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Yoshiya (Josh) Yamada MD FRCPC Department of Radiation Oncology

Advances in the management of Vertebral Mets in the Era of Spine SRS IAEA Singapore SBRT Symposium Singapore National Cancer Institute. Yoshiya (Josh) Yamada MD FRCPC Department of Radiation Oncology Memorial Sloan Kettering Cancer Center NY NY USA. Disclosures.

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Yoshiya (Josh) Yamada MD FRCPC Department of Radiation Oncology

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  1. Advances in the management of Vertebral Mets in the Era of Spine SRSIAEA Singapore SBRT SymposiumSingapore National Cancer Institute • Yoshiya (Josh) Yamada MD FRCPC • Department of Radiation Oncology • Memorial Sloan Kettering Cancer Center • NY NY USA

  2. Disclosures The Institute for Medical Education, Speakers Bureau Varian Medical Systems, Consultant

  3. Uranium ore Henri Becquerel April 1896 Pitchblend Uranium, Polonium, & Radium Marie Curie Natural Radioactivity 1896 “Radioactivity” 1898 Isolated Radium

  4. Radium Beer Radium Therapy 1910-1920’s: Pitchblende and Carnotite Malignancy Subacute and Charcot Joint Muscular Conditions High Blood pressure Nephritis Simple and Pernicious Anemias

  5. Household Products

  6. Early x-ray facilities

  7. Early Radiation Technology: Fluoroscopy

  8. Radiotherapy as an Emerging Technology • 1895 - Rontgen discovers x-rays. • 1896 - Becquerel discovers radioactivity. • Victor Despeignes reports treating stomach cancer with X rays • 1901 - Rontgen receives the Nobel Prize in Physics for the discovery of x-rays. • 1905 - The first English book on Chest Radiography is published. • Niels Finsen reports 50% success rate treating lupus with x rays • 1913 -Coolidge introduces the hot cathode tube. • 1914 - Von Laue receives the Nobel Prize in Physics for x-ray diffraction from crystals. • 1915 - Bragg and Bragg receive the Nobel Prize in Physics for crystal structure derived from x-ray diffraction. • 1917 - Barkla receives the Nobel Prize in Physics for characteristic radiation of elements. • 1918 - Eastman introduces radiographic film. • 1920 - The Society of Radiographers is formed. • 1923 – Coutard reports 23% cure rate for head and neck cancers with fractionated RT • 1924 - Siegbahn receives the Nobel Prize in Physics for x-ray spectroscopy. • 1951 – Co60 Teletherapy • 1953 – Linear accelerator

  9. Emerging Technologies • 0.1 – 1.0 Gy per minute • Used 1920-1950’s • Over 10,000 in use in the early 1950’s

  10. Scientific Shoe Fitting

  11. IGRT as an Emerging Technology: Do We Have All the Facts? • Hypofractionation and high dose single fraction radiation appear to have different responses compared to conventional fractionation • Radiosensitivity is not histology dependent • High dose hypofractionation/single fraction RT appears to be ablative “SABR” • What are the mechanisms of response?

  12. Deficiencies of the LQ Model for SBRTResponseKirkpatrick et al. SemRadiatOncol 18, 2008 • Brain metastases are well controlled with 15-20Gy (25-35Gy calculated) • Cancer stem cells may require a higher threshold dose of radiation to overcome inherent radioresistance (>13 Gy for intestinal stem cells) • LQ model doesn’t model threshold effects • Classical radiobiology based upon in vitro rather than in vivo data • LQ model can’t account for other in vivo mechanisms of response at high doses

  13. Endothelial Apoptosis: Fuks/Kolesnick Model of an In Vivo Effect for High Dose Radiosurgery

  14. 14.5Gy + G6-31 (n=5) 14.5Gy (n=6) 1000 1000 750 750 Tumor volume(mm3) 500 500 250 250 0 0 0 20 30 40 50 60 70 80 90 0 20 30 40 50 60 70 80 90 Days after tumor implantation Days after tumor implantation Anti-VEGF G6-31 Sensitizes MCA/129 Fibrosarcoma to singly dose radiotherapy when given immediately prior to radiation Anti-VEGF G6-31 Sensitizes MCA/129 Fibrosarcoma Truman et al. PLoS One 2010

