**3. Enucleation**

Enucleation is the preferred option for most children presenting with advance tumor (group E eyes), especially if unilateral [17–21]. Other indications for enucleation are failure of all possible effective therapies, active tumor in an eye with no visual potential, anterior segment invasion, secondary neovascular glaucoma, and when the visualization of the tumor is compromised due to corneal opacity, cataract, or vitreous hemorrhage [22]. Enucleation is rarely indicated for bilateral retinoblastoma due to devastating functional limitation that follows such decision. The goal during enucleation is to obtain as much optic nerve as possible (usually 8–12 mm) to make sure that the surgical margin is free from tumor [23, 24]. Surgeons should avoid perforation of the globe during the procedure to minimize the potential risk of tumor seeding into the orbital tissue [25]. Histopathologic evaluation post enucleation allows for evaluation of high-risk features that requires additional chemotherapy. These features include retrolaminar optic nerve invasion, choroidal invasion, scleral and orbital invasion, and anterior chamber seeding [26–28]. At the time of enucleation, an orbital implant is placed to ensure proper growth of the orbit and allows for free movement of the prosthesis when attaching the extraocular muscles to the implant [4, 29]. Many different orbital implants can used and are generally divided to porous and nonporous implants. The most commonly used are porous implants, hence allowing vascular growth in the tiny pores within the implant. This can serve in the stabilization of the implant while minimizing the risk of exposure and extrusion or infection [4, 25].

## **4. External beam radiation therapy (EBRT)**

External beam radiation therapy is an important modality used in the treatment of retinoblastoma. However, due to serious adverse effects, it has fallen out of use and became preserved for moderately advanced disease where retinoblastoma is refractory or progressive after chemotherapy to salvage the eye from enucleation. EBRT techniques have improved overtime, and new methods aim to eliminate the disease and minimize normal tissue exposure to avoid any adverse effects [30–33].

The main EBRT techniques used in treating retinoblastoma are photon or electron radiation therapy (ERT), intensity-modulated radiation therapy (IMRT), and proton radiation therapy (PRT). IMRT and PRT allow for more conformal radiotherapy options in addition to a unique physical property of PRT. Rather than traversing the target, protons stops at energy-dependent depth and with a reduced exit dose to almost zero where it reduces the injury to uninvolved structures and limit the radiation beams to a specific area. This physical property has shown to decrease unwanted adverse effects, making PRT become superior to photon therapy [30, 31].

EBRT treatment sessions are usually scheduled over a period of weeks where multiple small fractions of radiation are delivered via an external machine targeting the lesion. This increases tumor sensitivity to radiation by allowing time for reoxygenation and reassortment of cell cycle. It also spares normal tissues by allowing time for repair in between fractions. Conversely, PRT is delivered in one or a few large fractions, but to small discrete volumes, hence minimizing the volume of surrounding irradiated normal tissue [30, 34].

The outcome of patients who were treated with EBRT has been studied over the past decades. Enucleation was ultimately required in 18–37.5% of eyes, and local failure after radiotherapy was similar between PRT and ERT. Vision was preserved in most of the cases with an outcome showing up to 70% of patients having no or mild visual impairment. Moderate visual impairment is seen in 10–23% of eyes, whereas poor or no useful vision was in 20–41.7% of non-enucleated eyes. The best visual outcomes are noted in patients with early stages that spared the optic disc, macula, and fovea, suggesting that the location of tumors has an impact of visual outcome even after PRT [35–38].

Acute toxicities that can be seen after therapy sessions include local erythema of the skin, hyperpigmentation, erythema of the conjunctiva, and loss of eyelashes. Patients treated with PRT had a similar rate of acute toxicities, compared to patients treated with ERT. Cataracts were the most common long-term complication in eyes treated with EBRT. Other ocular complications noted are radiation retinopathy, glaucoma, neovascularization, vitreous hemorrhage, retinal detachment, strabismus, and less common toxicities [35–38].

