Epidemiology, Clinical Presentation and Treatment of Uveal Melanoma

Author(s): Marlana Orloff, Shingo Sato, Matias E. Valsecchi, Takami Sato.

Journal Name: Clinical Cancer Drugs

Volume 2 , Issue 1 , 2015

Become EABM
Become Reviewer

Abstract:

Uveal melanoma represents the most common primary intraocular tumor in adults. However, it remains a relatively infrequent malignancy where large clinical trials are difficult to accomplish. However, during the last couple of years we have witnessed an unprecedented expansion of our understanding of this disease. New genetic and molecular pathways were found to play key roles in the development of uveal melanoma and they represent potential targets for future therapies. At the same time there were some improvements in the delineation of prognostic features as well as treatment options for metastatic disease, with both liver-directed strategies as well as targeted agents. In this review we will try to summarize and update the reader with the most relevant information in terms of its pathogenesis, clinical presentation, prognostic factors– cytogenetic and genetic profiling –, state of the art management of liver only as well as systemic metastatic disease. Finally we will also discuss current ongoing clinical trials as well as future directions in terms of research and clinical investigation.

Keywords: Uveal melanoma, immune therapy, targeted agents, BAP1, GNAQ, GNA11, chemoembolization, immunoembolization, selumetinib and sunitinib.

