1. Intracoronary Brachytherapy Albert E. Raizner, MD Methodist DeBakey Heart Center Houston, Texas

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3. Intracoronary Brachytherpay: Topics to Cover Radiation physics and dosimetry Radiation vascular biology Effects on restenosis Pivotal clinical trials Adverse effects of brachytherapy Brachytherapy team

4. Radiation Physics The result of a nuclear reaction is the liberation of small particles, energy, or both. Alphaparticulate2 protons, 2 neutrons beta (+)particulatepositron beta (-) particulateelectron gammaelectromagneticphoton

5. Radiation Physics Penetrating distances Easily shielded Clinically used alphaVery short (<mm) YesNo beta (+)Short (1-2 cm) No beta (-)Short (1-2 cm) Yes gammaFar (meters) NoYes

6. Beta: lower energy = less exposure, less shielding shorter delivery time (2-10 min) concerns about efficacy in larger vessels Beta and Gamma Radiotherapy Gamma: highest energy = more exposure, more shielding longer delivery time (15-30 min) broader spectrum of vessel sizes

7. Isotopes Used in Intracoronary Brachytherapy IsotopeEmissionHalf-lifeEnergy in MeV AvgMax 192 IrGamma74 days0.370.67 32 PBeta14 days0.691.7 90 SrBeta28 years0.200.5 90 YBeta64 hours0.902.3

8. Radiation Dosimetry: Definitions Absorbed Dose: a measure of the amount of energy absorbed per unit mass (ie target volume) Unit is the Gray (Gy) 1 Gy = 100 Rad Dose equivalent: a measure of absorbed dose multiplied by the quality factor (biological effectiveness). QF = 1 for beta or gamma Unit is the Sievert (Sv) 1 Sv = 100 Rem

9. Radiation Dosimetry: Definitions Source activity: radioactivity is measured as disintegrations per second Unit is the Bq = 1 disintegration / sec 1 mCi = 37 million Bq Dose prescription: Dose to a specific target Centered source – eg. 20 Gy to 1 mm into artery wall Non-centered source – 18.4 Gy to 2 mm from source Dwell time: amount of time a source must remain in position to provide the prescribed dose Depends upon 1) source activity; 2) dose prescription; 3) lumen diameter (centered source); 4) dose-depth curve

10. Dose vs Distance for Beta and Gamma sources P-32Ir-192

11. Radiation Biology: Cellular and Molecular Effects S G1G2 M cell cycle Cell division G0 * * = Most radiosensitive phase Radiation produces base damage, single and double strand breaks, and crosslinking The Target: DNA

12. Radiation Biology: Cellular and Molecular Effects Direct action –Interaction of electrons with DNA Indirect action –Ionization with production of free radicals (OH - ) that damage DNA

13. Radiation Biology: The Vascular Target Cell Types –Myofibroblasts (adventitial) –Smooth muscle cells (medial) –Monocytes –Macrophages Location in artery wall –Inner adventitia –Media

14. Radiation Biology: Mechanisms of Restenosis Early elastic recoil Neo-intimal proliferation Late vascular constriction (constrictive remodeling)

15. Radiation Biology: Effects of Radiotherapy on Restenosis Inhibits neo-intimal proliferation Promotes dilative remodeling

16. Pivotal Clinical Trials

17. SCRIPPS IWRIST GAMMA I RandomizedYesYesYes Importance1 st RadioRx Trial1 st ISR TrialDefinitive ISR Trial Number of pts55130252 InclusionsIn-stent/POBAIn-stentIn-stent RestenosisRestenosisRestenosis SourceIr-192Ir-192Ir-192 Pivotal Gamma Radiotherapy Trials

18. P=0.048 SCRIPPS I and WRIST: In-Lesion Restenosis Rates at 6 Months P=0.001 54% 61% 46% 21% 60% 23% In-Lesion Segment

19. SCRIPPS I and WRIST: MACE Events 26% 57% P=0.381 P=0.001 68% 29% 41% 31%

20. In-Lesion Segment GAMMA I: In-Stent and In-Lesion Restenosis Rates at 6 Months 57.2% 41.4% P=0.001 In-Stent 50% 21% 55% 32%

