Skip to main content
SpringerLink
Log in

Uveal Melanoma: Adjuvant Therapy

  • Chapter
  • First Online:
Book cover Clinical Ophthalmic Oncology

  • 560 Accesses

Abstract

Uveal melanoma is a rare, aggressive cancer arising from melanocytes of the uveal tract. It is the most common primary intraocular malignancy in adults. Despite excellent rates of local disease control, nearly 50% of patients will develop metastatic disease, with the most common initial site being the liver. Outcomes are exceedingly poor following the development of distant disease, with a median survival ranging from 4 to 15 months. Advances in molecular profiling have enabled a more accurate prediction of metastatic risk. Given the poor prognosis associated with metastatic disease, the development of effective adjuvant therapies is critical to the management of high-risk patients. In this chapter, we provide a comprehensive review of historical, current, and future approaches to adjuvant therapy including chemotherapy, targeted therapy, immunotherapy, epigenetic drugs, liver-directed therapy, and other novel treatment strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 139.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Kivelä TT. The first description of the complete natural history of uveal melanoma by two Scottish surgeons, Allan Burns and James Wardrop. Acta Ophthalmol. 2018;96(2):203–14.

    Article  PubMed  Google Scholar 

  2. Aziz HA, Al Zahrani YA, Bena J, et al. Episcleral brachytherapy of uveal melanoma: role of intraoperative echographic confirmation. Br J Ophthalmol. 2017;101(6):747–51.

    Article  PubMed  Google Scholar 

  3. Harbour JW, Murray TG, Byrne SF, et al. Intraoperative echographic localization of iodine 125 episcleral radioactive plaques for posterior uveal melanoma. Retina (Philadelphia, Pa). 1996;16(2):129–34.

    Article  CAS  Google Scholar 

  4. Gragoudas ES, Egan KM, Seddon JM, et al. Intraocular recurrence of uveal melanoma after proton beam irradiation. Ophthalmology. 1992;99(5):760–6.

    Article  CAS  PubMed  Google Scholar 

  5. Seibel I, Cordini D, Rehak M, et al. Local recurrence after primary proton beam therapy in uveal melanoma: risk factors, retreatment approaches, and outcome. Am J Ophthalmol. 2015;160(4):628–36.

    Article  PubMed  Google Scholar 

  6. Walter SD, Chao DL, Feuer W, et al. Prognostic implications of tumor diameter in association with gene expression profile for uveal melanoma. JAMA Ophthalmol. 2016;134(7):734–40.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Dogrusoz M, Bagger M, van Duinen SG, et al. The prognostic value of AJCC staging in uveal melanoma is enhanced by adding chromosome 3 and 8q status. Invest Ophthalmol Vis Sci. 2017;58(2):833–42.

    Article  PubMed  Google Scholar 

  8. Damato B, Dopierala J, Klaasen A, et al. Multiplex ligation-dependent probe amplification of uveal melanoma: correlation with metastatic death. Invest Ophthalmol Vis Sci. 2009;50(7):3048–55.

    Article  PubMed  Google Scholar 

  9. Harbour JW. A prognostic test to predict the risk of metastasis in uveal melanoma based on a 15-gene expression profile. Methods Mol Biol (Clifton, NJ). 2014;1102:427–40.

    Article  CAS  Google Scholar 

  10. Singh AD, Topham A. Survival rates with uveal melanoma in the United States: 1973-1997. Ophthalmology. 2003;110(5):962–5.

    Article  PubMed  Google Scholar 

  11. Mahendraraj K, Lau CS, Lee I, et al. Trends in incidence, survival, and management of uveal melanoma: a population-based study of 7,516 patients from the surveillance, epidemiology, and end results database (1973-2012). Clin Ophthalmol (Auckland, NZ). 2016;10:2113–9.

    Article  Google Scholar 

  12. Kujala E, Makitie T, Kivela T. Very long-term prognosis of patients with malignant uveal melanoma. Invest Ophthalmol Vis Sci. 2003;44(11):4651–9.

    Article  PubMed  Google Scholar 

  13. Kolandjian NA, Wei C, Patel SP, et al. Delayed systemic recurrence of uveal melanoma. Am J Clin Oncol. 2013;36(5):443–9.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Achtaropoulos AK, Mitsos AP, Detorakis ET, et al. Late isolated brain metastasis following enucleation for choroidal melanoma. Ophthal Surg Lasers Imaging: Off J Int Soc Imag Eye. 2005;36(2):151–4.

    Article  Google Scholar 

  15. Collaborative Ocular Melanoma Study Group. Assessment of metastatic disease status at death in 435 patients with large choroidal melanoma in the Collaborative Ocular Melanoma Study (COMS): COMS report no. 15. Arch Ophthalmol (Chicago, Ill : 1960). 2001;119(5):670–6.

