Regional Therapy for Metastatic Neuroendocrine Tumors. Janette Durham, MD Professor of Radiology University of Colorado School of Medicine

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1 Regional Therapy for Metastatic Neuroendocrine Tumors Janette Durham, MD Professor of Radiology University of Colorado School of Medicine

2 Introduce regional therapy for mnet Arterial therapies Injection of particles into the hepatic artery to block the oxygen supply with addition of chemotherapeutic or radiation source Trans-arterial embolization (TAE) Trans-arterial chemoembolization (TACE) Conventional chemoembolization (ctace) Drug-eluting bead embolization (DEB-TACE) Trans-arterial radioembolization with Y90 (TARE) Ablation therapy Place needle probe directly into tumor to heat, freeze, or poison tumor cells

3 Interventional Radiologist Member of a multi-disciplinary cancer team Image guided therapy (minimally invasive surgery) Supportive therapy Biopsies Central venous access Fluid drainage paracentesis /thoracentesis Enteral feeding Non-operative management of post operative complications Non-surgical palliative cancer therapy

4 Disclosure NET tumors are rare 5.25 per 100,000 with prevalence of 100,000 in US. (2014)* Evidence for regional therapy is limited to small retrospective single institutional reviews Tumor location - pnet vs. carcinoid (foregut, midgut, hindgut) was not initially considered Tumor biology including tumor staging, proliferation index (Ki67,MIB-1), angioinvasion, and mitoses typically not considered Castellano. Cancer Chemother Pharmacol 2014.

5 Background Curative liver resection feasible in 10% of patients with liver metastasis 73% 4-Y survival Regional therapy has a role in the treatment of metastatic disease to liver that is not amenable to surgery for anatomic or clinical reasons, when liver involvement is dominant Anatomic considerations Multiple lesions Bilobar disease

6 Indication 1. Management of hormone symptoms refractory to somatostatin analogues 2. Disease progression 3. Mass symptoms from large tumors or extensive tumor burden-pain, abdominal distention, early satiety Treatment of early disease remains controversial due to the indolent nature of the disease

7 Patient selection Clinical considerations Good performance status ECOG < 2.0 Adequate liver reserve Bilirubin mg/dl Normal (correctable) coagulation profile

8 Contraindications Liver insufficiency or obstructive jaundice Involvement of > 50% of liver Renal insufficiency Biliary-enteric anastomosis Significant portal vein thrombosis Reduction in cardiac ejection fraction <50%

9 Mechanism of intra-arterial therapy Dual blood supply to the liver Dominant low oxygen portal circulation - 80% High oxygen hepatic arterial circulation - 20% NET lesions are hypervascular and fed from the hepatic artery Delivery of agent into hepatic arterial circulation at level dictated by anatomic distribution of lesions High concentration of agent near the tumor with low concentration escaping to the systemic circulation

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13 Trans-arterial embolization (TAE) micron spherical embolic particles introduced to block high oxygen blood supply to tumors causing tumor necrosis. Embolization to stasis of arterial vasculature of hemiliver vs. segment Perfusion to uninvolved liver is maintained by the portal vein permitting selective targeting of tumor 2-3 sessions separated by 4-6 weeks Repeatable until vasculature does not support therapy.

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15 Factors affecting morbidity, mortality, and 30 day survival 320 consecutive procedures in 137 patients ( ) mean OS 43 months (similar for carcinoid and pnet) OS 82,57,35M 1,3,5Y Factors negatively effecting OS Urgent HAE for symptom management > 50% tumor involvement Extrahepatic mets Additive effect with OS of 86 m cw 8.5 m if all three factors present Factors negatively effecting 30 day mortality Urgent therapy Male Sofocleous. JVIR 2014:25:22

16 Conventional trans-arterial chemoembolization (ctace) Chemotherapy mixed with a carrier (Lipiodol) injected into the hepatic artery. Distributed by blood flow, concentrating drug in tumors 5:1. Chemotherapy delivered in high concentration enhances coagulative tumor necrosis Followed by particle embolization to cause ischemic necrosis. Hypoxia further enhances effect of drug. 2-3 sessions separate by 6-8 weeks Repeatable until vasculature does not support therapy or cumulative drug limit reached.

