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
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
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
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. 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
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. 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
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. 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
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. 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. CHEMOEMBOLIZATION
DEBDOX FOLLOWED BY BCNU
SURVIVAL BY TUMOR TYPE
Nodular vs Infiltrative Disease
Nodular
Infiltrative
Time (months)
SurvivalProbability(%)
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
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
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. “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. 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. 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
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. Multiple liver metastases seen
during attempted resection of
solitary liver lesion
Imaging only noted solitary lesion
SURGICAL RESECTION AND ABLATION
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. 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. 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