Cancers involving the eye are rare compared with lung, prostate,

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1 ANNUAL REVIEW Update on Ophthalmic Oncology 2013: Retinoblastoma and Uveal Melanoma Jasmine H. Francis, MD and David H. Abramson, MD Purpose: The aim of this study was to discuss the clinical and translational content of the literature as well as advancement in our knowledge pertaining to retinoblastoma and uveal melanoma that were published from January to December Design: This study is a literature review. Methods: The search terms retinoblastoma and uveal melanoma were used in a MEDLINE literature search. Abstracts were studied, and the most relevant articles were selected for inclusion and further in-depth review. Results: In retinoblastoma, fewer eyes are lost because of the expanded use of ophthalmic artery chemosurgery and intravitreal melphalan, and the past year marks a deepening in our understanding of these modalities. Knowledge on the genetic underpinnings of uveal melanoma has broadened to include genes associated with a favorable prognosis. This is accompanied by promising results in the treatment of metastatic uveal melanoma. Conclusions: This past year, there were important advancements in our knowledge of retinoblastoma and uveal melanoma. Key Words: uveal melanoma, retinoblastoma, ophthalmic oncology, cancer (Asia-Pac J Ophthalmol 2014;3: 241Y256) Cancers involving the eye are rare compared with lung, prostate, and breast cancer. They pose a special challenge because they can influence both vision and life. Progress in the field focuses on these 2 elements: improving efficacy to treat the disease and save a life as well as limiting the consequence of treatment to maintain vision. Retinoblastoma and uveal melanoma (UM) are the most common primary intraocular malignancies in pediatric and adult patients, respectively. There are considerable clinical, translational, and basic science efforts directed toward furthering our understanding of these diseases, and each year, our comprehension of these tumors advances. Here, we review last year s published contributions and highlight the major findings. We divide the discussion of each tumor into clinical and translational sections, with further subdivisions within. RETINOBLASTOMA Retinoblastoma is the most common primary intraocular tumor of children, with approximately 5000 cases per year worldwide. Throughout the world, survival rates vary widely, from well lower than 50% and up to 99% in the United States and Europe. The history of retinoblastoma treatment is of increasingly localized delivery of therapy with the aims of superior efficacy, while limiting adverse effects. The knowledge gained this past year presented no exception to these goals. From the Ophthalmic Oncology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. Received for publication April 30, 2014; accepted July 2, The authors have no funding or conflicts of interest to declare. Reprints: Jasmine H. Francis, MD, Memorial Sloan Kettering Cancer Center, 70 E. 66th St, New York, NY francij1@mskcc.org. Copyright * 2014 by Asia Pacific Academy of Ophthalmology ISSN: DOI: /APO Ophthalmic Artery Chemosurgery In 2006, after the work of the Japanese, 1 we introduced intraarterial delivery of chemotherapy with the unique feature of entering the ostium of the ophthalmic artery. Since this time, more than 40 countries worldwide have attempted ophthalmic artery chemosurgery (OAC). This past year saw first-time reports from institutions in San Francisco and Valencia (Table 1). The San Francisco group reported their single-institution experience of treating 20 retinoblastoma eyes [International Classification (IC) AYE] with single-agent intra-arterial melphalan. 2 They had an overall ocular survival of 55%, with comparable rates between naive and previously treated eyes. 2 The results confirmed previous findings that less advanced eyes do better, and vitreous seeds are particularly difficult to treat. 2 Systemic and ocular toxicity were consistent with previous reports and consisted of eyelid edema/ erythema (n=2), vitreous hemorrhage (n=3), retinal pigment and choroid atrophy (n=1), grade 4 neutropenia (n=2), bronchospasm (n=1), ophthalmic artery vasospasm (n=1), as well as stroke (n=1). 2 Finally, they calculated a mean per eye per procedure radiation exposure of 20.2 mgy, which is comparable with other groups and remains lower than the dose for increased cataract and sarcoma risk. 2 A Spanish group from Valencia reported on their successful implementation of a new intra-arterial chemotherapy involving 8 eyes of 5 patients. 3 At the time of reporting, they had an eye retention rate of 88%, with the only adverse event being a single case of forehead erythema. 3 Like others have previously concluded, the authors express the importance of collaborative work among a team of specialists for optimal implementation of a new intra-arterial technique. 3 In addition to reports on an initial experience, there were also follow-up reports from Siena and Argentina (Table 1). Hadjistilianou and colleagues 4 describe the use of intra-arterial melphalan in treating retinoblastoma (IC B-D) located in the macula. They report on 5 eyes that received 3 infusions of intraarterial melphalan and had impressive tumor regression. 4 They cite this technique as an alternative to other treatment modalities for tumors located in the macula, in which the trade-off exists between treatment-related and tumor-related visual loss. 4 The same group also published an update on their previous cohort, focusing on 52 eyes (IC B and D) that had received intra-arterial melphalan alone 5 (Table 1). They estimated a 2-year Kaplan- Meier ocular survival of 48% for naive eyes and 78% for those eyes that were previously treated. 5 Approximately 15% of the eyes had localized or diffuse chorioretinal/retinal pigment epithelium damage. There were no deaths, metastatic disease, or major periprocedural complications. 5 Meanwhile, there was some attention paid to drug infusions other than melphalan (Table 1). Taich et al 6 assessed the clinical pharmacokinetics of combining intra-arterial melphalan with topotecan. They concluded that melphalan pharmacokinetics were unchanged by the addition of topotecan and not influenced by the order of drug administration. 6 The combination of both drugs was deemed effective, well tolerated, and with no change in the proportion of patients with neutropenia. 6 On the subject of other drugs beyond melphalan, our group Asia-Pacific Journal of Ophthalmology & Volume 3, Number 4, July/August

