MHC class II-transduced tumor cells originating in the immune-privileged eye prime and boost CD4(+) T lymphocytes that cross-react with primary and metastatic uveal melanoma cells

Uveal melanoma, the most common malignancy of the eye, has a 50% rate of liver metastases among patients with large primary tumors. Several therapies prolong survival of metastatic patients; however, none are curative and no patients survive. Therefore, we are exploring immunotherapy as an alternative or adjunctive treatment. Uveal melanoma may be particularly appropriate for immunotherapy because primary tumors arise in an immune-privileged site and may express antigens to which the host is not tolerized. We are developing MHC class II (MHC II)-matched allogeneic, cell-based uveal melanoma vaccines that activate CD4(+) T lymphocytes, which are key cells for optimizing CD8(+) T-cell immunity, facilitating immune memory, and preventing tolerance. Our previous studies showed that tumor cells genetically modified to express costimulatory and MHC II molecules syngeneic to the recipient are potent inducers of antitumor immunity. Because the MHC II-matched allogeneic vaccines do not express the accessory molecule, Invariant chain, they present MHC II-restricted peptides derived from endogenously encoded tumor antigens. We now report that MHC II-matched allogeneic vaccines, prepared from primary uveal melanomas that arise in the immune-privileged eye, prime and boost IFNgamma-secreting CD4(+) T cells from the peripheral blood of either healthy donors or uveal melanoma patients that cross-react with primary uveal melanomas from other patients and metastatic tumors. In contrast, vaccines prepared from metastatic cells in the liver are less effective at activating CD4(+) T cells, suggesting that tumor cells originating in immune-privileged sites may have enhanced capacity for inducing antitumor immunity and for serving as immunotherapeutic agents.     

The left ventricle as the first site of uveal melanoma metastasis 13 years after treatment of the primary tumor

Treatment of patients with metastatic uveal melanoma is very challenging because the tumor commonly spreads to the liver, surgical resection of metastases is rarely possible, and there is no standard effective systemic therapy. We report the case of a 38-year-old man, who presented with metastatic involvement of the left ventricle as the first site of uveal melanoma recurrence 13 years after treatment of his primary tumor. The metastatic tumor was considered unresectable. We describe the patient's medical management over the next 3 years, the course of his disease, and the results of our review of the literature.     

Whole-body F-18-fluoro-2-deoxyglucose positron emission tomography/computed tomography imaging in the follow-up of metastatic uveal melanoma

Metastasis has been reported in the follow-up of up to 50% of uveal melanoma patients. Established oncological diagnostic modalities in tumor follow-up so far have limited sensitivity and specificity. The diagnostic value of combined positron emission tomography (PET)/computed tomography (CT) scans in the follow-up of patients with metastatic uveal melanoma was assessed. Eleven patients with successfully treated and one patient with suspected uveal melanoma underwent combined PET/CT scan. The indication for PET/CT scan was heterogenous and ranged from suspected metastatic choroidal melanoma in conventional imaging (n=3) to exclusion of further organ involvement before local therapy of liver metastases (n=5) and restaging after local or systemic therapy of metastases (n=4). PET/CT scan showed vital metastases from uveal melanoma in all patients (n=12). Ten patients showed vital hepatic metastases (83%), five osseous (42%), four lymphatic (33%), two pulmonary (17%), one adrenal (8%) and one had muscular metastases (8%). Six patients showed multiple organ involvement (50%). In addition, PET/CT scan correctly identified a primary intraocular tumor and ruled out pulmonary metastatic involvement with suspicious intrapulmonary findings in a CT scan and chest X-ray in two patients. It could also confirm an equivocal intrahepatic finding in an MRI scan as a vital metastasis. PET/CT scan is a very sensitive and specific tool for the detection and localization of metastatic disease in patients with uveal melanoma, assessing both anatomical morphology and cell metabolism in one single examination. With novel therapeutic approaches in evolution, PET/CT scanning can be of great importance for therapy planning and monitoring.     