21. GAMMA I: MACE Events, TLR and TVR 36% 34% P=0.007 P=0.020 25% P=0.002 46% 29% 44% 48% 43% 30%

22. GAMMA I: Influence of Diabetes on In-Lesion Restenosis Rates 52% P=0.001 P=0.049 33% % Strong Efficacy in Diabetics

23. BERTPREVENT STARTINHIBIT RandomizedNoYesYes Yes RandomizedNoYesYes Yes Importance1 st Beta Trial2nd Beta Trial ISR Trial ISR Trial Importance1 st Beta Trial2nd Beta Trial ISR Trial ISR Trial Number of pts55105476 322 Number of pts55105476 322 InclusionsDeNovoDeNovo,In-stentIn-stent RestenosisRestenosisRestenosis InclusionsDeNovoDeNovo,In-stentIn-stent RestenosisRestenosisRestenosis SourceSr90/Y90P-32Sr90/Y90 P-32 SourceSr90/Y90P-32Sr90/Y90 P-32 Pivotal Beta Radiotherapy Trials

24. INHIBIT and START Angiographic Restenosis Rates (%) INHIBIT ( 32 P) Up to 47 mm START ( 90 Sr) Up to 22 mm Lesion Length

25. START Trial 8-Month Clinical Outcomes % p=0.028p=0.039p=0.009 22.4 25.9 24.1 13.1 18.0 16.0  34%  31%  42% 18.0 25.9  31% p=0.039 Mean lesion length 16.1 mm + 7.4

26. p = 0.0001  60%  56% p = 0.0002 TheINHIBITTrial 9 Month ClinicalOutcomeProtocolEndpoints

27. To assess the safety and effectiveness of beta radiation in patients with de novo coronary lesions using a 30mm 90 Sr/ 90 Y source train in conjunction with: –Stand alone balloon angioplasty, or –Provisional stent placement in which balloon angioplasty was suboptimal BetaCath Trial (Novoste) The only large trial of brachytherapy in de novo lesions

28. BetaCath Trial: Late (>30 days) Treatment Site Thrombosis Sr-90Placebo % n = 2 n = 17 n = 3 p=ns p<0.001p=ns Both were bailout stents High incidence of late thrombosis in patients receiving new stents and traditional (<30d) antiplatelet therapy (APT)!

29. BetaCath Trial: Clinical Outcomes at 8 Month (%) p=0.09p=0.19p=0.08  12 % p=ns  10 % p=ns  9 % p=ns No significant clinical benefit in denovo lesions

30. FDA Approved Brachytherapy Systems Gamma: Cordis CheckMate TM

31. FDA Approved Brachytherapy Systems Beta: Novoste BetaCath TM Delivery Catheter 3-lumen, closed end Transfer device using hydraulic delivery of the source train

32. Centering Catheter 27mm / 2.5-3.5mm 32 P 27mm.018in Nitinol Wire 27mm Source Delivery Unit FDA Approved Brachytherapy Systems Guidant: Galileo TM System

33. Contra- indications Source Vessel diameter Lesion Length Lesion Type Cannot take antiplatelet or anticoagulant Beta ( 90 Sr/ 90 Y) 2.7 – 4.0 mm “Treatable with 20 mm balloon” In-stent restenosis in native coronary artery Novoste BetaCath TM Cannot take antiplatelet or anticoagulant Gamma ( 192 Ir) 2.75 – 4.0 mm Up to 45 mm In-stent restenosis in native coronary artery Cordis Checkmate TM Cannot take antiplatelet of anticoagulant Beta ( 32 P) 2.4 – 3.7 mm Up to 47 mm In-stent restenosis in native coronary artery Guidant Galileo TM FDA Approved Systems: Clinical Indications and Usage

34. Radiotherapy-Adverse Effects “Edge effects” Late thrombotic occlusion Stent/vessel separation Long-term effects

35. “Edge Effect” Post-StentBrachytherapy6 Months Stent Edge Edge of Radiation Zone “Edge Effect” Occurrence: 3-15% Related to “Geographic Miss” (injury + low dose radiation) Mechanism: Paradoxical neointimal hyperproliferation and constrictive remodeling Minimized by use of wide (3-5 mm) radiation margin

36. BRIE Trial P=0.09P=0.01P=0.002 Geographic Miss (GM) and Likelihood of Edge Restenosis Geographic miss is the primary cause of edge restenosis

