1.Ocular Oncology Service, Department of Ophthalmology, Hacettepe University School of Medicine, Ankara, Turkey
Table 2. International Classification of Retinoblastoma (Murphree).
1. Chemotherapy: Systemic chemotherapy has become the most commonly used method worldwide within the past 10 years for almost all intraocular retinoblastomas. The rationale is to shrink the tumor (chemoreduction) so that subsequent local consolidation treatments are used to further destroy the tumor and thus avoid enucleation or external beam radiotherapy. In general, eyes having a potential of a useful vision but containing large tumors untreatable with local methods, children under the age of one year, and advanced bilateral cases are eligible for chemoreduction. Current protocols include vincristine, carboplatin and etoposide or teniposide. A successful outcome can be obtained in 100% of group A, 93% in group B, 90% in group C, and 47% in group D eyes. Most tumors regress more than 50% within 3-4 weeks. The most important complication of chemoreduction therapy is recurrence of the tumor, which is more common in macular tumors. Also, new ocular tumors may develop while under systemic chemotherapy. Transient myelosuppression, cytopenia and neutropenia occur in 100% of patients. The development of secondary non-ocular cancers following chemotherapy is an unresolved issue. Preliminary studies suggest an increased incidence of AML particularly in patients who had received teniposide, which acts on chromosome 11q35. (see Figure 2A and 2B).
2. Local chemotherapy: Local administration of chemotherapeutic agents is in use to deliver higher concentrations of the drug into the eye and avoid systemic toxicity and side effects. Large molecules can easily pass the sclera regardless of lipophilicity. Injection of carboplatin into the subtenon space is effective against localized mild amounts of vitreous seedings but this effect is transient and rarely curative. Additionally, carboplatin is rapidly cleared from the vitreous limiting its effects. To overcome this inconvenience, a sustained delivery system of carboplatin from fibrin sealants is developed. Recently, supraselective intra-arterial infusion of melphelan into the ophthalmic artery resulted in satisfactory tumor regression in eyes that would otherwise have to be enucleated.
3. Enucleation: This time-honored surgical treatment is indicated for most of group E or RE V eyes where there is no prospect of vision. Eyes with elevated intraocular pressure, rubeosis iridis, tumor in the anterior chamber, buphthalmus and evidence for optic nerve involvement need to be enucleated. Failure of prior chemotherapy and radiotherapy are other indications for enucleation. In general, enucleation becomes necessary in 75% of unilateral cases because of the advanced stage at the time of diagnosis. Likewise, enucleation of at least one eye (the worst eye) becomes unavoidable in 60% of bilateral cases. Bilateral enucleation may be performed in 1% of cases.
4. Cryotherapy: Rapid freezing of the tumor to -90°C damages the vascular endothelia causing platelet plugs to form thrombosis and induces tumor ischemia. In addition, intracellular ice crystal formation causes rupture of the cellular membranes. All tumors with less than 5 mm basal diameter and few vitreous seedings close to the tumor can successfully be treated with cryotherapy.
5. Brachytherapy: Iodine-125 and Ruthenium-106 radioactive plaques are widely used to treat solitary tumors having 6-15 mm basal diameters and less than 9 mm thickness. The trend is to prescribe 4000-4500 cGy radiation to the tumor apex. To overall success rate is 90% but there is a tumor recurrence rate of 12% at one year. Radiation induced retinopathy and optic neuropathy are the most common complications.
6. Transpupillary thermotherapy (TTT): 810 nm infrared diode laser is used for this treatment. Tumors smaller than 3 mm of basal diameter without vitreous seedings can be reliably treated with TTT either primarily or following chemoreduction. Because of technical difficulties, peripheral tumors are avoided. The power is usually set at 200-1000 mW and 1.2 to 3 mm spot sizes are used for 1 minute each, aiming directly the tumor. The result is a flat and atrophic scar. There is an overall 86% success rate with complications including focal iris atrophy, lens opacities, optic disc atrophy, retinal tractions, vascular occlusions, and retinal hemorrhages. (see Figure 2C and 2D).
7. External Beam Radiotherapy (EBRT): This modality continues to be very effective in selected patients despite fears for secondary cancers. Eyes with multifocal tumors not treatable by other local techniques, macular tumors where other methods may ultimately destroy the central vision, and advanced bilateral disease are good candidates for EBRT. Also, EBRT can be performed after failure of other methods as a salvage therapy, in patients with extraocular orbital tumor invasion or tumor at the surgical margin of the resected optic nerve. The target tumor receives 4200-4600 cGy radiation in 180-200 cGy fractionated doses daily. Local tumor control rates vary between 50% to 88% depending on the stage of the disease. If vitreous seedings are present the success rate of EBRT is only 17%. The most significant concern with the use of EBRT is the development of second non-ocular and periocular cancers particularly in survivors of hereditary retinoblastoma. There is a 400-600 fold increase in the risk of developing second cancers in hereditary retinoblastoma if treated with EBRT and this risk is further multiplied by 8 if the treatment is given below the age of 1 year. Second malignant tumors develop in 4.4% of patients during the first 10 years, in 18.3% within 20 years and in 26.1% after 30 years. The most common second cancers include osteogenic sarcoma, leiomyosarcoma, pinealoblastoma, skin melanoma, Hodgkins lymphoma, lung and breast carcinomas. (see Figure 2E).
8. Gene Therapy: The preliminary results of intravitreal injection of adenovirus carrying the coding sequence of thymidine kinase followed by ganciclovir injection appear promising. In human subjects, this treatment decreased vitreous seedings but main tumors remained intact.
9. Experimental Therapies: - COX-2, which is expressed in retinoblastoma, is a prostaglandin synthetase promoting angiogenesis, suppressing apoptosis and increasing tumor invasiveness. The role of COX-2 inhibitors is investigated in retinoblastoma.- Oxidative stress, which is high in retinoblastoma, upregulates aA-crystallins, member of heath shock proteins, helping tumor cells to escape apoptosis. Anti-aA-crystallin therapy is thought to have a potential to limit tumor growth in retinoblastoma.- Retinoblastoma cells can produce VEGF and basic fibroblast growth factor both of which induce angiogenesis. The initial enthusiasm on anti-angiogenic drugs vanished because it was found that these drugs were active against immature vasculature found in the periphery of the tumor. Vessels that are more central had pericyte components and thus became mature no more dependant on angiogenic stimuli. This seriously limits the effects of anti-angiogenic agents.- Arsenic trioxide has been shown to have effect on retinoblastoma cells by generating reactive oxygen species which oxidize lipids in the mitochondria membranes. This results in cytochrome C release and activation of the caspase system leading to apoptosis.- Retinoblastoma contains many hypoxic areas where cellular proliferation is slower compared to areas close to blood vessels. These slow proliferating cells usually do not respond to available chemotherapeutic drugs. 2-deoxy-D-glucose (2-DG), a glycolytic inhibitor, holds promise against these non-responding cell populations.
Hayyam Kiratli ; Berçin Tarlan
Head and neck: Retinoblastoma
Atlas Genet Cytogenet Oncol Haematol. 2009-08-01
Online version: http://atlasgeneticsoncology.org/solid-tumor/5008/head-and-neck-retinoblastoma