Ординатура / Офтальмология / Английские материалы / Ocular Oncology_Albert, Polans_2003

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354 Abramson and Schefler

Table 1 Five-Year Survival Rates from Recent Retinoblastoma Series in the Developing World

aThree-year survival rate reported only.

B.Goals of Treatment

The primary goal of retinoblastoma treatment is to ensure the survival of these children. Secondary but also important goals include retention of the eye(s) and of vision. A final goal is the avoidance of facial bony deformities or other physical changes that can affect functional well-being [3].

C.Unique Challenges in the Treatment of Retinoblastoma

Since 1949, clinicians involved in the treatment of retinoblastoma patients have recognized that second nonocular cancers can develop years after successful treatment of the primary disease [14]. It is important that young patients, as well as their parents be counseled regarding their risk for additional malignancies and the need for appropriate screening. The relationship between treatment type, genetics, and the risk for additional nonocular tumors is complex and was elucidated primarily at our center, where we have followed a large cohort of patients since 1916. This extensive follow-up period has enabled us to assess specific risk factors associated with the development of second cancers, as discussed in Sec. III.

D.Diagnostic Considerations

1.Extent of Disease Workup

Patients suspected to have retinoblastoma should undergo indirect ophthalmoscopy and fundus photography as well as ophthalmic ultrasonography. Ultrasonography can be useful for this disease, as it demonstrates masses with high reflectivity that block sound, causing characteristic shadowing behind the tumor [6]. False-positive results on ultrasound are not uncommon, however. Needle biopsies are rarely if ever indicated in retinoblastoma, as puncturing of the eye can lead to tumor seeding and orbital invasion [6].

Computed tomography (CT) scans may no longer be appropriate for retinoblastoma patients, as a recent analysis has demonstrated an increased lifetime

risk of other cancers in pediatric patients subjected to this imaging modality [15]. Instead, as part of an extent of disease workup, magnetic resonance imaging (MRI) is routinely performed. In addition to its excellent resolution in the diagnosis of extraocular soft tissue disease, MRI can readily distinguish between retinoblastoma and Coats disease, as due to proteinaceous exudate, Coats disease appears brighter than retinoblastoma on T2-weighted images [6]. One disadvantage of MRI is that calcification, a key feature of retinoblastoma, is more easily demonstrated with CT than MRI.

2.An Approach to the Treatment and Examination Schedule

In our center, 28 months is the oldest age at which a patient with a positive family history of retinoblastoma has developed his or her first tumor in a previously documented disease-free eye [16]. As a result, we have developed a predesigned examination schedule for newborns with a positive family history of retinoblastoma, in whom screening is initiated at birth. Infants are examined in the newborn nursery within 24–48 hr of birth and again at 3, 6, and 10 weeks of age. All of these initial examinations are performed without anesthesia. Serial examinations are typically performed at 16, 24, 34, 44, and 54 weeks of age under general anesthesia. Following the 54-week examination, patients are examined every 12 weeks until they are at least 28 months of age.

For all patients who are referred to our center with suspected retinoblastoma other than those described above, no predesigned examination schedule has been developed. The reason for this practice is that the rate of formation of new retinoblastoma foci, the rate of recurrence of previously treated tumors, and the rate of formation of tumors in the fellow eye vary widely from patient to patient. The examination and treatment schedule is highly individualized and catered toward the patient’s specific risk factors.

Treatment approaches for retinoblastoma are based on whether the patient presents with extraocular or intraocular disease. The treatment of extraocular disease is reviewed in Chap. 23. A discussion of the treatment of intraocular disease follows.

II.TREATMENT OF INTRAOCULAR DISEASE

A.Enucleation

1.History

The first surgical removal of an eye was an unsuccessful attempt performed by Hayes in 1767 [17]. James Wardrop was the first to propose early enucleation in a publication. He published 35 cases in 1809, after which time the clinical application of enucleation became widespread [2]. Currently, enucleation is the most commonly employed technique for treating retinoblastoma.

2.Indications

The patients considered for enucleation are those with unilateral or bilateral ReeseEllsworth Group V eyes, patients with active tumor in a blind eye, and patients who develop glaucoma from tumor invasion. Patients are also considered for enucleation if they have failed all other forms of treatment or if they active tumor and cannot be followed [3].

3.Technique

In children, enucleation is performed under general anesthesia, though the patients do not require overnight hospitalization. A dilated fundoscopic exam is performed on both eyes prior to surgery. Critical elements of the surgery include avoiding any perforation of the globe and obtaining a long stump of optic nerve. To avoid perforation of the globe, the Brown-Addison forceps are preferred for aiding in traction. In the past, a suture was passed through the stump of the medial rectus muscle, resulting in several cases of inadvertent needle penetration into the eye and rupture of the globe [18]. To obtain a long stump of optic nerve, a gently curved enucleation scissors is used with a nasal approach and the nerve is cut in one motion. A silicone or plastic ball is inserted in place of the eye, and 3 weeks later a thin prosthesis similar to a contact lens is molded and painted by an ocularist to match the fellow eye.

4.Results

Greater than 99% of patients with unilateral retinoblastoma without microscopic or macroscopic extraocular disease are cured by enucleation [19]. The balls rarely need to be replaced, and the prosthesis is removed once a month to once a year for cleaning.

5.Complications

The main complications of enucleation are hemorrhage and infection. Hemorrhage is best controlled during surgery with direct digital pressure and, if necessary, thrombin-soaked patties, FloSeal, or Avitene (bovine collagen). Postoperative ecchymosis usually subsides with use of a pressure patch and ice compresses. Infection is rare in patients who are not receiving chemotherapy. Those patients who develop recurrent infections of the socket are managed effectively with topical antibiotic therapy. Giant papillary conjunctivitis (GPC) may develop years after successful prosthesis fitting and is treated with topical mast-cell stabilizers.

