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Current Management of Retinoblastoma
mayo SYMPOSIUM ON OCULAR TUMORS—Part IV
Current Management of Retinoblastoma JERRY A. SHIELDS, M.D.,
AND CAROL L. SHIELDS, M.D.
Objective: The recommended management of retinoblastoma based on personal experience with the assessment and treatment of more than 450 children with this intraocular malignant lesion is presented. Recommendations: Although retinoblastoma is usually managed by enucleation, the treatment of each case must be individualized; in an increasing number of children, the techniques of irradiation, photocoagulation, or cryotherapy are being used. In some patients, a combination of these techniques is necessary. Chemotherapy is often used to prevent distant metastatic involvement, although its effectiveness as a prophylactic treatment has
not been clearly established. Because metastatic retinoblastoma is often fatal, intense chemotherapy is recommended in this setting. Conclusion: The prognosis for vision and life in patients with retinoblastoma has improved considerably during the past century, primarily because of earlier recognition of the tumor and use of modern therapeutic methods. All children of parents with a family history of retinoblastoma should be examined by a qualified ophthalmologist immediately after birth in order to detect and treat this condition as early as possible. (Mayo Clin Proc 1994; 69:50-56)
Retinoblastoma is the most important intraocular malignant tumor of childhood, with an incidence of about 1 in 15,000 live births in the United States. The heritable variant of this tumor is usually bilateral and multifocal, whereas nonheritable retinoblastoma is invariably unilateral and solitary.1" The affected child usually has a white pupillary reflex (leukokoria) (Fig. 1). The diagnosis is established by recognition of the typical clinical features of the tumor in combination with judicious use of ancillary diagnostic studies, particularly ultrasonography and computed tomography. In the recent literature on retinoblastoma, the clinical features,13 genetics,lb differential diagnosis,lc and diagnostic approachesld have been discussed. This review provides an update on the current clinical management of this childhood tumor based on personal experience with more than 450 affected children. The management of retinoblastoma can be extremely complex, and establishing firm treatment guidelines is impossible. For each case, therapy should be individualized on the basis of the overall clinical situation. Proper management necessitates the ability to use the various instruments,
familiarity with the disease, and, of foremost importance, experience in dealing with retinoblastoma. Several options are available for treating retinoblastoma, and the method selected should depend on the size and extent of the tumor (or tumors), the site of involvement (unilateral or bilateral), and the patient's systemic status. The currently used methods include enucleation, external beam irradiation, scierai plaque irradiation, cryotherapy, photocoagulation, chemotherapy, and, occasionally, other modalities.le·2·3 In many cases, various combinations of treatment may be needed to achieve a satisfactory result. ENUCLEATION Although enucleation is still the most commonly used treatment of retinoblastoma, earlier recognition of the tumor has allowed the use of more conservative eye-saving therapeutic methods in recent years than in the past.4 Enucleation is probably indicated for all unilateral tumors that fill most of the globe and for which little hope exists of salvaging any viable retina or useful vision (Fig. 1). If half the retina is free of tumor, other methods of treatment can be considered.le In bilateral cases, the eye with the more advanced tumor has traditionally been enucleated, and the less involved eye is managed with irradiation or other methods. If the eye with more advanced tumor has sparing of more than half the retina, salvage of both eyes with treatment can be attempted.
From the Ocular Oncology Service, Wills Eye Hospital, Philadelphia, Pennsylvania. This study was supported in part by the Eye Tumor Research Foundation, Inc., Philadelphia. Individual reprints of this article are not available. Mayo Clin Proc 1994; 69:50-56
50
© / 994 Mayo Foundation for Medical Education and Research
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and their families, the globe should be opened immediately after enucleation to harvest fresh tissue. The specific method for harvesting such tissue is too detailed for inclusion in this review but has been outlined in the recent literature.16 Few major complications are associated with enucleation. Hemorrhage at the time of operation may be controlled with orbital compression and sterile thrombin solution. Ecchymoses of the eyelids usually subside with use of a pressure patch and ice compresses postoperatively. In patients who are receiving chemotherapy, recurrent infections of the socket often develop but can be managed with appropriate antibiotic therapy. The results of enucleation for retinoblastoma are generally excellent. If the child had external radiotherapy in addition to enucleation, the cosmetic result is often less satisfactory because of a sunken orbit and temporal fossa. Use of the integrated hydroxyapatite implant improves the motility of the prosthesis.