[1]
Singh AD, Turell ME, Topham AK. Uveal melanoma: trends in incidence, treatment, and survival. Ophthalmology 2011; 118(9): 1881-5.
[2]
Singh AD, Topham A. Incidence of uveal melanoma in the United States: 1973-1997. Ophthalmology 2003; 110(5): 956-61.
[3]
Zloto O, Pe’er J, Frenkel S. Gender differences in clinical presentation and prognosis of uveal melanoma. Invest Ophthalmol Vis Sci 2013; 54(1): 652-6.
[4]
Spagnolo F, Caltabiano G, Queirolo P. Uveal melanoma. Cancer Treat Rev 2012; 38(5): 549-53.
[5]
Shields CL, Kaliki S, Furuta M, Mashayekhi A, Shields JA. Clinical spectrum and prognosis of uveal melanoma based on age at presentation in 8,033 cases. Retina 2012; 32(7): 1363-72.
[6]
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.
[7]
Novais GA, Fernandes BF, Belfort RN, Castiglione E, Cheema DP, Burnier MN Jr. Incidence of melanocytic lesions of the conjunctiva in a review of 10 675 ophthalmic specimens. Int J Surg Pathol 2010; 18(1): 60-3.
[8]
Eschelman DJ, Gonsalves CF, Sato T. Transhepatic therapies for metastatic uveal melanoma. Semin Intervent Radiol 2013; 30(1): 39-48.
[9]
Cruz F, Rubin BP, Wilson D, et al. Absence of BRAF and NRAS mutations in uveal melanoma. Cancer Res 2003; 63(18): 5761-6.
[10]
Prescher G, Bornfeld N, Hirche H, Horsthemke B, Jockel KH, Becher R. Prognostic implications of monosomy 3 in uveal melanoma. Lancet 1996; 347(9010): 1222-5.
[11]
Shields CL, Ganguly A, Bianciotto CG, Turaka K, Tavallali A, Shields JA. Prognosis of uveal melanoma in 500 cases using genetic testing of fine-needle aspiration biopsy specimens. Ophthalmology 2011; 118(2): 396-401.
[12]
Singh AD, Shields CL, Shields JA. Prognostic factors in uveal melanoma. Melanoma Res 2001; 11(3): 255-63.
[13]
Toloi DdA Scaranti M, Fraile NMP, et al. Influence of histopathologic features and other risk factors on the outcomes of uveal melanoma patients submitted to ocular enucleation. ASCO Meeting Abstracts. 2014;32(15_suppl):e20028..
[14]
Becher R, Korn WM, Prescher G. Use of fluorescence in situ hybridization and comparative genomic hybridization in the cytogenetic analysis of testicular germ cell tumors and uveal melanomas. Cancer Genet Cytogenet 1997; 93(1): 22-8.
[15]
White VA, Chambers JD, Courtright PD, Chang WY, Horsman DE. Correlation of cytogenetic abnormalities with the outcome of patients with uveal melanoma. Cancer 1998; 83(2): 354-9.
[16]
Onken MD, Worley LA, Ehlers JP, Harbour JW. Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death. Cancer Res 2004; 64(20): 7205-9.
[17]
Onken MD, Worley LA, Char DH, et al. Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. Ophthalmology 2012; 119(8): 1596-603.
[18]
Harbour JW, Chen R. The DecisionDx-UM Gene Expression Profile Test Provides Risk Stratification and Individualized Patient Care in Uveal Melanoma. PLoS Curr 2013; 5.
[19]
Zuidervaart W, van Nieuwpoort F, Stark M, et al. Activation of the MAPK pathway is a common event in uveal melanomas although it rarely occurs through mutation of BRAF or RAS. Br J Cancer 2005; 92(11): 2032-8.
[20]
Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417(6892): 949-54.
[21]
Van Raamsdonk CD, Griewank KG, Crosby MB, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med 2010; 363(23): 2191-9.
[22]
Arguello D, Bender R, Sato T, Gatalica Z. Comprehensive profiling of uveal melanoma.ASCO Meeting Abstracts. 2014; 32 (15_suppl):e20036
[23]
Piperno-Neumann S, Kapiteijn E, Larkin JMG, et al. Landscape of genetic alterations in patients with metastatic uveal melanoma.ASCO Meeting Abstracts. 2014;32(15_suppl):9043.
[24]
Besaratinia A, Pfeifer GP. Uveal melanoma and GNA11 mutations: a new piece added to the puzzle. Pigment Cell Melanoma Res 2011; 24(1): 18-20.
[25]
Harbour JW, Onken MD, Roberson ED, et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 2010; 330(6009): 1410-3.