  15. Modulating Response: VEGF and Endothelial Apoptosis

  16. Uptake curves of representative voxels from DCE-MRI of B16 melanoma irradiated in wild-type and asmase-/- mice asmase+/+ Before 20Gy 20 Gy 20 Gy Before 20Gy Fold-change in S/S0 [rel.u.] After 20Gy After 20Gy asmase-/- Before 20Gy Fold-change in S/S0 [rel.u.] After 20Gy Time after GD-DTPA injection [seconds] Slide courtesy of Z Fuks MD

  17. High Dose IGRT and Vascular Response • Vascular collapse an important aspect of high dose RT response • Significant endothelial apoptosis (ceramide repressed by VEGF inhibition) –within minutes of RT! • Radioresistant phenotypes become radiosensitive with VEGF suppression—ceramideactiviation • Dose de-escalation for IGRT+ VEGF inhibitors? • DCE MRI changes: Evidence for the vascular effect?

  18. DCE Parameters Tumor lower Vp than Normal Tissue High “leakage” if Ktrans is high Quick “washout” if Kep is high Necrosis: slow Kep Two-compartment tracer pharmacokinetic model, in which Vp = intravascular volume, Ve = interstitial volume, Ktrans = rate constant of Gd leakage from the intravascular to interstitial space, and Kep = elimination rate constant. Modified From Figure Provided by A Holodny MD

  19. Materials and Methods 5 male patients with spine metastasis • 4 metastatic prostate: T5, T10, L2, L3 • 1 metastatic thyroid: L4 • T1 weighted DCE MRI performed on a 1.5 Tesla magnet utilizing dynamic imaging processing software (NordicICE) prior to and within one hour after undergoing single fraction HD-IGRT • All metastasis were treated to 24Gy in a single fraction • Patients were given steroids before treatment.

  20. MRI studies were acquired with a 1.5T GE scanner using an 8 channel cervical-thoracic-lumbar (CTL) surface spinal coil. • T1 weighted DCE MR images were obtained with 3D fast SPGR sequence with following MR parameters: • NordicNeuroLab T1DCE perfusion software TR= 3.6sec TE= 1.1sec number of phases = 80 slice thickness = 10 mm flip angle =30° FOV=34 cm matrix size 256 × 256

  21. Materials and Methods • Vp and Ktrans of the metastasis were normalized as a ratio to adjacent nonirradiated marrow and compared pre and 1 hour post RT T1 Ktran Vp Courtesy Eric Lis MD

  22. Materials and Methods • Ratios of Vp and Ktrans to adjacent marrow were plotted on a graph. Percent change Pre and one hour Post RT also computed. L2 metastatic prostate

  23. Results Patient 1 tx Local control at 26 month follow up. Courtesy Eric Lis MD

  24. Results • On average Vp decreased by 64% after 1 hour • On average Ktrans decreased by 34% after 1 hour • Average follow up of 23 months- No local progression

  25. DCE: A Window into the Tumor L4 L4 L4 L4 L4 L4 2400cGyx1 Prior to RT Day 10 Day 50

  26. Case 1 • 57 yo F w/ oligometastatic breast cancer • HPI: • Dx w/ T2N1 triple neg IDC of left breast on 9/1/10 • NeoadjuvantddAC-T, L WLE/ALND w/ re-excision, adjuvant RT (completed 1/4/11) • Staging CT CAP (5/2012)MR sacrum (6/15/12): right sacral metastasis • Palliative RT to Sacrum: • 2400cGy in 1 fx(7/9/12) • Presents for follow-up on 9/13/12

  27. Imaging: MRI of Sacrum (S1) Post-RT (9/6/12) Pre-RT (6/15/12)

  28. Case1- Perfusion Images Pre-RT (6/15/12) Post-RT (9/6/12) Vp = 4.04 Vp = 13.73 Change in Vp = -70.6%

  29. Plasma Volume and Recurrence

  30. Results Local Recurrence Ktrans Vp Peak AUC Vp Ktrans AUC Peak p>0.0001

  31. Recurrence 1: Patient #40 Fractions: 1 Tx date: 5/18/11 Recurrence date: 11/10/11 Time to recurrence: 6 mos Surgery date: 7/30/12 Time to last FU: 14 mos Perfusion parameters increased at least 4 mos before recurrence!