The hypothalamus-pituitary axis is known to be affected in EBRT as it is exposed to radiation beams. Growth hormone deficiency and thyroid-stimulating hormone abnormality are noted in patients treated with EBRT. However, due to PRT physical properties that eliminate the radiation to midline structures, these adverse effects

**61**

*Retinoblastoma: Update on Current Management DOI: http://dx.doi.org/10.5772/intechopen.88624*

are noted to be less than in conventional radiation therapy. Therefore, endocrinopa-

Lastly, the quality of life was observed, and no difference was noted between children and their parents regarding the quality-of-life outcomes compared to the

Brachytherapy is a form of radiotherapy where a source of radiation is placed inside or next to the treatment area. In retinoblastoma the radioactive implant is placed on the sclera corresponding to the tumor base and fixed surgically to irradiate the tumor. Implantation technique requires excellent surgical skills and is applied under general sedation where the implant is fixed on the sclera and maintained for few days and removed with the patients remaining in the hospital during the entire treatment [42]. Iodine-125 and Ruthenium-106 are the most common radioactive agents to be used in intraocular lesions. Other agents can be used such as Ruthenium-106, Palladium-103, Strontium-90, Cobalt-60, and Iridium-192 [42, 43]. Like EBRT, the use of brachytherapy has been limited to progressive disease and to preserve the eye from enucleation. However, brachytherapy offers less spread of radiation, and its complications that can be associated with EBRT can be prevented where damage of normal tissue can be minimized which can lead to deformities and more importantly reduce the risk of radiation-induced second cancers [42, 44, 45]. Brachytherapy can be used as primary modality to treat retinoblastoma where the tumor is found solitary and located anterior to the equator as per the American Brachytherapy Society-Ophthalmic Oncology Task Force (ABS-OOTF) recommendations. As for secondary treatment where retinoblastoma failed to respond to other treatment modalities, it can be used irrespective of its location [43]. Brachytherapy is also an effective method that can be used post enucleation to prevent recurrence [46]. Plaque brachytherapy achieved tumor control in 83–89% of cases in some studies reaching up to 88% when used as a primary modality and appears to be the best choice in patients who failed laser photocoagulation, thermotherapy, cryotherapy, or chemoreduction, but it is less successful in patients who failed EBRT [45, 47, 48].

Another adverse effect reported is craniofacial deformities where the facial and bony structures tend to be affected in EBRT. These include hypoplasia, hyperpigmentation, or soft tissue fibrosis. Long-term dentofacial anomalies have also been reported [36, 38, 40]. Risk of new cancers is a major concern in retinoblastoma patients treated with radiotherapy. The cumulative incidence of a second cancer at 50 years after diagnosis of retinoblastoma was 36% for hereditary retinoblastoma. Bone, nasal cavity, connective and soft tissue, and other neoplasms have been associated in retinoblastoma survivors who received EBRT. Osteosarcomas and soft tissue sarcomas are the most common tumors reported in irradiated patients reaching up to 76% of all cancer in ages younger than 25 years old. On the other hand, in unilateral retinoblastoma patients who did not receive radiation, sarcomas did not occur. In addition, the subsequent risk of cancer was noted to be higher in irradiated patients than nonirradiated whether the patients had hereditary or non-hereditary disease. Also, elevated doses of radiation were associated with increased risk of subsequent tumors. However, no subsequent cancers were noted among hereditary patients treated with chemotherapy. Furthermore, a comparison between photon and proton radiotherapy techniques was done and it showed that the 10-year cumulative incidence of malignancies was significantly higher in photon therapy compared to proton therapy. Therefore, patients treated with radiotherapy should have long

thies were almost limited in patients treated with PRT [38, 39].

follow-ups regardless of the modality used [32, 33, 41].

general population [38].

**5. Brachytherapy**

#### *Retinoblastoma: Update on Current Management DOI: http://dx.doi.org/10.5772/intechopen.88624*

*Retinoblastoma - Past, Present and Future*

choroidal invasion, scleral and orbital invasion, and anterior chamber seeding [26–28]. At the time of enucleation, an orbital implant is placed to ensure proper growth of the orbit and allows for free movement of the prosthesis when attaching the extraocular muscles to the implant [4, 29]. Many different orbital implants can used and are generally divided to porous and nonporous implants. The most commonly used are porous implants, hence allowing vascular growth in the tiny pores within the implant. This can serve in the stabilization of the implant while minimiz-

