Liver Directed Therapy - Marlana Orloff, MD

MRFCURE-OM6th Annual

Patient and Caregiver

Symposium3.11.17

LIVER DIRECTED THERAPY FOR

METASTATIC UVEAL MELANOMA

Marlana Orloff, MDAssistant Professor

Department of Medical OncologyThomas Jefferson University

Sidney Kimmel Cancer Center

Approximate 5 year survival 70-80%About 50% of patients will develop metastatic diseaseOne 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

SITE OF METASTASES

J G Lorigan et al 1991

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

RAPID GROWTH

MRI normal 6 months prior

RAPID GROWTH

12/17/2013

4/30/2014 6/2/2014

SLOW GROWTH

12/30/15 12/20/16

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

Melanoma in the liver

Embolization drugs administered through catheter

Melanoma

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

IMMUNOEMBOLIZATION

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

IMMUNOEMBOLIZATIONRATIONALE

Purpose was to investigate feasibility and safety2000 – 2004, single institution34 of 39 patients had MUM<50% tumor involvement, unresectableLobar 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

IMMUNOEMBOLIZATIONPHASE 1

JCO 2008 26:5436-5442

6 procedures/patient (median, range 1-14)32% responded (2 CR, 8 PR)32% stable diseaseOS: 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

IMMUNOEMBOLIZATIONPHASE 1

JCO 2008 26:5436-5442

IMMUNOEMBOLIZATION

2 months later

Initial

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

IMMUNOEMBOLIZATIONCOMPARED TO HISTORIC PHASE II TACE WITH BCNU

* P < 0.5Radiology 2009; 252:290-298

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

RADIOEMBOLIZATION

Yttrium-90 radioactive beads administered IHAMultiple 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

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

RADIOEMBOLIZATIONJEFFERSON EXPERIENCE

Am JCO; 2016;39:189-195

RADIOEMBOLIZATION

Pre: 7/21/16 Post: 2/7/17

CHEMOEMBOLIZATION

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

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

50 patients with >50% tumor replacement at presentation (Jan 2004 – Nov 2011)

200 mg BCNUMedian survival 7.1 months22% 1 yr. survivalNeither pre-treatment LDH (> or < 500) nor tumor burden

(50-59%, 60-75%, > 75%) had effect on survival

CHEMOEMBOLIZATIONJEFFERSON EXPERIENCE

AJR 2015; 205:429-433

CHEMOEMBOLIZATION WITH BCNU

2/19/2016 1/22/2017

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):131-7Annals G & H 2012; 3:9-14

19 patients, no prior treatments July 2011 – January 2013, retrospective reviewPoor 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 chemoembolizationBased on disparate response, patients divided into “nodular”

vs. “infiltrative” pattern, based on MRI appearance

CHEMOEMBOLIZATIONDEBDOX FOLLOWED BY BCNU

JEFFERSON EXPERIENCE

JVIR 2014; 25: S45


SURVIVAL BY TUMOR TYPE

Nodular vs Infiltrative Disease

Nodular

Infiltrative

Time (months)

Sur

viva

l Pro

babi

lity

(%)

Nodular (n=11): 3 PR, 7 SD, 1 PD Infiltrative (n=8): 1 PR, 3 SD, 4 PD

SurvivalMean (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 = 8.4p value = 0.0037





Initial

15 months later

PERCUTANEOUS AND ISOLATED HEPATIC

PERFUSION

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

Infusion catheter

Venous Return

Filter

Blood post liver and pre-filter


"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

“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


AM J Clin Onc. 2017 Jan 04

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


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; 21:466-72Ann Surg 2014 May;259(5):953-9

SURGICAL RESECTION AND ABLATION

Reserved for limited clinical situationsSolitary 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

diseaseAblation is a less invasive approach to attack on solitary

metastases Radiofrequency Cryoablation Other techniques


Multiple liver metastases seen during attempted resection of solitary liver lesion Imaging only noted solitary

lesion


ABLATION

ABLATION

6/3/2015 12/8/2016

LIVER DIRECTED THERAPY PROGRAM AT

THOMAS JEFFERSON

National referral center (+ Canada)3/4 of our patients live outside of PA, NJ, DEWeekly MUM multidisciplinary conference Weekly MUM multidisciplinary clinic with two medical

oncologist, three interventional radiologists, radiation oncology, and surgery

> 600 hepatic embolization procedures per yearAll 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

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 TherapyOptions

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 InhibitorReferral

+/- *Combinatio

n 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

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 THERAPYLIMITATIONS AND CONSIDERATIONS

THANK YOU

Liver Directed Therapy - Marlana Orloff, MD

Education

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