Uveal melanoma: natural history and treatment options for metastatic disease

In order to evaluate the natural history, prognostic parameters and treatment modalities for metastatic uveal melanoma, a review of the clinical data from the current literature was performed based on a Medline database search. Uveal melanoma represents approximately 5% of all melanomas. It is a distinct clinico-pathological entity, differing in many aspects from cutaneous melanoma. The clinical course is unpredictable and metastatic disease can develop very late after a long disease-free interval. Uveal melanoma metastasizes haematogenously, predominantly to the liver. The most Important prognostic parameters for primary uveal melanoma are tumour diameter, the patient's age and gender, histological features and tumour location. Systemic chemotherapy that is effective in cutaneous melanoma has failed to show activity in uveal melanoma. So far only the BOLD chemotherapy regimen (dacarbazine, lomustine, vincristine and bleomycin) combined with interferon-alpha has been shown to produce an objective tumour response in approximately 20% of previously untreated patients. For metastatic disease localized to the liver, intra-arterial application of fotemustine or carboplatin or chemoembolization with cisplatin have shown useful activity, resulting in a response in up to 40% of patients. Selected patients may benefit from palliative surgery. Immunotherapy with interleukin-2 or interferon-alpha has not shown consistent activity in metastatic uveal melanoma. In conclusion, patients with uveal melanoma metastatic to the liver should undergo one of the local treatment options. Carefully selected patients with extrahepatic disease or patients failing local treatment may benefit from systemic therapy using the BOLD regimen combined with interferon.     

Protracted survival after resection of metastatic uveal melanoma

BACKGROUND: The objective of this study was to evaluate the usefulness of resection of metastatic uveal melanoma and to analyze the characteristics of patients who may benefit from surgical intervention. PATIENTS AND METHODS Twelve patients underwent surgical removal of metastasis between 1976 and 1998. Data regarding primary uveal melanoma, systemic metastasis, surgical procedures, and outcomes were reviewed retrospectively. RESULTS: There were seven patients with liver metastases, two with lung metastases, one with brain metastasis, and two patients with metastases in the liver and other organs. Median time to systemic metastasis was 8 years. Seven of 12 patients were asymptomatic when they were found to have metastasis. Ten patients underwent complete resection of metastasis. No significant surgical complications were experienced. Median recurrence free and overall survival periods after complete resection were 19 months (range, 6-78 months) and greater than 27 months (range, 11-86 months), respectively. Recurrence free and overall 5-year survival rates of those patients were 15.6% and 53.3%, respectively. Three of these patients had no further systemic recurrence. All patients whose time to systemic metastasis was within 5 years developed further systemic recurrence within 2 years after surgery. In contrast, in 8 patients whose time to systemic metastases was greater than 5 years, 4 patients either were recurrence free or developed second metastasis more than 4 years after surgery. CONCLUSIONS: Complete surgical removal of metastatic uveal melanoma provided unexpectedly long survival without significant morbidity for the selected patients. These results are encouraging and justify a trial in which patients eligible for resection are randomized between standard treatment and surgery.     

Targeted therapy for uveal melanoma

Uveal melanoma is the most common primary intra-ocular malignancy in adults. Overall mortality rate remains high because of the development of metastatic disease, which is highly resistant to systemic therapy. Improved understanding of the molecular pathogenesis of cancers has led to a new generation of therapeutic agents that interfere with a specific pathway critical in tumor development or progression. Although no specific genes have been linked to the pathogenesis of uveal melanoma, which differs from that of cutaneous melanoma, progress has been made in identifying potential targets involved in uveal melanoma apoptosis, proliferation, invasion, metastasis, and angiogenesis. This review focuses on the prospects for improving the systemic therapy of uveal melanoma using molecularly targeted agents that are currently in clinical use as well as agents being tested in clinical trials. Preclinical studies suggest potential benefit of inhibitors of Bcl-2, ubiquitin-proteasome, histone deactylase, mitogen-activated protein kinase and phosphatidylinositol-3-kinase-AKT pathways, and receptor tyrosine kinases. Modifiers of adhesion molecules, matrix metalloproteinase, and angiogenic factors also have demonstrated potential benefit. Clinical trials of some of these approaches have been initiated in patients with metastatic uveal melanoma as well as in the adjuvant setting after primary therapy.     

