younger patients and those with a positive family history are more likely to develop additional tumors.

14.6.4 Subtenon (Subconjunctival) Chemotherapy

Carboplatin can be administered by the treating ophthalmologist into the subconjunctival space. This modality is undergoing testing in clinical trials (see Section 14.8) and is generally used in conjunction with systemic chemotherapy and local ophthalmic therapies for patients with retinoblastoma with vitreous seeding. This approach offers some promise in this group of patients.

14.6.5 Unilateral Disease

Because unilateral disease is usually extensive, often with no expectation that useful vision can be preserved, surgery (enucleation) is usually undertaken. However, recent studies in patients with unilateral disease have used chemotherapy in an attempt to preserve vision in the affected eye [2, 24, 25]. One study [26] revealed that children with retinoblastoma who present with obvious external findings of leukocoria, strabismus, or red eye detectable by their family or pediatrician most often require enucleation. Children who manifest no obvious external findings can often avoid enucleation [26].

When there is potential for preservation of vision, treatment with globesparing modalities (radiation therapy, photocoagulation, cryotherapy, thermotherapy, chemoreduction, and brachytherapy) should be considered. In select children with unilateral disease, chemoreduction reduced the need for enucleation or EBRT within 5 years of treatment to 68%. R–E group correlated with successful chemoreduction: 11% of children classified as having R–E group II or III disease, 60% of children having R–E group IV disease, and 100% of children having R–E group V disease required enucleation or EBRT within 5 years of treatment [27].

Because a proportion of children who present with unilateral retinoblastoma will eventually develop contralateral disease, it is important that children with unilateral retinoblastoma receive periodic examinations of the unaffected eye. Asynchronous bilateral disease occurs most frequently in families with affected parents.

Careful examination of the enucleated specimen by an experienced pathologist is necessary to determine whether features indicating high risk for metastatic disease are present. These include anterior chamber seeding, choroidal involvement, tumor beyond the lamina cribrosa, intraocular hemorrhage, and scleral and extrascleral extensions [12, 14]. Systemic adjuvant therapy has been suggested to prevent the development of metastatic disease in patients with certain high-risk features detected on pathologic review after enucleation. Clinical trials are currently ongoing to determine precisely what features indicate the highest risk for metastatic spread (see Section 14.8).

14.6.6 Bilateral Disease

The management of bilateral disease depends on the extent of the disease in each eye. Systemic therapy should be chosen based on the eye with more extensive disease.

Usually the disease is more advanced in one eye, with less involvement in the other. The standard of care in the past has been to enucleate the more involved eye; however, if there is potential for preservation of vision, chemoreduction with close follow-up for response and focal treatment (e.g., cryotherapy or laser therapy) is indicated.

A number of large centers in Europe and North America have published results of trials using systemic chemotherapy for patients whose intraocular tumors are not initially amenable to local management [2, 18, 20, 22, 23, 25–40]. Examples of such tumors are those that are too large to be treated with cryotherapy, laser photocoagulation, or plaque radiation therapy (brachytherapy). Another example is the newborn with a tumor over the optic nerve head. All of these situations share the likelihood that local therapy would limit vision and would not be curative. Most centers have limited this approach to patients with bilateral disease, reasoning that for patients with unilateral disease, the morbidity of enucleation is modest.

In all cases, the goal of chemotherapy is the reduction (hence the term chemoreduction) of tumor volume, making possible the use of focal therapy (cryotherapy, laser photocoagulation, thermotherapy, plaque radiation therapy).

The backbone of the chemoreduction protocols has generally been carboplatin, etoposide, and vincristine. Studies from the Children’s Hospital of Philadelphia and Wills Eye Hospital reported complete success in the avoidance of enucleation or EBRT in R–E group I, II, and III eyes when patients were treated for six cycles. However, local control was often transient in patients with vitreous seeding or very large tumors (R–E group V). Several strategies have been used in an attempt to overcome this problem. Researchers reported the use of nine courses of carboplatin, etoposide, and vincristine with the addition of high-dose cyclosporine A as a modulator of the p-glycoprotein for eight R–E group V eyes with an 88% (seven of eight eyes) success rate (no need for EBRT or enucleation). However, researchers using this regimen in 10 R–E group V eyes reported only a 20% (2 of 10 eyes) success rate.

Using the international classification system for intraocular retinoblastoma applied to these data retrospectively, approximately 30% of group C and 70% of group D eyes failed systemic chemotherapy alone (i.e., chemotherapy was not enough) and achieved responses in pilot studies [30].

This has led to newer adjuvant therapies, including subtenon (subconjunctival) carboplatin, in pilot studies that also use higher doses of carboplatin or etoposide [41–44] (see Section 14.8).

Currently unresolved issues include long-term tumor control and the long-term consequences of chemotherapy. Most of these patients treated by chemotherapy are exposed to etoposide, which has been associated with secondary leukemia in patients without predisposition to cancer; however, the risk of secondary leukemia