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Beyond Eye Treatment

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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. 

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Beyond Eye Treatment

  1. 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. 2. Disclosures - Off label use of medications and devices will be discussed - Advisory Board, Castle Biosciences, Inc. - Clinical trial support, Genentech/Roche
  3. 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. 4. Critical Goals in Uveal Melanoma 1. Saving Life 2. Saving the Eye 3. Saving Vision
  5. 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. 6. Risk of Death COMS • 25% at 5 years • 34% at 10 years Kujala (Scandinavia) • 50% at 25 years
  7. 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. 8. Risk of Death - Mechanism
  9. 9. Genetic Abnormalities Associated with Metastasis Monosomy 3 Isodisomy 3 (5-10% of cases) 1p- 6p+ 6q- 8p- 8q+
  10. 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. 11. Risk of Death – Molecular Targets GNAQ/GNA11, EIF1AX, SF3B1 & BAP1 testing is now available on FNAB specimens
  12. 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. 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. 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. 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. 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. 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. 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. 19. Risk of Blindness – CU Cohort Results
  20. 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. 21. Risk of Blindness – Predicting Damage Dosimetry calculation to lens, sclera, macula and optic nerve Courtesy of TA Rice, MD, Stanford, USA
  22. 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. 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. 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. 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. 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. 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. 28. Maculopathy – How does vision loss occur? 1 year after treatment vision is 20/25
  29. 29. Maculopathy – ischemia and edema 18 mos – 20/25 24 mos – 20/25 30 mos – 20/125
  30. 30. Maculopathy – How does vision loss occur? Macular edema – Macular ischemia – TREATABLE NOT TREATABLE
  31. 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. 32. Scott Oliver, M.D. Associate Professor Department of Ophthalmology UCHealth Eye Center Scott.Oliver@ucdenver.edu

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