Journal of Pediatric Ophthalmology and Strabismus

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Review 

Recent Developments in the Management of Retinoblastoma

Carol L Shields, MD; Jerry A Shields, MD

Abstract

ABSTRACT

The management of retinoblastoma has gradually changed over the past few decades. There is a trend away from enucleation and external beam radiotherapy toward focal conservative treatments. This is primarily because of earlier detection of the disease and more focused treatment modalities. Enucleation is still employed for retinoblastoma that fills most of the eye, especially when there is a concern for tumor invasion into the optic nerve or choroid. After enucleation, an integrated orbital implant, provides improved motility and appearance of the prosthesis.

External beam radiotherapy continues to be an important method of treating less advanced retinoblastoma, especially when there is diffuse vitreous or subretinal seeding. Plaque radiotherapy is useful for controlling small- to medium-sized retinoblastomas, even those with focal vitreous seeds.

Tumors that recur after failure of other methods are often suitable for plaque treatment. When plaque radiotherapy is employed in a child receiving chemotherapy, eventual radiation retinopathy can occur.

Cryotherapy and photocoagulation provide excellent control of selected small tumors. Advanced laser delivery systems, particularly those that have been adapted to the indirect ophthalmoscope, have facilitated the visualization for treatment of tumors. Thermotherapy is the newest focal method for retinoblastoma. When combined with chemotherapy, thermotherapy provides satisfactory tumor control, leaving the child with a reasonably small scar, thus preserving more vision. Chemoreduction, using intravenous or subconjunctival routes, is often employed to reduce initial tumor volume and thus allow for focal treatment to eradicate the residual smaller tumor.

Many children with advanced retinoblastoma can be spared external beam radiotherapy and enucleation mostly as a result of chemoreduction and focal methods. Chemoreduction combined with cryotherapy, thermotherapy, and plaque radiotherapy plays an important role in the current management of many children with retinoblastoma.

Abstract

ABSTRACT

The management of retinoblastoma has gradually changed over the past few decades. There is a trend away from enucleation and external beam radiotherapy toward focal conservative treatments. This is primarily because of earlier detection of the disease and more focused treatment modalities. Enucleation is still employed for retinoblastoma that fills most of the eye, especially when there is a concern for tumor invasion into the optic nerve or choroid. After enucleation, an integrated orbital implant, provides improved motility and appearance of the prosthesis.

External beam radiotherapy continues to be an important method of treating less advanced retinoblastoma, especially when there is diffuse vitreous or subretinal seeding. Plaque radiotherapy is useful for controlling small- to medium-sized retinoblastomas, even those with focal vitreous seeds.

Tumors that recur after failure of other methods are often suitable for plaque treatment. When plaque radiotherapy is employed in a child receiving chemotherapy, eventual radiation retinopathy can occur.

Cryotherapy and photocoagulation provide excellent control of selected small tumors. Advanced laser delivery systems, particularly those that have been adapted to the indirect ophthalmoscope, have facilitated the visualization for treatment of tumors. Thermotherapy is the newest focal method for retinoblastoma. When combined with chemotherapy, thermotherapy provides satisfactory tumor control, leaving the child with a reasonably small scar, thus preserving more vision. Chemoreduction, using intravenous or subconjunctival routes, is often employed to reduce initial tumor volume and thus allow for focal treatment to eradicate the residual smaller tumor.

Many children with advanced retinoblastoma can be spared external beam radiotherapy and enucleation mostly as a result of chemoreduction and focal methods. Chemoreduction combined with cryotherapy, thermotherapy, and plaque radiotherapy plays an important role in the current management of many children with retinoblastoma.

INTRODUCTION

Retinoblastoma is the most common malignant intraocular tumor in childhood. The clinical features of this disease are well recognized: leukocoria and strabismus represent the two most common external findings and solitary or multiple yellow-white retinal tumors as the classic fundus finding.1 It can present in unilateral or bilateral forms with sporadic or familial hereditary patterns. Several classifications of retinoblastoma have been developed to assist in prediction of globe salvage (Tables 1, 2). Despite the classic appearance of retinoblastoma, nearly 50% of patients initially diagnosed with retinoblastoma prove, on referral to ocular oncologists, to have a simulating condition.2 The most common pseudoretinoblastomas include persistent hyperplastic primary vitreous, Coats' disease, and ocular toxocariasis.2 It is important that the clinician be familiar with these simulating conditions when managing children with possible retinoblastoma.