2 Francis and Abramson Asia-Pacific Journal of Ophthalmology & Volume 3, Number 4, July/August 2014 TABLE 1. Studies on OAC for Retinoblastoma From January to December 2013 Ocular Survival Author Subject No. Eyes IC Rb Naive Previously Treated F/u, mo Thampi et al 2 First report 20 AYE 50% 63% 14.5 Valero Garcia et al 3 First report 5 NR 88% NR Bracco et al 5 Melphalan OAC only 52 B and D 2 y KM 48% 2 y KM 78% 39.6 Shields et al 9 After failed systemic chemotherapy 14 D and E 2 y 57% Francis et al 7 OAC with plaque 15 BYE 18 mo 79.4% 19 Schaiquevich et al 10 OAC vs peri/systemic 18 RE: IIIYV 1 y KM 87% 30 F/u indicates follow-up; IC Rb, International Classification of Retinoblastoma; KM, KaplanYMeier estimate; NR, not reported; peri, periocular chemotherapy; RE, Reese-Ellsworth Classification. described the utility of carboplatin in ophthalmic artery chemotherapy infusions. 7 Carboplatin has a number of advantages: besides having low systemic and ocular toxicity (it does not result in the medial periocular erythema seen with melphalan), it does not require filtration before administration, and unlike melphalan, its stability deems it time insensitive. 7 Although its superiority to melphalan has not been established, it is an attractive drug choice, particularly for treating the fellow eye in a bilateral case that has already met the melphalan dose limit (0.4 mg/kg). 7 As groups are becoming more accustomed to OAC and extending its use to treat less advanced eyes, there are reports of combining its use with other modalities, including systemic chemotherapy and brachytherapy (Table 1). Shields and associates 8 report on 14 eyes (IC D and E) that received primary intravenous followed by secondary intra-arterial chemotherapy, the latter of which was necessary because of recurrent tumor, subretinal seeds, vitreous seeds, or persistent vitreous seeding. A median of 3 intra-arterial infusions were required, resulting in a 57% globe salvage at a mean of 2 years of follow-up and no metastatic event. 8 The authors describe the use of salvage OAC for eyes that have failed systemic chemotherapy and in which enucleation is the alternative and assert that OAC can save just more than half (57%) of these eyes without evidence for an increased risk for metastases. 8 Francis et al 9 evaluated15eyes(icbye) on the efficacy and toxicity of plaque brachytherapy after intra-arterial chemosurgery for both adjuvant and salvage treatment of retinoblastoma eyes. Despite 12 of 15 eyes having localized vitreous seeding, the 18-month Kaplan-Meier estimate of ocular survival was 79.4%. 9 The study also found that ocular complications were statistically more frequent in eyes with a shorter latency between the 2 treatment modalities (Figs. 1, 2). 9 The authors concluded that brachytherapy after OAC is effective, with the majority of eyes maintaining stable or improved electroretinogram recordings. 9 In Argentina, they demonstrated that OAC is superior to sequential periocular and intravenous chemotherapy as a salvage treatment of relapsed retinoblastoma. 10 In their study of 18 eyes, OAC was more effective, with 1-year Kaplan-Meier estimates of ocular survival being 87% compared with 10% in eyes treated with periocular and intravenous chemotherapy. 10 The systemic toxicity profile of OAC was deemed more favorable with no cases of neutropenia, compared with 5 episodes of grade 4 neutropenia in the periocular/systemic chemotherapy group. 10 Aside from reports of OAC s superiority, there were some cases of more obscure consequences related to the treatment. There was a first report describing blue toe syndrome: a distal peripheral vascular complication secondary to OAC for retinoblastoma. 11 The authors presumed it to result from thrombus formation due to intimal injury from the needle, guide wire, or catheter manipulation. 11 In addition, another case described cataract formation in a patient who had received repetitive intraarterial chemosurgery, but in an eye that also had viable tumor seeding on the lens, the ciliary body, and the anterior chamber. 12 The group from London looked at the visual outcome after intra-arterial melphalan by evaluating 14 eyes with good visual potential and healthy foveola. 13 They found that 42% of eyes had severe visual loss, which the authors attributed to technical difficulties in catheterization and toxicity from nonyage-adjusted melphalan doses. 13 As the authors pointed out, the majority of eyes retained good vision and the other eyes had better vision compared with the alternative of enucleation. 13 Finally, there were a couple of reports that taught us about vascular anatomy and supply, as it related to OAC. One case described a macular tumor (IC C) responding to 2.5 mg of intraarterial melphalan, despite the presence of an infantile hemangioma competing for arterial blood supply. 14 Another group used gadolinium-enhanced magnetic resonance imaging (MRI), to demonstrate that the superselective infusion of chemotherapy FIGURE 1. Representative retinoblastoma case treated with combination plaque brachytherapy and OAC. A, Before treatment, vitreous seeds were observed in the periphery. B, These vitreous seeds were successfully treated after plaque brachytherapy and OAC * 2014 Asia Pacific Academy of Ophthalmology

3 Asia-Pacific Journal of Ophthalmology & Volume 3, Number 4, July/August 2014 Update on Ophthalmic Oncology 2013 FIGURE 2. Representative retinoblastoma case treated with intravitreal melphalan. A, Before treatment, recurrent tumor with vitreous seeding is apparent. B, After intravitreal melphalan (and OAC), the tumor has regressed and vitreous seeding is no longer visible. into the ophthalmic artery delivers drug to the tumor and the subretinal space. 15 Intravitreal Chemotherapy Historically, any technique that breached the ocular surface of retinoblastoma eyes was avoided for fear of extraocular extension. Previously, there had been insufficient evidence to determine how risky this was for retinoblastoma patients. However, this past year, Smith and Smith 16 surveyed the world s literature on intravitreal injections to determine the associated risk for tumor spread. Including 1304 injections during a mean follow-up of 72.1 months, they calculated that the proportion of patients with extraocular tumor spread secondary to intravitreal injection was They concluded that the risk for tumor dissemination after intravitreal injections is rare and potentially attributable to safety techniques that have been adopted. 16 The year 2012 marked a resurgence in the use of intravitreal melphalan for the treatment of retinoblastoma, in large part because of seminal articles from Munier et al 17,18 on the injection technique and its efficacy. This past year, the same group gave us a current account of their intravitreal injection technique and perspectives for the future. 19 They described eligibility criteria (excluding patients with nonviable vitreous tumor or nontumorous vitreous material and unidentifiable retinal source of seeding) and revisited their safety-enhanced injection procedure. 