Presentation by Carol Shields, MD, Summarized by Jonathan F. Russell, MD, PhD

In this year’s Victor Curtin and Taylor Smith Lecture, titled “Intraocular Tumors: A Look Into the Future,” Carol L. Shields, MD, reviewed recent work she and her colleagues completed and ventured some ideas about where ocular oncology is headed. This article summarizes portions of her presentation.

UVEAL MELANOMA

A recent paper by Shields and colleagues delineated the multimodal imaging findings (OCT, autofluorescence, B-scan) helpful for evaluation of small choroidal melanocytic tumors.1 In a large cohort of choroidal nevi, they identified risk factors for transformation to melanoma. Risk factors included thickness greater than 2 mm on B-scan ultrasonography, subretinal fluid on OCT, symptoms of vision loss (20/50 or worse on Snellen acuity), orange pigment on autofluorescence, hypoechogenicity on B-scan, and diameter greater than 5 mm by fundus photography. Each risk factor has a multimodal imaging correlate. The most important risk factor was thickness greater than 2 mm.2 Similarly, as the number of risk factors present increases, the risk of transformation from nevus to melanoma within 5 years escalates.

Uveal melanoma is often treated with plaque radiotherapy, which is effective but can cause complications such as radiation retinopathy. Anti-VEGF therapy seems to lessen the visual decline associated with radiation maculopathy, and this was confirmed in a large comparative analysis of patients at 1, 2, 3, and 4 years post-plaque.3,4,5 In her lecture, Dr. Shields said she typically administers intravitreal bevacizumab (Avastin, Genentech) every 4 months after plaque brachytherapy for uveal melanoma to prevent or minimize radiation maculopathy.5

A light-activated nanoparticle therapy (AU-011, Aura Biosciences) is in development for treatment of uveal melanoma. This nanoparticle binds selectively to tumor cells. The nanoparticle is coupled with a photosensitive drug, and application of laser causes immediate necrosis of the tumor. This drug candidate has been tested in a limited number of patients, with preliminary data suggesting preservation of visual acuity much better than plaque radiotherapy. This nanoparticle can control tumor growth, although slightly less (with current methods) in comparison to plaque brachytherapy. There is associated anterior and posterior segment inflammation, which might imply an immune response that could have an impact for circulating tumor cells. Trials are ongoing.

Regarding the genetics of uveal melanoma, Shields and colleagues found that the risk for metastasis is high if mutations are present on chromosomes 3 and 8, whereas the risk is low if no mutations are found on these chromosomes.6

Vichitvejpaisal and colleagues7 used The Cancer Genome Atlas to classify uveal melanoma based on genetics into four classes, A through D, with classes C and D having higher risk of metastasis at 4 years than A and B. Adjuvant sunitinib (Sutent, Pfizer) can be used to prevent metastasis in patients with class C and D disease; this tyrosine-kinase inhibitor has a moderate effect that appears more pronounced in younger patients.8

When uveal melanoma metastasizes, experimental treatments include immune mobilizing monoclonal T-cell receptors against cancer, or ImmTACs (Immunocore). ImmTACs are bispecific molecules that bind to melanoma cells and T-cells to facilitate the T-cell attacking the melanoma. This therapy requires weekly infusions but can be remarkably effective.

A recent paper suggests the involvement of protein kinase C in uveal melanoma metastasis, and treatments targeted at this molecule are in development.9

UVEAL METASTASES

In a recent study of more than 1,000 patients with uveal metastasis, nearly two-thirds of patients had a primary cancer site of either breast or lung.10 Most uveal metastases occur in middle-age or older adults.11 Children with uveal metastases have worse survival rates than adults. Women with uveal metastases have a better prognosis than men because they have a higher incidence of breast cancer that can be controlled with novel systemic therapies.

Whether the primary cancer is discovered before the uveal metastasis or the uveal metastasis is discovered before the primary cancer, no effect on survival has been noted. Breast cancer is usually discovered before uveal metastasis is noted, whereas uveal metastasis from lung cancer is usually found before the lung cancer itself. When small choroidal metastases are present, photodynamic therapy is effective.12

RETINOBLASTOMA

Today, 99% of patients with retinoblastoma (RB) survive, and the globe is salvaged in 95% of patients. Treatment is with chemotherapy, utilizing various modalities including intravenous chemoreduction for bilateral RB, intra-arterial chemotherapy for unilateral RB, intravitreal chemotherapy for active vitreous seeds, and intracameral chemotherapy for active aqueous seeds. Following intravenous chemotherapy, 50% of patients have 20/40 or better VA, and survival is excellent out to 20 years.13