Table

TABLE 1Reese-Ellsworth Classification for Conservative Treatment of Retinoblastoma

TABLE 1

Reese-Ellsworth Classification for Conservative Treatment of Retinoblastoma

The prognosis for life and vision in patients with retinoblastoma has vastly improved over the past century, primarily because of earlier detection of the disease as well as improved treatment methods.1·3'5 One hundred years ago, retinoblastoma was nearly always fatal. Gradually, the prognosis improved and approximately 30% of affected patients survived in the 1930s, 80% in the 1960s, and nearly 95% in the 1990s.1,3-4

The management of retinoblastoma is complex. The goals of treatment are, most importantly, to save the child's life and, secondly, to salvage the eye or vision if possible. Therapy is tailored to each individual case and is based on the overall situation, including threat of metastatic disease, risks for second cancers, systemic status, laterality of the disease, size and location of the tumor(s), and visual prognosis. There are several options for treatment of retinoblastoma and the ocular oncologist should be thoroughly familiar with the indications, technique, and expected results of all treatment methods, as well as the expected systemic and visual problems.6 Available treatment methods for retinoblastoma include enucleation, external beam radiotherapy, plaque radiotherapy, laser photocoagulation, cryotherapy, thermotherapy, chemothermotherapy, intravenous chemoreduction, subconjunctival chemoreduction, systemic chemotherapy for possible metastatic disease, and orbital exenteration.

Table

TABLE 2The Essen Classification for Conservative Sight-saving Treatment of Retinoblastoma

TABLE 2

The Essen Classification for Conservative Sight-saving Treatment of Retinoblastoma

ENUCLEATION

Enucleation is a common method for managing retinoblastoma. If advanced disease with no hope for useful vision in the affected eye is present, or if invasion of the tumor into the optic nerve, choroid, or orbit is possible, enucleation is appropriate. Those eyes with secondary glaucoma, pars plana seeding, or anterior chamber invasion are also generally best managed with enucleation.

In the past, most children with unilateral retinoblastoma were managed with enucleation and those with bilateral retinoblastoma usually had the most advanced eye treated with enucleation and the lesa advanced eye treated with external beam radiotherapy.1 This management philosophy has been gradually modified with the availability of newer, more conservative methods.3,5,7

Fig 1: Enucleation and fresh tissue harvesting. A: A long section of optic nerve is obtained with the globe after enucleation of an eye with retinoblastoma. The posterior aspect of the optic nerve is cut and submitted to pathology separately for analysis of optic nerve invasion. B: A trephine is used to cut an opening in the sclera to alfaw access for retinoblastoma tissue harvest. C: Harvested fresh retinoblastoma is submitted in a cassette immediately for DNA analysis. The surgeon must replace his or her surgical gloves after fresh tissue harvesting to avoid contamination of the patient's orbit.

Fig 1: Enucleation and fresh tissue harvesting. A: A long section of optic nerve is obtained with the globe after enucleation of an eye with retinoblastoma. The posterior aspect of the optic nerve is cut and submitted to pathology separately for analysis of optic nerve invasion. B: A trephine is used to cut an opening in the sclera to alfaw access for retinoblastoma tissue harvest. C: Harvested fresh retinoblastoma is submitted in a cassette immediately for DNA analysis. The surgeon must replace his or her surgical gloves after fresh tissue harvesting to avoid contamination of the patient's orbit.

Over recent decades, a substantial decrease in the frequency of enucleation has occurred.8 In a review of 324 consecutive cases of retinoblastoma managed on the Oncology Service at Wills Eye Hospital from 1974 to 1988, Shields and colleagues found that unilateral retinoblastoma was managed with enucleation in 96% cases from 1974 to 1978, in 86% cases from 1979 to 1983, and in 75% cases from 1984 to 1988.8 A similar decreasing trend was found with bilateral retinoblastoma.8 The necessity for enucleation is even less today with the advent of new modalities.