18 They discussed their dose escalation starting at 20 Kg and increasing to 30 Kg at2-to4-kg increments according to older patient age, diffuse or high-density disease, as well as previous intraarterial or intravitreal melphalan. 19 Finally, the superior efficacy of this technique is reaffirmed with 2-year Kaplan-Meier ocular survival estimates at 84.1%. 19 Similar to the technique previously reported by Munier et al, a single case report from China documents the successful treatment of vitreous seeding with 6 intravitreal injections of melphalan 20 mg/0.05 ml. 20 No retinal toxicity was mentioned. Ghassemi and Amoli offered the first report on the histopathology of eyes clinically treated with intravitreal melphalan. 21 Eight eyes were enucleated (because of phthsis or recurrent tumor or at the patient s request) and examined, with no evidence of tumor involvement at the needle site. 21 All 6 eyes treated with 10 Kg of melphalan had viable retinal tumor, although only 2 eyes had viable vitreous seeds. 21 The 2 eyes injected with 50 Kg of melphalan demonstrated no viable tumor cells but had appreciable retinal toxicity with gliosis, vascular occlusion, retinal necrosis, hemorrhage, and neovascularization. 21 These results speak to the narrow window for intravitreal melphalan injections, such that the dose is high enough to effectively kill the tumor but not so high that it destroys the retina. In an effort to study alternatives to melphalan, Buitrago et al 22 reported their preclinical findings of intravitreal topotecan in rabbit eyes. They demonstrated nonlinear pharmacokinetics after a single intravitreal delivery of 0.5 or 5 Kg of topotecan. 22 Adoseof0.5Kg of intravitreal topotecan maintained potentially cytotoxic levels for 5 hours after injection, compared with a dose of 5 Kgofintravitreal topotecan, which maintained cytotoxic levels for 16 hours after injection. 22 Neither dose, given 4 times weekly, resulted in retinal toxicity (by electroretinogram as well as clinical and histological findings) or systemic toxicity. 22 The authors posit these findings as being potentially translatable to the clinic setting, particularly in the case of refractory vitreous seeding. 22 Also on the subject of topotecan, Yousef et al 23 examined the effects of subtenon topotecan with fibrin sealant on 10 retinoblastoma eyes using forced duction testing. Unlike previous reports with periocular carboplatin, they concluded that subtenon topotecan does not affect ocular muscles or soft tissue and did not translate to any adverse effects on ocular motility. 23 Systemic Chemotherapy Whereas our center and others abandoned first-line systemic chemotherapy for the treatment of retinoblastoma, other centers continue to use it as their standard of care. Bartuma et al 24 report on their 10-year experience with systemic chemotherapy at a Swedish national referral center. They looked at 46 eyes in 24 patients, all of whom had hereditary retinoblastoma and were primarily treated with 4 to 6 cycles of vincristine, etoposide, and carboplatin. 24 Ocular survival was 100% for group A (n = 8), 88% for group B (n = 25), 0% for group C (n = 1), 9% for group D (n = 11), and 0% for group E (n = 1). 24 There were no cases of metastases, no trilateral retinoblastoma, 1 osteosarcoma, and no deaths. 24 Berry and colleagues looked at the long-term outcome of 55 group D eyes treated with triple-drug chemoreduction and low-dose intensity-modulated radiation therapy as salvage for recurrent tumor. 25 Chemoreduction-only was required in 47% of eyes (n = 26/55), whereas 29 eyes had recurrent tumor, of which 24 were irradiated. The mean follow-up was 54.2 months. Kaplan-Meier ocular survival estimates were 82% at 1 year and dropped to 68% at 60 months. Strikingly, the 12-month Kaplan-Meier ocular survival estimate for eyes receiving chemoreduction and focal treatment was only 41%. Defined as at least 20/200 or fix and follow vision, the authors find that more than half of the eyes in their series retained useful vision. It is striking that the ocular survival of eyes receiving systemic chemotherapy alone was less than half the calculated rates in similar eyes receiving intra-arterial chemosurgery. 26 In our cohort, the 2-year ocular salvage of naive eyes with vitreous and subretinal seeding is 83% [95% confidence interval (CI), 27%Y97%]. 26 High-Risk Retinoblastoma There continues to be controversy over the utility of adjuvant systemic chemotherapy for high-risk retinoblastoma, and * 2014 Asia Pacific Academy of Ophthalmology 243

4 Francis and Abramson Asia-Pacific Journal of Ophthalmology & Volume 3, Number 4, July/August 2014 many of the articles on this subject are difficult to compare because of the differing definitions of risk. Last year, there were 2 groups that retrospectively reviewed their data and an article from France describing a prospective analysis of adjuvant therapy for high-risk features. Chantada and colleagues 27 retrospectively looked at the impact of chemoreduction on 177 retinoblastoma patients who were separated into 3 treatment eras in Argentina: 1988 to 1995, external beam radiation (EBRT) as primary treatment; 1995 to 2003, carboplatin-based systemic chemoreduction; and 2003 to 2009, periocular carboplatin added and pre-enucleation chemotherapy for buphthalmic eyes. They concluded that, although chemoreduction did not affect overall or disease-free survival, it did reduce the need for EBRT in eyes with less advanced disease and improved 5-year ocular survival in advanced eyes. 27 They interpreted their data as suggesting that adjuvant chemotherapy in cases with high-risk pathological features does not provide protection against the development of metastases; however, there may be benefit from pre-enucleation chemotherapy targeted at retrolaminar tumor. 27 Three children died of acute myeloid leukemia and 3 developed pineoblastoma. 27 Also retrospectively, Kaliki and associates 28 reviewed 519 enucleated retinoblastoma eyes (87 in group D and 432 in group E) for the presence of high-risk pathological features consisting of anterior chamber involvement, isolated massive choroidal involvement, isolated postlaminar optic nerve invasion, or a combination of choroidal invasion and optic nerve involvement. They determined that 17% of group D (n = 15) and 24% of group E (n = 102) had high-risk features and were at risk for metastatic disease. 28 A total of 71% of patients (n = 83) had adjuvant systemic chemotherapy. None of the group D eyes or the eyes without high-risk features developed metastases. 28 Ten percent (n = 10/102) of group E eyes developed metastases: 4 patients had received prior adjuvant chemotherapy and 6 had not. 28 Five patients died of their metastases, and it is unclear which of these patients had received prior adjuvant chemotherapy. 28 Of group E eyes with high-risk pathological features, 8% of patients developed systemic metastases. 