    Article  Google Scholar 

  16. Borthwick NJ, Thombs J, Polak M, et al. The biology of micrometastases from uveal melanoma. J Clin Pathol. 2011;64(8):666–71.

    Article  PubMed  Google Scholar 

  17. Grossniklaus HE. Progression of ocular melanoma metastasis to the liver: the 2012 Zimmerman lecture. JAMA Ophthalmol. 2013;131(4):462–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Aaberg TM Jr, Cook RW, Oelschlager K, et al. Current clinical practice: differential management of uveal melanoma in the era of molecular tumor analyses. Clin Ophthalmol (Auckland, NZ). 2014;8:2449–60.

    Article  Google Scholar 

  19. Lane AM, Kim IK, Gragoudas ES. Survival rates in patients after treatment for metastasis from uveal melanoma. JAMA Ophthalmol. 2018;136:981.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Long RT, Donegan WL, Evans AM. Extended surgical adjuvant chemotherapy for breast carcinoma. Am J Surg. 1969;117(5):701–4.

    Article  CAS  PubMed  Google Scholar 

  21. Singh AD. Uveal melanoma: implications of tumor doubling time. Ophthalmology. 2001;108(5):829–31.

    Article  CAS  PubMed  Google Scholar 

  22. Callejo SA, Antecka E, Blanco PL, et al. Identification of circulating malignant cells and its correlation with prognostic factors and treatment in uveal melanoma. A prospective longitudinal study. Eye (Lond). 2007;21(6):752–9.

    Article  CAS  Google Scholar 

  23. O'Neill PA, Butt M, Eswar CV, et al. A prospective single arm phase II study of dacarbazine and treosulfan as first-line therapy in metastatic uveal melanoma. Melanoma Res. 2006;16(3):245–8.

    Article  CAS  PubMed  Google Scholar 

  24. Sacco JJ, Nathan PD, Danson S, et al. Sunitinib versus dacarbazine as first-line treatment in patients with metastatic uveal melanoma. ASCO Meeting Abstracts. 2013;31(15_suppl):9031.

    Google Scholar 

  25. Carvajal RD, Piperno-Neumann S, Kapiteijn E, et al. Selumetinib in combination with dacarbazine in patients with metastatic uveal melanoma: a phase III, multicenter, randomized trial (SUMIT). J Clin Oncol. 2018;36(12):1232–9.

    Article  CAS  PubMed  Google Scholar 

  26. Carvajal RD, Sosman JA, Quevedo JF, et al. Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial. JAMA. 2014;311(23):2397–405.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Hendrix MJ, Seftor EA, Seftor RE, et al. Regulation of uveal melanoma interconverted phenotype by hepatocyte growth factor/scatter factor (HGF/SF). Am J Pathol. 1998;152(4):855–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Spagnolo F, Grosso M, Picasso V, et al. Treatment of metastatic uveal melanoma with intravenous fotemustine. Melanoma Res. 2013;23(3):196–8.

    Article  CAS  PubMed  Google Scholar 

  29. Peters S, Voelter V, Zografos L, et al. Intra-arterial hepatic fotemustine for the treatment of liver metastases from uveal melanoma: experience in 101 patients. Ann Oncol. 2006;17(4):578–83.

    Article  CAS  PubMed  Google Scholar 

  30. Leyvraz S, Piperno-Neumann S, Suciu S, et al. Hepatic intra-arterial versus intravenous fotemustine in patients with liver metastases from uveal melanoma (EORTC 18021): a multicentric randomized trial. Ann Oncol. 2014;25(3):742–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377(19):1813–23.

    Article  CAS  PubMed  Google Scholar 

  32. Piperno-Neumann S, Kapiteijn E, Larkin JMG. Landscape of genetic alterations in patients with metastatic uveal melanoma. J Clin Oncol. 2014;32(15 suppl):abstr 9043.

    Article  Google Scholar 

  33. Mallikarjuna K, Pushparaj V, Biswas J, et al. Expression of epidermal growth factor receptor, ezrin, hepatocyte growth factor, and c-Met in uveal melanoma: an immunohistochemical study. Curr Eye Res. 2007;32(3):281–90.

    Article  CAS  PubMed  Google Scholar 

  34. Gardner FP, Serie DJ, Salomao DR, et al. c-MET expression in primary and liver metastases in uveal melanoma. Melanoma Res. 2014;24(6):617–20.

    Article  CAS  PubMed  Google Scholar 

  35. All-Ericsson C, Girnita L, Muller-Brunotte A, et al. c-Kit-dependent growth of uveal melanoma cells: a potential therapeutic target? Invest Ophthalmol Vis Sci. 2004;45(7):2075–82.