[26]
Scheuermann JC, de Ayala Alonso AG, Oktaba K, et al. Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB. Nature 2010; 465(7295): 243-7.
[27]
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.
[28]
Murali R, Wiesner T, Scolyer RA. Tumours associated with BAP1 mutations. Pathology 2013; 45(2): 116-26.
[29]
Carbone M, Yang H, Pass HI, Krausz T, Testa JR, Gaudino G. BAP1 and cancer. Nat Rev Cancer 2013; 13(3): 153-9.
[30]
Valsecchi ME, Asija A, Sato T, et al. Development of renal cell carcinoma in patients with primary uveal melanoma. ASCO Meeting Abstracts. 2013;31(15_suppl):e15563.
[31]
Field MG, Harbour JW. Recent developments in prognostic and predictive testing in uveal melanoma. Curr Opin Ophthalmol 2014; 25(3): 234-9.
[32]
Damato B. Treatment of primary intraocular melanoma. Expert Rev Anticancer Ther 2006; 6(4): 493-506.
[33]
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(7): 969-82.
[34]
Pereira PR, Odashiro AN, Lim LA, et al. Current and emerging treatment options for uveal melanoma. Clin Ophthalmol 2013; 7: 1669-82.
[35]
Shields JA, Shields CL. Management of Posterior Uveal Melanoma: Past, Present, and Future: The 2014 Charles L. Schepens Lecture. Ophthalmology. 2014.
[36]
Desjardins L, Dorval T, Lévy C, Cojean I, Schlienger P, Salmon R. Randomised study on adjuvant therapy by DTIC in choroidal melanoma. Ophtalmologie 1998; 12(3): 168-73.
[37]
Voelter V, Schalenbourg A, Pampallona S, Peters S, Halkic N, Denys A. Adjuvant intra-arterial hepatic fotemustine for high-risk uveal melanoma patients. Melanoma Res 2008; 18(3): 220-4.
[38]
Lane AM, Egan KM, Harmon D, Holbrook A, Munzenrider JE, Gragoudas ES. Adjuvant interferon therapy for patients with uveal melanoma at high risk of metastasis. Ophthalmology 2009; 116(11): 2206-12.
[39]
Valsecchi ME, Shockley N, Summers D, Shields CL, Shields JA, Mastrangelo MJ. Adjuvant sunitinib in high-risk patients with uveal melanoma: A pilot study. ASCO Meeting Abstracts. 2012;30(15_suppl):8560.
[40]
Surriga O, Rajasekhar VK, Ambrosini G, Dogan Y, Huang R, Schwartz GK. Crizotinib, a c-Met inhibitor, prevents metastasis in a metastatic uveal melanoma model. Mol Cancer Ther 2013; 12(12): 2817-26.
[41]
Francis JH, Patel SP, Gombos DS, Carvajal RD. Surveillance options for patients with uveal melanoma following definitive management. Am Soc Clin Oncol Educ Book 2013; 382-7.
[42]
Augsburger JJ, Correa ZM, Trichopoulos N. Surveillance testing for metastasis from primary uveal melanoma and effect on patient survival. Am J Ophthalmol 2011; 152(1): 5-9.e1.
[43]
Torres V, Triozzi P, Eng C, Tubbs R, Schoenfiled L, Crabb JW. Circulating tumor cells in uveal melanoma. Future Oncol 2011; 7(1): 101-9.
[44]
Bidard FC, Madic J, Mariani P, Piperno-Neumann S, Rampanou A, Servois V. Detection rate and prognostic value of circulating tumor cells and circulating tumor DNA in metastatic uveal melanoma. Int J Cancer 2014; 134(5): 1207-13.
[45]
Barak V, Kaiserman I, Frenkel S, Hendler K, Kalickman I, Pe’er J. The dynamics of serum tumor markers in predicting metastatic uveal melanoma (part 1). Anticancer Res 2011; 31(1): 345-9.
[46]
Triozzi PL, Singh AD. Blood biomarkers for uveal melanoma. Future Oncol 2012; 8(2): 205-15.
[47]
Frenkel S, Zloto O, Pe’er J, Barak V. Insulin-like growth factor-1 as a predictive biomarker for metastatic uveal melanoma in humans. Invest Ophthalmol Vis Sci 2013; 54(1): 490-3.
[48]
Singh AD, Borden EC. Metastatic uveal melanoma. Ophthalmol Clin North Am 2005; 18(1): 143-50. [ix.].
[49]
Sugihara K, Uetake H. Therapeutic strategies for hepatic metastasis of colorectal cancer: overview. J Hepatobiliary Pancreat Sci 2012; 19(5): 523-7.
[50]
Mariani P, Piperno-Neumann S, Servois V, Berry MG, Dorval T, Plancher C. Surgical management of liver metastases from uveal melanoma: 16 years’ experience at the Institut Curie. Eur J Surg Oncol 2009; 35(11): 1192-7.