The insulin-like growth factor-I receptor inhibitor picropodophyllin causes tumor regression and attenuates mechanisms involved in invasion of uveal melanoma cells.

PURPOSE: Uveal melanoma has a high mortality rate due to a high incidence of metastasis (up to 50%), which preferentially occurs in the liver. Conventional chemotherapy, being the only therapeutic option today against metastatic uveal melanoma, has not proved to be effective. Therefore, new molecular targets important for malignant phenotype of uveal melanoma have to be found to design efficient pharmacologic agents. EXPERIMENTAL DESIGN: We previously reported data indicating that the insulin-like growth factor-1 receptor (IGF-IR) is a metastasis predictor as well as a therapeutic target for uveal melanoma. In the present study, we made use of the cyclolignan picropodophyllin (PPP), which is an inhibitor of the IGF-IR. RESULTS: We showed that PPP efficiently blocks growth and viability of uveal melanoma cells in cultures and causes tumor regression in xenografted mice. In addition, treatment with PPP inhibited several mechanisms involved in metastasis, including tumor cell adhesion to extracellular matrix proteins, activity and expression of matrix metalloproteinase 2, and cell migration as well as invasion through basement membranes and endothelial cell layers. Furthermore, PPP significantly delayed establishment of uveal melanoma tumors and drastically reduced the incidence of liver metastasis in mice. CONCLUSIONS: Our data suggest that IGF-IR is crucial for growth and survival as well as invasion and metastasis of uveal melanoma cells. Targeting this receptor may therefore comprise a strategy to treat ongoing disease (today incurable) as well as a strategy to prevent development of metastases in patients with primary disease.     

NBS1 expression as a prognostic marker in uveal melanoma.

PURPOSE: Up to half of uveal melanoma patients die of metastatic disease. Treatment of the primary eye tumor does not improve survival in high-risk patients due to occult micrometastatic disease, which is present at the time of eye tumor diagnosis but is not detected and treated until months to years later. Here, we use microarray gene expression data to identify a new prognostic marker. EXPERIMENTAL DESIGN: Microarray gene expression profiles were analyzed in 25 primary uveal melanomas. Tumors were ranked by support vector machine (SVM) and by cytologic severity. Nbs1 protein expression was assessed by quantitative immunohistochemistry in 49 primary uveal melanomas. Survival was assessed using Kaplan-Meier life-table analysis. RESULTS: Expression of the Nijmegen breakage syndrome (NBS1) gene correlated strongly with SVM and cytologic tumor rankings (P < 0.0001). Further, immunohistochemistry expression of the Nbs1 protein correlated strongly with both SVM and cytologic rankings (P < 0.0001). The 6-year actuarial survival was 100% in patients with low immunohistochemistry expression of Nbs1 and 22% in those with high Nbs1 expression (P = 0.01). CONCLUSIONS: NBS1 is a strong predictor of uveal melanoma survival and potentially could be used as a clinical marker for guiding clinical management.     

Effect of an anti-CD54 (ICAM-1) monoclonal antibody (UV3) on the growth of human uveal melanoma cells transplanted heterotopically and orthotopically in SCID mice

We have shown that administration of a novel anti-CD54 monoclonal antibody (UV3) results in long-term survival of SCID mice bearing human myeloma xenografts. Previous studies have demonstrated a link between the expression of CD54 and the progression of uveal melanoma. Our study assessed the expression of CD54 on 7 human uveal melanoma cell lines and 3 cell lines established from uveal melanoma metastases. In vivo studies examined the efficacy of systemic and local administration of UV3 antibody on the progression of uveal melanoma cells transplanted either heterotopically or orthotopically into SCID mice. Five of the 7 primary uveal melanoma cell lines and all 3 of the metastases cell lines expressed CD54. Intraperitoneal injection of either IgG or F(ab')2 fragments of UV3 significantly inhibited the growth of subcutaneous and intraocular melanomas. Subconjunctival injection of either IgG or F(ab')2 fragments of UV3 produced a significant reduction in the growth of intraocular melanomas, even if the antibody was administered after the appearance of intraocular tumors. The results indicate that both primary and metastatic human uveal melanoma cells express CD54. The marked inhibition of intraocular and subcutaneous uveal melanoma progression suggests that UV3 antibody is a promising therapeutic agent for further evaluation in patients with uveal melanoma. This is especially noteworthy, as no existing therapeutic modality prevents metastasis of uveal melanoma or prolongs the survival of patients with uveal melanoma.     

