1/13/2014 Ries et al (eds). At: 2

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1 1/13/2014 1

2 1/13/2014 Ries et al (eds). At: 2

3 1/13/2014 Coldwell et al, General Selection Criteria of Patients for Radioembolization of Liver Tumors AJCO

4 1/13/2014 Am J Clin Oncol Oct 8 Am J Clin Oncol Oct 8 4

5 1/13/2014 Am J Clin Oncol Oct 8 Am J Clin Oncol Oct 8 Am J Clin Oncol Oct 8 5

6 1/13/2014 British Journal of Cancer (2010) 103, British Journal of Cancer (2010) 103, Am J Clin Oncol Oct 8 6

7 1/13/2014 Eur J Radiol Apr;74(1):

8 1/13/2014 Answer: Survival Advantage and Quality of Life! Fatigue (100%) Anorexia (75%) Fever (50%) Gastritis (25%) Liver Dysfunction (Minimal) Pain (Rare) 8

9 1/13/2014 9

10 VuMedi Y 90 Webinar 2014 Challenges of Sirspheres and Dealing with Complications Charles Nutting, DO, FSIR SkyRidge Medical Center Lone Tree, CO Disclosures Proctor- Sirtex Medical Consultant- Surefire Medical 2 Challenges of Sirspheres Setting up the infrastructure of a radioembolization program Multidisciplinary team FDA approved AU status Single dose 3 Gbq vial allows flexibility Lobar, segmental, split dose (single session whole liver) 3 1

11 Complications Early (within 30 days) Inadvertent deposition of radioactive microspheres Late Toxicity related 4 Complications PRS % Gastrointestinal ulcer -5% Cholecystitis 1% Hepatic Infection-rare RILD-rare General selection criteria of patients for radioembolization of liver tumors International Working Group Coldwell et al. AJCO

12 Minimize side effects medications Preprocedure decadron, ondansetron, hydration 100 ug octreotide subq or IV for NE disease Post procedure medrol dose pack proton pump inhibitor narcotic, antiemetic 7 Potential Complications Cystic artery Cholecystitis, GB rupture Violated ampulla hepatic absecess Chemotherapeutic/Biologic agents Toxicity/decreased dose to tumor REILD hepatic failure 8 Cystic Artery- Embolize or Not 3

13 Cystic Artery 10 Cystic Artery 11 Prophylactic embolization of the cystic artery before radioembolization: feasibility, safety, and outcomes 46 pts proximal cystic artery embolization 35 gelfoam pledgets 11 coils 100% technical success 2/46 developed significant RUQ pain 1/46 required cholecystectomy McWilliams et al. Cardiovasc Intervent Radiol Aug;34(4):

14 Risk of Hepatic Abscess from Radioembolization Traditionally patients with biliary-enteric anastamoses have been excluded from hepatic embolization procedures due to the high risk of cholangitis and abscess Documented complication rates due to infection range from 12-50% with CE 13 Violated Ampulla Results Retrospective multi-institutional review 27 patients underwent 35 infusions Follow ups is between 3 weeks 60 months The mean number of radioembolization treatments was 1.5 (range 1-2) The median length of outpatient stay was 2.5 (2-4) hours GEST

15 Complications No 30 day mortality 3 infusions of 16 developed transient low grade fever and chills 2 patients developed hepatic abscesses requiring drainge (7.4%) 1 patient died of sepsis 6 weeks after radioembolization treatment (3.7%) GEST 2008 Violated Ampulla Relative Contraindication Whipple, ampullotomy, metallic or plastic stent We medicated with levaquin and metronidazole 500mg iv levaquin, 500 iv flagyl day of procedure Followed by 500 levaquin po QD x 5 days. 500 mg flagyl 500 po TID x 5 days. Minimize Catheter Related Complications Non-target delivery Reflux Adverse events Limit dose Pre-treatment coils Distal treatment Anti-reflux catheter Lopez-Benitez, R., et al., Analysis of nontarget embolization mechanisms during embolization and chemoembolization procedures. Cardiovasc Intervent Radiol, (4): p

