Presentation by Scott Oliver, MD. Presented at the 2018 Eyes on a Cure: Patient & Caregiver Symposium, hosted by the Melanoma Research Foundation's CURE OM initiative. 

1. Beyond Eye Treatment
CureOM Patient & Caregiver Symposium
Melanoma Research Foundation
Scott Oliver, MD
Director, Eye Cancer Program
Chief, Retina Service, University of Colorado

2. Disclosures
- Off label use of medications and devices
will be discussed
- Advisory Board, Castle Biosciences, Inc.
- Clinical trial support, Genentech/Roche

3. Acknowledgements
Nurse Navigator:
- Sarah Andre, RN
Research Intern:
- Samantha Little
Ophthalmic Epidemiology
- Jenna Patniak, PhD
- Anne Lynch, PhD
Medical Physics:
- Quentin Diot, PhD
- David Westerley, PhD
- Leah Schubert, PhD
- Bernard (Tripp) Jones, PhD
Radiation Oncology:
- Brian Kavanagh, MD
- Arthur Liu, MD
Cutaneous (Medical) Oncology
- Matthew Rioth, MD
- Karl Lewis, MD
- Rene Gonzales, MD
- Bill Robinson, MD

4. Critical Goals in Uveal Melanoma
1. Saving Life
2. Saving the Eye
3. Saving Vision

5. Diener-West M, Earle JD, Fine SL et
al. The COMS randomized trial of
iodine 125 brachytherapy for
choroidal melanoma, III: initial
mortality findings. COMS Report No.
18. Arch Ophthalmol 2001; 119: 969–
982.
Risk of Death

6. Risk of Death
COMS
• 25% at 5 years
• 34% at 10 years
Kujala (Scandinavia)
• 50% at 25 years

7. Risk of Death – Natural History
42 patients medium tumor
patients in COMS refused
treatment
• 22 subsequently treated
• Unadjusted death risk = 1.8 RR
• Control for dimension and age,
RR = 1.5 (95% CI 0.9-2.6).
Straatsma BR, Diener-West M, Caldwell R, Engstrom RE; Collaborative Ocular Melanoma Study Group.
Mortality after deferral of treatment or no treatment for choroidal melanoma. Am J Ophthalmol. 2003
Jul;136(1):47-54.

8. Risk of Death - Mechanism

9. Genetic Abnormalities
Associated with Metastasis
Monosomy 3
Isodisomy 3 (5-10% of cases)
1p-
6p+
6q-
8p-
8q+

10. Commercially available prognostic tests
Aggregated 10 year survival prediction
determined by:
• MPLA test for chr 1, 3 loss, 6p gain, 8p gain.
GNAQ/GNA11 testing to confirm melanoma lineage
• Clinical and histology features, including age, size,
CB involvement, epithelioid cells, closed loops,
mitotic count
• Data based on known predictive factors & clinical
risk calculator (Damato, Coupland)
Benefits: long term data, lower cost, multiple
well known risk factors
Limitations: tissue heterogeneity, specificity
¤ 5 year multi-center, prospectively
validated survival data based on
expression of 20 genes:
¤ Specificity supercedes clinical and
aneusomy predictors
¤ Benefits: protein expession reduces
risk of tissue heterogeneity false neg.
¤ Limitations: higher cost, propriety
methodology from single source
(Harbour), no 10 year data

11. Risk of Death – Molecular Targets
GNAQ/GNA11, EIF1AX, SF3B1 &
BAP1 testing is now available on
FNAB specimens

12. After Treatment - Surveillance for Metastasis
Frequency and tests are usually stratified based on risk
Liver is most common site of metastasis
- MRI liver is most sensitive (small risk, high cost)
- Abdominal ultrasound is very sensitive (no risk, low cost)
Lung is second most common
- Non-contrasted chest CT scan (some risk, medium cost)
- Chest X-ray (low risk, low cost)
PET scan (high cost, some risk, very sensitive)

13. Risk of Globe Loss
Jampol LM, Moy CS, Murray TG et al. The COMS randomized trial of iodine 125 brachytherapy for choroidal
melanoma: IV. Local treatment failure and enucleation in the first 5 years after brachytherapy. COMS report
no.19. Ophthalmology 2002; 109: 2197–2206
CU Secondary
Enucleation Rate:
7/127 plaques
= 5.5%

