**9. Cryotherapy**

*Retinoblastoma - Past, Present and Future*

outcome [45, 47].

Reirradiation of local recurrence with brachytherapy can be considered as an option to salvage the eye from enucleation, and it may provide tumor control and eye preservation [48]. Complications related to radiation included radiation retinopathy, maculopathy, papillopathy, cataract, and glaucoma. Fortunately, no second cancers

Visual acuity in patients was found to be good in 64% and poor in 24–32% of non-enucleated eyes who were treated with plaque radiotherapy. The poor visual outcome was mainly associated with macular lesions, macular edema, vitreous hemorrhage, and phthisis bulbi. It appears that there is no significant difference whether brachytherapy was used as a primary or secondary modality in visual

In many centers, Iodine-125 is used as the standard isotope for plaque brachytherapy. This is due to the physical properties like its half-life, low energy, adequate dose distribution, and ease of shielding [42, 43]. In a study, the use of Iodine-125 as salvage treatment in 84 recurrent lesions after chemoreduction is reported. It showed 95% control in those who failed chemoreduction and 100% control in patients who failed a combination of chemoreduction and EBRT. Complications were higher in patients who received EBRT and included papillopathy, vitreous

Ruthenium-106 has some advantages over Iodine-125 where it's lower in cost, has longer half-life, and is safer in terms of radioprotection. It has shown tumor control achievement up to 73%, and some studies achieved eye preservation in 89% of cases. Local recurrence with Ruthenium-106 is noted to reach 6.3%. Complications of Ruthenium-106 are generally similar to those found in other radiation modalities such as proliferative retinopathy which can lead to vitreous hemorrhage, radiation maculopathy radiation optic neuropathy, exudative retinal detachment, neovascularization, neovascular glaucoma, and cataracts. Previous treatment with EBRT was shown to be associated with increased risk of some complications such as optic neuropathy, retinal detachment, and cataracts. However, studies of efficacy of Ruthenium-106 in retinoblastoma compared to Iodine-125 are

Focal therapy in treatment of retinoblastoma is used either alone in small retinoblastomas (group A or B) (1, 2 laser) or after chemoreduction, usually after two or

Thermotherapy is based on increasing the tissue temperature from 45 to 60°C to induce a cytotoxic effect, through applying an 810-nm diode laser below the coagulative threshold to prevent retinal vessels from coagulation, and it can be used alone for small retinoblastomas that are 3 mm in diameter without vitreous or subretinal seeds [57, 58]. In a study of 91 tumors, 92% of the tumors that were 1.5 mm in diameter were controlled with thermotherapy alone [59]. Out of 188 treated by thermotherapy, complete regression of the tumor was achieved in (85%) 161 tumors, where the mean tumor size is 3.0 mm base and 2.0 mm thickness [60]. Complications of transpupillary thermotherapy include iris atrophy, cataracts, tumor seeding into the

three cycles, or for small recurrent tumors or subretinal seeds [55–57].

related to plaque brachytherapy were reported in the literature [45, 47–50].

hemorrhage, cataract, and neovascularization [50].

limited in the literature [51–54].

**7. Transpupillary thermotherapy (TTT)**

vitreous, retinal fibrosis, transition, and vascular occlusion.

**6. Focal therapy**

**62**

Cryotherapy induces rapid decrease (freeze) of tumor tissue, and this will cause damage to the tumor blood vessel endothelium and lead to vascular thrombosis, which results in tumor ischemia and infarction. It is used as primary treatment for small equatorial and peripheral retinal tumors (<3.5-mm base and <2-mm thickness). Treatment protocol is based on three applications for each session every 4–6 weeks until complete regression of the tumor. Complications of cryotherapy include retinal tears and detachment, proliferative vitreoretinopathy, and chorioretinal atrophy. Cryotherapy can be used 2–3 hours before chemotherapy administration, and that can increase the permeability of blood retinal barrier and increase the effect of chemotherapy [61, 63].

## **10. Chemotherapy**

Chemotherapy is considered as one of the most important modalities used to treat retinoblastoma. It has been used as a main therapeutic modality achieving tumor control in up to 78% with the elimination of the need for enucleation as well as EBRT and its risk of developing second new cancers [64]. Chemotherapeutic agents can be delivered via four main routes which are intravenous chemotherapy, intra-arterial chemotherapy (IAC), intravitreal chemotherapy, and periocular chemotherapy. The most common chemotherapeutic agents used are vincristine, etoposide, and carboplatin. This (VEC) regimen is the most popular combination preferred by many experts, and this stems from its proven effect on neuronal tumors in the pediatric age group as well as its good penetration into the eye [65]. Melphalan is considered as the best and most effective agent in intra-arterial chemotherapy, and it is the most commonly used [66]. Tumor control, chemoreduction, and outcome differ from one modality and route of administration to another. Outcome also depends on the ICRB where chemotherapy can be successful in 100% in group A and it drops as low as 50% in groups D and E. Visual outcome can be maintained with a visual acuity of 6/60 or better in around two-thirds of patients [16, 67]. Adverse effects of chemotherapy observed are different from one modality to another. For instance, common side effects seen with systemic chemotherapy include transient pancytopenia, fever, and alopecia. Intra-arterial chemotherapy complications are attributed either to the procedure itself or to the chemotherapeutic agent. It can result in endovascular complications, allergy, and hematoma at the site of entry. IAC can also result in ocular vascular complications. Neutropenia is another important complication noted in IAC. Among the most frequent side effects of intravitreal chemotherapy are retinal pigment epithelium changes, iris depigmentation and atrophy, chorioretinal atrophy with vitreous hemorrhage, and retinal detachment. Fortunately, second primary malignancy

risk in chemotherapy is almost eliminated compared to EBRT which has made chemotherapy more superior in treating retinoblastoma [68–75]. A more detailed information is mentioned in the chapter entitled Retinoblastoma Management: Advances in Chemotherapy.