    Article  PubMed  Google Scholar 

  36. Mouriaux F, Kherrouche Z, Maurage CA, et al. Expression of the c-kit receptor in choroidal melanomas. Melanoma Res. 2003;13(2):161–6.

    Article  CAS  PubMed  Google Scholar 

  37. Gabrilovich DI, Chen HL, Girgis KR, et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med. 1996;2(10):1096–103.

    Article  CAS  PubMed  Google Scholar 

  38. Ohm JE, Gabrilovich DI, Sempowski GD, et al. VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression. Blood. 2003;101(12):4878–86.

    Article  CAS  PubMed  Google Scholar 

  39. el Filali M, Missotten GS, Maat W, et al. Regulation of VEGF-A in uveal melanoma. Invest Ophthalmol Vis Sci. 2010;51(5):2329–37.

    Article  PubMed  Google Scholar 

  40. Tarhini AA, Frankel P, Margolin KA, et al. Aflibercept (VEGF trap) in inoperable stage III or stage iv melanoma of cutaneous or uveal origin. Clin Cancer Res. 2011;17(20):6574–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Mahipal A, Tijani L, Chan K, et al. A pilot study of sunitinib malate in patients with metastatic uveal melanoma. Melanoma Res. 2012;22(6):440–6.

    Article  CAS  PubMed  Google Scholar 

  42. Valsecchi ME, Orloff M, Sato R, et al. Adjuvant sunitinib in high-risk patients with uveal melanoma: comparison with institutional controls. Ophthalmology. 2017;125:210.

    Article  PubMed  Google Scholar 

  43. Shields CL, Ganguly A, Bianciotto CG, et al. Prognosis of uveal melanoma in 500 cases using genetic testing of fine-needle aspiration biopsy specimens. Ophthalmology. 2011;118(2):396–401.

    Article  PubMed  Google Scholar 

  44. Woodward JK, Elshaw SR, Murray AK, et al. Stimulation and inhibition of uveal melanoma invasion by HGF, GRO, IL-1alpha and TGF-beta. Invest Ophthalmol Vis Sci. 2002;43(10):3144–52.

    PubMed  Google Scholar 

  45. Surriga O, Rajasekhar VK, Ambrosini G, et al. Crizotinib, a c-Met inhibitor, prevents metastasis in a metastatic uveal melanoma model. Mol Cancer Ther. 2013;12(12):2817–26.

    Article  CAS  PubMed  Google Scholar 

  46. Wu X, Zhou J, Rogers AM, et al. c-Met, epidermal growth factor receptor, and insulin-like growth factor-1 receptor are important for growth in uveal melanoma and independently contribute to migration and metastatic potential. Melanoma Res. 2012;22(2):123–32.

    Article  CAS  PubMed  Google Scholar 

  47. Daud A, Kluger HM, Kurzrock R, et al. Phase II randomised discontinuation trial of the MET/VEGF receptor inhibitor cabozantinib in metastatic melanoma. Br J Cancer. 2017;116(4):432–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Scheulen ME, Kaempgen E, Kielholz U. STREAM: A randomized discontinuation, blinded, placebo-controlled phase II study of sorafenib (S) treatment of chemonaive patients (pts) with metastatic uveal melanoma (MUM). J Clin Oncol. 2017;35(15 suppl):abstr 9511.

    Article  Google Scholar 

  49. McLean IW, Berd D, Mastrangelo MJ, et al. A randomized study of methanol-extraction residue of bacille Calmette-Guerin as postsurgical adjuvant therapy of uveal melanoma. Am J Ophthalmol. 1990;110(5):522–6.

    Article  CAS  PubMed  Google Scholar 

  50. Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14(1):7–17.

    Article  CAS  PubMed  Google Scholar 

  51. Richtig E, Langmann G, Schlemmer G, et al. Safety and efficacy of interferon alfa-2b in the adjuvant treatment of uveal melanoma. Ophthalmologe. 2006;103(6):506–11.

    Article  CAS  PubMed  Google Scholar 

  52. Lane AM, Egan KM, Harmon D, et al. Adjuvant interferon therapy for patients with uveal melanoma at high risk of metastasis. Ophthalmology. 2009;116(11):2206–12.

    Article  PubMed  Google Scholar 

  53. Bol KF, van den Bosch T, Schreibelt G, et al. Adjuvant dendritic cell vaccination in high-risk uveal melanoma. Ophthalmology. 2016;123(10):2265–7.

    Article  PubMed  Google Scholar 

  54. Prescher G, Bornfeld N, Hirche H, et al. Prognostic implications of monosomy 3 in uveal melanoma. Lancet. 1996;347(9010):1222–5.