14. Alternative Therapies - Aura Biosciences
Light-activated AU-011
- Viral nanoparticles derived from HPV, conjugated to infrared-activated small
molecules
- Administered through an intravitreal injection
- Viral nanoparticle binds selectively to cancer cells in the eye, then are activated
with a laser
- Currently in Phase 1B/2 for small to medium UM
- Alternative to brachytherapy for small tumors
early results in 6 patients at 3 and 6 months without major SAEs
anterior and posterior uveitis did occur
one patient progressed at 6 months

15. Risk of Blindness - COMS
COMS results of 623
patients at 3 years:
• 49% lost ≥ 6 lines of vision
• 45% had visual acuity ≤ 20/200
The Collaborative Ocular Melanoma Study Group.
Collaborative Ocular Melanoma Study (COMS)
randomized trial of I-125 brachytherapy for medium
choroidal melanoma. 1. Visual acuity after 3 years. COMS
Report no. 16. Ophthalmology 2001; 108: 348–366

16. Risk of Blindness – Predictive Factors in COMS
Factors associated with poor visual
outcome:
• Greater apical height
• Shorter distance from tumor to FAZ
• Other factors: DM, collar-button
shape, serous RD
The Collaborative Ocular Melanoma Study Group.
Collaborative Ocular Melanoma Study (COMS) randomized
trial of I-125 brachytherapy for medium choroidal melanoma.
1. Visual acuity after 3 years. COMS Report no. 16.
Ophthalmology 2001; 108: 348–366

17. Risk of Blindness – CU Cohort
Retrospective analysis to determine predictors of poor visual outcome
vA cohort of 122 consecutive patients were treated using brachytherapy for uveal melanoma
vPrimary outcomes: a) visual acuity with a cut-point of 20/200 at 1 year post-surgery b) incidence of
radiation retinopathy in the form of CME or capillary non-perfusion
vPrimary exposures: a) greatest linear diameter (GLD) b) apical height, c) radiation doses sustained in five
parts of the eye d) total radiation and total energy e) treatment depth
vData was collected through medical record abstraction and radiation treatment plans
vData was then entered into Excel and analyzed with SAS using logistic regression modeling

18. Risk of Blindness – CU Cohort Predictors
At one year, 12/78 patients (15%) with recorded vision had a visual acuity < 20/200
- GLD mean 10.1mm
- apical height mean 4.3mm
- radiation dose to macula mean 65.8Gy
- radiation dose to the tumor apex averaged 120.2Gy
Duration of treatment, GEP class, and age at diagnoses were not associated with a bad
visual outcome.

19. Risk of Blindness – CU Cohort Results

20. Risk of Blindness – CU Cohort Results
Table 1: Statistical Analysis of Primary exposures and the Primary
Outcome of Bad Vision (20/200 or worse 1 year post-surgery)
Table 2: Multivariate Analysis of Significant Primary Exposures and the
Primary Outcome of Bad Vision (20/200 or worse 1 year post-surgery)
Table 3: Forward Stepwise Selection Analysis (a method that
selects variables that are significant and drops variables that
are no longer significant) and the Primary Outcome of Bad
Vision (20/200 or worse 1 year post-surgery)
No patient with a macular dose less
than 34 Gy had a poor visual outcome.

21. Risk of Blindness – Predicting Damage
Dosimetry calculation to lens, sclera, macula and optic nerve
Courtesy of TA Rice, MD,
Stanford, USA

22. Brachytherapy Complications:
Keratitis and Dry Eye
Generally rare and not debilitating
8.3% dry eye, 3.8% keratitis
For anterior melanomas, keratitis was
20.9% at 2 years, decreased to 2.8% at 5
years
Quivey JM, et al. Int J Radiat Oncol Biol Phys 1993.
Lumbrosos-Le Rouic L, et al., Eye 2004.