External beam radiation therapy is an important modality used in the treatment of retinoblastoma. However, due to serious adverse effects, it has fallen out of use and became preserved for moderately advanced disease where retinoblastoma is refractory or progressive after chemotherapy to salvage the eye from enucleation. EBRT techniques have improved overtime, and new methods aim to eliminate the disease and minimize normal tissue exposure to avoid any adverse effects [30–33]. The main EBRT techniques used in treating retinoblastoma are photon or electron radiation therapy (ERT), intensity-modulated radiation therapy (IMRT), and proton radiation therapy (PRT). IMRT and PRT allow for more conformal radiotherapy options in addition to a unique physical property of PRT. Rather than traversing the target, protons stops at energy-dependent depth and with a reduced exit dose to almost zero where it reduces the injury to uninvolved structures and limit the radiation beams to a specific area. This physical property has shown to decrease unwanted

adverse effects, making PRT become superior to photon therapy [30, 31].

EBRT treatment sessions are usually scheduled over a period of weeks where multiple small fractions of radiation are delivered via an external machine targeting the lesion. This increases tumor sensitivity to radiation by allowing time for reoxygenation and reassortment of cell cycle. It also spares normal tissues by allowing time for repair in between fractions. Conversely, PRT is delivered in one or a few large fractions, but to small discrete volumes, hence minimizing the volume of

The outcome of patients who were treated with EBRT has been studied over the past decades. Enucleation was ultimately required in 18–37.5% of eyes, and local failure after radiotherapy was similar between PRT and ERT. Vision was preserved in most of the cases with an outcome showing up to 70% of patients having no or mild visual impairment. Moderate visual impairment is seen in 10–23% of eyes, whereas poor or no useful vision was in 20–41.7% of non-enucleated eyes. The best visual outcomes are noted in patients with early stages that spared the optic disc, macula, and fovea, suggesting that the location of tumors has an impact of visual

Acute toxicities that can be seen after therapy sessions include local erythema of the skin, hyperpigmentation, erythema of the conjunctiva, and loss of eyelashes. Patients treated with PRT had a similar rate of acute toxicities, compared to patients treated with ERT. Cataracts were the most common long-term complication in eyes treated with EBRT. Other ocular complications noted are radiation retinopathy, glaucoma, neovascularization, vitreous hemorrhage, retinal detachment, strabis-

The hypothalamus-pituitary axis is known to be affected in EBRT as it is exposed to radiation beams. Growth hormone deficiency and thyroid-stimulating hormone abnormality are noted in patients treated with EBRT. However, due to PRT physical properties that eliminate the radiation to midline structures, these adverse effects

ing the risk of exposure and extrusion or infection [4, 25].

**4. External beam radiation therapy (EBRT)**

surrounding irradiated normal tissue [30, 34].

outcome even after PRT [35–38].

mus, and less common toxicities [35–38].

**60**

are noted to be less than in conventional radiation therapy. Therefore, endocrinopathies were almost limited in patients treated with PRT [38, 39].

Another adverse effect reported is craniofacial deformities where the facial and bony structures tend to be affected in EBRT. These include hypoplasia, hyperpigmentation, or soft tissue fibrosis. Long-term dentofacial anomalies have also been reported [36, 38, 40].

Risk of new cancers is a major concern in retinoblastoma patients treated with radiotherapy. The cumulative incidence of a second cancer at 50 years after diagnosis of retinoblastoma was 36% for hereditary retinoblastoma. Bone, nasal cavity, connective and soft tissue, and other neoplasms have been associated in retinoblastoma survivors who received EBRT. Osteosarcomas and soft tissue sarcomas are the most common tumors reported in irradiated patients reaching up to 76% of all cancer in ages younger than 25 years old. On the other hand, in unilateral retinoblastoma patients who did not receive radiation, sarcomas did not occur. In addition, the subsequent risk of cancer was noted to be higher in irradiated patients than nonirradiated whether the patients had hereditary or non-hereditary disease. Also, elevated doses of radiation were associated with increased risk of subsequent tumors. However, no subsequent cancers were noted among hereditary patients treated with chemotherapy. Furthermore, a comparison between photon and proton radiotherapy techniques was done and it showed that the 10-year cumulative incidence of malignancies was significantly higher in photon therapy compared to proton therapy. Therefore, patients treated with radiotherapy should have long follow-ups regardless of the modality used [32, 33, 41].

Lastly, the quality of life was observed, and no difference was noted between children and their parents regarding the quality-of-life outcomes compared to the general population [38].
