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Liver Directed Therapy - Marlana Orloff, MD

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Marlana Orloff, MD presents on Liver Directed Therapy at the 2017 CURE OM Patient & Caregiver Symposium.

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Liver Directed Therapy - Marlana Orloff, MD

  1. 1. MRF CURE-OM 6th Annual Patient and Caregiver Symposium 3.11.17 LIVER DIRECTED THERAPY FOR METASTATIC UVEAL MELANOMA Marlana Orloff, MD Assistant Professor Department of Medical Oncology Thomas Jefferson University Sidney Kimmel Cancer Center
  2. 2. Approximate 5 year survival 70-80% About 50% of patients will develop metastatic disease One year survival 13-15%* Median survival after development of metastatic disease ranges 2-15 months* Liver most common site of metastases  About 50% of patients with metastatic disease may have liver only disease for majority of their disease course UVEAL MELANOMA * In the literature though not necessarily reflective of more current clinical experience
  3. 3. SITE OF METASTASES J G Lorigan et al 1991
  4. 4. Patients presenting with varied disease presentations  Liver only : small disease burden  Liver only : large disease burden  Liver predominant but extra-hepatic present  Extra-hepatic only  Metastatic disease at time of eye diagnosis  Recurrence during adjuvant treatment  Recurrence >15+ years after eye diagnosis  Treatment naïve  Heavily pre-treated  Some tumors grow very fast  Some tumors grow slower  … And everything in between PATIENT PRESENTATIONS
  5. 5. RAPID GROWTH MRI normal 6 months prior
  6. 6. RAPID GROWTH 12/17/2013 4/30/2014 6/2/2014
  7. 7. SLOW GROWTH 12/30/15 12/20/16
  8. 8. MERITS OF TRANS-ARTERIAL CATHETER- DIRECTED TREATMENT OF LIVER TUMORS Liver tumors obtain the majority of their blood supply from the hepatic artery. Normal liver parenchyma has a dual blood supply  Portal vein (~75%)  Hepatic artery (~25%) Trans-arterial catheter-directed therapies allow localized treatment to liver tumors while sparing normal liver parenchyma Delivery of medication to liver tumors at a higher concentration could be achieved while minimizing systemic toxicity
  9. 9. Melanoma in the liver Embolization drugs administered through catheter Melanoma
  10. 10.  Bland embolization  Immunoembolization  GM-CSF +/- IL-2  Radioactive microspheres  SirSpheres  Chemoembolization  BCNU  Chemoembolization with Drug-Eluding Beads  DEBDOX  DEBIRI  Hepatic arterial infusion  Fotemustine  BCNU  Percutaneous Hepatic Perfusion (PHP)  Melphalan  Isolated Hepatic Perfusion (IHP)  Melphalan  *Surgical Resection / Ablation TYPES OF LIVER DIRECTED TREATMENTS
  11. 11. IMMUNOEMBOLIZATION
  12. 12. Destruction of tumor by embolization could control tumor progression locally and provide tumor antigens to the local immune system Concurrent use of GM-CSF and IL-2 induces an inflammatory response in the tumor and surrounding tissue which may improve the anti-cancer immune response Local stimulation of the immune system may result in the development of a systemic immune response against tumor cells which may suppress the growth of distant tumors IMMUNOEMBOLIZATION RATIONALE
