second, independent primary malignancies (eg, osteosarcoma) that is exacerbated by exposure to external-beam radiotherapy

2.the potential for radiation-related sequelae, which include midface hypoplasia, radiation-induced cataract, and radiation optic neuropathy and retinopathy

Evidence suggests that combined-modality therapy that uses lower-dose external-beam radiotherapy coupled with chemotherapy may allow for increased globe conservation with decreased radiation morbidity. In addition, the use of systemic chemotherapy may delay the need for externalbeam radiotherapy, allowing for greater orbital development and significantly decreasing the risk of second malignancies once the child is older than 1 year.

Plaque Radiotherapy (Brachytherapy)

Radioactive plaque therapy may be used both as salvage therapy for eyes in which globe-conserving therapies have failed to destroy all viable tumor and as a primary treatment for some children with relatively small to medium-sized tumors. This technique is generally applicable for tumors less than 16 mm in basal diameter and 8 mm in apical thickness. The most commonly used isotopes are iodine 125 and ruthenium 106. Intraoperative localization with ultrasound enhances local tumor control for plaque brachytherapy. A greater likelihood of radiation optic neuropathy or retinopathy may be associated with this radiotherapy modality compared with external-beam radiotherapy. Limiting the radiation dose to periocular structures may lower the incidence of radiation-induced second malignancies.

Targeted Therapy

New frontiers in the treatment of retinoblastoma include the use of gene therapy and small-molecule inhibition. Adenoviral-mediated transfection of tumor cells with thymidine kinase renders the tumor susceptible to systemically administered ganciclovir. Phase 1 clinical trials have been completed, documenting both safety and efficacy. Although this targeted therapy is currently reserved as salvage therapy for eyes failing all conventional modalities of treatment, there is hope that it may become a mainstream treatment. The use of small-molecule inhibitors in aberrant cellular pathways has shown promise in preclinical models.

Spontaneous Regression

Retinoblastoma is one of the more common malignant tumors to undergo complete and spontaneous necrosis (although this is rarely recognized with active disease). Spontaneous regression is recognized clinically after involutional changes such as phthisis have occurred. The incidence of spontaneous regression is unknown, as no child with active retinoblastoma is observed with the hope of spontaneous involution. Although the mechanism by which spontaneous regression occurs is not understood, its histologic appearance is diagnostic. The vitreous cavities of these phthisical eyes are filled with islands of calcified cells embedded in a mass of fibroconnective tissue. Close inspection of the peripheral portion of these calcified islands reveals the ghosted contours of fossilized tumor cells. The process is often accompanied by exuberant proliferation of retinal pigment and ciliary epithelia.

Prognosis

Children with intraocular retinoblastoma who have access to modern medical care have a very good prognosis for survival, with overall survival rates of over 95% for children in developed countries. The most important risk factor associated with death is extraocular extension of tumor, either directly through the sclera or, more commonly, by invasion of the optic nerve, especially to the surgically resected margin (see Chapter 11, Fig 11-43). The importance of choroidal invasion is unclear. Although a multivariate analysis of a large case series has shown that choroidal invasion is not predictive of metastases, the significance of this pathologic finding remains the subject of debate. A current multicenter study is investigating this further. Some evidence suggests, however, that bilateral tumors may increase the risk of death because of their association with primary intracranial tumors (see the discussion of trilateral retinoblastoma earlier in this chapter).

Children who survive bilateral retinoblastoma have an increased incidence of nonocular malignancies later in life. The mean latency for second tumor development is approximately 9 years from management of the primary retinoblastoma. The RB1 mutation is associated with approximately a 25% incidence of second tumor development within 50 years in patients treated without exposure to radiation therapy. External-beam radiation therapy decreases the latency period, in turn increasing the incidence of second tumors in the first 30 years of life, as well as increasing the proportion of tumors in the head and neck. The most common type of second cancer in these patients is osteogenic sarcoma. Other relatively common second malignancies include pinealomas, brain tumors, cutaneous melanomas, soft-tissue sarcomas, and primitive unclassifiable tumors (Table 19-6). Estimates suggest that up to 20% of patients who have bilateral retinoblastoma will develop an apparently unrelated neoplasm within 20 years and that up to 40% will develop a third malignancy within 30 years. The prognosis for survival in retinoblastoma patients who later develop sarcomas is less than 50%.

Table 19-6