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Retinoblastoma updates

Genetics: Retinoblastoma tumors can be either heritable and associated with a germline mutation of the RB1 gene, or non-heritable. Heritable mutations typically present in the 1st year of life with bilateral disease. In comparison, the non-heritable form typically presents slightly later and is primarily unilateral. In 1971, Knudson proposed his “two-hit” hypothesis for the development of retinoblastoma tumors.3 Following his seminal work, the retinoblastoma gene was the first tumor suppressor gene discovered in the human genome.4 Over the decades, the RB gene has been shown to be a key regulator of the cell cycle through inhibitory effects on the transcription factor elongation factor-2 (EF2) and cellular differentiation through effects on tissue-specific transcription factors. Recent evidence suggests a decision-making role for the RB gene, mediating proliferation, apoptosis, and differentiation.5 Knudson’s “two-hit” hypothesis has recently been challenged, as it has been proposed that the previously held belief of RB gene mutation leading to retinoblastoma tumors simplifies a complex genetic process, with genomic instability and aneuploidy more likely responsible.6 Using microarray analysis, other investigators analyzed the genomic expression of human retinoblastoma tumors. They found that 1004 genes were upregulated and 481 genes were downregulated compared to control eyes with clusters of differentially expressed genes identified on chromosomes 1, 6, and 17.7 Other investigators have shown that in unilateral, sporadic tumors may be subclassified according to the presence or absence of loss of heterozygosity on chromosome 13, as well as novel regions of amplification or loss on a number of other chromosomes.8 More recently, using the LHBETATAG retinoblastoma murine model, microarray analysis showed that regional and temporal variations in genomic expression were evident in retinoblastoma tumors. More advanced tumors showed dysregulated genes involved in networks involved in angiogenesis, hypoxia, and cellular metabolism.9 Genomic expression analysis provides a greater understanding of the pathogenesis of retinoblastoma tumors, identifying potential gene targets and signaling pathways for adjuvant treatments. However, further studies are needed to correlate animal studies with human tumors.

Epidemiology: A recent editorial on the epidemiology of retinoblastoma made the following comment: “retinoblastoma is the most frequent primary intraocular cancer and is gaining importance rapidly.”10 Based on the epidemiologic studies of several investigators, retinoblastoma affects approximately 1 in 16,000 – 18,000 births, for an incidence of 7000 – 8000 new cases annually worldwide.11, 12 It is estimated that there is an annual incidence of 3.5 per million children younger than 15,13 and 11.8 per million children younger than 5.11 The estimated cumulative incidence is 53 – 62 per million children younger than 14.10, 13 Survival rates in the US approach 100%, with survival in other continents, primarily developing nations, much lower. Survival rates in developed Latin America countries has been reported to be 80 – 89%,1416 83% in Iran,1781% in China,18, 19 48% in India,20 and as low as 20 – 46% in Africa.1, 2 As a result, it has been estimated that 3000 – 4000 deaths occur annually worldwide.10 Amazingly, if survival rates worldwide approached those of developed countries such as those in Europe, the US, and Japan, retinoblastoma deaths could potentially be reduced by 88%, for approximately 400 children. These epidemiologic studies stress the importance of early detection and referral to tertiary care centers. Additionally, with the growing populations, especially in Asia and Africa, retinoblastoma is “gaining importance rapidly.”10Retinoblastoma is a highly curable cancer, and there is still much progress to made worldwide to combat this pediatric ocular malignancy.

Local Chemotherapy:

Intravenous chemotherapy combined with local consolidation has shifted management of retinoblastoma in favor of globe-salvage. However, successful tumor control in advanced tumors still often requires enucleation or radiation therapy. Additionally, systemic chemotherapy has been associated with systemic toxicities such as neutropenia and infection, as well as risks for second malignancies. To avoid systemic toxicities, local administration of chemotherapy has been proposed.

Subconjunctival carboplatin has been investigated for Group C and D eyes with long-term results of single therapy showing high failure rates.38 The Children’s Oncology Group advocates the combined use of 20 mg of carboplatin as a sub-Tenon’s injection with chemoreduction and consolidation for tumors classified as group C and D.25 Additionally, Leng et al.39 showed early retinoblastoma tumors that progress despite laser ablative therapy can be effectively controlled with adjuvant treatment using subconjunctival carboplatin (Figure 3). As a result, focal subconjunctival injection of carboplatin may potentially be used to enhance tumor control in advanced retinoblastoma tumors as well as supplementing laser therapy for early tumors. Side effects have been reported, some severe, including ocular motility changes, optic nerve necrosis and atrophy, and periorbital fat necrosis.4042 Further studies are needed to determine the role subconjunctival chemotherapy will play in retinoblastoma treatment as well as the long-term risk profile. We anticipate an ongoing multicenter trial combined with systemic chemotherapy to answer some of these questions.

More recently, intra-arterial chemotherapy has been investigated after selective ophthalmic artery infusion was demonstrated in 2004. Yamane et al.43 showed that with cannulation of the internal carotid artery with distal balloon occlusion, selective infusion of melphalan could be successfully administered to the ophthalmic artery 97.51% of the time. Additionally, in 187 patients undergoing 563 cannulations, there were no reported complications from cannulation, including hemorrhage, stroke, or death.43 However, the study did not report on tumor control rates or visual outcomes, and intra-arterial chemotherapy was combined with other treatments. Following this pioneering technique, techniques were developed to selectively cannulate the ophthalmic artery, eliminating the need for balloon occlusion (Figure 4). In a phase I/II study, Abramson et al.44 demonstrated that 7 of 9 children with advanced tumors (R-E V) could be spared enucleation, with evidence of tumor regression, including vitreous and subretinal seeds. Importantly, no severe side effects were observed, and all but 1 patient had stabilization or improvement in vision. Since these initial studies, several investigators have reported on their experience with supraselective ophthalmic artery infusion of chemotherapy. Abramson et al.45 reported on their 3-year experience on 28 eyes of 23 children newly diagnosed with retinoblastoma were enrolled. The majority (25 eyes) were R-E stage V, with one each of stage II, III, IV, with zero receiving prior treatment. All children were successfully cannulized and were treated with 1 – 6 infusions (mean 3.2). Twelve patients were treated with melphalan, 7 with melphalan plus topotecan, 3 with melphalan plus topotecan and carboplatin, and 1 with melphalan plus carboplatin. Only 1 of 28 eyes required enucleation because of disease progression, with the remainder also avoiding systemic chemotherapy and radiation. Kaplan-Meier estimates for globe-salvage was 100% at 1 year and 89% at 2 years (95% CI, 43 – 98%). Ophthalmic complications were mild, including lid edema, forehead hyperemia, and eyelash loss. Importantly, there were no deaths, strokes or hemorrhages, and several grade 3 and one grade 4 neutropenia, with zero requiring hospitalization.45 The same group also reported on 4 patients with bilateral, advanced retinoblastoma (R-E stage V) who were treated initially with bilateral infusions during the same session (tandem therapy). All 4 eyes avoided enucleation or radiation, with no adverse effects observed, except one grade 3 neutropenia. Tumors underwent focal ablative therapy with TTT or cryotherapy following chemosurgery.46

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