A Frank Chat About OMcloud2.snappages.com/9a36f676fc96ee7727f8ccd1c88a... · 3/2/2012 · Uveal Melanoma Background • Uveal tract – iris, ciliary body, choroid • Most common

A Frank Chat About OMDave Eschelman, MDInterventional Radiologist, Thomas Jefferson University

Takami Sato, MD, PhDDirector, Metastatic UM Program, Thomas Jefferson University

Eye Am Not Alone (EANA) Patient RetreatFriday Session - March 2, 2012

Do not distribute or copy without the express permission of the Ocular Melanoma Foundation (OMF).

These materials are for educational use only.

No information provided herein constitutes a medical diagnosis, advice, or treatment. Please consult a healthcare professional for a specific examination and evaluation of your condition. Under no circumstances shall OMF nor the authors listed herein be held liable for anything that may arise from anyone following any advice, treatment, etc. included herein.

Dave Eschelman, MD

David Eschelman is an Associate Professor of Radiology at Jefferson Medical College and Associate Director of Interventional Radiology at Thomas Jefferson University Hospital in Philadelphia. After graduating from Jefferson Medical College, he completed his internship in general surgery and residency in diagnostic radiology at Boston University and Boston City Hospitals, followed by a fellowship in vascular andinterventional radiology at Thomas Jefferson University Hospital. He is board certified by the American Board of Radiology, with a certificate of added qualificationsin vascular and interventional radiology. He currently focuses on liver-directed therapies for patients with metastatic uveal melanoma, working closely with Takami Sato, M.D., Ph.D. and Carin Gonsalves, M.D.

Takami Sato, MD, PhD

Takami Sato is a Professor of Medical Oncology at Jefferson Medical College of Thomas Jefferson University and at Thomas Jefferson University Hospitals in Philadelphia. Currently, he serves as the Director of the Metastatic Uveal Melanoma Program in the Department of Medical Oncology at Thomas Jefferson University Hospitals, the Co-leader of the Immunology Program at the Kimmel Cancer Center at Jefferson and as the Associate Director for International Affairs at the Kimmel Cancer Center at Jefferson. Dr. Sato has been named to Americas Top Oncologists (2007) and Best Doctors In America (2004-2008). Having led multiple clinical trials and been awarded numerous research grants, Dr. Sato now serves as Chief Editor to What’s New in Oncology as well as on the editorial board of the Medical Science Monitorand as a reviewer for five scientific journals; International Journal of Cancer, Medical Science Monitor, Cancer Immunology and Immunotherapy, Cancer Research and Cancer.

Dr. Sato received his medical degree at Jichi Medical School in Japan and went on to his post graduate training in Internal Medicine and Pediatrics at Oita Prefectural Mie Hospital. He completed his fellowship training in Pediatric Oncology at Jichi Medical School. Dr. Sato received his PhD in 1997 from Jichi Medical School in Japan.

A Frank Chat about Ocular Melanoma

David J. Eschelman, M.D.Associate Professor of Radiology,

Jefferson Medical CollegeAssociate Director of Interventional Radiology,

Thomas Jefferson University Hospital

Takami Sato, M.D., Ph.D.Professor of Medical Oncology,

Jefferson Medical CollegeDirector, Metastatic Uveal Melanoma Program

Thomas Jefferson University Hospital

Disclosures

• I will discuss unapproved uses of commercial products.

• I am a consultant for Guerbet, the manufacturer of one of these products (Lipiodol).

So what exactly is aninterventional radiologist?

Interventional radiology (often abbreviated IR) is a sub-specialty of radiology involving the use of minimally-invasive image-guided procedures to diagnose and treat diseases. The purpose of IR is to diagnose and then treat patients using the least invasive techniques possible in order to minimize risk and improve outcomes.

Interventional radiologists invented angioplasty and the catheter-delivered stent. They often use x-ray, CT scan, ultrasound, MRI, and other types of imaging to map the pertinent areas and then use direct interventional instruments, usually performed using needles and narrow tubes called catheters.

Many conditions that once required surgery can now be treated non-surgically by interventional radiologists. By minimizing the physical trauma to the patient, these procedures can reduce complications and recovery time, as well as shorten hospital stays.