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20 Drug-eluting bead trans-arterial chemoembolization (DEB-TACE) Chemotherapy loaded on to bead Beads carry drug to peritumoral capillary bed Drug slowly elutes off beads over days creating highly concentrated prolonged exposure to drug

21 LC Beads Drug delivery system comprising biocompatible, non resorable hydrogel beads loaded with anthracyclin derivatives Higher tumor concentrations and lower systemic concentrations of doxorubicin compared to ctace Better tolerated permitting repeat procedures in shorter intervals. Concern about biliary injuries

22 Results Response in 52-86% patients with duration of response often longer than 12 months Complete symptomatic response in 70% Survival 36M favoring carcinoid over pnet (Hur) 123 patients - 33M vs 23M favoring carcinoid over pnet(gupta) 103 patients 7Y when sunitinib, everolimus, and somatostatin analogs added (debarre) Hur. JVIR 2013;24 Gupta.Cancer 2005;104 debarre.eurj Endo 2014;e

23 Transarterial radioembolization (TARE) micron resin or glass beads loaded with Yttrium 90 injected into peritumoral capillary bed Targeted doses of 120 Gy or greater to tumor

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25 Yttrium 90 Microspheres β particle emitter (.936 MeV) as it decays to stable zirconium-90 Maximum penetration < 10mm (mean < 2.5 mm) Half life of 64 hrs, mean life of 3.85 days 94% of radiation delivered in 11 days Tumor to non-tumor uptake may triple the absorbed dose in tumor Classified as brachytherapy devices Regulated by the US Nuclear Regulatory Commission

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28 Results 40 patients treated with TheraSphere Median dose 113 Gy CR 20%; PR43% (EASL) Time to response was 4.9M OS 72.5,62.5,45% at 1,2,3 Y Memon.Int J Radiat Oncol Biol Phys 2012;83

29 Pre procedure management Octreotide prior to procedure added to monthly maintainace dose? Hold angiogenic inhibitors Sutent, Everolimus Hydration Antibiotics Prophylactic single dose When biliary intervention or enteric anastomosis prolonged administration Single dose steroids Anti-emetics for nausea Sedation

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33 Case 1 58 yo M with non-resected pnet with progression of liver mets ECOG 0 Bilirubin.9 Alb 3.9

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44 7 M Baseline 7 months later

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48 Case 2 50 F with resected pnet and history of prior gastric surgery. Progression of liver mets 7 months post operatively. ECOG 0 Normal liver function No hormonal symptoms

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54 1) TAE ANTERIOR RIGHT LOBE 2) TAE POSTERIOR RIGHT LOBE 3) ABLATION SINGLE LESION LEFT LOBE

55 Ablation therapy PEI-percutaneous ethanol injection RFA-radiofrequency ablation frictional heating resulting from RF current Microwave- excitation of water molecules IRE Irreversible electroporation - non thermal ablation with electric current (some promise in the pancreas)

56 Microwave Electromagnetic radiation More efficient energy deposition Desiccation and charring not limiting Faster heating, higher temperatures, larger ablation volumes, shorter ablation times Less susceptibility to heat sink Maybe safer around bile ducts Easier to use no grounding pads, easier to run machine

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60 Ablation Laparoscopic, at time of surgery vs. percutaneous 1 lesion < 5 cm or up to 3 lesions <3 cm (8cm total) Location-liver, lung, bone

61 Contraindications Close to structures of hilum- bile ducts Close to large vessels Close to the gut Subcapsular

62 Ablation complications General anesthesia Overnight admission for pain control Morbidity 7 %; mortality < 1% Bleeding requiring transfusion 1% Liver abscess 1% Higher risk if biliary enteric anastomosis Tract seeding 1-3% Gervais. JVIR 2009;20.

63 Trans-arterial complications Sedation complications Arteriography complications Contrast induced renal failure transient Vascular access injury Access hematoma Prolonged PES and severe dehydration Transient hyperbilirubinemia Liver fibrosis

64 Post embolization syndrome (PES) 2 week course of pain, nausea, low grade fever, fatigue, leukocytosis Control Hydration Anti-emetics Pain medication Narcotics Anti-inflammatories Steroids

65 Unusual complications Alopecia Acute carcinoid crisis Renal failure - permanent Contrast induced renal failure Tumor necrosis Dehydration Liver abscess Infection rare unless biliary tree compromised Radiation induced liver disease (RILD)

66 What therapy when? Differences in these therapy have not been evaluated head to head Response rates felt to be about 50% for all intraarterial therapies Approved therapies Newer beads are FDA approved for hyper vascular lesions TARE approved for primary liver cancers and CRC metastasis Perhaps chemo does not add much particularly for carcinoid tumors Perhaps more biliary complications after DEB bead use Perhaps easier PES course after Y90

67 What therapy when? Anatomy is critical to decision making Pre-operative high-quality, 3 phase CT liver imaging important for best decisions Because of the indolent nature of NET all therapies have a role Due to less post embolization syndrome following Y90 I choose this therapy to start in patients with Large disease burden But Cumulative radiation exposure limits repetition TAE over TACE to avoid exposure to drug therapy that may not provide additional benefit unless single lesion is being targeted where cumulative injury may be beneficial When limited disease ablation may be the most efficient