[51]
Frenkel S, Nir I, Hendler K, Lotem M, Eid A, Jurim O. Long-term survival of uveal melanoma patients after surgery for liver metastases. Br J Ophthalmol 2009; 93(8): 1042-6.
[52]
Alexander HR Jr, Libutti SK, Pingpank JF, Steinberg SM, Bartlett DL, Helsabeck C. Hyperthermic isolated hepatic perfusion using melphalan for patients with ocular melanoma metastatic to liver. Clin Cancer Res 2003; 9(17): 6343-9.
[53]
Alexander HR Jr, Butler CC. Development of isolated hepatic perfusion via the operative and percutaneous techniques for patients with isolated and unresectable liver metastases. Cancer J 2010; 16(2): 132-41.
[54]
Pingpank JF, Hughes MS, Alexander HR, Faries MB, Zager JS, Royal R. A phase III random assignment trial comparing percutaneous hepatic perfusion with melphalan (PHP-mel) to standard of care for patients with hepatic metastases from metastatic ocular or cutaneous melanoma. ASCO Meeting Abstracts. 2010; 28 (18_suppl):LBA8512.
[55]
Patel SP. Latest developments in the biology and management of uveal melanoma. Curr Oncol Rep 2013; 15(6): 509-16.
[56]
Carrasco CH, Wallace S, Charnsangavej C, Papadopoulos NE, Patt YZ, Mavligit GM. Treatment of hepatic metastases in ocular melanoma. Embolization of the hepatic artery with polyvinyl sponge and cisplatin. JAMA 1986; 255(22): 3152-4.
[57]
Patel K, Sullivan K, Berd D, Mastrangelo MJ, Shields CL, Shields JA. Chemoembolization of the hepatic artery with BCNU for metastatic uveal melanoma: results of a phase II study. Melanoma Res 2005; 15(4): 297-304.
[58]
Dayani PN, Gould JE, Brown DB, Sharma KV, Linette GP, Harbour JW. Hepatic metastasis from uveal melanoma: angiographic pattern predictive of survival after hepatic arterial chemoembolization. Arch Ophthalmol 2009; 127(5): 628-32.
[59]
Gupta S, Bedikian AY, Ahrar J, Ensor J, Ahrar K, Madoff DC. Hepatic artery chemoembolization in patients with ocular melanoma metastatic to the liver: response, survival, and prognostic factors. Am J Clin Oncol 2010; 33(5): 474-80.
[60]
Venturini M, Pilla L, Agostini G, Cappio S, Losio C, Orsi M. Transarterial chemoembolization with drug-eluting beads preloaded with irinotecan as a first-line approach in uveal melanoma liver metastases: tumor response and predictive value of diffusion-weighted MR imaging in five patients. J Vasc Interv Radiol 2012; 23(7): 937-41.
[61]
Golfieri R, Giampalma E, Renzulli M, Cioni R, Bargellini I, Bartolozzi C. Randomised controlled trial of doxorubicin-eluting beads vs conventional chemoembolisation for hepatocellular carcinoma. Br J Cancer 2014; 111(2): 255-64.
[62]
Sato T, Eschelman DJ, Gonsalves CF, Terai M, Chervoneva I, McCue PA. Immunoembolization of malignant liver tumors, including uveal melanoma, using granulocyte-macrophage colony-stimulating factor. J Clin Oncol 2008; 26(33): 5436-42.
[63]
Yamamoto A, Chervoneva I, Sullivan KL, Eschelman DJ, Gonsalves CF, Mastrangelo MJ. High-dose immunoembolization: survival benefit in patients with hepatic metastases from uveal melanoma. Radiology 2009; 252(1): 290-8.
[64]
Eschelman DJ, Gonsalves CF, Terai M, Laudadio M, Sullivan KL, Mastrangelo MJ. The results of a randomized phase II study using embolization with or without granulocyte-macrophage colonystimulating factor (GM-CSF) in uveal melanoma patients with hepatic metastasis. ASCO Meeting Abstracts. 2011; 29 (15_suppl): 8577.
[65]
Valsecchi ME, Terai M, Eschelman DJ, et al. Double-Blinded, Randomized Phase II Study Using Embolization with or without Granulocyte-Macrophage Colony-Stimulating Factor in Uveal Melanoma with Hepatic Metastases. J Vasc Interv Radiol 2015.
[66]
Kennedy AS, Nutting C, Jakobs T, Cianni R, Notarianni E, Ofer A. A first report of radioembolization for hepatic metastases from ocular melanoma. Cancer Invest 2009; 27(6): 682-90.