  13. 13. Purpose was to investigate feasibility and safety 2000 – 2004, single institution 34 of 39 patients had MUM <50% tumor involvement, unresectable Lobar hepatic artery embolization every 4 weeks using escalating dose of GM-CSF (25-2000 mcg) emulsifiedwith Ethiodol followed by Gelfoam, for 6 treatments Imaging (CT, MRI) and clinical assessment after every other treatment to assess response (RECIST) Primary end-points were dose-limiting toxicity and maximum tolerated dose IMMUNOEMBOLIZATION PHASE 1 JCO 2008 26:5436-5442
  14. 14. 6 procedures/patient (median, range 1-14) 32% responded (2 CR, 8 PR) 32% stable disease OS: 14.4 months (median)  (33.7 months for CR/PR, 12.4 months SD/PD) Survival: 1 yr. 62%, 2 yr. 26% PFS-liver: 4.8 months (median) PFS-systemic: 10.4 months (median) 1 patient remains alive > 10 years IMMUNOEMBOLIZATION PHASE 1 JCO 2008 26:5436-5442
  15. 15. IMMUNOEMBOLIZATION 2 months laterInitial
  16. 16. IMMUNOEMBOLIZATION 2 months laterInitial
  17. 17. High dose IE (>1500mcg) vs historic data from Phase II TACE with BCNU  Excluded those with >50% liver involvement Longer OS (20.4 vs. 9.8 months, median)* Longer PFS-L (9.3 vs. 6.4 months, median) Longer PFS-S (12.4 vs. 4.8 months, median)* Systemic progression was delayed in the high-dose IE group, suggesting an induction of a systemic immune response against the melanoma cells IMMUNOEMBOLIZATION COMPARED TO HISTORIC PHASE II TACE WITH BCNU * P < 0.5 Radiology 2009; 252:290-298
  18. 18. About 10% of patients have an amazing response to immunoembolization  After receiving a few treatments stabilization, sometimes shrinkage, and decreased viability  Treatment breaks for months to years  Embolic agent transient so repeated procedures possible EXCEPTIONAL RESPONDERS 10/2010 1/2017
  19. 19. RADIOEMBOLIZATION
  20. 20. Yttrium-90 radioactive beads administered IHA Multiple series of showing Y90 in MUM patients  11 patients treated across 5 centers between 2005-2007  77% response rate  80% 1 year survival  13 patients 2005-2011 as salvage therapy  Median tumor burden 31%  62% response rate  Median survival 7 months RADIOEMBOLIZATION
  21. 21. Retrospective  71 patients, 82% salvage; 2007 - 2012  Median PFS-L 5.9 months  Median OS after treatment 12.3 months  Median OS following diagnosis of liver mets 23.9 months (range, 6.2 – 69 months) Current Prospective Trial  Just finished accrual  48 patients – half first line and half post IE  11/2011 - 3/2017  Biomarker correlates and pre-treatment biopsies  Data pending RADIOEMBOLIZATION JEFFERSON EXPERIENCE Am JCO; 2016;39:189-195
  22. 22. RADIOEMBOLIZATION Pre: 7/21/16 Post: 2/7/17
  23. 23. CHEMOEMBOLIZATION
  24. 24. CHEMOEMBOLIZATION Author Pt # Drug (s) OS Resp* OS Non-Resp Median OS Mavligit ’88 30 Cisplatin 14 6 11 Cantore ’94 8 Carboplatin -- -- 15 Bedikian ’95 44 Cisplatin 14.5 5 6 Sato ’95 14 Cisplatin -- -- 6.6 Patel ’05 24 BCNU (100mg) 21.9 3.3 5.2 Huppert ’09 14 Cisplatin/Carboplatin 14.5 10 11.5 Vogl ’07 12 Mitomycin C 21 16.5 21 Dayani ’09 21 Mitomycin C, Cisplatin, Doxorubicin 12.7 3.7 7.6 (mean) Gupta ’10 125 Mostly Cisplatin 15.8 6.1 6.7
  25. 25. MD Anderson experience  125 patients (Jan 1992-Dec 2005)  122 received cisplatin  65 also received vinblastine or vinblastine/dacarbazine Overall Survival 6.7 months (median, n=113):  < 25% 14 months  25-50% 5.1  >50-75% 5.5  >75% 2.4 Recommend against treatment when >75% tumor replacement CHEMOEMBOLIZATION
  26. 26. 50 patients with >50% tumor replacement at presentation (Jan 2004 – Nov 2011) 200 mg BCNU Median survival 7.1 months 22% 1 yr. survival Neither pre-treatment LDH (> or < 500) nor tumor burden (50-59%, 60- 75%, > 75%) had effect on survival CHEMOEMBOLIZATION JEFFERSON EXPERIENCE AJR 2015; 205:429-433