16 Lobar vs Whole Liver Whole Liver Infusions * 53% Lobar infusions 40% Segmental infusions 7% Technique *Per individual based on performance status, LFT s and prior chemotherapy 19 Split Dose Single Session Whole Liver Allows more distal delivery of radioembolic Stays away from extrahepatic hilar arteries that most commonly arise from the proper hepatic and proximal left hepatic branches 20 Typical Whole Liver Single Session Resin Infusion 21 7

17 Typical Whole Liver Single Session Resin Infusion 22 REILD RadioEmbolization Induced Liver Disease Hepatic sinusoidal obstruction syndrome (VOD) that presents clinically as jaundice and ascites in the absence of tumor progression 23 Liver Tolerance - Radiation RILD Radiation induced Liver Disease 25 Gy 35 Gy Gy 50 Gy Effective Doses: Testicular Ca, Lymphoma, Myeloma Curative Doses: Adenocarcinoma Preoperative Radiation Rectal Ca 24 8

18 REILD Pre Treatment 3 months Post Treatment 25 REILD Clinical Picture jaundice and ascites 4 to 8 weeks after RE Increases in alk phos minimal change in transaminases Hyperammonemia Sangro, B Liver disease induced by Radioembolization of liver tumors 26 Cancer 2008 REILD Histology 27 9

19 REILD Veno-occlusive disease is histologic hallmark 9 patients (20%) developed REILD Potential Causes Low tumor burden Whole liver treaments polychemotherapy Sangro, B Liver disease induced by Radioembolization of liver tumors Cancer Treatment for REILD Steroids Diuretics Lactulose TIPS 29 Concurrent Chemotherapy- Challenges FOLFOX Decrease oxaliplatin FOLFIRI No need to dose reduce Gemcitabine Hold one week prior and 2 weeks post Y-90 infusion Bevacizumab 30 10

20 Percent Change Bevacizumab Angiogenesis inhibitor via VEGF pathway May be unable to deliver spheres through attenuated vessels Half life 20 days 31 Challenge-Response to Therapy PET imaging 91% Tumor markers -70% CT imaging 35% CEA After 90 Y-Microspheres Weeks After Treatment Kennedy et al. Resin Y90 microsphere therapy for unresectable colorectal liver metastasis: Modern USA Experience Int J Rad Onc Physics June Limit Complications-Know When Not to Treat Poor hepatic reserve Worsening ascites Increasing bilirubin levels which are uncorrectable Poor performance status Significant extrahepatic disease not responding to therapy 33 11

21 Summary-Challenges and Minimizing Complications Multidisciplinary team, become an AU Resin microspheres allow customization of the dose to be delivered, the day of procedure Don t be too concerned about the cystic artery Safer to treat an instrumented biliary tree with RE than CE Be aware of chemotherapy regimen and keep pt off bevacizumab 4 weeks prior REILD is rare but potentially fatal 34 12

22 1/10/2014 Therasphere! Aaron Shiloh, MD Section Chief, IR Diagnostic Imaging, Inc. Philadelphia Therasphere Disclosures: Consultant for BTG 84 year old female with chronic autoimmune hepatitis LFTs elevation lead to CT PMH: Atrial Fibrillation, Hypertension, hypothyroidism ECOG 0, CP A T. Bili 0.8, cr 0.8, AFP

23 1/10/2014 BEFORE 6 months later 2

24 1/10/2014 Therasphere Introduction Epidemiology of HCC Indications Mechanism of action Patient selection Contraindications Starting a program Therasphere HCC Epidemiology HCC one of most common forms of cancer worldwide (est. 1 million new cases annually) In US, NCI estimate 19,160 new cases and 16,780 deaths in Incidence increasing with rise in hepatitis C-induced cirrhosis 5-10% of HCC patients are resectable 2 1 National Cancer Institute (accessed December 1, 2008) 2 Llovet, JM. Current Treatment Options for Gastroenterology. 2004;7: Therasphere Limited Treatment Options for HCC Therapeutic Options: Resection or transplantation Unresectable HCC treatment options: Radiofrequency ablation Transarterial chemoembolization (TACE or Drug Eluting Beads) Transarterial TheraSphere, Y90 Glass Microspheres External Beam radiation Systemic therapy (ie. Sorafenib) No treatment 3