Fig. 1. A, Infant with leukokoria attributable to advanced retinoblastoma in left eye. (Patient also had coincidental cleft lip and palate.) B, Photograph of sectioned eye after enucleation, showing extensive retinoblastoma. Enucleation is the preferred treatment for such advanced tumors.
If both eyes have far advanced tumors and no hope exists for any vision, bilateral enucleation may rarely be necessary. The technique of enucleation for retinoblastoma differs slightly from the standard enucleation performed by most ophthalmic surgeons. Because retinoblastoma is a loosely cohesive malignant tumor, precautions should be taken to be extremely gentle during the procedure and, of utmost importance, to prevent perforation of the globe at the time of surgical intervention. As long a section of optic nerve as possible should be obtained (Fig. 2), a result that can be accomplished better with long enucleation scissors that have a lesser curve than with short scissors that have a steeper curve. We do not recommend using snares or clamps on the optic nerve because they induce more trauma and can produce crush artifact in the optic nerve. Such damage can lead to difficulty for the pathologist in distinguishing meningothelial cells from crushed retinoblastoma cells. We use the integrated hydroxyapatite implant to provide optimal ocular motility for the patient.3 Because DNA analysis of fresh tumor tissue is important for research and future genetic counseling of patients
EXTERNAL BEAM RADIOTHERAPY In general, retinoblastoma is an extremely radiosensitive tumor; thus, irradiation can be effective.16-2·5 The treatment should be administered by physicians experienced in childhood ocular radiotherapy in close cooperation with an ophthalmologist. Most often, external beam irradiation is used to treat the second eye in patients with bilateral retinoblastoma after the eye with the more advanced tumor has been enucleated. This therapeutic modality is generally preferred if the second eye has a tumor larger than 15 mm in diameter, a tumor adjacent to the optic disk or fovea, or multiple tumors or if extensive vitreous seeding of tumor cells is present. If both
Fig. 2. Photograph of eye with retinoblastoma immediately after enucleation, showing long section of optic nerve. (From Shields and Shields.1' By permission of Saunders.)
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eyes have moderately advanced tumors with sparing of half the retina, bilateral external beam irradiation may be justified. Solitary tumors smaller than 15 mm in diameter can often be managed by scierai plaque radiotherapy without subjecting the entire eye to radiotherapy. External beam irradiation to the anophthalmic orbit is indicated when the tumor is found histopathologically after enucleation to extend into the optic nerve posterior to the lamina cribrosa or to the line of surgical transection. It is also indicated for orbital recurrence of the tumor after enucleation and possibly for cases with extensive choroidal invasion of tumor. Irradiation probably is contraindicated in cases in which the tumor fills the entire globe and is producing secondary glaucoma. Such eyes should usually be enucleated. For retinoblastoma, the method of external beam irradiation most commonly used in the United States is irradiation by a combination of anterior and lateral portals, as directed by experienced radiation oncologists. Although 7,000 to 8,000 cGy previously was used, 3,500 to 4,000 cGy delivered in divided doses during a 4- to 5-week period currently is the treatment of choice. In comparison with the lateral portal, the anterior portal technique involves a greater risk of producing a radiation-induced cataract but provides irradiation to the ora serrata region. In contrast, the temporal portal approach is less likely to produce a cataract but may miss the anterior aspects of the retina, especially on the nasal side. Our radiation oncologists generally use combined lateral and anterior portals, in conjunction with shielding of the lens in hopes of preventing development of a cataract. If a cataract does develop, it can be removed surgically. For radiation-induced cataract in eyes with retinoblastoma, surgical removal is often successful.6