The technique of enucleation is to gently remove the eye intact without seeding the malignancy into the orbit. Special care is given to perform all steps in a controlled fashion, to avoid globe perforation or compression. Our technique has been described1,9,10 and is slightly different than that performed by most ophthalmic surgeons. We handle the rectus muscles delicately when hooking them, as the underlying sclera is thin at the site of muscle insertions. The hook is placed flat along the sclera without vigorous movement to avoid scleral perforation. At the time of optic nerve cutting, we avoid scleral or muscle insertion traction sutures as inadvertent globe perforation can occur. Mild traction with a hemostat on the medial rectus muscle stump is used to lift the globe. This step should be performed with caution as inadvertent lamellar rips of the sclera and cornea can occur and threaten the integrity of the eye. We avoid optic nerve snares or clamps as they induce more vigorous trauma to the eye and can produce crush artifact in the optic nerve, which can cause difficulty for the pathologist when interpreting retinoblastoma invasion in the optic nerve. We prefer to employ minimally curved enucleation scissors to achieve a long optic nerve section.

After the globe is removed, it is placed on a separate tray and fresh tissue is harvested in the operating room for DNA analysis, using a specific technique10 (Fig 1). The surgeon must change sterile gloves after this step to avoid the risk of tumor contamination into the child's orbit.

Years ago, an orbital implant was usually not placed after enucleation for retinoblastoma because it interfered with palpation of the socket and clinical detection of orbital tumor recurrence. But with improved knowledge of the behavior of retinoblastoma and its risks for local orbital recurrence, surgeons will place an orbital implant more readily. In addition, available orbital imaging modalities of computed tomography and magnetic resonance imaging (MRI) allow detailed orbital analysis despite the presence of an implant.

The orbital implant provides a more natural cosmetic appearance of the patient's artificial eye, minimizing sinking of the prosthesis and enabling motility to the prosthesis. There are several available orbital implants, including polymethylmethacrylate sphere, coralline hydroxyapatite, bovine hydroxyapatite, or polyethylene.9,11 We usually provide a tissue wrap to these implants so that the four rectus muscles can be anatomically reattached to the implant and provide implant motility with little resistance in the orbit. Available tissue wraps are many, including banked, povidone iodine-treated human sclera, irradiated human sclera, bovine pericardium, fascia lata, and vicryl mesh. The motility implant, when properly placed surgically, appears to be a well-tolerated motility implant for children and adults.9,10,12

Table

TABLE 3Comparison of Globe Salvage Rate Using External Beam Radiotherapy (EBRT) Alone, EBRT and Salvage Treatment, and Chemoreduction and Focal Adjuvant Treatment

TABLE 3

Comparison of Globe Salvage Rate Using External Beam Radiotherapy (EBRT) Alone, EBRT and Salvage Treatment, and Chemoreduction and Focal Adjuvant Treatment

EXTERNAL BEAM RADIOTHERAPY

Retinoblastoma is generally a rathosensitive tumor. External beam radiotherapy is a method of delivering whole eye irradiation to treat advanced retinoblastoma, particularly with diffuse vitreous seeding. Various treatment plans have been employed and the whole-eye and lens-sparing technique were recently reviewed by a group at St. Bartholomew's Hospital in London.13,14 They found that the eye preservation rate had improved markedly from reported older series and the rate of ocular salvage depended on the stage of the disease (Reese-Ellsworth stage) (Tables 1, 3) at the time of treatment as well as the availability of focal therapy for limited recurrence.1314 Recurrence of retinoblastoma after external beam radiotherapy continues to be a problem, and can develop within the first 1 to 4 years after treatment.15 Tumor recurrence in other series has also been related to the stage of the disease and largest tumor size at the time of treatment.15"18 Prophylactic radiotherapy to a normal fellow eye is almost never indicated today.19

Little has been written on the visual outcome after external beam radiotherapy for retinoblastoma. Radiation damage to the retina, optic nerve, and lens can be challenging to manage.20 In patients with macular retinoblastoma, the visual outcome appears to be dependent on the size of the tumor and the degree of involvement of the fovea.21 Superimposed amblyopia can pose a problem and patching therapy should be employed when hope for vision remains.