28 A multicenter, prospective study conducted in France reported on the overall survival and event-free survival in retinoblastoma patients with Reese-Ellsworth Group V eyes. A total of 123 eyes were enucleated and received adjuvant therapy depending on 3 groups of pathological risk factors: low, intermediate, and high risk. Seventy patients were found to have lowrisk features (minimal or no choroidal involvement, prelaminar or no optic nerve involvement) and received no adjuvant therapy. Fifty-two patients had intermediate-risk features (massive choroidal involvement and/or intralaminar or retrolaminar optic nerve and/or intrascleral involvement) and received 4 cycles of adjuvant chemotherapy. A single patient had a tumor at the cut section of the optic nerve with massive choroidal involvement, was considered high risk, and received 6 cycles of chemotherapy. During a median follow-up of 71 months, survival was 100% and eventfree survival was 100%: there were no deaths, progression of disease, relapse, or distant metastases. The authors point out that 42% (n = 22) of their intermediate-risk group had isolated massive choroidal involvement, which some groups believe is not a risk feature that necessitates adjuvant therapy. The authors admit that this subset of patients benefited from treatment, although the others were exposed to avoidable toxicities. There have been efforts to establish the degree of high-risk retinoblastoma by using methodologies besides enucleation. For instance, Sirin et al 29 reviewed the optimal MRI setting for determining high-risk features of retinoblastoma. They included 36 children who had postgadolinium MRI produced with sufficient image quality and settings as well as enucleation with histopathologically proven retinoblastoma. 29 They concluded that T1-weighted images without fat saturation were of superior quality with improved anatomical detail and gave a better appreciation of choroidal invasion, 29 whereas T1-weighted images with fat saturation allowed for improved detection of optic nerve infiltration and tumor enhancement. 29 In summary, they assert that combined T1-weighted MRI imaging with and without fat saturation gave the best assessment of retinoblastoma tumor assessment. 29 Another group explored the means of predicting central nervous system (CNS) relapse once high-risk disease has been identified. Laurent and colleagues 30 investigated the detection of minimally disseminated disease in the cerebrospinal fluid (CSF) of children with high-risk retinoblastoma by reverse transcriptaseypolymerase chain reaction (PCR) for GD2 synthase messenger RNA (mrna). They evaluated the CSF of 26 patients at high risk for CSF relapse. Minimally disseminated disease was evident by positive GD2 synthase mrna in 23% of patients (n = 6), 3 of which later had a CSF relapse. 30 Thirteen patients had negative GD2 synthase mrna, and one of these patients developed CNS relapse. 30 It was calculated that the proportion of CSF relapse was 0.50 in children with positive GD2 synthase mrna and 0.08 for those with a negative test. 30 This difference is statistically significant (P = 0.03). The authors conclude that GD2 synthase mrna may be positive in the CSF of retinoblastoma patients with CNS involvement (particularly in those with optic nerve involvement or elevated intraocular pressure)vand a prompt identification of minimally disseminated disease with this method might be useful in directing more intensive therapy for this high-risk group. 30 Extraocular Retinoblastoma On the subject of extraocular retinoblastoma, groups debated on the appropriate staging system. Chantada et al 31 compared 4 different staging systems for extraocular retinoblastoma by retrospectively reviewing disease-free survival (defined as extraocular relapse) in 533 patients. They concluded that only the International Retinoblastoma Staging System (IRSS) accurately identified all high-risk patients with microscopically disseminated disease. 31 Similarly, only the IRSS and St. Jude Children s Research Hospital systems provided stage assignments with increasing risk for extraocular relapse. 31 They further added that 3 histopathological factors (focal choroidal invasion, anterior chamber, and prelaminar optic nerve invasion) could safely be omitted for staging because they were of little predictive value. 31 Meanwhile, Radhakrishnan and colleagues 32 proposed a new staging system to predict event-free and overall survival in patients with IRSS stage III (regional extension) treated with neoadjuvant chemotherapy. The staging system was based on postchemotherapy optic nerve characteristics including extent of involvement, optic nerve thickening, and contrast enhancement. 32 The study demonstrated that distal optic nerve involvement (defined as thickening or enhancement of 95 mm of intraorbital, optic canal, or intracranial nerve) was significantly associated with worse outcome. 32 This was particularly predictive of outcome compared with globe perforation, extrascleral extension, or proximal optic nerve enhancement without thickening. 32 In a prospective study, Sethi et al 33 followed 36 eyes with extraocular retinoblastoma in India and, on the basis of histopathology, determined that 75% of eyes contained viable tumor after neoadjuvant systemic chemotherapy. They confirmed previous findings that prolonged lag time from initial symptoms to start of treatment was related to increased risk for extraocular retinoblastoma * 2014 Asia Pacific Academy of Ophthalmology

5 Asia-Pacific Journal of Ophthalmology & Volume 3, Number 4, July/August 2014 Update on Ophthalmic Oncology 2013 Finally, Chantada et al 34 describe the consensus of the International Society of Pediatric Oncology-Pediatric Oncology in Developing Countries and their recommendations for graduatedintensity treatment of retinoblastoma in developing countries. Recommendations for treatment vary according to disease classification (laterality and extent of disease) and treatment settingvwhich is divided into 3 according to a country s available resources and technology. 34 Pineal Cysts/Pineoblastoma This past year, there was some attention to the subject of pineal gland abnormalities in retinoblastoma patients. Ramasubramanian and associates reviewed the cases of 408 retinoblastoma patients and determined that 8% of patients had a pineal gland cyst. 35 The prevalence of pineal cysts in the healthy pediatric population is believed to be approximately 1% to 2% (although, on the basis of autopsy findings, this number may be much higher). The higher reported incidence in retinoblastoma patients is consistent with the findings of other groups, which have suggested a relationship between germline retinoblastoma and pineal cysts. 36,37 Furthermore, they investigated the prevalence of pineoblastomav a malignancy that can afflict germline retinoblastoma patients in the first decade of life. Ramasubramanian and associates detected pineoblastoma in 1% of patients, all of whom exclusively carried a germline RB1 mutation. 