25 1/10/2014 Therasphere Indications In the United States, TheraSphere 1 is indicated for: Radiation treatment or as a neoadjuvant to surgery or transplantation in patients with unresectable HCC who can have placement of appropriately positioned hepatic arterial catheters HCC patients with partial or branch portal vein thrombosis/occlusion, when clinical evaluation warrants the treatment Approved for use in EU, Canada, Russia, India, Saudi Arabia & S. Africa 1 TheraSphere US Package Insert Therasphere TheraSphere designated as Humanitarian Use Device (HUD) Legally marketed under Humanitarian Device Exemption (HDE) Demonstrated safety and probable clinical benefit HDE Requirements: IRB oversight/approval required Use within approved labelling does not constitute research or investigational use What is Therasphere mm glass microspheres Y-90 is an integral constituent of the glass matrix Innovative treatment to deliver powerful, targeted radiation inside the liver Y-90 glass microspheres comparison to human hair TheraSphere dose vial 4

26 1/10/2014 Therasphere Administered via hepatic artery catheter Targeted internal radiation due to tumor hypervascularity Microspheres are trapped in the tumor arterioles and are minimallyembolic (microembolization) Pure beta-emitter Average beta emission energy is MeV Average penetration range in tissue is 2.5 mm Physical half-life is 64.2 hours and decays to stable zirconium-90 Mechanism of Action Therasphere Benefits Overview: Low toxicities: well tolerated Targeted Therapy: Sparing Healthy Tissue Outpatient procedure Minimal PES syndrome (TACE vs. TheraSphere) Promising survival data Bridge to transplant, downstaging Neoadjuvant to surgery Use in Portal Vein Thrombosis Post-TheraSphere patients eligible for further therapeutic options due to preserved liver vascularity Patient Selection The ideal candidate for TheraSphere presents with: Non-infiltrative tumor type Elevated AFP Child-Pugh A Bilirubin < 2 mg/dl AST/ALT < 5 x ULN Tumor volume < 50% and Albumin > 3 5

27 1/10/2014 Contraindications Standard contraindications to angiography Inability to safely deploy the Therasphere due to anatomic variants Extremely high lung shunt fraction Hepatic mapping Lung Shunt study and LSF calculation 6

28 1/10/2014 Liver volume assessment Dose calculation Administer 7

29 1/10/2014 Getting Started! Figure 1. TheraSphere Program Overview Flowchart Estimated Timeline Week 0 TheraSphere Introductory Presentation Site Enrollment Requirements Reference Manual Provided TheraSphere Introduction by BTG Week 2 Week 8-10 Week 10 IRB Submission IRB Approval Letter Customer Information Form BTG Customer Service Radioactive Materials License (RAML) Application/Amendment RAML License Information from Hospital (assisted by BTG) Week Shipment of TheraSphere Administration System Center of Excellence Training TheraSphere University (TSU) Information/supplies required prior to 1st treatment Week 16 Patient Selection Dose Ordering Proctoring of first 3 TheraSphere Patients TheraSphere Patient Treatment Subsequent TheraSphere Patient Treatments TheraSphere Training and 1st Three (3) Treatments (coordinated with BTG) 8

30 1/10/2014 Challenges with Glass Microspheres Daniel B. Brown, MD FSIR Professor of Radiology and Radiologic Sciences Director, Division of Interventional Oncology Vanderbilt University Topics of Interest Ulcer Lung Shunt Fraction Non-target via the Umbilical Artery 2 nd Week Dosing Non-Target Therapy Best advice is AVOIDANCE ALWAYS select the lobar/segmental artery(ies) at the level you will be infusing Power inject and do delayed runs to look for anything suspicious Know where the RGA and GDA are If not sure if a problem, embolize 1

31 1/10/2014 Why the obsession? Problem Who Gets Embolized? 2

32 1/10/2014 Lung Shunt Fraction 3

33 1/10/2014 Umbilical Artery 4

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