Of course, external beam radiotherapy may induce a second cancer in the field of irradiation. The 30-year, cumulative incidence for a second cancer in bilateral retinoblastoma has been reported at 35% for patients who received radiation therapy compared with 6% for those who did not.22 Overall, the cumulative probability of death from second primary neoplasms was reported at 26% at 40 years after bilateral retinoblastoma diagnosis; further, external beam radiotherapy may further increase the risk of mortality from second neoplasms.23 Abramson and Frank found that external beam radiotherapy increased the incidence of second cancers in the field of radiation, but did not stimulate second cancers outside the field of irradiation.24 Importantly, the risk for radiation-induced cancers was strongly dependent on patient age at the time of irradiation and patients younger than 12 months had a much poorer prognosis than patients older than 12 months.24

PLAQUE RADIOTHERAPY

Plaque radiotherapy is a method of brachytherapy in which a radioactive implant is placed on the sclera over the base of a retinoblastoma to irradiate the tumor transclerally. Generally, it is limited to tumors less than 16 mm in base and 8 mm in thickness. It requires an average of 2 to 4 days of treatment time to deliver the total dose of 4000 cGy to the apex of the tumor.

Plaque radiotherapy can be used as a primary treatment or as a secondary treatment.25,28 (Fig 2) In fact, in 70% of cases, plaque radiotherapy is used as a secondary treatment to salvage a globe after prior failed treatment, usually external beam radiotherapy or chemotherapy.25,28 in one series, solitary plaque radiotherapy was used in 91 cases of recurrent or residual retinoblastoma, in which the only other option was enucleation.28 Tumor control and globe salvage was achieved in nearly 90% of these eyes, many of which were destined for enucleation.28

Overall, one application of plaque radiotherapy provides an almost 90% tumor-control rate.29 Carefully selected retinoblastomas, even juxtapapillary and macular tumors, can be successfully treated with plaque radiotherapy. The visual outcome varies with tumor size and location as well as radiation problems of retinopathy and papillopathy. The visual outcome has been reported to be good in 62% and the measured vision was 20/20 to 20/30 in more than half the cases.25 Radiation retinopathy and papillopathy become clinically manifest at approximately 18 months after irradiation and these complications are more prominent in children who have been exposed to systemic chemotherapy. In an effort to avoid these problems with chemotherapy-treated eyes, we have decreased the tumor apex dose to 3500 cGy and attempted to wait at least 1 month after the child has discontinued chemotherapy before applying the irradiation. Innovations with custom design of plaques, especially those for small tumor recurrence have also assisted in avoiding radiation retinopathy. Plaque radiotherapy has not yet been associated with induction of second cancers, likely as a result of its focal, shielded radiation field.

LASER PHOTOCOAGULATION

Laser photocoagulation is a method of treating small posterior retinoblastomas with argon laser, diode laser, or xenon arc photocoagulation. The tumor size is important to the success of the treatment and this method is usually limited to tumors 4.5 mm or less in base and 2.5 mm or less in thickness with no evidence of vitreous seeds.30"31 The treatment is directed to delimit the tumor and specifically coagulate all blood supply to the tumor (Fig 3). Two or three sessions at 1-month intervals are usually adequate to control most tumors. Use of the indirect ophthalmoscope laser photocoagulation system has greatly improved the facility of laser delivery.32 Laser treatment of properly selected cases of retinoblastoma offers a 70% tumor-control rate and a 30% recurrence rate. Recurrence often is treated with plaque radiotherapy. Complications of treatment include transient serous retinal detachment, visually significant retinal vascular occlusion, retinal traction, retinal hole, and preretinal fibrosis.

CRYOTHERAPY

Cryotherapy is a useful method for managing equatorial and peripheral small retinoblastomas. It is most successful if limited to tumors measuring 3.5 mm or less in diameter and 2.0 mm or less in thickness, with no evidence of vitreous seeds.33 Tumor destruction is usually achieved with One or two sessions of triple freeze thaw cryotherapy delivered at 1-month intervals.

