New Retinoblastoma Tumors in Children Undergoing Systemic Chemotherapy

Traditionally, bilateral retinoblastoma has been treated by enucleating the most involved eye and applying external beam radiotherapy to the second eye. More recently, simultaneous bilateral external beam radiotherapy has been shown to be an effective treatment for medium-sized retinoblastomas. However, external beam radiotherapy of pediatric patients with germline mutations predisposing to retinoblastoma development is associated with a 35% risk of secondary neoplasms by 30 years of age and a 90% risk of cosmetic deformity and cataracts.^1,2 Therefore, although chemotherapy has been reserved for extraocular extension of retinoblastoma and systemic and central nervous system metastases in the past, there is now increasing interest in treating intraocular retinoblastoma with chemotherapy. Indeed, chemotherapy combined with focal laser therapy and cryotherapy has been shown to be a successful primary treatment for intraocular retinoblastoma.^3,4 In this article we report 4 cases in which patients developed new retinoblastoma tumors while being treated with chemotherapy.

A 4-month-old boy was seen with Reese-Ellsworth stage IIIA retinoblastoma in the right eye. Systemic evaluation (including brain computed tomography with and without contrast, bone marrow aspiration, and lumbar puncture) demonstrated no evidence of metastatic tumor and the patient was treated with 9 cycles of vincristine, carboplatin, and etoposide (1 cycle every 3 weeks). The patient underwent an examination under anesthesia every 3 to 4 weeks. After the sixth cycle of chemoreductive therapy, a new tumor was found (Figure 1) and was treated with laser hyperthermia. Four months after the ninth and final cycle of chemotherapy, a new tumor was found and treated with laser hyperthermia.

A 2-month-old boy was seen with Reese-Ellsworth stage IVB retinoblastoma in the right eye and Reese-Ellsworth stage IIIA retinoblastoma in the left eye. After computed tomography of the brain with and without contrast, bone marrow aspiration, and lumbar puncture demonstrated no metastatic disease, the patient was treated with 9 cycles of vincristine, carboplatin, and etoposide. Examinations under anesthesia were performed every 3 to 4 weeks. After the fourth cycle of chemotherapy, a new tumor was noted in the left eye and treated with laser hyperthermia. After 7 cycles of chemotherapy, a new tumor was found in the right eye and was treated with laser hyperthermia. Two and 6 months after the ninth cycle of chemotherapy, new tumors in the right eye were treated with cryotherapy. There was no new tumor activity during the next 6 months.

A 7-month-old girl was seen with bilateral retinoblastoma (Reese-Ellsworth stage VB in the right eye and IIIB in the left eye) and, after computed tomography of the brain with and without contrast, bone marrow aspiration, and lumbar puncture demonstrated no metastatic disease, the patient was treated with 10 cycles of carboplatin, etoposide, and cyclosporine. Examinations under anesthesia were performed every 3 to 4 weeks. After 5 cycles of chemotherapy, a new retinoblastoma tumor was noted in each eye (Figure 2) and was treated with laser hyperthermia. No new tumor activity developed during the subsequent 24 months of follow-up.

A 34-month-old girl was seen with Reese-Ellsworth stage II retinoblastoma in the right eye and stage VB retinoblastoma in the left eye. After computed tomography of the brain with and without contrast, bone marrow aspiration, and lumbar puncture demonstrated no metastatic disease, the patient underwent primary enucleation of the left eye and was treated with 9 cycles of vincristine, carboplatin, and etoposide. Examinations under anesthesia were performed every 3 to 4 weeks. After 2 cycles of chemotherapy, a new retinoblastoma tumor was noted in the right eye and treated with cryotherapy. Ongoing follow-up shows no new tumor activity.

It is unclear whether the development of new tumors in patients being treated with chemotherapy results from primary tumor resistance, selection of a resistant tumor cell line, or inadequate chemotherapeutic levels within tumor cells. Small tumors may have little intrinsic vascularity and, therefore, may not receive adequate chemotherapeutic doses. A major concern, of course, is that if chemotherapy for intraocular retinoblastoma facilitates selection of chemoresistant tumor cells, the armamentarium of treatment options for those patients who develop extraocular disease is reduced. Although cyclosporine has been associated with a reversal of chemoresistance in retinoblastoma,^3,5 one of the patients in our series developed a new retinoblastoma tumor while receiving chemotherapy and cyclosporine.

While it is impossible to prove that the new tumors were not preexisting tumors overlooked on prior examinations, all children underwent multiple examinations under anesthesia by multiple investigators before the new tumors were found; the likelihood that these tumors were previously overlooked is small. Another possibility is that the new tumors represent subretinal or vitreous seeding. However, subretinal seeding is typically associated with exudative retinal detachment and vitreous seeding is generally associated with noncohesive tumors. In the patients described in this report, new tumors developed in eyes without vitreous seeding on presentation (in case 3, new tumors were noted in both eyes, while vitreous seeding on presentation was observed in only the right eye). The clinical impression of a number of ophthalmologists experienced in examining retinoblastoma patients was that the lesions noted in this series represent new tumor foci that developed in children who were actively being treated for retinoblastoma with systemic chemotherapy.

This series emphasizes the importance of close follow-up of patients on systemic chemotherapy for the treatment of retinoblastoma, since prompt identification of new tumors permits curative focal treatment. Our small sample size does not permit the identification of clinical factors (eg, younger age at diagnosis) that may predispose a patient who is undergoing chemotherapy for retinoblastoma to new tumor development. In addition, since the duration and regimen of chemotherapy employed in our practice varies little among patients, we cannot analyze the potential prognostic implications of these variables. The National Cancer Institute (Bethesda, Md) has funded an international clinical trial to evaluate systemic chemoreductive therapy in the management of patients with large bilateral retinoblastomas. This clinical trial has the potential to determine the incidence of new tumor development and to investigate clinical factors associated with new tumor development in patients undergoing systemic chemotherapy for retinoblastoma.

This study was supported in part by a Heed Ophthalmic Foundation Fellowship (Dr Scott) and a Ronald G. Michels Fellowship (Dr Scott).

Corresponding author: Timothy G. Murray, MD, Bascom Palmer Eye Institute, 900 NW 17th St, Miami, FL 33136.