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 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

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

The Past

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)

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

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.

Gamma Knife

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

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

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

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

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

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

“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

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

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

The Present

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)

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

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

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 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

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)

Literature for Radiosurgery for Benign Extramedullary Spinal Tumors

Moving targets

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

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

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

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

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

Thoracic SBRT Conventional vs. SBRT dose distribution

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%

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%)

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

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

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

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)

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)

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.

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

Future Directions

Goldfinger (1964)

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

“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)

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)

Radiosurgery

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Radiosurgery — Presentation Transcript

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