Significantly, cryotherapy will usually fail if there is overlying vitreous seeds. In these failed cases, plaque radiotherapy is usually employed. Complications of cryotherapy include transient serous retinal detachment. retinal tear, localized preretinal fibrosis, and rhegmatogenous retinal detachment.34

THERMOTHERAPY AND CHEMOTHERMOTHERAPY

Thermotherapy is a method of delivering heat to the eye using ultrasound, microwaves, or infrared radiation. The heat can be delivered to the whole eye with an attempt to spare the anterior segment35 or the heat can be focused on one portion of the eye. The goal is to deliver a temperature of 42°C to 600C, a temperature that is below the coagulative threshold, therefore, sparing the retinal vessels of photocoagulation. The combination of chemotherapy and heat is termed chemothermotherapy; the combination of heat and radiation is termed thermoradiotherapy. Heat has a synergistic effect with both chemotherapy and radiation therapy for the treatment of systemic and ocular cancers.36

The selection of the modality of thermotherapy or chemothermotherapy depends on many factors, including tumor size, location, laterality, status of the opposite eye, presence of subretinal fluid and seeds, presence of vitreous seeds, and prior or ongoing chemoreduction. For example, if a patient has small retinoblastomas outside the retinal vascular arcades measuring 3 mm or less in size without vitreous or subretinal seeds, then thermotherapy alone without chemotherapy may be appropriate. However, the addition of other factors, such as larger tumors or seeds often necessitates chemotherapy combined with thermotherapy for best tumor control.

When employing thermotherapy alone, the goal is to heat the tumor to 45°C to 600C, leaving a gray-white scar at the site. In general, small tumors require approximately 300 mW power for 10 minutes or less, each delivered over three sessions at 1-month intervals (Fig 4). Tractional and vaso-occlusive complications can occur within the retina as a result of the prolonged heating. When employing chemothermotherapy, the goal is to heat the tumor to 42°C to 45°C for 5 to 20 minutes, depending on the tumor size and location. Tumors up to 15 mm in base can be adequately treated with chemothermotherapy, especially if the patient is receiving three agent chemoreduction. The result from chemothermotherapy is a light gray scar with less risk for tractional and retinal vascular problems found with thermotherapy alone.36

There are several different chemothermotherapy protocols, varying in chemotherapeutic agents and methods of delivery. Kaneko and colleagues reported preliminary results in the Japanese literature using systemic and superselective ophthalmic artery injection of chemotherapy combined with thermotherapy.37 Murphree and Munier later employed a specific protocol of intravenous carboplatin tightly coupled with thermotherapy.38 Shields and associates later reported a different technique that was more practical for those children simultaneously on a chemoreduction protocol for large or multiple tumors36,39-40 (Figs 5, 6, 7). They coupled thermotherapy within 4 hours of a chemoreduction regimen, thereby achieving the benefit of chemotherapy for both tumor reduction and consolidation.36,39-41

Fig 2: laque radiotherapy. A: Macular retinoblastoma in month-old boy before plaque radiotherapy.

Fig 2: laque radiotherapy. A: Macular retinoblastoma in month-old boy before plaque radiotherapy.

B: Regressed retinoblastoma after plaque radiotherapy with moderate preservation of the fovea.

B: Regressed retinoblastoma after plaque radiotherapy with moderate preservation of the fovea.

Fig 3: Laser photocoagulation. A· Small posterior retinoblastoma with dilated feeder vessels undergoing treatment with laser photocoagulation.

Fig 3: Laser photocoagulation. A· Small posterior retinoblastoma with dilated feeder vessels undergoing treatment with laser photocoagulation.

B: After three sessions of laser photocoagulation, the tumor has regressed to a flat scar.

B: After three sessions of laser photocoagulation, the tumor has regressed to a flat scar.

In our practice, if a child is receiving chemoreduction, we generally initiate the thermotherapy for tumor consolidation at cycle 2 or 3 of the chemoreduction protocol and repeat thermotherapy as necessary at each of the remaining chemoreduction cycles until the six cycles are completed. Using this method for 188 retinoblastomas, we have achieved complete tumor control in 86% of the tumors.36 However, it is important to be selective in choosing tumors suitable for this treatment.

In our experience, smaller tumors without subretinal fluid or tumor seeds show the best response. In a recent study from our department on thermotherapy and chemothermotherapy for retinoblastoma, we found that tumors with less than a 3-mm base responded best with complete control and few complications.36 Tumors with greater than a 6-mm base are at increased risk for recurrence of the main tumor or associated seeds, often requiring plaque radiotherapy.