Liver metastases from melanoma: hepatic intra-arterial chemotherapy. A retrospective study

The liver is the primary site of metastases in most uveal melanoma patients. We retrospectively investigated intraarterial chemotherapy (IAC) as treatment for patients with hepatic melanoma metastases.Twenty-three patients (18 with uveal melanoma) received fotemustine (14 patients, 61.9%) or carboplatin (9 patients, 31.1%) via hepatic IAC delivery. The catheter was introduced through percutaneous access to the femoral artery with drugs delivered directly to the hepatic artery, and was removed at the end of each treatment cycle. A total of 3 cycles was planned, repeated every 21 days. However, patients with a clinical response could receive more than 3 cycles, provided that the toxic effects were acceptable.IAC was well tolerated and no catheter-related complications or grade 4 toxicities were reported. Considering only uveal melanoma patients, the overall response rate and disease control rate was 16.7% and 38.9%, respectively. Median time to progression was 6.2 months (95% CI 3.7-10.5) and median overall survival was 21 months (95% CI 8-39).IAC is well tolerated and is a valid choice for patients with a poor prognosis since median survival rates are among the longest reported.     

Variates of survival in metastatic uveal melanoma.

PURPOSE: The course and outcome of metastatic uveal melanoma are not well described. We evaluated the survival of our patients with metastatic uveal melanoma, described factors that correlated with survival, and evaluated the influence of screening tests on time of detection and survival. PATIENTS AND METHODS: All patients with metastatic uveal melanoma seen at Memorial Sloan-Kettering Cancer Center between 1994 and 2004 were identified from our database. We recorded date of initial diagnosis, date of metastatic disease, date of last follow-up, site of the first metastasis, how the first metastasis was discovered, treatment, and outcome of therapy. RESULTS: The estimated median survival of the 119 patients analyzed was 12.5 months; 22% of patients were alive at 4 years. Five variates correlated independently with prolonged survival: Lung/soft tissue as only site of first metastasis, treatment with surgery or intrahepatic therapy, female sex, age younger than 60, and a longer interval from initial diagnosis to metastatic disease. Discovering metastatic disease in asymptomatic patients did not correlate with overall survival; 89% of patients had a single organ as the site of first metastasis. Although liver was the most common site, 39.5% of patients had nonliver sites, most commonly lung, as the first site of metastasis. CONCLUSION: A substantial subset of patients with metastatic uveal melanoma survive more than 4 years with metastatic disease. Data on variates of survival and site of first metastasis may guide strategies for screening patients, although our data failed to show a survival advantage in discovering asymptomatic metastatic disease.     

Prognostic factors in uveal melanoma

Uveal melanoma is the most common primary intraocular malignant tumour, with an annual incidence of approximately six cases per million per year. Approximately 40% of patients with posterior uveal melanoma develop metastatic melanoma to the liver within 10 years after initial diagnosis. Despite high accuracy of diagnosis and availability of various methods of treatment; the mortality due to uveal melanoma has remained unchanged. The prognosis in uveal melanoma depends on clinical, histopathological and cytological factors. Clinical factors that relate to prognosis include location, size, and configuration of the tumour. Uveal melanoma can arise in the iris, the ciliary body or the choroid. Iris melanomas have the best prognosis and ciliary body melanomas have the worst prognosis. Based on retrospective studies, the mortality rates for uveal melanoma for comparable sized tumours treated by enucleation or other globe conserving methods such as radiotherapy appear to be similar. Histopathological factors such as cell type, mitotic activity, microcirculation architecture, tumour-infiltrating lymphocytes and the presence of extrascleral extension are also significant predictors of survival. More recently, cytological factors such as cell proliferation, cytogenic, and molecular genetic prognostic markers have been identified with the hope of detecting high risk cases for adjuvant systemic immune therapy or chemotherapy. At present, the role of these therapeutic methods is not clearly established.     