MUM at Jefferson(Metastatic Uveal Melanoma)

• National referral center (+ Canada)• 3/4 of our patients live outside of PA, NJ, DE• Weekly MUM multidisciplinary conference

(Medical Oncologist, IR, MRI, +/- Rad Onc)• Weekly MUM multidisciplinary clinic• 400 hepatic embolization procedures/yr.• Approx. ¼ of primary UM tumors in U.S.

initially treated at Wills Eye Hospital

MUM at Jefferson

Background on Uveal Melanoma

Uveal MelanomaBackground

• Uveal tract – iris, ciliary body, choroid• Most common primary intraocular malignant

tumor in adults• Incidence < 1/100,000/yr. (1/25th that of

cutaneous melanoma)• Approx. 2500 new diagnoses/yr. in U.S.• > 95% have disease limited to the eye at time of diagnosis• Classified as an “orphan disease” by NIH


Demographics• Mean age 50-60, incidence peaks at age 70 with

24.5 cases/million men, 17.8 cases/million women• 90% are caucasian (fair skin, blue eyes)• Usually not hereditary• Incidence is not increasing• Very weakly linked to UV exposure? (probably not)• Weakly linked to cutaneous melanoma• Associated with dysplastic nevus syndrome


• Iris – least common site, best prognosis (early detection, slow growing, rarely mets)

• Ciliary body – uncommon, worst prognosis (prone to extrascleral extension)

• Choroid – large majority• Diagnosis – ophthalmologic

exam; US, fluorescein angio


Symptoms• None! (most common)• Blurred vision• Floaters• Flashes• Visual field defects• Shadows/misting• Pain is rare


Treatments• Observation (advanced age, poor health)• Transpupillary thermotherapy (laser, high failure as

primary therapy, good adjunct)• Plaque radiotherapy (I-125 brachytherapy, most

common therapy, 10 yr. local recurrence rate 3.5%)• Charged particle therapy• Local resection (selected anterior tumors)• Enucleation (large tumors, anterior chamber/optic

nerve invasion, extraocular extension, recurrence)


• Approx. 5 yr. survival – 70%• Approx. 10 yr. survival – 60%• Almost 50% will develop systemic

metastases• Median survival after development of visceral metastases (1991):

2 months without treatmentup to 5 months with some form of treatment13% one year survival


• Liver is predominant organ of involvement in >90% of patients with metastases, and tends to be first (and in half only) manifestation of the disease

• Other sites of metastases include lungs, bone, brain, subcutaneous tissues, other visceral organs/peritoneum

• Clinical course of patients with metastases is generally determined by progression of the disease in the liver

• Pattern of metastases very different from cutaneous melanoma (lymph nodes, lung, subcutaneous tissues)


Risk Factors for Metastasis• Increased patient age• Male gender• Increased tumor size

(especially > 7 mm thick, > 10 mm diameter)• Anterior tumor location• Epithelioid cell type (vs. spindle cell)• Lymphocyte infiltration• Extracellular matrix patterns• Extrascleral tumor extension• Mitotic index of the tumor• Tumor blood vessel morphology


Estimated Time to Metastases (Unfavorable Characteristics)• > 60 yo, male, tumor > 10 mm diameter

20 months (median)Estimated Time to Metastases (Favorable Characteristics)• < 60 yo, female, tumor < 10 mm diameter

76 months (median)

5 yr. Mortality based on Tumor Thickness• Small (< 2.5 mm thick) 16%• Medium (2.5 – 10 mm thick) 32%• Large (> 10 mm thick) 53%


• Improved treatment of the primary tumor has not resulted in prolonged survival

• Hematogenous micrometastases have occurred prior to diagnosis of eye tumor


Genetic Risk Factors for Metastasis• Monosomy 3

70% of patients die of mets within 4 yrs.Inactivation of BAP1 gene (tumor suppressor)

• Partial duplication of 8q (worse)• Gain of 6p (better)• Loss of 1p and 8p

Chromosomal heterogeneity!


Gene Expression Profiling

• Class 1- very low risk of metastasis

• Class 2- very high risk of

metastasis

(172 patients) J Mol Diagn 2010; 12:461-468


• Unlike cutaneous melanoma, there is no effective systemic chemotherapy regimen for MUM.