The main complication of thermotherapy is focal iris atrophy related to heat effects on the pigmented iris tissue(Shields & Shields, unpublished data, 1998) (Fig 6). In some instances, the lens develops a focal paraxial opacity. Chemothermotherapy is especially suited for small tumors adjacent to the fovea and optic nerve where radiation or laser photocoagulation would possibly induce more profound visual loss. It is a time-consuming, tedious process that requires careful observations, recordings, judgments, and treatment of subtle tumor findings. In addition, the cooperation of experienced facilities with pediatric oncologists, radiation oncologists, ocular oncologists, and patient counselors is essential for such a program.

INTRAVENOUS CHEMOREDUCTION FOR INTRAOCULAR RETINOBLASTOMA

Chemoreduction is a method of reducing tumor volume to allow for more focused, less damaging therapeutic measures. It has evolved into an important component of the initial management of retinoblastoma. The chemotherapy agents vary depending on the preference of the pediatric oncologist and we presently employ carboplatin, etoposide, and vincristine7·42-46 (Table 4).

Fig 4: Chemothermotherapy. A; Juxtapapillary retinoblastoma in a young girl with bilateral familial retinoblastoma.

Fig 4: Chemothermotherapy. A; Juxtapapillary retinoblastoma in a young girl with bilateral familial retinoblastoma.

B: After three sessions of chemothermotherapy, the tumor has regressed to an atrophic scar, with preservation of the optic disc and fovea.

B: After three sessions of chemothermotherapy, the tumor has regressed to an atrophic scar, with preservation of the optic disc and fovea.

Fig S: Chemoreduction and chemothermotherapy. Bilateral familial retinoblastoma in a young boy. A: Right eye. Large retinoblastomas in the posterior pole of the eye. JB: Right eye. After chemoreduction and chemothermotherapy, the tumors have dramatically regressed, leaving localized atrophie scars and partially preserved macular function. C: Left eye. Large macular retinoblastoma overhanging the optic disc. D: Left eye. After chemoreduction and chemothermotherapy, the tumor has regressed to a calcified regressed scar.

Fig S: Chemoreduction and chemothermotherapy. Bilateral familial retinoblastoma in a young boy. A: Right eye. Large retinoblastomas in the posterior pole of the eye. JB: Right eye. After chemoreduction and chemothermotherapy, the tumors have dramatically regressed, leaving localized atrophie scars and partially preserved macular function. C: Left eye. Large macular retinoblastoma overhanging the optic disc. D: Left eye. After chemoreduction and chemothermotherapy, the tumor has regressed to a calcified regressed scar.

There are several modifications of this regimen.43 The chemotherapy regimen is given for six cycles to allow for adequate tumor reduction. Focal therapy to the individual tumors is delivered at cycle 2 or cycle 3 with the intention to avoid enucleation and external beam radiotherapy.

The ocular salvage rate has improved with the addition of chemoreduction to the treatment regimens.43"45 Kingston and associates showed that the ocular salvage rate in advanced retinoblastoma treated with external beam radiotherapy alone was 30%, whereas the ocular salvage rate in those eyes treated with chemoreduction prior to external beam radiotherapy was nearly 70%^ (Table 3). Reports from our department have shown similar promising results with chemoreduction for retinoblastoma.7,42·47 Overall, we found a mean decrease of 35% in tumor base and nearly 50% in tumor thickness using our protocol.42 Subretinal fluid resolved in 76% of cases and both vitreous and subretinal seeds showed regression with the treatment.47 After chemoreduction provides tumor regression, the regressed tumor scar requires consolidation with focal measures for complete control (Fig 5, 7). We generally institute consolidation treatment at the second or third chemoreduction cycle so that this coincides with the chemotherapy, particularly important for tumors that are treated with thermotherapy methods.