37. Radiotherapy-Specific Effects “Edge effects” Late thrombotic occlusion Stent/vessel separation Long-term effects

38. Late (>30 d) Thrombotic Events After Vascular Brachytherapy Occurrence: 5 - 10% in early trials Primarily (but not entirely) in newly stented arteries!!! Attributed to delayed reendothelialization Minimized by prolonged antiplatelet (thienopyridines) therapy

39. Late Clinical Thrombosis in Radiotherapy Trials for In-Stent Restenosis With Prolonged Antiplatelet (Thienopyridine) Therapy and Provisional Stenting 1%928%6INHIBIT 0%921%3START 0%629%6WRIST Plus 0%626%6SCRIPPS III Late Thrombosis Months of F/U % New Stents Months of Ticlid/Plavix Trial

40. Radiotherapy-Specific Effects “Edge effects” Late thrombotic occlusion Stent/vessel separation Long-term effects

41. Late Vessel/Stent Separation Post-Procedure 6 month F/U

42. Late Stent/Vessel Separation Results from dilative remodeling in a newly stented artery segment Appears to be an infrequent finding No clinical events have been documented to be caused by this phenomenon Could it be a cause of “late thrombotic occlusion”?

43. Radiotherapy-Specific Effects “Edge effects” Late thrombotic occlusion Stent/vessel separation Long-term effects

44. Delayed Restenosis (Rare) Pre-PTCA Post-PTCA 6 Months 19 Months

45. Pseudoaneurysms (Rare)

46. Radiotherapy Team ( Mandated by FDA Regulation) Interventional cardiologist Radiation oncologist Medical physicist Radiation safety officer

47. Intracoronary Brachytherapy Sample question

48. A 58 year old man presents to the emergency department with a 3 day history of substernal tightness radiating to his jaw. Initially, the pain occurred while walking but occurred at rest on the day of admission. He is known to have CAD. Nine months ago a stent was placed in the LAD, and 3 months ago balloon PCI was done because of in-stent restenosis. His current symptoms are similar to those he experienced before each prior procedure. An ECG shows 0.5 mm ST segment depression in V 3 -V 5. He is started on i.v. NTG, I.v. heparin and metoprolol with relief of symptoms. CK-MB and Troponin I are normal. The next day, coronary angiography is done, and shows… Case Presentation

50. Question 1 The most appropriate next step in the management of this lesion is: A) Optimize beta blocker dosage, and obtain an adenosine cardiolite stress test to assess the severity of ischemia. B) Rotational atherectomy to debulk the stenosis, followed by low pressure balloon dilatation. C) Balloon dilatation with high pressures, followed by intracoronary brachytherapy. D). CABG of the LIMA to the LAD.

51. C) Balloon dilatation with high pressures, followed by intracoronary brachytherapy. Answer to Question 1

52. Question 2 He returns 6 months after receiving brachytherapy for routine follow-up. He has been feeling well. A treadmill cardiolite stress study is done and shows reversible anterior hypoperfusion. Coronary angiography is most likely to show: A) No significant obstructive disease in the LAD. B) Diffuse in-stent restenosis. C) Stenosis in the LAD proximal to the stent segment, with no renarrowing within the stent. D) Complete occlusion of the LAD

53. Answer to Question 2 He returns 6 months after receiving brachytherapy for routine follow-up. He has been feeling well. A treadmill cardiolite stress study is done and shows reversible anterior hypoperfusion. Coronary angiography is most likely to show: A) No significant obstructive disease in the LAD. B) Diffuse in-stent restenosis. C) Stenosis in the LAD proximal to the stent segment, with no renarrowing within the stent. D) Complete occlusion of the LAD

54. Question 3 Coronary angiography shows the following:

55. Question 3 The likely cause of this new stenosis is: A) Unrecognized dissection of the artery from the high pressure dilatations performed 6 months ago. B) Trauma from the brachytherapy catheter. C) An inadequate margin of radiation coverage at the proximal site of balloon injury. D) Bad genes. I knew we should’ve done a CABG!

56. Answer to Question 3 The likely cause of this new stenosis is: A) Unrecognized dissection of the artery from the high pressure dilatations performed 6 months ago. B) Trauma from the brachytherapy catheter. C) An inadequate margin of radiation coverage at the proximal site of balloon injury. D) Bad genes. I knew we should’ve done a CABG!