  32. Recurrence 6: Patient #78 Fractions: 1 Tx date: 12/3/09 Recurrence date: 8/4/11 Time to recurrence: 21 mos Surgery date: 8/5/11 Time to last FU: 21 mos Perfusion parameters may have increased 18 mos before recurrence!

  33. Prelim Results • Local control (n=36) • Average Vp decreased 70% • Average Ktransdecreased 60% • Local recurrence (n=6) • Average Vpincreased 34% • Average Ktrans decreased 15% • Vp: p=0.0007

  34. Discussion • DCE MRI is feasible in spine metastases • Plasma volume was the only factor that was associated with tumor response • Decreases in Vp likely represent reduced tumor vascularity and hence treatment response • mean reduction of 66% for locally controlled leisons • Increases in Vp represent increased tumor vasculature and hence tumor growth

  35. Conclusion • Vascular changes may be important in the response of tumors to high dose RT • Supports endothelial apoptosis • MRI DCE may be predictive of tumor response to high dose per fraction RT • MRI DCE may provide a “window” into the tumor even when standard MRI only demonstrates “stable” findings within the marrow • Continued work is ongoing to confirm these findings in a larger dataset

  36. Future Directions • Diagnostic tool: sensitivity and specificity • Threshold values for control and failure • Predictive tool • Preliminary results suggest that DCE findings can predict for tumor recurrence before standard MRI findings • Other body sites? • Assess response to other types of therapy?

  37. High Dose Radiotherapy: Multi Compartment Targets

  38. High Dose RT and Immunologic Response with Ipilimumab • Abscopal effect of CTLA 4 (T cell) stabilizer • Phenomenon noted with Hypofractionation • Increased immunogenicity with high dose RT

  39. RT Dec 2010

  40. Mucosal Melanoma • 65 yo M with mucosal melanoma of the right maxilla. • Maxillectomy, orbital extent /  flap reconstruction • Multiorgan metastases • Chemo (cis/decarbazine/vinblastine, 6/2011) • Post op bed: Hypofractionated radiation (9/2011, 36Gy/3 fractions)  with Ipilimumab

  41. 9/23/2011

  42. 3/29/2012

  43. Abscopal Effect • Systemic response on PET imaging • Near complete resolution of all multiple peritoneal, hepatic, splenic, osseus, LN lesions • No evidence of maxillary recurrence

  44. Multiple Osseus and Visceral Metastases Near Complete Systemic Response 9/23/2011 3/29/2012

  45. IL 2 and Melanoma and RCC + SBRTS Seung, BD Curti, et al. Science Translational Medicine 2012 • IL 2 CR + PR = 6% and 10% for melanoma • IL 2 CR + PR = 8% and 7% for RCC • Median time of response 40 months and 54 months • 70% of melanoma CR are without recurrence at 15 years • 70% of RCC CR are disease free at 10 years • SBRT: 20Gy x 1-3 • IL 2 (600,000 IU/kg every 8 hours x 14 doses) start Monday after RT, repeated 16 days later • 100% CR of irradiated lesions

  46. IL 2 and High Dose SBRT: Abscopal Effects S Seung, BD Curti, et al. Science Translational Medicine 2012

  47. IL 2 and High Dose SBRT: T Cell Effects S Seung, BD Curti, et al. Science Translational Medicine 2012

  48. Reduced response to 20Gyx1 if the wild type CD8+ T cells are depleted T cell deficient (nude mice) significantly less response to 25Gyx1 compared to the wild type Lee et al. Blood 2009 114(3): 589-595.

  49. SBRT/SABR and Tumor Immunology From: Finkelstein SE, Timmeramn R, et al. The Confluence of Stereotatic Ablative Radiotherapy and Tumor Immunology. Clinical and Developmental Immunology 2011

  50. Threshold Effect for High Dose Radiosurgery Immune Response

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