35 This is in line with previous findings that demonstrate a reduced incidence of pineoblastoma in the postirradiation era. 38 However, because of the small numbers, the authors admit that there was no statistically significant data to support the role of previous treatment in reducing the incidence of pineoblastoma in this patient population, 35 including the protective role of systemic chemotherapy. Furthermore, Chantada et al 27 similarly reported that 1.5% (n = 177) of their retinoblastoma patients developed pineoblastoma, and all 3 patients received systemic chemotherapy before the development of trilateral disease. Long-term Follow-up Our group catalogued the long-term medical outcomes in survivors of extraocular retinoblastoma. Nineteen patients treated between 1992 and 2009 were included, with a median follow-up of 7.8 years (2Y17.8 years) from extraocular retinoblastoma diagnosis. 39 All patients received conventional chemotherapy (cisplatin or carboplatin, cyclophosphamide, vincristine, and etoposide) for their diagnosis of extraocular retinoblastoma, plus high-dose chemotherapy with autologous stem cell transplantation (n = 17) and/or consolidative EBRT (n = 15). 39 We reported that the most common long-term nonvisual outcomes were hearing loss, 79% (n = 15); short stature, 37% (n = 7); and secondary malignancies, 31% (n = 6). 39 All patients with grade 3 hearing loss had been exposed to platinum agents: all had received cisplatin as part of their conventional chemotherapy and 7 of 8 had been treated with high-dose carboplatin. 39 The 6 patients with secondary malignancies developed osteosarcoma, and 2 patients died of this. 39 Three of the 7 patients with short stature had previously received EBRT to the skull base and were determined to be growth hormone deficient. 39 Given these findings, attention should be drawn to the long-term auditory outcomes and development of secondary cancers. 39 Our group attempted to address these issues by performing a pilot study to determine whether annual whole-body MRI could detect secondary cancers of the bone and the soft tissue in retinoblastoma survivors. 40 Forty-one whole-body MRI scans were performed in 25 asymptomatic hereditary retinoblastoma patients. 40 Five osseous lesions were detected: 3 were benign and 2 were high-grade osteosarcomas of the extremity. 40 Three months after a normal scan result, 1 patient was diagnosed with an osteosarcoma. 40 The sensitivity and the specificity of detecting a secondary cancer was calculated as 66.7% and 92.1%, respectively, with a positive predictive value of 0.4 and a negative predictive value of In conclusion, it is unclear whether whole-body MRI impacts secondary-canceryrelated mortality or whether the risk-benefit ratio warrants routine use of wholebody MRI. 40 Country Specific An English group examined secondary and subsequent tumors in 1927 retinoblastoma patients, and like other reports, they show that retinoblastoma survivors are at increased risk for secondary cancers compared with the general population. 41 Their standardized incidence ratios for all secondary tumors were 13.7 (95% CI, 11.3Y16.5) and 1.5 (95% CI, 0.9Y2.3) for heritable and nonheritable cases, respectively. 41 In line with other cohorts, the predominant secondary cancers were leiomyosarcoma, osteosarcoma, and skin melanoma. 41 They also discuss the increased risk for uterine leiomyosarcoma, which was previously reported by our group. 42 In fact, this last year brought reports from other countryspecific cohorts. Alkofide et al 43 describe the efficacy of vincristine and carboplatin for advanced retinoblastoma in Saudi Arabia. Gündüz and colleagues described their 192 Turkish patients with both intraocular and extraocular retinoblastoma. 44 A group from Singapore calculated their 5-year survival rate for unilateral and bilateral retinoblastoma as 97% (n = 35) and 76% (n = 16), respectively. 45 They cited advanced presentation as well as noncompliance with treatment and follow-up as reasons for the lower survival rate compared with Western countries. 45 Similar woes regarding late presentation and poor acceptance of enucleation were echoed by groups from Beijing 46 and Tamilnadu, India. 47 Work from Uttar Pradesh, India, reports that half its patients abandoned treatment, and this was related to rural back ground, financial constraint, and hesitancy toward enucleation. 48 They found that telephone calls were better at tracing patients TABLE 2. Detection Rates for the RB1 Gene in Studies From January to December 2013 Bilateral Unilateral Author Method Specimen No. Det % No. Det % Ahani et al 49 MLPA Blood and tumor Saliminejad et al 50 AMRS-PCR Blood Seo et al 51 Exon sequence, MLPA Blood Price et al 52 Combined* Blood *Combined indicates conformational analysis with sequencing, dosage analysis, methylation testing, and loss of heterozygosity analysis. AMRS indicates amplification refractory mutation system; Det %, detection percentage (percentage with detected mutation). * 2014 Asia Pacific Academy of Ophthalmology 245

6 Francis and Abramson Asia-Pacific Journal of Ophthalmology & Volume 3, Number 4, July/August 2014 compared with letters, and preabandonment counseling helped to reduce abandonment rates. 48 Genetics The RB1 gene is located on 13q14, consists of 27 exons, and spans approximately 180 kilobase of genomic DNA. The large size of the gene and the limited number of mutation hotspots make a full gene analysis cumbersome and expensive. Therefore, groups have attempted to develop more focal methods of detection (such as exome sequencing) and presented their results in the past year (Table 2). Ahani et al used multiplex ligationydependent probe amplification (MLPA) to screen 121 patients with retinoblastoma (55 unilateral, 66 bilateral/familial) on 121 blood and 43 tissue samples. 49 Multiplex ligationydependent probe amplification is able to detect duplications/deletions but not the translocations and inversions that can be picked up by other methods. In their study, the frequency of deletions/duplications was 9.1% in unilateral and 16.6% in bilateral tumors, which is in accordance with other studies. The authors conclude that MLPA is a fast, powerful, and reliable tool in the detection of deletions/duplications in retinoblastoma patients. The same group also developed an amplification refractory mutation systemypcr to screen for the most recurrent mutation in RB1 harbored by retinoblastoma patients. 50 Their mutation detection rates in 121 patients were 3.6% (2/56) in unilateral patients and 43.1% (28/65) in bilateral patients. 50 The authors tout this method as a simple, efficient, and fast tool that could be used in combination with other detection techniques. 