In this issue

Director's Corner by Dr. David Poplack

The Genetics of Retinoblastoma by Dr. Sharon Plon

T Cell Therapies for Lymphoma by Dr. Catherine Bollard

Shedding Light on Retinoblastoma by Dr. Murali Chintagumpala

New Advances in Treating Pulmonary Langerhan's Cell Histiocytosis by Dr. Kenneth McClain

	Dr. Murali Chintagumpala

Shedding Light on Retinoblastoma
By Murali Chintagumpala, M.D.

Affecting approximately 1 in 18,000 children under age 5, retinoblastoma is the most common malignant ocular tumor in childhood. In some Central and South American countries, retinoblastoma is among the most common solid tumor malignancies in children. Retinoblastoma can affect one eye, and in 20 percent to 30 percent of affected children, it affects both eyes.

The cause of retinoblastoma is the inactivation of the retinoblastoma protein that controls the growth of cells in our body including retinal cells. Children with unilateral disease develop a mutation in one of the normal retinoblastoma genes in a retinal cell. Children with bilateral disease and approximately 15 percent of patients with unilateral disease have the hereditary form of retinoblastoma with an inactivated retinoblastoma gene in all the cells in the body. Some of the cells that contain this first mutation undergo loss of the normal second gene in a retinal cell or cells, which gives rise to retinoblastoma. The chance of a child with the hereditary form of the disease where every cell in the body already has a mutation in one retinoblastoma gene losing the second retinoblastoma gene and developing more than one tumor is relatively high. Therefore, most children with the hereditary form of the disease develop tumors in both eyes. Children with the non-hereditary form of the disease only develop a single tumor in one eye.

As long as the disease has not spread beyond the eye, cure can be achieved in more than 90 percent of children by removing the eye surgically (enculeation). This is the usual treatment for children with unilateral disease because they often present with advanced disease with no hope for vision salvage. The removed eye is carefully examined under a microscope and if there is evidence of significant tumor involvement in the deeper layers of the eye (choroid) or if the disease has spread along the optic nerve beyond the lamina cribrosa, chemotherapy usually is recommended to prevent further dissemination of the disease. Patients with disseminated disease have a very poor outcome. However, if the choroid alone is involved, some medical experts feel that further therapy is not indicated.

To shed further light on this issue, the Children’s Oncology Group (COG) is initiating a clinical trial to evaluate the histopathologic risk factors after enculeation in patients with unilateral disease and the role of adjuvant therapy in children who have certain risk factors which may put them at high risk for spread of the disease. The risk factors that will be evaluated include invasion of the choroid and involvement of the optic nerve beyond the lamina cribrosa. A minority of children with unilateral disease present with smaller lesions. These usually are managed with chemotherapy and local therapies, including cryotherapy and laser therapy.

In children with bilateral disease, the initial therapy usually is the use of chemotherapeutic agents to shrink the tumors in both eyes and salvage as much vision as possible. Eventually the most affected eye with very poor vision is enucleated. Often external beam radiotherapy is used to control the disease after initial chemotherapy. Infrequently both eyes have to be removed to cure a child with bilateral retinoblastoma when the tumors cannot be controlled.

The general goal in the treatment of children with bilateral disease or hereditary retinoblastoma is to avoid or at least delay radiotherapy until the child is over 1 year old. Most children with the hereditary form of the disease have an increased incidence of second malignancies later in life, including osteogenic sarcomas of the skull and long bones, soft tissue sarcomas and pineoblastomas.

One of the most difficult challenges of treating retinoblastoma is the presence of vitreous seeds, which are foci of tumor of varying sizes and usually arise from a large tumor already present within the eye. These foci grow in the vitreous without a blood supply and are relatively inaccessible to the reach of chemotherapy agents. An eye with vitreous seeds in children with unilateral disease usually will be enucleated. However, in children with bilateral disease, higher doses of chemotherapy in conjunction with subtenon carboplatin are administered in an effort to preserve the eye with vitreous seeds. These efforts are not always successful with subsequent recurrence of vitreous seeds. External beam radiotherapy in these children may control the growth of vitreous seeds but is not always satisfactory, especially with increased risk of second non-ocular tumors in children with bilateral disease.

The impact of innovative treatment
A recent innovative trial at Texas Children’s Cancer Center used “suicide” gene therapy to address the issue of vitreous seeds. The trial consists of incorporating the herpes simplex thymidine kinase gene into an adenoviral vector (AdV-TK) that has been engineered so it cannot replicate. The adenoviral vector carrying the herpes simplex thymidine kinase gene (AdV-TK) is injected intraocularly adjacent to the area with viteous seeds. This injection is followed 24 hours later by intravenous ganciclovir given twice a day for seven days. Treatment is repeated one to four times depending on the response. In eight patients who initially had bilateral disease complicated by vitreous seeds and had exhausted all conventional therapies to save both eyes, this approach was used. All patients had a clinical or histopathologic complete response to therapy.

Inflammatory response to disintegrating tumor or the adenoviral vector injections resulted in a decrease in visual acuity in patients who had received higher concentrations of the adenoviral vector. Most of these patients eventually had improved visual acuity. It may be a promising approach to treat patients with vitreous seeds soon after diagnosis. Further studies are under way to better delineate the role of this therapy in patients with retinoblastoma.

About the author
Murali M. Chintagumpala, M.D., is the clinical director of Texas Children’s Cancer Center’s Brain Tumor Program and associate professor of pediatrics at Baylor College of Medicine. Within the Children’s Oncology Group, Dr. Chintagumpala is a member of the Brain Tumor Committee and study chairman for a new protocol for children with low-grade gliomas. He is the chairman of a study in COG to better delineate the risk factors for the development of metastases in children with retinoblastomas and the principal investigator for a multi-institutional study for the treatment of medulloblastomas at Texas Children’s Cancer Center.

References
Uusitalo, M. S. et al. "Evaluation of chemoprophylaxis in patients with unilateral retinoblastoma with high-risk features on histopathologic examination." Arch Ophthalmol 119.1 (2001): 41-48.

Honavar, S. G. et al. "Postenucleation adjuvant therapy in high-risk retinoblastoma." Arch Ophthalmol 120.7 (2002): 923-3.

Chevez-Barrios, P. et al. "Response of retinoblastoma with vitreous tumor seeding to adenovirus-mediated delivery of thymidine kinase followed by ganciclovir." J Clin Oncol. 23.31 (2005): 7927-35.

Shields, C. L. et al. "Practical approach to management of retinoblastoma." Arch.Ophthalmol. 122.5 (2004): 729-35.

Murphree AL. "Intraocular Retinoblastoma: the Case for a New Group Classification." Ophthalmol Clin N Am.18 (2005): 41-53.

Chantada, G. Doz F. and et al. A Proposal for an International Retinoblastoma Staging System. Pediatric Blood Cancer (2006 - in press).