B.External-Beam Radiation

1.History

External-beam radiation therapy (EBR) has been successfully employed for retinoblastoma since Hilgartner experimented with x-ray treatments in Austin, Texas, in 1903 [20]. Early experience demonstrated the efficacy of tumor regression with radiation therapy. However, significant complications were frequently observed due to the techniques employed [14,21]. Complications included keratitis sicca,

keratinization of conjunctiva and sclera, lacrimal gland atrophy/fibrosis, loss of lashes, corneal ulcers/perforation, hyphema, rubeosis iridis, glaucoma, iritis/uveitis, cataract, vitreous hemorrhage, retinal vascular damage, optic nerve infarction, fat atrophy in the orbit, and arrest of orbital growth [3]. Currently most of these complications have been eliminated or minimized by reducing the total radiation dose, by changing the source of radiation and positioning of the portals, and by utilizing fractionated doses.

2.Indications

EBR is one means of preserving vision in a child with retinoblastoma [18]. Unlike focal therapies—including photocoagulation, cryotherapy, and episcleral plaque therapy—fractionated external-beam radiation provides an excellent opportunity for useful vision in a macula undestroyed by tumor. EBR is considered as a primary treatment option in children with small tumors located within the macula, since treatment options other than systemic chemotherapy often destroy central vision. EBR is also considered for multifocal tumors for which focal therapy is ineffective. In cases of bilateral advanced intraocular disease in which clinical judgment cannot predict which eye is more likely to have useful vision, EBR can be used bilaterally. In these cases, one or both eyes may eventually require salvage enucleation. EBR is often the salvage treatment of choice after focal therapies have failed. Finally, for children with advanced extraocular or metastatic disease, radiation therapy also plays a role in palliation and even potential cure of these sites along with chemotherapy [18].

3.Technique

Radiation therapy for retinoblastoma in the unenucleated eye is designed to encompass the entire tumor-bearing portion of the globe and at least 1 cm of optic nerve. The fields are designed so that the radiosensitive lens receives a significantly lower dose than the tumor. For children with bilateral disease, parallel opposing lateral D-shaped fields are used to avoid subsequent radiation-induced cataracts, which are more common when anterior fields are used [22]. Fields are designed using a CT simulator or plain films taken in the conventional radiation therapy simulator unit. Information about globe size and lens position is derived from a head CT or MRI study. For children with bilateral disease who have had one eye enucleated, a similar field arrangement is employed that involves a single field or bilateral fields, with the empty orbit receiving some exit dose of radiation. For patients with unilateral disease, a pair of superior and anterior wedged oblique ‘‘D’’ fields are used, with more radiation supplied to the superior oblique field to avoid a significant exit dose to the frontal lobe [23].

The dose prescribed to the retinal target volume ranges from 4200 to 4600 cGy. Children under the age of 6 months typically receive lower doses, while children with advanced bilateral disease receive higher doses [6,18]. The dose is administered in 180 to 200 cGy daily fractions five times per week.

4.Results

Survival of children who undergo external beam radiation in the United States is 85– 100%, mirroring the excellent survival rates of children with this disease in general [18]. Local control in the radiated eye, defined as preservation of the eye, varies in different series from 58 to 88% [18,24–29]. In our series, preservation of the eye is 95% for Reese-Ellsworth stage I to III eyes that are treated with the lateral beam technique. Radiation therapy has only a 50% local control rate in Reese-Ellsworth stages IV and V [18]. Location of the tumor determines the likelihood that it will respond to EBR: tumors in the posterior pole tend to have the best results with this treatment.

Five regression patterns have been described following EBR for retinoblastoma [30]. Larger tumors are more likely to form a type I pattern. In this pattern, the tumor shrinks in size, loses vascularity, and forms an irregular, glistening white mass. This mass consists of DNA-calcium complexes that continue to change in shape and shrink over time [3,18]. Tumors as large as 15 disc diameters (dd) have been found to undergo this type of regression, although the median size of tumors that form a type I pattern is 5 dd. In the type II pattern, a gray, translucent color develops and there is less shrinkage and no calcification. These tumors may occasionally reactivate. The type III pattern is a combination of types I and II and is the type observed most frequently. The center of the tumor becomes calcified and is surrounded by a variable amount of amorphous translucent gray remnants. The type IV pattern is most often observed after the use of plaque radiotherapy and manifests itself as destruction of the overlying retina with a white appearance signifying visible sclera. In recent years, a fifth regression pattern has been observed, labeled type 0. This pattern describes a situation in which the posttreatment examination reveals no evidence of the previously existing retinoblastoma. It is uncommon except in the smallest tumors.

The pretreatment size of the tumor is the most important predictor of the regression pattern. In one study, the median size of 58 tumors that disappeared after radiation was 1 dd, and 95% of those that disappeared were 3 dd or less. The median size of 26 tumors that formed a type I regression pattern was 5 dd; 23% of these were 3 dd or less [31].

5.Complications

All patients experience skin erythema within the area of the radiation portal, but the skin rarely becomes infected. For patients with lesions between the equator and the ora serrata, the anterior edge of the field is brought forward to include the lens, increasing the risk for a cataract [18].

Another potential side effect of EBR is damage to the vascular endothelium. Injury ranges from optic nerve damage to total retinal vascular occlusion and vitreous hemorrhage. At the doses currently employed, the incidence of vascular complications is approximately 5% [3].

Facial and temporal bone hypoplasia can occur following EBR in very young children. This deformity is most marked when both eyes are treated with parallel opposing fields and when children are treated under the age of 6 months [32]. With the use of the three field–modified lateral beam technique described above,