Lax Karolinska Stereotactic treatments of abdominal
Blomgren tumors (1994)
1994 Adler Stanford First clinical use of prototype of
Cyberknife
1995 Hamilton Arizona First report of SBRT case in North America
Lulu
2000 Murphy Stanford Introduces image-guided radiotherapy
2003 Le/Whyte Stanford Lung tumor SBRT
Timmerman Indiana
2004 Fuss San Antonio SBRT with tomotherapy
Salter

24. “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

25. Prototype CYBERKNIFE CIRCA 1991

26. Robotic SRS at Stanford 1994

27. Historical Landmarks in Radiosurgery
1994 -2009 SBRT
Year Author Location Event
1991 Lax Karolinska First to propose extending SRS outside of
Blomgren the skull
1994 Lax Karolinska Stereotactic treatments of abdominal
Blomgren tumors (1994)
1994 Adler Stanford First clinical use of prototype of
Cyberknife
1995 Hamilton Arizona First report of SBRT case in North America
Lulu
2000 Murphy Stanford Introduces image-guided radiotherapy
2003 Le/Whyte Stanford Lung tumor SBRT
Timmerman Indiana
2004 Fuss San Antonio SBRT with tomotherapy
Salter

28. Hamilton Rigid Stereotactic Spine
Frame
Hamilton et al Neurosurgery 36(2):311-19, 1995
Hamilton et al Stereo Funct NS, 1995

29. The Present

30. Exquisite Accuracy Required
for Spinal Radiosurgery
• The spine moves during treatment
Solution for Need for Accuracy:
– Vertebrae can move independent of one
another
– Rigid transformation may be of limited
Image-guidance
value in many cases
• Adjacent structures necessitate exquisite
precision and accuracy (preferably <1mm)

31. Targeting System Imaging X-ray sources
Cyberknife
Robotic
Synchrony™ Manipulator
camera Linear
accelerator
Image
detectors
Cyberknife™
Robotic Delivery
System

32. Radiosurgery Treatment
Planning: Cyberknife
• 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
Gibbs et al Rad & Onc, 2007

34. 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

35. Current Techniques in
Radiosurgery
• Image-guidance
• Extracranial Radiosurgery (SBRT)
- Spinal Tumors
- Lung Tumors
- Liver/Pancreas Tumors
- Prostate Tumors
• 4-D planning & treatment delivery

36. Current Spinal Radiosurgery Devices
System Immobilization Image-guidance Error Analysis
Cyberknife Head mask, Xsight skeletal Phantom- 0.61± 0.27mm
(Accuray, Inc) cradle, tracking or Patient- 0.49 ± 0.22 mm
vacuum bag Fiducial tracking
Novalis Head mask, Orthogonal images Measure iso dose 2-4%
(BrainLAb, cradle, to set-up Patient- 1.36 ± 0.11 mm
Inc.) vacuum bag Optical tracking
TomoTherapy Head mask, CT Phantom- ± 0.6 -1.2 mm
(Tomotherapy vacuum bag Patient- ± 4-4.3 mm
Inc.)
Synergy S BodyFix (Elekta) Conebeam CT Patient (w/o image guidance)-
(Elekta, Inc.) HexaPOD robotic 5.2 ± 2.2 mm
couch Patient (with image guidance)-
0.9 -1.8 mm (translational)
0.8 – 1.6 o (rotational)
In-house Stereotactic body frame CT Patient- varies from 1-3.6 mm
systems or body cast
Adapted from Sahgal et al IJROBP 71(3): 652–665, 2008
Kim et al IJROBP 73 ( 5),:1574–1579, 2009

37. Selected Spinal Radiosurgery Series
Author Lesion # #pts/ Total Length Prior RT Pain
(Institution) type/ Fraction #lesions dose(Gy) FU relief(%)/
Treatment (presc. Comments
system Isodose)
Ryu, Rock Mets/ 1 49/ 61 10-16 36 -- 65% dose escal
(Henry Ford, Novalis (90%) study
2003, 2005) 18 36 92%(neuro
Post op improv/stable
Chang Mixed/ 3 or 5 63/74 30 Gy in 5 50 -- 77% 1-yr FFP
(MDACC, 2007) In-house 27 Gy in 3 84% LC
Yamada LINAC/ 1 103 18-24 51 none 90% LC/
(MSKCC, 2008) IMRT pain relief
Henderson Mixed/ 3-5 151/ -- 21 – 24 Gy 18 125 >97%
(Georgetown, Cyberknife mets in 3 fractions Objective
2009) – 37.5 Gy in QOL/assessmen
5 fractions ts
Gibbs Mets 1-5 74/ 102 16 – 25 33 50 84%
(Stanford, Cyberknife (80%)
2007)
Gerszten Mets/ 1 500 12- 25 53 344 92%
(Pittsburgh, Cyberknife (80%)
2005)