Expression of the receptor tyrosine kinase Axl promotes ocular melanoma cell survival

Metastatic tumor cells originating from cancers of a variety of tissues such as breast, skin, and prostate may remain dormant for long periods of time. In the case of uveal melanoma, the principal malignancy of the eye, complete removal of the primary tumor by enucleation can nonetheless be followed by metastatic tumor growth in distant organs months, years, or even decades later. This suggests that tumor cells have already spread to secondary sites at the time of treatment and remain dormant as micrometastases. Identifying factors that govern long-lived survival of metastatic tumor cells is therefore key to decreasing mortality associated with this and other diseases. While investigating factors differentially expressed in melanoma cells and normal melanocytes, we identified the receptor tyrosine kinase Axl and found up-regulation of Axl in uveal melanomas and melanoma cell lines by RNase protection, Western analysis, and immunohistochemistry. Axl has been shown to mediate cell growth and survival through its ligand Gas6 in non-transformed cells. To test whether stimulation of Axl can enhance survival of uveal melanoma cells, we assessed the degree of mitogenesis and cell survival by bromodeoxyuridine incorporation and trypan blue exclusion, respectively, upon stimulation of Mel 290 uveal melanoma cells with Gas6 in vitro. We show that Gas6 mediates mitogenesis and cell survival in Mel 290 cells. We further demonstrate that these effects occur specifically through the Axl receptor by modulating the expression of Axl with an antisense construct. cDNA microarray analysis of 12,687 genes then revealed that Gas6 stimulation of Axl in Mel 290 cells results primarily in the down-regulation of Cyr61, a member of the CCN protein family involved in tumor progression. These data show that the Axl pathway mediates increased survival of uveal melanoma cells, potentially advantageous during cancer dormancy, and that Axl may function in part through regulation of Cyr61.     

Circulating tumor cells in uveal melanoma

Despite advances in the diagnosis and local tumor control, the overall mortality rate for uveal melanoma remains high because of the development of metastatic disease. The clinical and histopathological systems currently being used to classify patients are not sufficiently accurate to predict metastasis. Tumor genotyping has demonstrated significant promise but obtaining tumor tissue can be problematic. Furthermore, assessment of tumor tissue does not indicate whether tumor cells have actually been shed and cannot indicate whether treatment is reducing metastasis. The detection of circulating tumor cells in blood has been shown to be a prognostic biomarker that can be used to monitor the effectiveness of therapy in patients with metastatic carcinoma. Uveal melanoma disseminates hematogenously, and the detection of circulating melanoma cells may potentially be useful for diagnosis, risk stratification, and the monitoring of disease progression and treatment efficacy. PCR-based and immunomagnetic cell isolation techniques, derived from studies in patients with cutaneous melanoma, have been tested. For various biological and technical reasons, they have not demonstrated the accuracy and reproducibility required for an effective prognostic assay in patients with uveal melanoma. Assessments have been confounded by false positives and negatives and thus, correlations between circulating melanoma cells and survival have not yet been established. Circulating melanoma cell detection is a valuable tool for investigating metastasis in uveal melanoma and also has the potential to become a standard part of uveal melanoma management. However, more research on the biology of uveal melanoma as well as improvements upon the current technologies are needed.     

New therapeutic agents in uveal melanoma

Uveal melanoma is the most common primary intraocular malignant tumour in adults. Five, ten and fifteen years after primary tumour treatment, up to 25%, 34% and 50% of patients may develop metastases, respectively. There are only a few systemic therapies that have been approved for uveal melanoma, all with doubtful efficacy. As the molecular knowledge over cancer has improved, new therapies are being developed. Several drugs, such as bortezomib, celecoxib, dacarbazine, anti-angiogenic agents (such as bevacizumab, sorafenib and sunitinib), temsirolimus, mitogen-activated protein kinase kinase (MEK) inhibitors, ipilimumab and AEB071 are candidate drugs, and studies are underway to determine the therapeutic effects of these drugs in uveal melanoma.     