50 Meanwhile, Seo et al 51 investigated the blood of 21 Korean patients (16 bilateral, 5 unilateral) for germline RB1 mutations. With the use of exon sequence analysis and MLPA, they detected mutations in 15 of 16 bilateral patients and none in the unilateral patients. 51 Their detection rate of 93.8% in bilateral retinoblastoma is compared with a rate of 100% that was achieved by a New Zealand group using a similar method. 51 Price et al 52 reported on their combined screening approach, which includes conformational analysis with sequencing, dosage analysis, methylation testing and loss of heterozygosity analysis. A total of 96% of bilateral/familial (n = 167) and 9.5% of unilateral (n = 42) retinoblastoma blood samples were found to have mutations. 52 Similarly 95% of tumor samples (n = 194) yielded mutations. They confirmed previous studies that have revealed a paucity of mutations in certain exons, specifically, 4, 5, 9, 13, and 25 to They calculated that their screen identified 53% of unilateral mutations and suggest that these low-level mosaic cases are beyond the detection threshold of their testing. 52 Overall, these are some of the highest detection rates for retinoblastoma mutations and highlight the need for a multimethod approach to detection. 52 Other groups are searching for connections between the genotype and the phenotype of a particular retinoblastoma mutation. Last year, there were 2 articles dedicated to this subject. Barbosa et al 53 screened 71 Brazilian retinoblastoma patients for alterations in RB1 using direct sequencing and MLPA. They identified 15 substitutions (11 exonic and 4 intronic) and attempted to establish an association between the phenotype of disease (survival rates) and the genetic alteration. 53 However, they found that survival rates were unrelated to the presence of genetic alterations. 53 Conversely, Ottaviani et al evaluated 144 families from Argentina with retinoblastoma and found a connection between the genotype and phenotypic characteristics of retinoblastoma. 54 Specifically, frameshift and nonsense mutations, which have a higher penetrance, occurred at a higher rate in familial and sporadic germline cases (n=20/25). On the contrary, aberrations that show incomplete penetrance such as missense, promoter, and splice mutations were more common in unilateral hereditary cases (n = 3/4). However, there were some cases that were an exception to these correlations. Epidemiology and Other Epidemiological studies continue their attempts to tease out risk factors of retinoblastoma. One case-control study looked at paternal occupational exposures and found an increased risk for sporadic germline retinoblastoma as well as paternal exposure to nonwelding metal and possible pesticides. 55 Another casecontrol study explored parental nutrient intake and risk for retinoblastoma, 56 and another group found an association with ambient exposure to air toxins in the perinatal period. 57 One report tried to connect retinoblastoma with cardiac disease. It described a family with heritable retinoblastoma and 2 family members with bicuspid aortic valves, and an association between the 2 disease entities was proposed. 58 The literature has established a controversial link between human papillomavirus and the development of retinoblastoma, with reports from India as well as South and North America. Although groups have established a link in a subset of patients, 59 others have found no association. 60 In line with the latter report, a group from Korea investigated 54 enucleated retinoblastoma specimens and found no evidence of human papillomavirusvsupporting the lack of association in this population. 61 Two final reports do not fall into the abovementioned subcategories but are worth mentioning. In one, Rootman et al 62 gave an account of their handheld high-resolution spectral domain optical coherence tomography for 19 retinoblastoma lesions. They described its use in the detection of early tumors, recurrences, and response to focal therapy and assert its utility in the diagnosis and surveillance of retinoblastoma. 62 Finally, the American Brachytherapy Society puts forth its recommendations for plaque brachytherapy treatment in retinoblastoma patients. Ideal tumors are those located anterior to the equator in unilateral patients. 63 Eyes necessitating secondary treatment may require plaque in any location, although the consensus suggests avoiding anterior segment and circumpapillary tumors. 63 The group also recommends that children at risk for extraocular extension should receive systemic evaluation before plaque brachytherapy. 63 UVEAL MELANOMA: CLINICAL (PRIMARY TUMOR) Uveal melanoma occurs in approximately 6 per million people per year and is more common in whites. This past year, Bishop and Olszewski used Surveillance Epidemiology and End Results data to perform a population-based study of ocular melanoma. 64 They determined that ocular melanomas comprise approximately 3.1% of all melanomas, and the 5-year relative survival is 78%Ywhich has an excess mortality of 5.7 times higher than that of cutaneous melanoma. 64 The age-adjusted incidence has remained relatively constant, and despite a shift toward treating the primary tumor with radiation, there is no improvement in survival. Approximately half of the patients will develop metastatic disease, and risk for disseminated disease is similar regardless of primary treatment with enucleation or radiation. This tells us that the potentially metastatic cells escape the eye early, often before treatment of the ocular tumor. For this reason, there has been long-standing attention drawn toward prognostication, particularly as it relates to genetics. In keeping pace with the oncology field, we are using technological advances to further our appreciation of the genetic underpinnings of the disease. With this knowledge, we can extract pertinent molecular pathways to generate targeted therapies, with the aim of clinical implementation and improvement in survival * 2014 Asia Pacific Academy of Ophthalmology

