Melanoma


with poor prognosis include epithelioid cell type, extracellular matrix pattern, mitotic figures, heterogeneous nuclear and nucleolar size, and tumor infiltration by macrophages and/or lymphocytes.6–8


prognosis include class 2 gene expression profile12 or underexpression of specific genes.13


Cytogenetic


factors associated with poor prognosis include monosomy 3 and gain of chromosome 8q.9–11


Molecular biologic factors associated with poor and overexpression


Because most uveal melanomas are currently managed by eye-preserving methods such as plaque and proton beam radiotherapy that do not yield a pathologic specimen, a number of investigators are currently performing biopsy (usually fine needle aspiration biopsy [FNAB])14 of uveal melanomas prior to, or at the time of, ocular treatment to obtain representative tumor specimens for cytopathologic, cytogenetic, and/or molecular biologic analysis. Gene expression profiling of tumor cells seems to distinguish accurately between tumors having low metastatic potential (class 1 signature) from those who also have a short term low metastatic potential but slightly higher mid to long term risk (class 1B), and those having short term high metastatic potential (class 2 signature).16 Gene expression profile assays use a RT-PCR to determine the expression of a panel of 15 genes, three of them controls, in the tumor sample. This assay can be performed in fresh/frozen tumor aspirates or paraffin preserved tissue.16


The Melanoma Molecular Map Project In recent years, many new discoveries about the cytogene tic and molecular biologic abnormalities in uveal melanoma cells, and the ways these features influence development and prognosis of metastatic tumors, have been published.12,16,17


involvement), aggressive local-regional treatments such as hepatic artery infusion chemotherapy with or with embolization (if the liver is the only involved site of metastasis)22–27


or surgical metastasectomy28–30


are frequently employed as first-line therapy in certain centers. While metastasectomy clearly reduces the tumor burden and hepatic artery infusion chemotherapy induces an objective response in a substantially higher percentage of patients with uveal melanoma metastasis than does intravenous chemotherapy,21–23


neither method of treatment


has ever been evaluated in a randomized Phase III clinical trial that included untreated, placebo-treated, sham-treated, or intravenous chemotherapy-treated patients with a similar limited substage of metastatic uveal melanoma. Consequently, the magnitude of any survival benefit of such treatments (if one exists at all) cannot be determined at present.


Although the median survival of selected groups of patients with limited substage metastatic uveal melanoma subjected to metastasectomy or hepatic infusion chemotherapy is usually substantially longer than the median survival of unselected groups of patients with advanced symptomatic metastatic uveal melanoma treated by intravenous chemotherapy or supportive care only, factors such as selection bias and surveillance bias are likely to explain much, if not all, of this difference.20


Adjuvant Therapy for Patients with Uveal Melanoma


Because of the sheer volume of information available in multiple scientific journals, no single clinician or basic scientist can keep up with all of this information. This circumstance allows us to suppose we may already have the pieces of information necessary to solve the puzzle of metastatic uveal melanoma but have not done so because of the complexity of putting them together.18


The Melanoma Molecular Map


Project college website (www.mmmp.org) was launched recently as an ambitious non-profit initiative to enable the scientific community dedicated to melanoma research to gather and share the ever-growing published knowledge on melanoma in a systematic fashion and in a translational perspective. Hopefully, this initiative will lead us closer to solving our puzzle and in turn ultimately lead to improved patient survival.


Most chemotherapy regimens that have been evaluated in prospective Phase I or Phase II clinical trials of metastatic uveal melanoma have produced few, if any, sustained objective favorable responses,19


Unfortunately, chemotherapy is about the only


anticancer therapy that can be offered to most patients with widespread metastatic disease.21


In patients with a limited substage of metastatic uveal melanoma (e.g., single or few metastatic tumors, small tumors, single organ


60


Treatment of Metastatic Uveal Melanoma Unfortunately, the impact of systemic therapy on the survival of patients with metastatic uveal melanoma is uncertain. Metastatic uveal melanoma has a dismal track record of responding to conventional intravenous chemotherapy.16–20


and no chemotherapy regimen has been shown to prolong survival of patients with metastatic uveal melanoma in a randomized Phase III clinical trial.20


In spite of the absence of compelling scientific evidence of any substantial survival benefit of any method of treatment for any substage of metastatic uveal melanoma at this time, several adjuvant therapy trials of different agents (including imatinib mesylate,24


sunitinib, vascular endothelial growth factor (VEGF) Trap,25


bortezomib, vorinostat, sorafenib, AZD2171,26


and lenalidomide) have been initiated in recent years in an attempt to prevent or delay the emergence of clinically detectable metastasis from primary uveal melanoma (see www.clinicaltrials.gov). Unfortunately, because none of the agents being tested in adjuvant trials has shown proven effectiveness against established metastatic uveal melanoma when administered systemically, there is little reason for optimism regarding any of them.


Surveillance Testing for Metastasis Many, if not most, patients with primary uveal melanoma are currently advised to undergo regular periodic surveillance testing for metastasis following excision of the primary tumor (e.g., enucleation, trans-scleral tumor resection) or obliterative treatment of the tumor (e.g., plaque radiation therapy, proton beam irradiation).


Although surveillance testing clearly identifies a higher percentage of the patients who eventually develop metastasis at an asymptomatic, limited substage of their metastasis than does systemic evaluation prompted by tumor-induced symptoms27–29


and although patients with limited


substage metastasis clearly have a longer life expectancy after initial detection of the metastasis than do patients with advanced substage metastasis,30


there is really no evidence that performing frequent


and/or intensive surveillance testing for metastasis really improves our patients’ survival.31,32


Consequently, we do not currently advocate regular


periodic surveillance testing for metastatic uveal melanoma except in patients enrolled in prospective clinical trials. n


US OPHTHALMIC REVIEW


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