Table

TABLE 4Chemoreduction Regimen (6 cycles) for Intraocular Retinoblastoma

TABLE 4

Chemoreduction Regimen (6 cycles) for Intraocular Retinoblastoma

Fig 6: Iris atrophy after thermotherapy for retinoblastoma

Fig 6: Iris atrophy after thermotherapy for retinoblastoma

The indications for chemoreduction are not clearly established. Retinal tumor and seed recurrence remain a worrisome problem with chemoreduction.7 Seeds in the vitreous or subretinal space can recur in about 30% of eyes and enlarge to a visual- and life-threatening state (Table 5). In Reese-Ellsworth groups I, II, III, and IV, we have been successful in saving most eyes using chemoreduction and adjuvant methods.7 However, in Reese-Ellsworth group V eyes, the risk for ultimate enucleation increases.7 In those eyes with Reese-Ellsworth group V retinoblastoma, we found that by using chemoreduction and carefully applied adjuvant treatment, complete tumor control occurred in more than 70% of cases.48 This treatment is tedious, however, and requires careful follow up.

Fig 7: Chemoreduction and chemothermotherapy. A: Macular retinoblastoma in a 5-month-old girl. JB: After two cycles of chemoreduction, the tumor has regressed to a partially calcified scar. C: After thermotherapy coupled with chemoreduction, complete regression with surrounding chorioretinal atrophy is found and a portion of the macula is spared.

Fig 7: Chemoreduction and chemothermotherapy. A: Macular retinoblastoma in a 5-month-old girl. JB: After two cycles of chemoreduction, the tumor has regressed to a partially calcified scar. C: After thermotherapy coupled with chemoreduction, complete regression with surrounding chorioretinal atrophy is found and a portion of the macula is spared.

Table

TABLE 5Recurrence of Retinal Tumor, Vitreous Seeds, and Subretinal Seeds Using Chemoreduction (Vincristine, Etoposide, Carboplatin [VEC]) in 130 Retinoblastomas In 52 Eyes

TABLE 5

Recurrence of Retinal Tumor, Vitreous Seeds, and Subretinal Seeds Using Chemoreduction (Vincristine, Etoposide, Carboplatin [VEC]) in 130 Retinoblastomas In 52 Eyes

Overall, chemoreduction is an effective initial measure for selected children with intraocular retinoblastoma. Definitive focal therapy is important once chemotheraPy reduces the tumor. The low-dose, six-cycle regimen may cause transient bone marrow suppression with a risk for infection. The main serious concern of risk for induction of second cancers exists but is predicted to be quite low as a result of the low-dose, short-term treatment period.42,49

SUBCONJUNCTIVAL CHEMOREDUCTION FOR INTRAOCULAR RETINOBLASTOMA

Interest in local delivery of chemoreduction for intraocular retinoblastoma has increased. It has been shown in animal models that carboplatin penetrates the sclera into the vitreous cavity, allowing for effective dosages within the eye with minimal toxicity.50-52 We have employed local subconjunctival injection of carboplatin under protocol in humans as both a secondary treatment and a primary treatment. Within 3 to 4 weeks, tumor response with regression usually occurs, but the response may not be lasting, thereby necessitating consolidation with other more lasting methods.

SYSTEMIC CHEMOTHERAPY FOR POSSIBLE METASTATIC DISEASE

Chemotherapy plays an important role in the management of retinoblastoma with invasion into the optic nerve, choroid, and orbit as well as distant metastatic disease. The two most common ways for retinoblastoma to gain access to the blood stream for metastatic dissemination are via optic nerve and choroid. The clinical features that predict invasion of retinoblastoma into the optic nerve and choroid have been identified,53·54 They include exophytic growth pattern, elevated intraocular pressure, and tumor thickness 15 mm or greater.53 The clinical factors predictive of choroidal invasion included increased intraocular pressure and iris neovascularization.54

Many different agents have been employed to treat systemic retinoblastoma and we presently use a regimen similar to our chemoreduction regimen previously mentioned but with a much longer course of 6 to 18 months depending on the circumstances.7,42 Others have found favorable results with similar chemotherapy regimens for extraocular retinoblastoma.55-59 White has reported on chemotherapy for retinoblastoma60 and recently advocated cyclophosphamide, etoposide, and vincristine as well as the support of peripheral stem cell rescue in multiple sequential courses for metastatic retinoblastoma.60

ORBITAL EXENTERATION

Orbital exenteration is rarely used for retinoblastoma management in the United States as most retinoblastoma patients present with no evidence of extraocular invasion.61 Exenteration is used most often for orbital recurrence after the child has received a maximum acceptable dose of irradiation and chemotherapy. In other countries, retinoblastoma is often recognized at a more advanced stage with orbital involvement. In these cases, exenteration, chemotherapy, and external beam radiotherapy are crucial to patient survival. Use of more advanced exenteration techniques, such as eyelid-sparing exenteration, allows for rapid healing of the wound within 1 month.62