Uveal melanomas. Conservation treatment

Eye conservation can be achieved in patients with uveal melanomas by several techniques, with external beam charged particle (proton) therapy and episcleral radionuclide plaque therapy being used most commonly. The probability of visual preservation and of eye retention with either technique is related to tumor size and location. If vision is poor or absent in the fellow eye, even very large tumors can be treated with the proton beam, with a 75% to 80% probability of eye salvage and preservation of some degree of visual function. Local control is achieved in a large proportion of treated eyes with either technique probably because of the large doses that can be focally administered to these relatively small tumors with those techniques. Achieving local control may also contribute to improved survival in some patients. Survival clearly has not been compromised. Useful vision is preserved in eyes with tumors occurring in a favorable location with respect to the optic disc or macula. A dose-searching trial, aimed at improving visual outcome in patients with tumors in unfavorable locations, has been completed and has provided data to aid in designing future trials. Successfully treating uveal melanoma without removal of the involved eye is one of the major oncologic triumphs of the latter part of the 20th century. Very high rates of local control can be achieved with heavy charged particle external beam radiotherapy or 125I episcleral plaque brachytherapy, with preservation of a functionally useful eye in many patients. The excellent results in the eye melanoma patients treated with external beam proton therapy also demonstrate that almost all the patients can successfully cooperate in their treatment by voluntarily fixating the eye on a particular point during treatment, so that their tumor is positioned properly in the beam during treatment. Conservative treatment can achieve local control rates similar to or superior to those achieved with radiation therapy alone in other commonly treated solid tumors, including early stage carcinomas of the breast, vocal cord, and prostate. Continued careful follow-up of conservatively treated patients will provide even better understanding of the radiation effects on uveal melanomas and on normal ocular structures. It is also impressive that these gains have not been achieved at a cost of increased mortality: survival rates in irradiated patients are at least as good as after enucleation. Further observation will reveal whether these initial dramatic and encouraging results will be maintained. The COMS Study may provide additional data in this regard at least regarding survival after brachytherapy relative to enucleation. It will not, however, clarify indications for the two types of radiotherapy (brachytherapy and charged particle therapy) nor will it allow direct comparisons of acute and chronic ocular effects of those therapeutic modalities. The UCSF-LBL trial mentioned previously, which compared helium ion therapy with 125I episcleral plaque treatment, has documented the superiority of charged particle therapy to plaque therapy in terms of local tumor control and eye retention. Of interest is a recent survey reporting that choice of treatment for uveal melanoma did not seem to be associated with large differences in quality of life when assessed at long-term follow-up. The distant failures and metastatic deaths in uveal melanoma patients, more common with larger and more anteriorly located tumors, are most distressing. A randomized clinical trial of adjuvant systemic therapy is clearly indicated but has not been mounted because of the relatively poor results obtained with systemic therapy in metastatic melanoma patients. The recent report of improved survival in cutaneous melanoma patients at high risk for metastasis who were treated with interferon is encouraging, and it led to the initiation of the nonrandomized study described previously, which uses interferon following proton eye irradiation for patients with increased risk of metastasis. Other trials would clearly be indicated if more effective systemic therapies become available.     

The treatment of brain metastases from malignant melanoma

Metastasis to the CNS develops in nearly half of patients with advanced melanoma; in 15% to 20% of these patients, the CNS is the first site of relapse. While systemic therapy for metastatic melanoma produces objective responses in 15% to 50% of patients, the available drugs do not penetrate well into the CNS, and these patients rarely benefit from systemic therapy. Although brain metastasis may be treated with surgery and/or stereotactic radiosurgery (SRS) when disease is limited to approximately one to three lesions, treatment for patients with large or multiple metastases is limited to whole brain irradiation (WBRT). While formal response and survival analyses of the impact of WBRT in melanoma have not been reported, the estimated median survival time for unselected patients with CNS metastases is only 2 to 4 months, with 1-year survival rates of less than 13%. In a selected population of patients with limited CNS involvement, surgical resection alone or in combination with WBRT appears to prolong median survival. More recently, SRS has been shown to be an effective local treatment for selected patients with brain metastases. In several retrospective reports of patients with melanoma CNS metastases, treatment with surgical resection alone or in combination with WBRT has been demonstrated to prolong median survival. More recently, SRS has been shown to be an effective local treatment for selected patients with brain metastases. In several retrospective reports, patients with CNS metastases from melanoma treated with a combination of WBRT plus SRS or SRS alone had median survivals and rates of control in the CNS superior to published reports for traditional WBRT. Most of these patients died from progressive extracranial disease with locally controlled CNS disease. Investigation of the contribution of newer systemic agents to the control of melanoma metastatic to the CNS has been based on the identification of drugs that have antitumor activity and the ability to cross the blood-brain barrier. Fotemustine is a nitrosourea that produced similar activity in CNS metastasis as in systemic disease, with a response rate of about 25%. Temozolomide (TMZ) is an oral alkylating agent that acts via the same mechanism as dacarbazine (DTIC), the most active single agent in melanoma. TMZ, which is highly active in brain tumors, has also been associated with activity in systemic and CNS metastases in melanoma patients, also in the 25% range. Efforts are underway to assess the additive benefit of TMZ and other drugs to WBRT or focused radiotherapy in this disease.     

