Uveal melanoma commonly spreads to the liver. This document discusses uveal melanoma (MUM) that has metastasized to the liver. It provides background on MUM, noting that half of patients develop metastases, usually first appearing in the liver. It describes genetic risk factors for metastasis and different risk classifications. The document advocates for locoregional therapies for liver metastases since there are no effective systemic therapies. It presents evidence that liver-directed therapies may prolong survival more than systemic treatments or surveillance alone.

1. Uveal Melanoma
Metastatic to the Liver
David J. Eschelman, M.D., FSIR
Professor of Radiology,
Sidney Kimmel Medical College of Thomas Jefferson University
Co-Director of Interventional Radiology,
Thomas Jefferson University Hospital

2. Disclosures
• I will discuss unapproved uses of
commercial products.
• I am a not a consultant for anyone!

3. So what is an
interventional radiologist?

4. MUM at Jefferson
(Metastatic Uveal Melanoma)
• National referral center
• 2/3 of our patients live outside of PA, NJ, DE
• Weekly MUM multidisciplinary conference
(Medical Oncologist, IR, MRI, +/- Rad Onc)
• Weekly MUM multidisciplinary clinic
• > 650 hepatic embolization procedures/yr.
• Approx. 1/4 – 1/3 of primary UM tumors in
U.S. initially treated at Wills Eye Hospital
An “Orphan Disease” that has Found a Home at Jefferson

5. Dr. Marlana Orloff (Medical
Oncology)
Drs. Eschelman (IR), Sato (Medical
Oncology) and Gonsalves (IR)
Dr. Robert Adamo (IR)
MUM PHYSICIANS
Dr. Rani Anne
(Radiation
Oncology)

6. TEAM EFFORT!!!!

7. Uveal Melanoma
Background
• Approximately half of patients will develop metastases
• 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)

8. Uveal Melanoma
Background
• Improved treatment of the primary tumor
has not resulted in prolonged survival
• Hematogenous micrometastases have
occurred prior to diagnosis of eye tumor

9. Uveal Melanoma
Background
• Unlike cutaneous melanoma, there is no effective
systemic chemotherapy regimen for MUM.
• Unlike cutaneous melanoma, immune checkpoint
blockade therapy has a poor response (<<5%) and
high complication rate. No BRAF mutation with
MUM.
• There is no proven adjuvant therapy for patients at
high risk for developing metastases. (Sutent?
gp100???)

10. Uveal Melanoma
Background
• 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 effective 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.

11. Uveal Melanoma
Background
Multiple liver
metastases in
patient
undergoing
planned resection
of solitary
metastasis.

12. Uveal Melanoma
Background
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!

13. Metastatic-free Interval According to Genomic Results
Br J Ophthalmol 2013-303867

14. Uveal Melanoma
Background
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

15. Uveal Melanoma
Background
Pigment Cell and Melanoma Research 2012; 25:171-181

16. Surveillance Imaging
• Surveillance Scheduling
– No consensus: Varies from center to center
– Depends on tumor histology and genetics
• Dr Sato protocol
– Low/intermediate risk: MRI q6-12 mo, CXR q12 mo
for 5 years
– High risk: MRI q3 mo + CT chest q 6 mo for 2 years,
then MRI q6 mo + CT q 12 mo for 3 years

17. NCCN Guidelines v1.2018
RISK OF DISTANT METASTASIS -
Low risk:
• Class 1A(x)
• Disomy 3
• Gain of chromosome 6p
• EIF1AX mutation
• T1 (AJCC) (See ST-1 and ST-2)
• Spindle cells
SYSTEMIC IMAGING BASED ON RISK STRATIFICATION
• Imaging to evaluate signs or symptoms as clinically indicated
• Consider surveillance imaging(y)

18. NCCN Guidelines v1.2018
RISK OF DISTANT METASTASIS -
Medium risk:
• Class 1B(x)
• SF3B1 mutation
• T2 and T3 (AJCC) (See ST-1 and ST-2)
• Mixed histology (spindle and epithelioid cells)
SYSTEMIC IMAGING BASED ON RISK STRATIFICATION
• Imaging to evaluate signs or symptoms as clinically indicated
• Consider surveillance imaging(y) every 6–12 months for
10 years, then as clinically indicated

19. NCCN Guidelines v1.2018
RISK OF DISTANT METASTASIS -
High risk:
• Class 2(x) • PRAME mutation
• Monosomy 3 • Epithelioid cells
• Gain of chromosome 8q • Extraocular extension
• BAP1 mutation • Ciliary body involvement
• T4 (AJCC) (See ST-1 and ST-2)
SYSTEMIC IMAGING BASED ON RISK STRATIFICATION
• Imaging to evaluate signs or symptoms as clinically indicated
• Consider surveillance imaging(y) every 3-6 months for 5 years,
then every 6-12 months for 10 years, then as clinically
indicated

20. NCCN Guidelines v1.2018
Surveillance:
The most frequent sites of metastasis are liver, lungs, skin/soft tissue,
and bones. At minimum, all patients should have contrast-enhanced MR
or ultrasound of the liver, with modality preference determined by
expertise at the treating institution. Additional imaging modalities may
include chest/abdominal/pelvic CT with contrast. However, screening
should limit radiation exposure whenever possible. Scans should be
performed with IV contrast unless contraindicated.
. . . . . but also add:
(y) Recognizing that there are limited options for systemic recurrence and
that regular imaging may cause patient anxiety, some patients may elect
to forgo surveillance imaging.

21. 8/11/2010

22. 10/27/2010

23. 12/23/2010

24. 4/09/2010

25. MRI is better than CT (another example)
CT
MRI

26. MRI is better than CT (yet another example)
CT MRI

27. So Does Screening Offer Any Benefit?
(Are there treatments that can prolong survival?)
Immunocore gp100
(pay attention later today)
But let’s move on to evidence supporting
liver-directed treatments . . .

28. So Does Screening Offer Any Benefit?
(Are there treatments that can prolong survival?)
Mayo Clinic -
• 101 patients, Jan 2000 – Aug 2013
• 59% male, median age 62, 92% ECOG 0-1
• Treatment with liver-directed therapy (LDT) was
better than systemic treatments
LDT 26 months median survival
Bevacizumab 12
Ipilimumab 13
Kinase inhibitors 13
(though patients undergoing LDT were in somewhat
better condition prior to starting treatment)
Melanoma Research 2015; 25:59-63

29. So Does Screening Offer Any Benefit?
(Are there treatments that can prolong survival?)
Jefferson Experience -
• Compared 101 patients presenting with liver metastases
1971 – 1993 (81% treated with DTIC-based systemic
treatments) to 655 patients 2000 – 2017 (88% started
treatment with liver-directed therapy)
• Primary eye tumors were similar in size, thickness, and
distribution of location between both cohorts
• In those patients who developed liver metastases, the
median time from eye tumor treatment to death was 3.4
years in the early cohort vs. 5.0 years in the later cohort.
Journal of Clinical Oncology 2018; 36: 9592s

30. Initial Presentation
MRI was normal 6 months ago

31. Rapid Growth without Treatment
12/17/2013
4/30/2014 6/2/2014