38. Literature for Radiosurgery for Benign
Extramedullary Spinal Tumors

39. Moving targets

40. The Solution for Moving Targets:
Image Guidance
• 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

41. 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.

42. Synchrony® Respiratory
Tracking System

43. Early lung cancer?
• 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)
Asamura H, J Thorac Oncol, 2008
Dosoretz D, Semin Radiat Oncol, 1996

44. Radiotherapy for Lung Cancer
Median OS 14 → 21 months with conventional RT
Wisnivesky, et al., Chest 2005
Cancer specific survival, unresected Stage I NSCLC

45. Can we improve radiotherapy?
MSKCC dose escalation study
3-D CRT, 1.8-2 Gy fractions
Dose intensification is
critical
Rosenzweig, et al., Cancer 2005

46. Thoracic SBRT
Conventional vs. SBRT dose distribution

47. Medically inoperable
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%

48. H Onishi / U Yamanashi / ASTRO 2007
Results of 300 stage I NSCLC patients
presented at ASCO 2006
Local control rate Cause-specific survival
Survival
BED>100Gy BED>100Gy (n=227)
P<0.0001
P < 0.0001
BED<100Gy BED<100Gy (n=73)
Time (years)
BED>100Gy BED>100Gy (n=227)
5y LC 83.1% (95% C.I. 76.8-89.5%) 5y CSS 77% (95% C.I. 70-85%)
BED<100Gy BED<100Gy (n=73)
5y LC 44.2% (95% C.I. 23.6-64.8%) 5y CSS 62% (95% C.I. 46-78%)

49. Thoracic SBRT
Indiana University Phase II experience – Toxicity
Timmerman, et al., J Clin Oncol 2006

50. Cooperative group trials
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

51. What about surgical candidates?
• 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?”
Ginsberg R, Ann Thorac Surg, 1995

52. H Onishi / U Yamanashi / ASTRO 2007
Surgical candidates
Local control rate (LC)
IA vs IB Sq vs Adeno
LC rate IA (n=65)
LC rate
5yLC 92% Squamous (n=25)
1 1
5yLC 95%
0.8 0.8
IB (n=22) 0.6 Adeno (n=54)
0.6
5yLC 82% 5yLC 85%
P =NS
0.4
0.4
P =0.06 Mean diameter
0.2
0.2 Squamous: 27.3mm
0 Adeno : 25.3mm
0
0 2 4 6 8 10 12
0 2 4 6 8 10 12
Time (years)

53. H Onishi / U Yamanashi / ASTRO 2007
Surgical candidates
Overall survival (OS) rate
IA vs IB Sq vs Adeno
OS rate OS rate
1 IA (n=65) 1 Squamous (n=25)
5yOS 76% 5yOS 73%
0.8 0.8
0.6 0.6 Adeno (n=54)
IB (n=22) 5yOS 73%
0.4 5yOS 64% 0.4 P =NS
Mean diameter
0.2 P =0.10 0.2
Squamous : 27.3mm
Adeno : 25.3mm
0 0
0 2 4 6 8 10 12 0 2 4 6 8 10 12
Time (years) Time (years)

54. Surgical Candidates
Comparison of 5-year overall survival by SBRT with that by surgery
Surgery SBRT
JNCCH2 National survey3
OS / LC
Clinical stage Mountain1 (Japan) (Japan)
Stage IA 61% 71% 77% 76% / 92%
Stage IB 40% 44% 60% 64% / 82%
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.

55. Current & Future Protocols
• 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

56. Future Directions

57. Goldfinger (1964)

58. SBRT for Prostate Cancer
SBRT using Cyberknife vs. HDR dosimetry comparison:
Courtesy of Don Fuller, Cyberknife San Diego

59. “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

60. Extending Current Endeavors
• Functional Radiosurgery

61. Uveal Melanoma
Treatment f/u 8 months

62. “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)

63. Radiosurgery
“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)