Retinoblastoma: Current Concepts in Management

Usha Singh
(Department of Ophthalmology, PGIMER, Chandigarh)

The management of retinoblastoma (RB) has gradually changed over the past few decades. There is a trend away from enucleation and external beam radiation therapy (EBRT) towards more focal conservative treatments. This is primarily because of earlier detection and more focussed treatment modalities.

Most children present with a white pupillary reflex or leukocoria. The differential diagnosis of retinoblastoma is mostly the differential diagnosis of leukocoria. A patient who has been noted to have one of the presenting signs, should have a complete eye examination including an estimate of visual acuity in both eyes and a dilated fundus examination. If the diagnosis of RB is fairly certain, patients should then be promptly scheduled for an examination under anaesthesia. Metastatic disease at the time of retinoblastoma diagnosis is rare. Therefore, routine bone marrow biopsy, lumbar puncture and bone scans are not indicated, except in situations where there is a high suspicion that the tumor has spread beyond the globe. The RB usually contains calcifications, so they show up well on CT scans, but fundus examinations is a much more accurate way to identify their position, size and characteristics. Ultrasonography may be helpful in distinguishing RB from non-neoplastic conditions. A large retinal drawing should be made to show the exact location and size of the tumors. This is helpful to the radiation therapists in planning radiation therapy and to the ophthalmologists in following the effects of treatment. Blood specimens should be obtained from the patient, parents, and any siblings for DNA analysis, which may help in genetic counseling.

Intraocular retinoblastoma : Treatment of RB should be planned after the extent of the tumor within and outside the eye is known. Goal of treatment should be complete control of the tumour and whenever possible, preservation of useful vision.

Enucleation : is indicated when there is no chance of preserving useful vision in an eye. These are patients with total retinal detachment and/or a posterior segment full of tumor and tumors anterior to ora serrata, especially with invasion of anterior segment, which respond poorly to radiation therapy.

Photocoagulation : is occasionally used alone for small tumors (<4mm) which are posteriorly located, distinct from optic nerve head and macula and without involvement of large nutrient vessels or choroidal involvement. In patients with early stages of disease, light coagulation is usually used in addition to radiation therapy or when there islimited recurrence following radiation therapy.

Thermotherapy delivered via infrared radiation is an alternative to laser photocoagulation.

Cryotherapy is used in addition to radiation or in place of photocoagulation for lesions smaller than 4 disc diameters in size in the anterior portion of the retina.

External beam radiation therapy (EBRT) : is recommended for eyes containing mutiple tumors one or more of which is greater than 4-5 disc diameters, for tumors arising in critical regions of the retina near the optic nerve head or macula, regardless of size.

Most authors agree for the choice of optimal dosage, reporting a high incidence of local control and minimal retinal (and visual) late effects when radiation doses of 4000 to 4500 cGy are used with conventional 200-cGy fractions, using a D-shaped ipsilateral temporal field. Classically the anterior border of this typical field has been at or slightly anterior to the bony canthus (correlating roughly to the equator of the eye) and other three field borders have included the bony orbit. Tumor control correlates with approximate doses at varying anatomic portions of the retina (48-89%).

Several new approaches to EBRT for treating retinoblastoma have been developed at selected institutions. The advantage of stereotactic photon treatment lies in close approximation of high dose radiation region to the complex retinal tumor volume combined with markedly decreased transit of normal tissue and a low lens dose.

The most devastating complication after irradiation of a child is induction of second malignant tumour. Such second tumours are seen frequently after irradiation of children with the hereditary form of RB. The cumulative probability of death from a second tumour was 26% after forty years in bilaterally affected children.

Brachytherapy with radioactive plaques is used for either focal unilateral presentations or recurrent disease following previous EBRT. It has 60% success rate. Radioactive plaque is attached within 1mm of sclera. The advantage with this is that only a limited portion of retina is irradiated. Disadvantage include potential for new tumor development and significant irradiation to the lens.

Historically, chemotherapy has played only a minor role in the management of RB. Its use has generally been limited to RB with local invasion into the optic nerve, choroid, orbit or with those tumours with distant metastatic disease. Chemoreduction is a method of reducing tumour volume to allow more focussed, less damaging therapeutic measures. It is evolving into an important component of the initial management of RB. All the institutional protocols have in common the use of cisplatinum and etoposide. Most centers add vincristine and/or one has advocated the use of cyclosporin A as a modulator of P-glycoprotein. Chemotherapy has been combined with diode laser hyperthermic local therapy. All centers reporting to date have demonstrated the short term goal is achievable, especially for tumours that are Reese-Ellsworth group IV or less, reporting responses in nearly 75% of eyes group V tumours, particularly those with vitreous seedling, have proven problematic. The unresolved issue is long term tumour control and the consequences of chemotherapy.

In Unilateral retinoblastoma : Patients usually have massive involvement at presentation and there is often no expectation that useful vision can be preserved, surgery is usually undertaken and radiation therapy is not given to the tumor bed. However, when there is potential for preservation of sight because the tumors are smaller, treatment with other modalities (EBRT, photocoagulation, cryotherapy, thermotherapy, chemoreduction and brachytherapy) instead of surgery should be considered. It is very important that children with unilateral RB receive periodic examination of the unaffected eye. Asynchronous bilateral disease occurs most frequently in families with affected parents.

In Bilateral disease : the management depends on the extent of the disease in each eye. The standard of care in the past has been to enucleate the more involved eye; however, if there is potential for vision in both eyes, bilateral irradiation with closed follow up for response is indicated.

A number of large centers in Europe and North America have begun to explore the utility of systemic chemotherapy for patients whose intraocular tumors are not initially amenable to local management. Examples of such tumors are those that are too large to be treated with either cryotherapy, laser photocoagulation for plaque radiation therapy.

There is no clearly proven effective therapy for the treatment of extraocular RB, although orbital irradiation and chemotherapy have been used. In general palliative therapy with radiation and / or intrathecal chemotherapy with methotrexate, cytarabine, and hydrocortisone, and supportive care has been used. The main goal of therapy for patients with extraocular RB is to improve the poor survival seen in the past. In addition to radiation therapy to the orbit, the following approaches are under evaluation.

i. Systemic chemotherapy. The usual are vincristine, cyclophosphamide and doxorubicin. However, carboplatin, ifosfamide, idarubicin and etoposide have also been used. Use as initial therapy for advanced or recurrent disease in a clinical setting is ongoing.

ii. Intrathecal chemotherapy in patients with central nervous system or meningeal disease.

The prognosis in retinoblastoma is good where promt and adequate medical care is available. The overall survival in RB in the United States and Great Britain is now greater than 85%. Where good medical care is available in the third world, the survival rate is comparable, but it is poor where access to care is limited. The survival with spread into the optic nerve is less good and declines as the growth of RB proceeds farther back in the optic nerve. Similarly, direct spread into the orbital tissues from the globe decreases survival but is still quite comfortable. Even patients with distant metastasis may enjoy long term survival.

Exciting discoveries have occurred in the past decade regarding the molecular genetic basis for this disease. The tumor suppressor RB gene has now been cloned and there exists a potential for prevention and other treatment advances arising from these discoveries. If the potential is realized, elimination of the need for surgical enucleation, radiation treatment, chemotherapy, or all of these would have great benefit for the affected child. The most difficult problem posed by radiogenic tumors will probably be solved only by molecular genetics approaches.

Until these prospects become reality, a number of problems continue to exist for which modifications of current treatment approaches may be useful.

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