  27. 27. CHEMOEMBOLIZATION WITH BCNU 2/19/2016 1/22/201 7
  28. 28. 10 patients 2007-2008  100-200 mg Irinotecan administered in 2-4 ml of 100-300/300-500 micron DC Beads  All 10 patients had objective response Single Arm Phase 2 trial  52 patients Jan 2007-Feb 2010  Median treatments per patient 1.6  100mg in 10 patients, remainder 200mg  Tumor reduction by imaging (“necrosis and reduction of contrast enhancement”):  > 90% (n=17)  80-90% (n=30)  60-80% (n=3)  PFS-L 7.5 months, OS 13.9 months (both median) CHEMOEMBOLIZATION WITH DRUG ELUDING BEADS: IRINOTECAN In Vivo. 2009 Jan0Feb;23(1):131-7 Annals G & H 2012; 3:9-14
  29. 29. 19 patients, no prior treatments July 2011 – January 2013, retrospective review Poor candidates for other liver-directed therapies  (Tumors > 5 cm, > 50% tumor burden, rapid growth) < 4 ml 100-300 micron LC Beads/150 mg adriamycin  (14/36 treatments received full dose) 13/19 patients proceeded to BCNU chemoembolization Based on disparate response, patients divided into “nodular” vs. “infiltrative” pattern, based on MRI appearance CHEMOEMBOLIZATION DEBDOX FOLLOWED BY BCNU JEFFERSON EXPERIENCE JVIR 2014; 25: S45
  30. 30. CHEMOEMBOLIZATION DEBDOX FOLLOWED BY BCNU SURVIVAL BY TUMOR TYPE Nodular vs Infiltrative Disease Nodular Infiltrative Time (months) SurvivalProbability(%)
  31. 31.  Nodular (n=11): 3 PR, 7 SD, 1 PD  Infiltrative (n=8): 1 PR, 3 SD, 4 PD Survival Mean (mos) 95% CI Median (mos) 95% CI Nodular 22.8 15.7 - 29.8 --- --- Infiltrative 4.7 1.6 - 7.9 2.9 1.8 -7.9 Overall 16.0 11.6 - 20.4 9.1 2.9 -12.8 Chi-square = 8.4 p value = 0.0037 CHEMOEMBOLIZATION DEBDOX FOLLOWED BY BCNU JEFFERSON EXPERIENCE
  32. 32. CHEMOEMBOLIZATION DEBDOX FOLLOWED BY BCNU JEFFERSON EXPERIENCE Initial 15 months later
  33. 33. PERCUTANEOUS AND ISOLATED HEPATIC PERFUSION
  34. 34. AKA PHP: Closed circuit perfusion of high doses of chemotherapy  “Chemosaturation” Melphalan is drug of choice at 3mg/kg  Whole liver infused at each treatment  Every 6 weeks for up to 6 treatments DELCATH catheter system Prior clinical trial followed by expanded access study PERCUTANEOUS HEPATIC PERFUSION
  35. 35. Infusion catheter Venous Return Filter Blood post liver and pre-filter
  36. 36. PERCUTANEOUS HEPATIC PERFUSION "Percutaneous Hepatic Perfusion for Unresectable Metastatic Ocular Melanoma to the Liver: A Multi-Institutional Report of Outcomes."   Recent presentation on 49 patients treated between 2008 and 2016 at either Moffitt Cancer Center or University Hospital Southampton  Total of 115 treatments  Median treatments per patient was 2  Hepatic response on 46 patients  45% CR or PR  37% with SD  Median overall survival predicted to be 657 days in all comers  1,207 days (3.4 years) in responders  Common side effects anemia, thrombocytopenia, and neutropenia Presented at Regional Cancer Therapies 12th International Symposium February 21, 2017
  37. 37. “Hepatic Progression-free and Overall Survival After Regional Therapy to the Liver for Metastatic Melanoma”  Retrospective review of 30 patients treated with either PHP or other liver directed treatment  12 patients PHP  6 patients radioembolization  12 patients chemoembolization  Median Hepatic PFS 361 versus 80 versus 54 days  Median OS 608 versus 295 versus 265 PERCUTANEOUS HEPATIC PERFUSION AM J Clin Onc. 2017 Jan 04