7 Asia-Pacific Journal of Ophthalmology & Volume 3, Number 4, July/August 2014 Update on Ophthalmic Oncology 2013 Unlike cutaneous melanoma, ultraviolet exposure is not considered a risk factor of developing UM. However, groups have searched for potentially modifiable factors that may influence the development of UM. There have been contradictory associations established between risk for UM and the number of children that women have, socioeconomic status, and cigarette smoking. Zinkhan et al 65 report on a German case-control study that included 455 UM patients and matched controls. They demonstrated that women with children have an increased odds ratio (1.59; 95% CI, 0.95Y2.66) compared with women without children, and patients of a higher socioeconomic level have a decreased odds ratio (0.68; 95% CI, 0.49Y0.94) for the development of UM. 65 The authors also conclude that cigarette smoking is not associated with an increased risk for UM. 65 However, there are other groups that report contrary associations. In 2010, a hereditary basis for UM was identified. Harbour et al discovered that BAP1 mutations are present in UM and particularly those that are at high risk for early metastases. 66 His group, along with others, has also revealed that germline mutations in BAP1 predispose to UM and a host of other cancers. 67 Since then, there has been an effort to establish the percentage of UM patients who have a germline mutation in BAP1, with estimates in the range of approximately 5%. 67 This past year, an Australian group used Sanger sequencing to determine 3% (n = 66) of UM patients who had a germline mutation in BAP1. 67 Furthermore, a group from Sweden reported on a family with a novel germline truncating mutation in BAP1, characterized by a phenotype consisting of UM but without a strong constellation of other cancers. 68 Treatment of Primary Uveal Melanoma Since the Collaborative Ocular Melanoma Study demonstrated identical survival outcomes for medium UM treated with enucleation or radiation, there has been an increase in the use of radiation. Most clinical reports on treatment of the primary tumor have focused on the radiation approach and its consequences. This past year, there were articles on brachytherapy as well as charged particle and stereotactic radiosurgery for UM. On the subject of brachytherapy, Semenova and Finger 69 report on their experience of treating 47 UMs that they termed larger (American Joint Committee on Cancer T3 and T4): 3.8 to 12.3 mm in height and 12.1 to 19.9 mm in diameter. They used palladium-103 plaque brachytherapy and obtained local tumor control in 91% of patients and ocular retention in 89% of patients at a median follow-up of 47 months. 69 Five-year Kaplan-Meier radiation-related complications were estimated as 76% for radiation maculopathy, 58% for radiation optic neuropathy, 27% for neovascular glaucoma (NVG), and 15% for vitreous hemorrhage. 69 Meanwhile, Murray et al 70 compared the treatment of UM with iodine-125 ( 125 I), dividing the patients into 2 dosing schemes: (1) 85 Gy prescribed to the apex of the tumor (n = 55) or (2) 85 Gy prescribed to a prescription point of 5 mm (n = 40). With a mean follow-up of 150 months, they found that dosing to the apical height of the tumor was as effective as treating to 5 mm and may reduce the likelihood of radiation-related complications. 70 Wang et al 71 performed a systematic review and metaanalysis on charged particle radiation therapy for UM. The authors used 27 studies of 8809 patients to compare endpoints with standard therapies including plaque brachytherapy and enucleation. 71 They found that the risk for recurrence, radiation retinopathy, and cataracts were all lower for charged particle therapy compared with brachytherapy but that there were no differences in mortality or ocular survival. 71 In UM patients who cannot tolerate the anesthesia required for brachytherapy or tantalum ring insertion for proton beam, gamma-knifeybased stereotactic radiosurgery offers an alternative radiotherapy treatment (Table 3). Sarici and Pazarli 72 report on 50 consecutive patients with medium and large melanomas treated with this radiation method during a single session under local anesthesia, with a 40-month median follow-up. The unique feature of their study was the low-dose standard peripheral dose: 30 Gy at the 50% isodose line for all patients. 72 Their 5-year rates for metastases and tumor control were in a similar range as that in previous studies: 14% and 90%. 72 However, ocular complications were striking, with a 5-year ocular survival of 83%. 72 Cataracts occurred in 34%; radiation maculopathy, in 30%; and NVG, in 14%Vthe latter for which 4 patients had their eye removed. 72 These complications had an impact on patients visual acuity, with 60% having a best-corrected visual acuity (BCVA) of 20/200 or worse by 40 months (in contrast to 45% at 3 years in the Collaborative Ocular Melanoma Study). 72 Although stereotactic radiosurgery has its advantages for nonsurgical candidates, it comes at the price of consequences to the eye and vision. Suesskind et al 73 compared single-dose stereotactic radiosurgery (25 Gy to the tumor margin) without (n = 60) and with (n = 18) tumor resection. They found a suggestion that local control was superior in the group that had tumor resection (100% at 3 years) compared with the group that did not (85% at 3 years), although this was not significant. 73 Eyes with unresected tumors also appeared to have more radiationrelated complications (P=0.07), but eye preservation, visual acuity outcomes, and metastases were similar between the groups. 73 The protocol was stopped after the unexplainable death of 3 patients in the resected group. 73 Local Recurrence There were 2 articles on the subject of recurrence after radiation of the primary UM. Caujolle et al 74 examined local recurrence of UM after proton beam therapy. Their rate of local recurrence was 6.1% at 5 years (n = 1102). Contrary to previous reports, they found that distance from the macula and the papilla, initial ciliary body involvement, and treatment margin were not significant risk factors of local recurrence. 74 Like other studies, they determined that local recurrence was significantly associated with increased risk for metastases and death: 10-year TABLE 3. Outcome and Ocular Complications After Stereotactic Radiation in Studies From January to December 2013 Author Treatment No. Patients F/u, mo Mets-Free Tumor Control Ocular Survival Cat Rad Ret NVG Sarici et al 11 Stereotactic y 86% 5 y 90% 5 y 83% 34% 30% 14% Suesskind et al 73 Stereotactic y 73% 3 y 85% 3 y 77% 62% 22% Stereotactic with resection y 85% 3 y 100% 3 y 87% 20% 0% Cat indicates cataract; F/u, follow-up; Mets-free, metastases-free survival; Rad ret, radiation retinopathy. * 2014 Asia Pacific Academy of Ophthalmology 247