TRILATERAL RETINOBLASTOMA

Trilateral retinoblastoma describes the association of bilateral retinoblastoma and neuroblastic tumor in the pineal gland or other midline structures. A report from our department revealed that this tumor occurs in children younger than 4, often with a fatal outcome.63

MRI or computed tomography are essential to the diagnosis. The disease is highly fatal despite aggressive treatment, such as chemotherapy, radiation therapy, or gamma knife therapy. Longer survival has been correlated with earlier tumor diagnosis in asymptomatic patients.

Trilateral retinoblastoma is a major cause of mortality in children within the first 5 years after diagnosis of bilateral retinoblastoma.64 Of the nearly 20 patients we have managed with pinealoblastoma, two have survived for 4 years with aggressive chemotherapy. We have observed no cases of pinealoblastoma in 147 children treated with initial chemoreduction followed for 1 to 4 years. Although follow up is limited, it is tempting to speculate that chemoreduction may reduce the risk for development of pinealoblastoma.

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4. Abramson DH, Niksarli K, Ellsworth, Servodidio CA. Changing trends in the management of retinoblastoma: 19511965 vs 1966-1980. J Pediatr Ophthalmol Strabismus. 1994;31:32-37.

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8. Shields JA, Shields CL, Sivalingam V. Decreasing frequency of enucleation in patients with retinoblastoma. Am J Ophthalmol. 1989;108:185-188.

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12. Shields CL, Shields JA Singh AD, et al. Lack of complications of the hydroxyapatite orbital implant in 250 consecutive cases. Trans Am Ophthalmol Soc. 1993;91:177-189.

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14. Toma NMG, Hungerford JL, Plowman PN, et al. External beam radiotherapy for retinoblastoma: II, lens sparing technique. Br J Ophthalmol. 1995;79:112-117.

15. Singh AD, Garway-Heath D, Love S, et al. Relationship of regression pattern to recurrence in retinoblastoma. Br J Ophthalmol. 1993;77:12-16.

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17. Fontanesi J, Pratt CB, Hustu HO, et al. Use of irradiation for therapy of retinoblastoma in children more than 1 year old: The St. Jude Children's Research Hospital experience and review of literature. Med Pediatr Oncol. 1995,24:321-326.

18. Ellsworth RM. Retinoblastoma. Modern Problems in Ophthalmology. 1977;96:1826-1830.

19. Plowman PN, Kingston JE, Hungerford JL. Prophylactic retinal radiotherapy has an exceptional place in the management of familial retinoblastoma. Br J Cancer. 1993;68:743-745.

20. Brooks HJL, Meyer D, Shields JA, Balas AG, Nelson LB, Fontanesi J. Removal of radiation-induced cataracts in patients treated for retinoblastoma. Arch Ophthalomol. 1990;108:1701-1708.

21. Weiss AH, Karr DJ, Kalina RE, et al. Visual outcomes of macular retinoblastoma after external beam radiation therapy. Ophthalmology. 1994;101:1244-1249.

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54. Shields CL, Shields JA Baez KA et al. Choroidal invasion of retinoblastoma: metastatic potential and clinical risk factors. Br J Ophthalmol. 1993;77:544-548.

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TABLE 1

Reese-Ellsworth Classification for Conservative Treatment of Retinoblastoma

TABLE 2

The Essen Classification for Conservative Sight-saving Treatment of Retinoblastoma

TABLE 3

Comparison of Globe Salvage Rate Using External Beam Radiotherapy (EBRT) Alone, EBRT and Salvage Treatment, and Chemoreduction and Focal Adjuvant Treatment

TABLE 4

Chemoreduction Regimen (6 cycles) for Intraocular Retinoblastoma

TABLE 5

Recurrence of Retinal Tumor, Vitreous Seeds, and Subretinal Seeds Using Chemoreduction (Vincristine, Etoposide, Carboplatin [VEC]) in 130 Retinoblastomas In 52 Eyes

10.3928/0191-3913-19990101-04

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