23. Brachytherapy Complications:
Radiation Cataract
Highly correlated with anterior location
and larger tumor size
COMS incidence = 68% at 5 years
• 92% if >24 Gy
• 65% if <12 Gy
Treated with standard phaco (66%
improved ≥ 2 lines in COMS)
Incidence of Cataract and Outcomes after Cataract Surgery in the First 5 Years after Iodine 125 Brachytherapy in the Collaborative
Ocular Melanoma Study COMS Report No. 27. Ophthalmology. Mar 3 2007.

24. Brachytherapy Complications:
Neovascular Glaucoma
Occurs in 4-23% at a mean of 27 months.
Associated with anterior tumor location
and horizontal muscle disinsertion.
Correlates with increased tumor height.
Requires multimodality treatment,
including surgery and anti-VEGF.
Puusaari I, Heikkonen J, Kivela T. Ocular complications after iodine brachytherapy for large uveal melanomas. Ophthalmology. Sep 2004;111(9):1768-1777.
Detorakis ET, Engstrom RE, Jr., Wallace R, Straatsma BR. Iris and anterior chamber angle neovascularization after iodine 125 brachytherapy for uveal melanoma.
Ophthalmology. Mar 2005;112(3):505-510.

25. Other complications
Scleral necrosis
• Histological atrophy in 33% of post-plaque eyes
Double vision / strabismus
• Up to 60% short term
• Persistent = 1.7% with 8 year follow-up
Ptosis (droopy eyelid) - common
Toivonen P, Kivela T. Pigmented episcleral deposits after brachytherapy of uveal melanoma. Ophthalmology. May 2006;113(5):865-873.
Petrovich Z, McDonnell JM, Palmer D, Langholz BM, Liggett PE. Histopathologic changes following irradiation for uveal tract melanoma. Am J Clin Oncol. Aug 1994;17(4):298-306.
Dawson E, Sagoo MS, Mehta JS, Comer R, Hungerford J, Lee J. Strabismus in adults with uveal melanoma following episcleral plaque brachytherapy. J AAPOS. 2007 Dec;11(6):584-8.

26. Brachytherapy Complications:
Radiation Optic Neuropathy
Manifests as sudden ONH edema,
exudate, heme, SRF
Incidence 8-16%, up to 46% with large
tumors
Median onset 16-22 mos
50% risk if tumor < 4 mm from disc
Quivey JM, Char DH, Phillips TL, Weaver KA, Castro JR, Kroll SM. High intensity 125-iodine (125I) plaque treatment of uveal melanoma. Int J Radiat Oncol Biol
Phys. Jul 15 1993;26(4):613-618.
Fontanesi J, Meyer D, Xu S, Tai D. Treatment of choroidal melanoma with I-125 plaque. Int J Radiat Oncol Biol Phys. Jul 15 1993;26(4):619-623.

27. Brachytherapy Complications:
Radiation Retinopathy & Maculopathy
Manifests as CME, non-perfusion, NV,
VH, exudation, CWS, microaneurysms
Associated with diabetes
Retinopathy 10-63%, maculopathy 13-
52%, mean onset 26 mos.
Median dose 49 Gy in one series to
develop maculopathy
Krohn J, Monge OR, Skorpen TN, Mork SJ, Dahl O. Posterior uveal melanoma treated with I-125 brachytherapy or primary enucleation. Eye. Jun 22 2007.
Wen JC, Oliver SCN, McCannel TA. Ocular Complications Following I-125 Brachytherapy for Choroidal Melanoma. Eye, 2009 Jun;23(6):1254-68.

28. Maculopathy – How does vision loss occur?
1 year after treatment vision is 20/25

29. Maculopathy – ischemia and edema
18 mos – 20/25 24 mos – 20/25 30 mos – 20/125

30. Maculopathy – How does vision loss occur?
Macular edema – Macular ischemia –
TREATABLE NOT TREATABLE

31. Treatment for Macular Edema
- Anti-VEGF agents (Avastin, Lucentis,
Eylea)
- Steroid (Ozurdex, Kenalog)
- Laser
Macular edema is a chronic condition
Requires repeat treatment
Very hard to catch up once it worsens

32. Scott Oliver, M.D.
Associate Professor
Department of Ophthalmology
UCHealth Eye Center
Scott.Oliver@ucdenver.edu