after etoposide treatment is modest compared to the risk of secondary tumors following EBRT in patients with heritable retinoblastoma. In a retrospective database and literature review, ocular and pediatric oncologists at referral centers in Europe and the Americas and the retinoblastoma databases at the National Institutes of Health and the Ophthalmic Oncology Service at Memorial Sloan-Kettering Cancer Center conducted a study of secondary acute myeloid leukemia among patients treated for retinoblastoma [45]. Fifteen patients were identified; 12 patients (79%) had received chemotherapy with a topoisomerase II inhibitor (etoposide or teniposide). Ten children died of their leukemia [45].

Whether patients with heritable retinoblastoma have greater susceptibility to chemotherapy-induced second tumors is unknown. Some patients will experience disease progression, and the risk of exposure to both chemotherapy and irradiation in this population has not been determined.

14.7 Focal Therapies

The need for supplemental focal therapy for the control and eradication of retinoblastoma has been demonstrated in several studies [28–30, 46]. Wilson et al. [30] utilized up to eight cycles of chemotherapy with carboplatin and vincristine, initially without focal therapy. A total of 36 eyes were treated (4 patients with unilateral and 16 with bilateral disease). Eighteen eyes had R–E group I, II, or III tumors, and 16 eyes had R–E group IV or V tumors. Only three eyes were treated successfully with chemotherapy alone; in 92% of eyes, disease progressed after completion of the treatment, and at the end of treatment, 42% of the eyes required EBRT.

14.7.1 Cryotherapy

Cryotherapy is used mainly with small peripheral tumors. It induces damage to the tumor vasculature through rapid freezing, with subsequent thrombosis and necrosis of the tissue. Usually patients are treated one to two sessions per month, and a triple freeze–thaw technique is used. A tumor control rate of up to 90% has been reported for small tumors (<3 mm) with minimal complications [31, 32]. Cryotherapy also can be used to treat small recurrences in tumors previously treated with other modalities.

14.7.2 Laser Photocoagulation

Focal laser therapy is occasionally used alone with small tumors. Photocoagulation is used for posteriorly located tumors that are smaller than four DD, distinct from the optic nerve head and macula, and without the involvement of large nutrient vessels or choroid involvement. Photocoagulation requires multiple (at least two to three)

sessions. Thermotherapy delivered via infrared radiation (see Section 14.7.4) is an alternative to laser photocoagulation [34].

14.7.3 Brachytherapy

Brachytherapy with radioactive plaques can be used for either focal unilateral presentations or recurrent disease following previous EBRT. The goal is to deliver up to 4000–4500 cGy transsclerally for a total of 2–4 days. The tumor must be no more than 16 mm wide and 8 mm thick. Shields et al. [33] reported in a series of 208 eyes that brachytherapy achieved tumor control in 79% of cases at 5 years and proved to be especially useful in tumors for which treatment with chemoreduction, laser photocoagulation, thermotherapy, or cryotherapy failed (see Section 14.7.5).

14.7.4 Thermotherapy

Thermotherapy involves the application of a source of heat (usually via infrared 810 nm laser) directly to the tumor to achieve temperatures up to 60◦C. As with other types of focal therapy, thermotherapy is used for small retinoblastoma tumors (less than 3 mm in diameter), and the success rate is reported to be up to 92% [34]. In many centers it is the preferred modality over traditional photocoagulation.

14.7.5 Radiation Therapy

Retinoblastoma is a radiosensitive tumor with control rates exceeding 90% with EBRT alone. Because of the potential late consequences of radiation therapy, however, the role of this modality has changed to a salvage role following failed chemoreduction. Technological advances for EBRT, including megavoltage photon and electron beams, three-dimensional treatment planning, intensity-modulated radiation therapy, and proton beam radiation, have allowed improved treatment conformality, which should, in theory, lead to a reduction of unwanted sequelae.

EBRT planning strategies should maximize conformality of high doses to the areas at risk and minimize the dose to surrounding uninvolved structures. In patients treated with EBRT, the radiation oncologist should explicitly understand the extent of tumor involvement, which requires direct communication with the evaluating ophthalmologist. This knowledge allows delineation of the gross tumor volume and definition of the clinical target volume to encompass the areas at risk of microscopic disease. The clinical target volume could extend from the ora serrata to the anterior 1 cm of the optic nerve, thereby including the vitreous body. Alternatively, in patients with discrete limited disease, the clinical target volume may not include the entire retina or vitreous body, allowing lens-sparing techniques to be used. The planning target volume, which includes an extra margin of uncertainty, is patient and