[67]
Gonsalves CF, Eschelman DJ, Sullivan KL, Anne PR, Doyle L, Sato T. Radioembolization as salvage therapy for hepatic metastasis of uveal melanoma: a single-institution experience. AJR Am J Roentgenol 2011; 196(2): 468-73.
[68]
Rule W, Timmerman R, Tong L, Abdulrahman R, Meyer J, Boike T. Phase I dose-escalation study of stereotactic body radiotherapy in patients with hepatic metastases. Ann Surg Oncol 2011; 18(4): 1081-7.
[69]
Bedikian AY, Papadopoulos NE, Kim KB, Vardeleon A, Smith T, Lu B. A pilot study with vincristine sulfate liposome infusion in patients with metastatic melanoma. Melanoma Res 2008; 18(6): 400-4.
[70]
Went PT, Dirnhofer S, Bundi M, Mirlacher M, Schraml P, Mangialaio S. Prevalence of KIT expression in human tumors. J Clin Oncol 2004; 22(22): 4514-22.
[71]
Pereira PR, Odashiro AN, Marshall JC, Correa ZM, Belfort R Jr, Burnier MN Jr. The role of c-kit and imatinib mesylate in uveal melanoma. J Carcinog 2005; 4: 19.
[72]
Penel N, Delcambre C, Durando X, Clisant S, Hebbar M, Negrier S. O-Mel-Inib: a Cancero-pole Nord-Ouest multicenter phase II trial of high-dose imatinib mesylate in metastatic uveal melanoma. Invest New Drugs 2008; 26(6): 561-5.
[73]
Mahipal A, Tijani L, Chan K, Laudadio M, Mastrangelo MJ, Sato T. A pilot study of sunitinib malate in patients with metastatic uveal melanoma. Melanoma Res 2012; 22(6): 440-6.
[74]
Chan KR, Gundala S, Laudadio M, Mastrangelo M, Yamamoto A, Sato T. A pilot study using sunitinib malate as therapy in patients with stage IV uveal melanoma.ASCO Meeting Abstracts. 2008; 26(15_suppl):9047.
[75]
Sacco JJ, Nathan PD, Danson S, Lorigan P, Nicholson S, Ottensmeier C. Sunitinib versus dacarbazine as first-line treatment in patients with metastatic uveal melanoma.ASCO Meeting Abstracts. 2013;31(15_suppl):9031.
[76]
Carvajal RD, Sosman JA, Quevedo JF, Milhem MM, Joshua AM, Kudchadkar RR. Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial. JAMA 2014; 311(23): 2397-405.
[77]
Piperno-Neumann S, Kapiteijn E, Larkin JMG, Carvajal RD, Luke JJ, Seifert H. Phase I dose-escalation study of the protein kinase C (PKC) inhibitor AEB071 in patients with metastatic uveal melanoma. ASCO Meeting Abstracts. 2014;32(15_suppl):9030.
[78]
Ambrosini G, Musi E, Ho AL, de Stanchina E, Schwartz GK. Inhibition of mutant GNAQ signaling in uveal melanoma induces AMPK-dependent autophagic cell death. Mol Cancer Ther 2013; 12(5): 768-76.
[79]
Khalili JS, Yu X, Wang J, Hayes BC, Davies MA, Lizee G. Combination small molecule MEK and PI3K inhibition enhances uveal melanoma cell death in a mutant GNAQ- and GNA11-dependent manner. Clin Cancer Res 2012; 18(16): 4345-55.
[80]
Musi E, Ambrosini G, de Stanchina E, Schwartz GK. The phosphoinositide 3-kinase alpha selective inhibitor BYL719 enhances the effect of the protein kinase C inhibitor AEB071 in GNAQ/GNA11-mutant uveal melanoma cells. Mol Cancer Ther 2014; 13(5): 1044-53.
[81]
Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363(8): 711-23.
[82]
Rodriguez PJM, de Olza OM, Codes M, Lopez-Martin JA, Berrocal A, Garcia M. Phase II study evaluating ipilimumab as a single agent in the first-line treatment of adult patients (Pts) with metastatic uveal melanoma (MUM): The GEM-1 trial. ASCO Meeting Abstracts. 2014;32(15_suppl):9033.
[83]
Deo MA. Long-term survival benefit from ipilimumab treatment in metastatic uveal melanoma patients.ASCO Meeting Abstracts. 2014; 32(15_suppl):3060.
[84]
Merelli B, Massi D, Cattaneo L, Mandala M. Targeting the PD1/PD-L1 axis in melanoma: biological rationale, clinical challenges and opportunities. Crit Rev Oncol Hematol 2014; 89(1): 140-65.


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 2
ISSUE: 1
Year: 2015
Page: [29 - 37]
Pages: 9
DOI: 10.2174/2212697X02666150203213809

Article Metrics

PDF: 13