8 Francis and Abramson Asia-Pacific Journal of Ophthalmology & Volume 3, Number 4, July/August 2014 survival was 68.7% for recurrence-free patients and 43.1% for patients with local recurrence. 74 On closer assessment, large tumor diameter and type of recurrence were independent risk factors of death: specifically, patients with marginal recurrences were less likely to develop metastases or to die at 10 years. 74 The authors suggest that this may be confounded by the fact that marginal recurrences were most likely treated by reirradiation (as opposed to enucleation)vwhich was previously shown to be a prognostically favorable method of treatment. 74 In their study of 7 patients with UM who were reirradiated with brachytherapy, a Brazilian group demonstrates a high probability of tumor control and globe retention. 75 The actuarial 2-year progression-free survival and local control were 60% and 87.5%, respectively. 75 All patients experienced diminished visual acuity and cataract; maculopathy developed in 2 patients and glaucoma developed in 1 patient. 75 No eyes were enucleated for radiation-related complications. 75 The authors deduce that reirradiation with brachytherapy can control recurrent tumor without compromising disease-free survival and is therefore a viable option for treatment of local failure. 75 Radiation Complications Although the visual potential for UM eyes treated with radiation is superior to enucleated eyes, the consequences of radiation usually do impair vision and adversely alter ocular architecture. Three articles described side effects of radiation, all with differing radiotherapy approaches. In one, Kaliki and associates 76 calculated the risk for scleral necrosis after brachytherapy for UM to be 1.4% in their cohort of 5057 patients. Approximately half of these cases remained stable, whereas the other half had progressive necrosis. 76 Three patients developed scleral perforation. 76 They determined that risk factors of necrosis included increased tumor thickness, elevated scleral radiation dose, and location (ciliary body or peripheral tumors). 76 However, as the authors point out, the latter factor is likely due to easier identification. 76 On the subject of another radiation technique, Klingenstein et al 77 looked at quality of life in UM patients treated with Cyberknife. They used the Short FormY12 Health Survey, which measures outcome of physical and mental health but is not ophthalmology specific. 77 Because of continuous improvement in mental health, they conclude that Cyberknife radiosurgery may aid in attenuation of emotional distress. 77 They confirmed that concomitant glaucoma had a significant impact on social function and mental health. 77 Finally, with modern proton treatment of UM, the rate of NVG ranges between 15% and 31%. 78 In a report by Mishra et al, 78 their 5-year rate of NVG in 704 patients receiving proton beam for UM was 12.7%, and the rate of NVG-related enucleation was 4.9%. Like previous studies, risk factors of NVG include increased tumor height, larger diameter, and older age of the patient. 78 Dose and location relative to both anterior and posterior structures were also important: NVG was more likely if ciliary body and lens involvement was more than 30% or if the entire optic disc and macula receive more than 28 GyVhighlighting the importance of tissue-sparing planning. 78 In a cohort of 171 choroidal melanoma patients treated with proton beam radiation, Cassoux and colleagues confirmed that endoresection after irradiation significantly reduced the risk for NVG when compared with proton beam alone. 79 Treatment of Radiation Complications The number of reports focusing on the complications of radiation is balanced with a similar number of articles devoted to its treatment. The use of antiyvascular endothelial growth factor (anti-vegf) agents for treatment of radiation retinopathy remains a controversial topic. In their study of 36 patients with radiationrelated macular edema after 125 I brachytherapy, Mashayekhi and associates 80 demonstrated that macular edema decreased in just more than half of the patients at 4 to 6 months. However, the BCVA improved in the minority of patients, and by 6 months after the fourth injection, the macular edema had increased in all patients. 80 This demonstrates that anti-vegf may improve architectural changes of the retina, but this is temporary and does not always translate to better vision. Another group reported on the additive effect of triamcinolone after anti-vegf injections for radiation maculopathy. Twenty-five patients were given a mean of 2 intravitreal triamcinolone injections (range, 1Y6) after intravitreal anti-vegf. 81 At the start of triamcinolone injections, the mean BCVA was 20/138, and by last follow-up (45.5 months after plaque brachytherapy), the BCVA was equivalent at 20/ However, the authors note that 9 patients had BCVA of 20/50 or better at the last follow-up. 81 Two articles considered the topic of retinal detachment repair after brachytherapy for UM. In one, Beykin et al 82 found tractional or tractional-rhegmatogenous retinal detachment to occur in only 1.8% (n = 473) of patients after brachytherapy for UM. These 7 patients had repair via pars plana vitrectomy, and in 5 patients, there was substantial improvement in visual acuity. The procedure appeared to be safe, with no evidence of recurrence or disseminated tumor at 18.4 months of follow-up. 82 In another report, Lonngi et al 83 analyzed the functional outcomes and complications after 23- or 25-gauge pars plana vitrectomy for retinal detachment after 125 I brachytherapy for UM. One hundred two eyes with retinal detachment underwent surgery for a mean of 38.1 (3.8Y178.6) months after plaque brachytherapy. 83 One patient had tumor cells in the vitreous biopsy, but no patient developed tumor recurrence or intraocular or extraocular dissemination. 83 The visual acuity was significantly improved after surgery, increasing from 20/258 to 20/113 at 1 year. 83 Therateof melanoma-related mortality was 0.9%. 83 Prognostication and Biopsy Tragically, more than half of UM patients will eventually die of metastatic disease despite adequate treatment of their primary tumor. In an attempt to make sense of this paradox, historically and presently, there is a great deal of effort dedicated toward generating an accurate prognosticator. Because of the recent commercialization of gene expression profiling, much attention has been drawn to this methodology. Last year, a group from Denmark generated their own microrna (mir) assay on 26 archived formalin-fixed, paraffin-embedded tissue. 84 Expression clustered into 3 distinct groups. They compared the prognostic significance of the mir expression analysis with other established prognosticator techniques including histopathological features and chromosomal alterations established by MLPA. 84 In their study of 36 archived tissue samples, chromosome 3 loss and 8q gain, cell type, as well as size were significant predictors of poor survival, but mir profile was not. In conclusion, the authors question the prognostic value of the mir expression analysis. 84 With the recent inception of gene expression profiling and its necessity for a small biopsy of tumor cells, renewed attention has been drawn toward fine-needle aspiration biopsy (FNAB) of UMs. Schefler et al 85 point out this recent increase in FNABs of uveal melanoma, particularly for prognostication. They describe 4 cases of orbital recurrence after ocular manipulation with vitrectomy, open biopsy, and aspiration techniques. 85 Although many centers have reported a low risk for extraocular extension with FNAB, this published series demonstrates that the complication is possible * 2014 Asia Pacific Academy of Ophthalmology