Enucleation is performed in about 5% of cases, but it is not curative in all patients. In the United States, at 5 years, despite enucleation, 4% of patients have a metastasis, and death occurs in 2% of patients. In high-income countries such as the United States, the mean age at diagnosis of RB is 14 months, and only 0.3% of patients die from RB metastasis. In contrast, in low-income countries, the mean age at diagnosis is 31 months, extraocular extension is common, and 19% of patients die from RB metastasis.14

Dr. Shields Summarizes Her Talk

CONCLUSION

In closing, Dr. Shields said she envisions a future in which ophthalmologists try to prevent the development of uveal melanoma, perhaps through annual examinations and self-exams, use of artificial intelligence strategies, and treatment of borderline lesions rather than waiting for growth. For detection and prevention of RB, she envisions germline testing at birth, preimplantation genetic diagnosis, screening to detect early lesions, and perhaps even the use of gene therapy.

1. Shields CL, Dalvin LA, Ancona-Lezama D, et al. choroidal nevus imaging features in 3,806 cases and risk factors for transformation into melanoma in 2,355 cases: the 2020 Taylor R. Smith and Victor T. Curtin Lecture. Retina. 2019;39(10):1840-1851.

2. Shields CL, Dalvin LA, Yu MD, et al. choroidal nevus transformation into melanoma per millimeter increment in thickness using multimodal imaging in 2355 cases: the 2019 Wendell L. Hughes Lecture. Retina. 2019;39(10):1852-1860.

3. Shah SU, Shields CL, Bianciotto CG, et al. Intravitreal bevacizumab at 4-month intervals for prevention of macular edema after plaque radiotherapy of uveal melanoma. Ophthalmology. 2014;121(1):269-275.

4. Kim IK, Lane AM, Jain P, Awh C, Gragoudas ES. Ranibizumab for the prevention of radiation complications in patients treated with proton beam irradiation for choroidal melanoma. Trans Am Ophthalmol Soc. 2016;114:T2.

5. Shields CL, Dalvin LA, Chang M, et al. Visual outcome at 4 years following plaque radiotherapy and prophylactic intravitreal bevacizumab (every 4 months for 2 years) for uveal melanoma: comparison with nonrandomized historical control individuals. JAMA Ophthalmol. 2019;138(2):136-146.

6. Shields CL, Say EAT, Hasanreisoglu M, et al. Personalized prognosis of uveal melanoma based on cytogenetic profile in 1059 patients over an 8-year period: the 2017 Harry S. Gradle Lecture. Ophthalmology. 2017;124(10):1523-1531.

7. Vichitvejpaisal P, Dalvin LA, Mazloumi M, Ewens KG, Ganguly A, Shields CL. Genetic analysis of uveal melanoma in 658 patients using the cancer genome atlas classification of uveal melanoma as A, B, C, and D. Ophthalmology. 2019;126(10):1445-1453.

8. Valsecchi ME, Orloff M, Sato R, et al. Adjuvant sunitinib in high-risk patients with uveal melanoma: comparison with institutional controls. Ophthalmology. 2018;125(2):210-217.

9. Shain AH, Bagger MM, Yu R, et al. The genetic evolution of metastatic uveal melanoma. Nat Genet. 2019;51(7):1123-1130.

10. Shields CL, Welch RJ, Malik K, et al. Uveal metastasis: clinical features and survival outcome of 2214 tumors in 1111 patients based on primary tumor origin. Middle East Afr J Ophthalmol. 2018;25(2):81-90.

11. Shields CL, Acaba-Berrocal LA, Selzer EB, et al. uveal metastasis based on patient age in 1,111 patients: comparison of clinical features and outcomes per age category. Retina. 2020;40(2):204-213.

12. Shields CL, Dalvin LA, Lim LS, et al. Circumscribed choroidal hemangioma: visual outcome in the pre-photodynamic therapy era versus photodynamic therapy era in 458 cases. Ophthalmol Retina. 2020;4(1):100-110.

13. Shields CL, Bas Z, Tadepalli S, et al. Long-term (20-year) real-world outcomes of intravenous chemotherapy (chemoreduction) for retinoblastoma in 964 eyes of 554 patients at a single centre [published online ahead of print, February 12, 2020]. Br J Ophthalmol.

14. Global Retinoblastoma Study Group; Fabian ID, Abdallah E, Abdullahi SU, et al. Global retinoblastoma presentation: Analysis by national income level. JAMA Oncology. 2020; 6(5):685-695.