Uveal Melanoma Metastatic to the Liver: Chemoembolization With 1,3-Bis-(2-Chloroethyl)-1-Nitrosourea

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1 Vascular and Interventional Radiology Original Research Gonsalves et al. BCNU Chemoembolization of Uveal Melanoma Metastases in Liver Vascular and Interventional Radiology Original Research Carin F. Gonsalves 1 David J. Eschelman 1 Bartley Thornburg 2 Andrea Frangos 1 Takami Sato 3 Gonsalves CF, Eschelman DJ, Thornburg B, Frangos A, Sato T Keywords: BCNU, chemoembolization, transarterial liver-directed therapy, uveal melanoma DOI: /AJR Received October 15, 2014; accepted after revision January 23, Based on a presentation at the Society of Interventional Radiology 2013 annual meeting, New Orleans, LA. D. J. Eschelman is a consultant for Guerbet. 1 Department of Radiology, Division of Interventional Radiology, Thomas Jefferson University Hospital, 132 S 10th St, Main Building, Ste 766, Philadelphia, PA Address correspondence to C. F. Gonsalves (carin.gonsalves@jefferson.edu). 2 Department of Radiology, Northwestern University, Evanston, IL. 3 Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA. AJR 2015; 205: X/15/ American Roentgen Ray Society Uveal Melanoma Metastatic to the Liver: Chemoembolization With 1,3-Bis-(2-Chloroethyl)-1-Nitrosourea OBJECTIVE. The purpose of this study is to evaluate whether chemoembolization with 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) is a safe and effective treatment for bulky uveal melanoma liver metastasis. MATERIALS AND METHODS. Over a 7-year period, 63 treatment-naïve patients presented with uveal melanoma metastasis replacing 50% or more of the normal liver parenchyma. Patients with Eastern Cooperative Oncology Group 0 2 performance status, no extensive extrahepatic metastases, and adequate liver and renal function were treated with BCNU (200 mg) chemoembolization. Pretreatment tumor burdens were classified by MRI as 50 75% and more than 75%. Lactate dehydrogenase (LDH) levels were divided into less than or equal to 500 and more than 500 IU/L (i.e., more than twice the normal level). Treatment toxicity was assessed using Common Terminology Criteria for Adverse Events (version 4.0). CT and MRI were used to determine best radiologic response (Response Evaluation Criteria in Solid Tumors). Overall survival (OS) and progression-free survival (PFS) were compared with tumor burden and LDH levels. RESULTS. Fifty patients (31 men; mean age, 59.1 years; range, years) met the inclusion criteria. A total of 271 chemoembolization procedures were performed. Grade 3 thrombocytopenia occurred in two patients, grade 3 hyperbilirubinemia (n = 2) was attributed to disease progression, and asymptomatic grade 4 transaminitis occurred after 16 treatments. Best radiologic response was as follows: partial response, n = 3; stable disease, n = 33; and disease progression, n = 12 (no follow-up imaging, n = 2). The median OS was 7.1 months (range, months), and the median PFS was 5.0 months (range, months). Eleven patients (22%) survived longer than 12 months (range, ) with one patient alive at follow-up. Tumor burden and LDH levels showed no statistically significant effect on OS (p = 0.20 and p = 0.14, respectively) or PFS (p = 0.10 and p = 0.34, respectively). CONCLUSION. BCNU chemoembolization should be considered as a treatment option for patients with bulky uveal melanoma hepatic metastases. U veal melanoma is the most prevalent primary intraocular malignant tumor in adults [1, 2]. After initial diagnosis and treatment of the primary tumor, up to 50% of patients subsequently develop systemic metastasis [3, 4]. The liver is the predominant organ of involvement in 70 90% of patients and tends to be the first manifestation of metastatic disease [5 7]. In general, without treatment, survival after the development of hepatic metastasis is poor, with a median survival of less than 6 months [8, 9]. Over the past few decades, research has suggested that transarterial catheter directed treatment, such as chemoembolization, is the most effective therapy for prolonging the survival of patients with uveal melanoma hepatic metastasis [10 16]. Studies have reported longer overall survival (OS) after chemoembolization for patients with limited intrahepatic tumor burden (< 50%) compared with those with bulky disease [10, 12 16]. However, in a phase 1 trial by Patel et al. [12], significant tumor regression was noted in two patients with more than 50% tumor burden after chemoembolization using 100 mg of 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) (Carmustine, Bristol-Myers Squibb). Those authors therefore suggested that BCNU chemoembolization be considered for treatment of bulky uveal melanoma hepatic metastasis for patients with good performance status and adequate hepatic and renal function [12]. The purpose of this study is to report our single-institution experience using 200 mg AJR:205, August

2 Gonsalves et al. of BCNU for the purpose of chemoembolization in patients with uveal melanoma presenting with hepatic tumor burdens 50% or greater. OS, progression-free survival (PFS), tumor response, and procedure-related toxicities are reviewed. A Materials and Methods Institutional review board approval was obtained for this retrospective study and informed consent was waived. A total of 63 treatment-naïve patients presented with uveal melanoma metastases occupying 50% or more of the normal liver parenchyma between January 2004 and November Patients with intrahepatic tumor burden 50% or more, no extensive extrahepatic metastases limiting life expectancy to less than 3 months, Eastern Cooperative Oncology Group (ECOG) 0 2 performance status, and adequate liver (bilirubin < 1.8 mg/dl, albumin > 3.0 g/dl, and no significant ascites) and renal function (creatinine 2.0 mg/dl) were included in the study. Patients who did not complete treatment of all intended metastases were excluded from the study. All patients underwent contrast-enhanced MRI and CT scans before treatment. CT of the chest, abdomen, and pelvis was primarily used to evaluate for extrahepatic disease. MRI was used to better delineate hepatic metastases and to determine intrahepatic tumor burden, which was divided into two categories: 50 75% and greater than 75%. Tumor burden, which is routinely categorized in radiology reports, was independently determined by board-certified MRI radiologists interpreting the imaging studies along with subsequent consensus of two interventional radiologists experienced in treating this disease. If imaging showed limited residual normal liver parenchyma, tumor burden was categorized as 75% or greater. If tumor burden was greater than the remaining normal liver parenchyma, tumor burden was categorized as 50 75%. Patients were clinically assessed by a medical oncologist and an interventional radiologist before undergoing chemoembolization in our multidisciplinary clinic. Hospital and clinic records were reviewed, and symptoms at the time of presentation, such as abdominal pain and fatigue, were documented. Patients were given an oral course of allopurinol (300 mg) 3 days before and 3 days after chemoembolization to prevent or decrease the incidence of tumor lysis syndrome [17]. Patients did not receive IV antibiotics before the procedure. To control symptoms related to postembolization syndrome, patients received IV steroids (dexamethasone 10 mg) the morning of the procedure and a tapered dose of oral steroids 6 days after the procedure [18]. Laboratory studies, including liver function tests, lactate dehydrogenase (LDH), complete blood counts, and sodium, potassium, creatinine, and blood urea nitrogen levels were obtained before each procedure, the day after the procedure, and weekly thereafter. On the basis of pretreatment LDH levels, patients were divided into two separate groups: less than or equal to 500 IU/L and more than 500 IU/L (which is an LDH level more than two times the upper limit of normal; the normal range is IU/L). Consecutive lobar chemoembolization, separated by 3- to 8-week intervals, was performed using 200 mg of BCNU dissolved in ethiodized oil followed by absorbable gelatin sponge (Gelfoam, Pfizer) embolization until near arterial stasis was achieved. The lobe with the larger amount of tumor burden was treated first, as determined by preprocedure MRI. After the procedure, patients were admitted to the hospital for overnight observation, IV hydration, and medical management of postembolization symptoms. Procedure-related toxicity was determined using Common Terminology Criteria for Adverse Events (version 4) [19]. Procedure-related complications were classified according to the Society of Interventional Radiology guidelines [20]. Treatment response was assessed using contrast-enhanced MRI and CT, 3 7 weeks after every treatment of all intended hepatic metastases. Cross-sectional imaging was repeated sooner than the scheduled follow-up period if tumor progression or treatment-related toxicity was suspected on the basis of laboratory results or clinical status of the patient. The best radiographic response for hepatic B tumors was determined using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 [21]. OS was measured from the initial chemoembolization procedure to patient death. PFS from liver metastases was measured from the initial chemoembolization procedure to confirmation of progression of hepatic metastases by MRI or death of the patient. OS and PFS for each tumor burden category and LDH level were compared using Kaplan-Meier analysis. Treatment toxicity (platelet, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and bilirubin level) was compared with tumor burden using the Pearson rank correlation coefficient test. All analyses and computations were performed using SAS (version 9.3, SAS Institute) and MedCalc (version , MedCalc Software) software. A p value of 0.05 was considered statistically significant. Results Fifty patients (31 men; mean age, 59.1 years; range, years) met the inclusion criteria and completed chemoembolization of all intended hepatic metastases. Thirteen patients were not included in our final data analysis. One patient with Waldenström macroglobulinemia completed bilobar chemoembolization and had stable disease on follow-up MRI. However, given the patient s history of a lymphoproliferative disorder, treatment was electively changed to radioembolization to avoid bone marrow toxicity, which may occur after repetitive chemoembolization using BCNU. Four patients were excluded from the study because of extensive extrahepatic disease (pulmonary, renal, and brain metastases, n = 1), elevated pretreatment bilirubin levels (n = 2), and poor performance status (ECOG 3 performance status, n = 1). Four patients presented with significant pain before initiating chemoembolization and elected for hospice care. The remaining patients did not complete treatment of all intended liver metastases for various reasons. One patient elected for radioembolization closer to home in hopes of Fig year-old man with 50 75% tumor burden in liver before treatment. A and B, Axial contrast-enhanced (20-minute delay) MRI with liver imaging with volume acceleration sequence was performed. Images show liver before (A) and 6 months after (B) chemoembolization. Image obtained at 6 months (B) shows decrease in size of largest tumors in right and left lobes. 430 AJR:205, August 2015

3 BCNU Chemoembolization of Uveal Melanoma Metastases in Liver decreasing the number of subsequent interventions. Two additional patients developed jaundice after unilobar treatment. Bilirubin levels were normal after treatment but were elevated the morning of the second procedure. MRI the same day showed progression of disease with diffuse infiltration of tumor in the untreated lobe. Finally, a dissection of the common hepatic artery occurred in one patient, preventing additional chemoembolization procedures. This patient underwent subsequent bland embolization of hepatic tumors via collateral supply to the liver, but eventually decided to forego further treatment after disease progression was diagnosed. Although this patient was not included in our study group, this complication would be considered a major complication according to the Society of Interventional Radiology guidelines [20]. Of the 50 patients who completed treatment, 35 (70%) presented with pain, weight loss, or fatigue, which prompted imaging leading to the diagnosis of liver metastases. The remaining patients were asymptomatic. Of the 50 patients, four (8%) had diagnoses of hepatic metastases based on liver enzyme elevation, eight (16%) received a diagnosis of metastatic disease on follow-up imaging after treatment of their primary eye tumor, and three (6%) had simultaneous diagnoses of primary and metastatic uveal melanoma. There were 43 patients with 50 75% tumor burden and seven patients with greater than Survival Probability (%) TABLE 1: Overall and Progression- Free Survival Based on Pretreatment Tumor Burden Percentages Percentage Time (mo) No. of Patients at Risk, by Group Group: 50 75% Group: > 75% Overall Survival Progression- Free Survival ( ) 7.0 ( ) > ( ) 3.4 ( ) p Note Data are median (range) duration of survival in months. 75% tumor burden (Table 1). There were 18 patients with LDH levels less than or equal to 500 IU/L (median, 360 IU/L; range, IU/L) and 31 patients with LDH levels greater than 500 IU/L (median, 1110 IU/L; range, IU/L) before initial treatment (Table 2). One patient did not have a preprocedure LDH level documented, but the LDH level was less than 500 IU/L 1 day after chemoembolization. Although this likely implies an LDH level less than 500 IU/L before the procedure, we did not include an LDH level for this patient in our analysis. A total of 271 chemoembolization procedures (median, 5 procedures; range, 2 14 procedures) with 200 mg of BCNU were performed for 50 patients. There were no treatment-related deaths and no major procedural complications. Asymptomatic grade 4 transaminitis occurred after 16 (5.9%) procedures in 13 patients, with one patient developing 50 75% > 75% Survival Probability (%) TABLE 2: Overall and Progression- Free Survival Based on Pretreatment Lactate Dehydrogenase (LDH) Level LDH Level (IU/L) a Overall Survival Progression- Free Survival ( ) 7.0 ( ) > ( ) 4.0 ( ) p Note Data are median (range) duration of survival in months. a For LDH level, 240 IU/L is the upper limit of normal. grade 4 transaminitis after four chemoembolization procedures. Of these 13 patients, four remained in the hospital for an additional 24 hours and five patients remained in the hospital for up to 48 hours after treatment. Patients received IV hydration and steroids until their liver enzymes decreased or returned to preprocedure baseline levels. After seven procedures, four patients with asymptomatic liver enzyme elevation were discharged home the morning after chemoembolization with the acknowledgment that repeat liver function tests would be performed in 1 week. In all patients, liver enzyme levels returned to preprocedure baseline levels before subsequent treatments were performed. We considered the prolonged hospitalization a minor complication because patients received nominal therapy and hospitalization did not extend beyond 48 hours. Addi % > 75% Time (mo) No. of Patients at Risk, by Group Group: 50 75% Group: > 75% Fig. 2 Overall survival (months) after 1,3-bis-(2-chloroethyl)-1-nitrosourea chemoembolization according to tumor burden (n = 49; one patient alive at follow-up). Fig. 3 Progression-free survival (months) of patients with hepatic metastases after 1,3-bis-(2-chloroethyl)-1-nitrosourea chemoembolization according to tumor burden. AJR:205, August

4 Gonsalves et al. tional toxicity related to BCNU chemoembolization included grade 2 (n = 3) and grade 3 (n = 2) thrombocytopenia. This required extending the interval between subsequent chemoembolization procedures, allowing time for platelet counts to increase. Platelet transfusions were not required. Finally, grade 2 (n = 8) and grade 3 (n = 2) hyperbilirubinemia were identified the morning before subsequent chemoembolization procedures and were attributed to disease progression as confirmed by MRI the same day. The best radiologic responses after chemoembolization included a partial response in three patients, stable disease in 33 patients, and progression of disease in 12 patients (Fig. 1). Two of the 50 patients did not have follow-up imaging because both received diagnoses of symptomatic brain metastases before obtaining repeat CT or MRI. LDH levels did decrease after chemoembolization in both of these patients, which could be interpreted as a response to treatment. However, because we had no follow-up imaging, these patients were not included in our final analysis of treatment response. Of the three patients who achieved partial response, all presented with 50 75% tumor burden. Of the seven patients who presented with greater than 75% liver involvement, two patients had progression of disease and five patients achieved stable disease. The median OS for the entire patient population (n = 50) was 7.1 months (range, months) (Fig. 2). Forty patients (80%) died because of progression of liver metastases. Eight patients died of extrahepatic disease, including brain (n = 4), pulmonary (n = 1), bronchial (n = 1), spinal cord (n = 1), and mesenteric and osseous (n = 1) metastases. Another patient died because of complications resulting from an automobile crash. The median OS for patients with 50 75% tumor burden was 7.3 months (mean, 9.0 months). The median OS for patients with greater than 75% tumor burden was 5.6 months (mean, 6.1 months). The median OS did not differ statistically significantly (p = 0.2) between the two pretreatment tumor burden categories (Table 1). Eleven patients (22%) survived longer than 12 months (range, months), with one patient alive at clinical follow-up (32.3 months). In addition, pretreatment LDH levels did not significantly affect OS (Table 2). The median PFS from liver metastasis for our patient population was 5.0 months (range, months) (Fig. 3). The median PFS for patients with 50 75% tumor burden was 7.0 months (mean, 9.1 months). PFS for patients with greater than 75% tumor burden was 3.4 months (mean, 6.1 months). PFS did not differ statistically significantly according to pretreatment tumor burden (p = 0.20) (Table 1) or LDH levels (p = 0.34) (Table 2). Discussion As previously mentioned, without treatment, patients with uveal melanoma hepatic metastases have a dismal prognosis. Despite the poor OS after dissemination of uveal melanoma, only a small percentage (3%) of North American ocular oncologists perform surveillance imaging after treatment of the primary eye tumor [22]. Two reasons for the lack of imaging surveillance include the absence of a cure for metastatic uveal melanoma and opposing opinions regarding the effect on OS with early detection of the disease [20]. Therefore, it is not rare to encounter patients with extensive hepatic metastases at the time of initial presentation, similar to most of the patients in the current report. Over the past decade, there have been multiple studies showing the benefit of transarterial catheter directed therapy for the treatment of uveal melanoma hepatic metastases [10 16]. Only a few of these reports have included or described outcomes for patients with metastases involving 50% or more of the liver parenchyma [11, 12, 15, 16]. Recently, Gupta et al. [16] reported results for 125 patients with uveal melanoma hepatic metastasis after chemoembolization using cisplatin, cisplatin and paclitaxel, or doxorubicin and mitomycin-c. Thirty-six (29%) of their patients treated with chemoembolization had greater than 50% tumor burden at the time of initial presentation. Their results showed a median OS of 5.5 months for 25 patients with 50 75% liver involvement and a 2.4-month median OS for 11 patients with tumor burden greater than 75%. They also reported a significantly shorter OS for patients with LDH levels greater than twice the normal compared with those with LDH levels less than twice the normal (median, 11.0 vs 3.6 months, respectively). Furthermore, the authors encountered significant complications after chemoembolization in patients with ECOG 2 performance status who complained of significant systemic symptoms before treatment. Therefore, that study concluded that chemoembolization is of little benefit for patients with tumor burden greater than 75%, ECOG 2 performance status, and significant systemic symptoms. The findings of the study by Gupta et al. [16] correlate well with the results of the study by Patel et al. [12], which used 100 mg of BCNU for chemoembolization of uveal melanoma hepatic metastases. The median OS for patients with greater than 50% tumor burden in that study was only 2.1 months. In addition, there also was a higher complication rate for patients with poor performance status and significant systemic symptoms. However, as previously mentioned, Patel et al. reported a significant response to BCNU chemoembolization in two patients who presented with bulky hepatic metastases. On the basis of this response to treatment, we continued to offer BCNU chemoembolization for patients with extensive tumor burdens at initial presentation. The use of 200 mg of BCNU was based on the limited toxicity seen in the phase 1 trial using the lower BCNU dose. The current study shows more favorable results than the two previously cited reports. After chemoembolization with 200 mg of BCNU, we failed to encounter significant complications even when patients presented with significant systemic symptoms related to their disease. This may be because of our periprocedural protocol (i.e., allopurinol, hydration, and steroids), but this cannot be stated with certainty in this retrospective report. Our OS and PFS were better than the results by Gupta et al. [16] and Patel et al. [12], which may be the result of the type of chemotherapy used and the increased dose of BCNU, respectively. Unlike cisplatin, paclitaxel, and doxorubicin, BCNU is a lipophilic agent that is easily dissolved in ethiodized oil. The BCNU and ethiodized oil emulsion becomes trapped within hepatic tumors because of their increased vascularity compared with normal liver parenchyma. In addition, because of the absence of Kupffer cells (which are responsible for phagocytosis of ethiodized oil in normal liver parenchyma) within tumors, BCNU dissolved in ethiodized oil allows regional concentration of this agent within uveal melanoma hepatic metastases [23]. This may increase the effectiveness of BCNU chemoembolization as opposed to water-soluble agents, which fail to mix well with ethiodized oil. There was no significant difference in patient OS between the different tumor burden categories or for patients with markedly elevated pretreatment LDH values. Although we excluded patients with very poor performance status (ECOG 3 performance status), most (70%) of our patients presented with systemic 432 AJR:205, August 2015

5 BCNU Chemoembolization of Uveal Melanoma Metastases in Liver symptoms before chemoembolization and we did not document any serious postprocedure complications. On the basis of these results and our experience treating uveal melanoma hepatic metastases, we routinely treat patients with bulky metastases because response to treatment and the potential to prolong survival are not always predictable. We acknowledge that this study has weaknesses, including its retrospective nature. However, because of our unique clinical practice, guidelines for laboratory and imaging follow-up are well defined, making patient information readily available for review. In addition, gene expression profiling of the primary tumor, which has suggested two highly prognostic molecular subgroups (class 1, low metastatic risk, and class 2, high metastatic risk), was not available for most of our patients and therefore was not included as part of this study [24]. Knowledge of gene expression profiling or chromosomal analysis of tumor may have provided insight regarding response to treatment after BCNU chemoembolization. In summary, chemoembolization using 200 mg of BCNU is a safe and effective treatment for patients presenting with bulky uveal melanoma hepatic metastases. We were pleased to learn that nearly a quarter of our patients lived longer than 1 year despite extensive tumor burdens at presentation. We cannot, however, overemphasize the need for early detection of metastatic disease. Although opinions vary regarding the survival benefit associated with early disease detection, patients with limited disease have a wider variety of treatment options from which to choose, including liver-directed therapies, such as immunoembolization and radioembolization. In our experience, immunoembolization and radioembolization are better suited for patients with less-extensive tumor burdens [11, 25]. 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