    Article  CAS  PubMed  Google Scholar 

  55. Weber J, Grob JJ, Margolin KA, et al. A Phase III study (CheckMate 238) of adjuvant immunotherapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage IIIb/c or stage IV melanoma (MEL) in patients (pts) at high risk for recurrence. J Immunother Cancer. 2015;3(Suppl 2):P166.

    Google Scholar 

  56. Patel SP, Glitza IC, Diab A. The safety and early efficacy of high-dose ipilimumab (IPI) and the combination nivolumab plus ipilimumab (NIVO + IPI) in patients (pts) with uveal melanoma (UM). J Clin Oncol. 2017;35(15 suppl):9554.

    Article  Google Scholar 

  57. Komatsubara KM, Carvajal RD. Immunotherapy for the treatment of uveal melanoma: current status and emerging therapies. Curr Oncol Rep. 2017;19(7):45.

    Article  PubMed  Google Scholar 

  58. Piulats JM, De La Cruz-Merino L, MTC G. Phase II multicenter, single arm, open label study of nivolumab (NIVO) in combination with ipilimumab (IPI) as first line in adult patients (pts) with metastatic uveal melanoma (MUM): GEM1402 NCT02626962. J Clin Oncol. 2017;35(15_suppl):9533.

    Article  Google Scholar 

  59. Herlihy N, Dogrusoz M, van Essen TH, et al. Skewed expression of the genes encoding epigenetic modifiers in high-risk uveal melanoma. Invest Ophthalmol Vis Sci. 2015;56(3):1447–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Robertson AG, Shih J, Yau C, et al. Integrative analysis identifies four molecular and clinical subsets in uveal melanoma. Cancer Cell. 2017;32(2):204–220 e215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Landreville S, Agapova OA, Matatall KA, et al. Histone deacetylase inhibitors induce growth arrest and differentiation in uveal melanoma. Clin Cancer Res. 2012;18(2):408–16.

    Article  CAS  PubMed  Google Scholar 

  62. Ambrosini G, Sawle AD, Musi E, et al. BRD4-targeted therapy induces Myc-independent cytotoxicity in Gnaq/11-mutatant uveal melanoma cells. Oncotarget. 2015;6(32):33397–409.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Almog N, Ma L, Raychowdhury R, et al. Transcriptional switch of dormant tumors to fast-growing angiogenic phenotype. Cancer Res. 2009;69(3):836–44.

    Article  CAS  PubMed  Google Scholar 

  64. Yang H, Grossniklaus HE. Combined immunologic and anti-angiogenic therapy reduces hepatic micrometastases in a murine ocular melanoma model. Curr Eye Res. 2006;31(6):557–62.

    Article  CAS  PubMed  Google Scholar 

  65. Yang H, Jager MJ, Grossniklaus HE. Bevacizumab suppression of establishment of micrometastases in experimental ocular melanoma. Invest Ophthalmol Vis Sci. 2010;51(6):2835–42.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Zhao Y, Morgan MA, Sun Y. Targeting Neddylation pathways to inactivate cullin-RING ligases for anticancer therapy. Antioxid Redox Signal. 2014;21(17):2383–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. van der Ent W, Burrello C, Teunisse AF, et al. Modeling of human uveal melanoma in zebrafish xenograft embryos. Invest Ophthalmol Vis Sci. 2014;55(10):6612–22.

    Article  PubMed  Google Scholar 

  68. Jin Y, Zhang P, Wang Y, et al. Neddylation blockade diminishes hepatic metastasis by dampening cancer stem-like cells and angiogenesis in uveal melanoma. Clin Cancer Res. 2017;24:3741.

    Article  PubMed  Google Scholar 

  69. Voelter V, Schalenbourg A, Pampallona S, et al. Adjuvant intra-arterial hepatic fotemustine for high-risk uveal melanoma patients. Melanoma Res. 2008;18(3):220–4.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Hematology/Oncology, Columbia University Medical Center, New York, NY, USA

    Jessica Yang & Richard D. Carvajal

  2. Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA

    Elaine Binkley & Arun D. Singh

Authors
  1. Jessica Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elaine Binkley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arun D. Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard D. Carvajal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jessica Yang .

Editor information

Editors and Affiliations

  1. University of Oxford, Oxford, UK

    Bertil E. Damato

  2. Cole Eye Institute Cleveland Clinic, Cleveland, OH, USA

    Arun D. Singh

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Yang, J., Binkley, E., Singh, A.D., Carvajal, R.D. (2019). Uveal Melanoma: Adjuvant Therapy. In: Damato, B., Singh, A. (eds) Clinical Ophthalmic Oncology. Springer, Cham. https://doi.org/10.1007/978-3-030-17879-6_21

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-17879-6_21

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-17878-9

  • Online ISBN: 978-3-030-17879-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation