Chemotherapy in retinoblastoma: current status and future directions.

In the past, chemotherapy has had only a minor role in the treatment of retinoblastoma. There are three clinical settings in which chemotherapy may be useful, namely, in intraocular retinoblastoma, in cases of micrometastatic spread, and where there are overt extraocular metastases. Clinical trials in all three settings have been impeded by biological, statistical, and ethical limitations. Extensive review of the literature, including case reports, small retrospective series, and occasional prospective studies, does not lead to any clear conclusions. However, responsiveness of retinoblastoma to chemotherapy in each of the above categories has been documented, and cyclophosphamide is consistently the most effective single agent. For small intraocular tumors, there may be a role for a combination of nonoperative treatment modalities. Whether decreased occurrence of extraocular relapse is produced by the use of adjuvant chemotherapy for presumed micrometastatic disease remains controversial A prospective randomized study of stratified high-risk categories of patients needs to be done on an international level. The most widely accepted regimen in this setting is the combination of cyclophosphamide and vincristine. Improving the survival of patients with overt metastases is a major challenge, which is especially relevant to the less developed parts of the world. Several multiagent regimens, particularly in combination with bone marrow transplantation, offer some promise. Experimental models are being used to overcome some of the limitations of clinical studies. Evaluations of responsiveness to chemotherapy, both in cell culture and animal models, are being conducted. Other areas being investigated include pharmacologic enhancement of radiotherapy and hematoporphyrin photodynamic therapy, use of tumor cell targeting techniques, differentiating agents, vitamin D, and immunotherapy. The nude mouse intraocular xenograft model appears to confirm clinical observations for responsiveness to conventional therapeutic agents.