Uveal melanoma: From diagnosis to treatment and the science in between

Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the United States, and their age‐adjusted risk is 5 per 1 million population. These less frequent melanomas are dissimilar to their more common cutaneous melanoma relative, with differing risk factors, primary treatment, anatomic spread, molecular changes, and responses to systemic therapy. Once uveal melanoma becomes metastatic, therapy options are limited and are often extrapolated from cutaneous melanoma therapies despite the routine exclusion of patients with uveal melanoma from clinical trials. Clinical trials directed at uveal melanoma have been completed or are in progress, and data from these well designed investigations will help guide future directions in this orphan disease. Cancer 2016;122:2299–2312 . © 2016 American Cancer Society.     

A prospective single arm phase II study of dacarbazine and treosulfan as first-line therapy in metastatic uveal melanoma

Uveal melanoma is relatively uncommon accounting for fewer than 5% of all melanoma cases. Localized tumours are curable by local therapy but a significant percentage of patients go on to have a relapse with metastatic disease. Uncertainty remains concerning the level of activity of dacarbazine in uveal melanoma as opposed to that in the cutaneous form. Recently, a possible role for treosulfan in uveal disease has been reported. A phase II study was therefore undertaken to assess the objective response rate of the combination of dacarbazine and treosulfan in previously untreated patients with metastatic uveal melanoma. All patients received dacarbazine 850 mg/m and treosulfan 8 g/m(2) every 21 days up to a maximum of six cycles. Fifteen patients enrolled in the study. As expected, the major toxicities were haematological (particularly thrombocytopaenia) but the treatment was generally well tolerated. No responses were seen; however, disease stabilization was achieved in two patients. Median progression free survival from the start of chemotherapy was 12 weeks and median overall survival was 30 weeks. This study, using the combination of dacarbazine and treosulfan, while well tolerated, did not confirm earlier reports suggesting treosulfan is active in uveal melanoma.     

Treatment of disseminated ocular melanoma with sequential fotemustine,interferon alpha,and interleukin 2

Malignant melanoma of the uvea is remarkable for purely haematogenous dissemination and its tendency to metastasise to the liver. Although the liver is involved in up to 95% of patients, 50% of these also develop extrahepatic metastases, most often in the lungs, bone, skin, and brain. The only effective treatments reported to date relied on hepatic arterial chemoembolisation or -perfusion. The objective of this study was to establish a therapy protocol addressing patients with both sole liver involvement and systemic disease. Forty-eight patients with metastatic ocular melanoma received fotemustine 100 mg m(-2) either as 60-min infusion into the hepatic artery or as 15-min infusion via a peripheral vein, depending on the metastatic sites involved, i.e., restriction to the liver or hepatic together with extrahepatic disease. For the first treatment cycle this infusion was repeated after one week. For all cycles, subsequent to a three week resting period, patients received an immunotherapy consisting of subcutaneous interleukin 2 and interferon alpha(2). Although objective responses were more frequent within the cohort receiving intraarterial fotemustine (21.7 vs 8%), this difference did not translate into a significant benefit in overall survival, i.e., 369 and 349 days, respectively. Of note, this overall survival is much longer than that repeatedly reported for stage IV uveal melanoma not treated with fotemustine, suggesting a therapeutic activity of this cytostatic drug even after systemic administration.