• There is no proven adjuvant therapy for patients at high risk for developing metastases.


• Because the clinical course of most patients with MUM is based on the status of the disease in the liver, loco-regional therapy is important for control of the metastases since there is no systemic therapy.

• Surgery and ablation techniques are rarely useful due to multiplicity of tumors. Very high recurrence rate following surgical resection within 5 yr. of initial UM diagnosis.


Multiple liver metastases in patient undergoing planned resection of solitary metastasis.

UM TreatmentOverview

MUM Treatments(Metastatic Uveal Melanoma)

Liver-Directed Therapies• Immunoembolization• Radioactive microspheres• Chemoembolization,

Drug-eluting beads• Fotemustine infusion• IHP/PHP

ChemoembolizationAuthor Pt # Drug (s) used for TACE Median Survival (mos)

Mavligit ’88 30 Cisplatin 11

Feun ’94 4 Cisplatin 7

Bedikian ’95 44 Cisplatin 6

Sato ’95 14 Cisplatin 6.6

Huppert ’09 14 Cisplatin/Carboplatin 11.5

Cantore ’94 8 Carboplatin 15

Patel ’05 24 BCNU 5.2

Vogl ’07 12 Mitomycin C 21

Dayani ’09 21 Mitomycin C, Cisplatin, Doxorubicin

7.6 (mean)

Author Pt # Drug (s) used for TACE Median Survival (mos)

Mavligit ’88 30 Cisplatin 11

Feun ’94 4 Cisplatin 7

Bedikian ’95 44 Cisplatin 6

Sato ’95 14 Cisplatin 6.6

Huppert ’09 14 Cisplatin/Carboplatin 11.5

Cantore ’94 8 Carboplatin 15

Patel ’05 24 BCNU 5.2

Vogl ’07 12 Mitomycin C 21

Dayani ’09 21 Mitomycin C, Cisplatin, Doxorubicin

7.6 (mean)

Carin F. Gonsalves, M.D., 2009

Comparison of Various TreatmentsResponders vs. Non-Responders (median values)

AJR 2011; 196:468-473

First Author Treatment Pt # Drug (s) OS (Responders) OS (Non-Responders) OS

Mavligit [9] TACE1st-line

30 Cisplatin 14 6 11

Bedikian [10] TACE1st-line

44 Cisplatin 14.5 5 6

Bedikian [10] TACE2nd-line

20 Cisplatin <6

Huppert[16]

TACE1st-line

14 CisplatinCarboplatin

14.5 10 11.5

Patel [15]

TACE1st-line

24 BCNU 21.9 3.3 5.2

Dayani [20] TACE1st-line

21 Mitomycin C, Cisplatin, Doxorubicin

12.7(mean)

3.7(mean)

7.6 (mean)

Vogl[19]

TACE1st-line

12 Mitomycin C 21 16.5 21

Leyvraz [11]

HAI1st-line

31 Fotemustine 14

Peters[21]

HAI1st-line

101 Fotemustine 15

Sato[17]

TAIE1st-line

34 GM-CSF 33.7 12.4 14.4

Alexander[13]

IHP1st-line

29 Melphalan 12.1

Immunoembolization at Jefferson

Takami Sato, M.D., Ph.D.

Kevin L. Sullivan, M.D.

Michael J. Mastrangelo, M.D.

Percutaneous Hepatic Perfusion (PHP)

J Clin Oncol 2005; 23; 3465-3474

Current Jefferson Treatment Algorithmfor Liver Metastases in MUM Patients

Following consideration of IHP/resection:

If < 50% liver involvement, limited extrahepatic mets:• Immunoembolization• SIRspheresIf > 50% liver involvement with liver dominant disease:• Chemoembolization (BCNU, LC Beads, Abraxane)Progression following immunoembolization:• Chemoembolization (BCNU, LC Beads, Abraxane)• SIRspheres (<50% tumor burden)

Documents

A Frank Chat About OMcloud2.snappages.com/9a36f676fc96ee7727f8ccd1c88a... · 3/2/2012 · Uveal Melanoma Background • Uveal tract – iris, ciliary body, choroid • Most common