  38. 38. FOCUS Phase III trial of PHP versus Best Alternative Care  1:1 Randomized trial  BAC options include chemoembolization, ipilimumab, pembrolizumab, or dacarbazine  Many active US sites  Multidisciplinary team required PERCUTANEOUS HEPATIC PERFUSION
  39. 39. AKA IHP: Surgical procedure resulting in closed circuit to allow perfusion of high doses of chemotherapy In a trial of 34 patients  OS with IHP was 24 months Retrospective 10 year long single center experience in 91 patients from 2003-2012 (UM/CM = 32)  Response rate for melanoma 51.7% Phase III versus BAC ongoing in Europe ISOLATED HEPATIC PERFUSION Ann Surg Onc 2014; 21:466-72 Ann Surg 2014 May;259(5):953-9
  40. 40. SURGICAL RESECTION AND ABLATION
  41. 41. Reserved for limited clinical situations Solitary metastases or true oligometastatic disease in patients often >5 years from primary eye diagnosis  Known different tumor velocity the longer one is from their primary eye diagnosis In early metastatic situations often see “peppering” at the time of the initial surgical attempt  Rarely get true negative surgical margin due to micrometastatic disease Ablation is a less invasive approach to attack on solitary metastases  Radiofrequency  Cryoablation  Other techniques SURGICAL RESECTION AND ABLATION
  42. 42. Multiple liver metastases seen during attempted resection of solitary liver lesion  Imaging only noted solitary lesion SURGICAL RESECTION AND ABLATION
  43. 43. ABLATION
  44. 44. ABLATION 6/3/2015 12/8/2016
  45. 45. LIVER DIRECTED THERAPY PROGRAM AT THOMAS JEFFERSON
  46. 46. National referral center (+ Canada) 3/4 of our patients live outside of PA, NJ, DE Weekly MUM multidisciplinary conference Weekly MUM multidisciplinary clinic with two medical oncologist, three interventional radiologists, radiation oncology, and surgery > 600 hepatic embolization procedures per year All discussed treatment options are offered except IHP  Immunoembolization (60%)  Radioactive microspheres (10%)  Chemoembolization, (30%)  Drug-eluting beads  Percutaneous Hepatic Perfusion CURRENT LIVER DIRECTED PROGRAM AT THOMAS JEFFERSON UNIVERSITY
  47. 47. Uveal Melanoma with Metastases Solitary or Oligometastatic disease greater than 5 (+/-) years after primary uveal melanoma treatment Consider Surgery, RFA, Cryoablation Liver Only or Liver Dominant Liver Directed Treatment† Systemic Therapy Options Yes No Immunoembolization* Radioembolization* Chemoembolization* Drug-Eluting Beads Percutaneous Hepatic Perfusion (On Trial) IHP (referral) Ipilimumab* Keytruda* Opdivo* VPA* Other HDACi* Clinical Trial IMC-gp100 (HLA A2) BET Inhibitor Referral +/- *Combination liver directed and systemic when appropriate † Liver directed options often based on disease burden after consideration for clinical trial •<50% and limited extrahepatic consider IE or RE •If <50% largest tumor > 5-6cm and nodular consider DEBDOX followed by BCNU •If >50% liver involvement with liver dominant CE •Progression after IE consider RE or CE
  48. 48. Certainly there are patients in whom it does not control hepatic disease despite best efforts Occasional anatomy issues exclude patients from certain treatments  Notably Radioembolization and PHP Extra-hepatic disease is always a concern  Combination systemic and hepatic strategies Need better tools to predict who more likely to be an “exceptional responder” and to what upfront therapy Requires skilled interventional radiologists LIVER DIRECTED THERAPY LIMITATIONS AND CONSIDERATIONS
  49. 49. THANK YOU

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