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The main complications of external beam irradiation are cataract, radiation-induced retinopathy, and optic neuropathy. Less severe but still important complications include a dry eye, a sunken orbit, and atrophy of muscle and subcutaneous tissues. Perhaps the most important long-term complication of external beam irradiation is the development of radiation-induced tumors.7·8 Radiation-induced orbital sarcomas in the field of irradiation are the most common, but other malignant lesions such as lymphomas and leukemias also have been recognized. The incidence of such tumors has diminished substantially since the total radiation doses were decreased from 8,000 to 4,000 cGy.910 Recently, new tumors distant from the site of irradiation have been detected. Furthermore, many second tumors have been detected in patients who had undergone no radiation therapy.7 The results of external beam irradiation are generally good. In most cases, the tumors can be controlled with this method (Fig. 3). In some treated cases, supplemental therapy with other modalities may be necessary. Some patients have atrophy of the temporal fossa and orbit, which causes the affected eye to appear sunken. Cosmetic repair can be undertaken when the child's head and face are fully developed. SCLERAL PLAQUE BRACHYTHERAPY An increasingly used alternative method of irradiation for retinoblastoma is the application of a radioactive plaque. Although we have used ^Co, 192Ir, and 106Ru in the past, currently we usually use 125I. In appropriately selected cases, fewer complications are associated with this technique than with external beam irradiation.
Fig. 3. A, Fundus photograph of retinoblastoma in macular area of right eye, showing superior position of retinoblastoma. B, Photograph taken 4 months after external beam irradiation, showing notable regression of tumor. (From Shields and Shields.1' By permission of Saunders.)
Mayo Clin Proc, January 1994, Vol 69
Relative indications for use of a radioactive plaque include a retinoblastoma that is smaller than 15 mm in diameter and less than 9 mm thick. Although investigators previously believed that tumors within 2 mm of the optic disk or the foveola could not be treated with a plaque, recent experience suggests that many such cases can be successfully treated with this technique. Custom-designed plaques and use of proper shielding are essential for tumors near the optic disk. This treatment can be used for unilateral retinoblastoma or for one or both eyes in patients with bilateral tumors. It can be used when mild to moderate vitreous seeding is present. Recurrent or residual tumors that have been uncontrolled with external beam irradiation, photocoagulation, or cryotherapy may be managed by plaque therapy. The surgical technique for plaque radiotherapy has been described in the literature.lf For retinoblastoma, approximately 3,500 to 4,000 cGy is delivered to the tumor apex. Most tumors show a dramatic response to irradiation within the first 3 weeks after removal of the plaque (Fig. 4). The regression patterns noted are similar to those seen after external beam irradiation. The potential complications of plaque therapy, such as cataract and radiation-related retinopathy, are the same as those associated with external beam irradiation. Whether radiation-induced sarcomas occur after plaque therapy, however, is uncertain. The calculated radiation dose to the orbit is considerably less with shielded plaques than with external beam radiation. As more follow-up data become available, such complications may be-evident.
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We reported our preliminary results with episcleral plaque radiotherapy for retinoblastoma in a study of 97 plaque applications to 51 eyes in 50 patients." After treatment of almost 200 patients with this technique, we believe that plaque radiotherapy can be used successfully as a primary treatment in selected cases of unilateral or bilateral retinoblastoma or as a supplemental treatment after other therapeutic modalities have failed. Three patterns of regression are seen after irradiation for retinoblastoma.2 Type 1 is characterized by a white calcified mass that resembles cottage cheese (Fig. 3). Type 2 is characterized by a pink translucent mass that lacks calcium and resembles fish flesh. Distinguishing type 2 regression ophthalmoscopically from residual viable tumor may be extremely difficult. In general, however, viable tumor has a more opaque appearance and has larger dilated tortuous feeder and drainer vessels. Type 3, a combination of types 1 and 2, typically shows areas of cottage cheese calcification and areas that resemble fish flesh. CRYOTHERAPY Cryotherapy may be used as the primary management modality for small peripheral retinoblastomas located near the ora serrata.12·13 It is also used for residual or recurrent tumors in the peripheral fundus after incomplete eradication with external beam irradiation. Usually, such recurrent lesions are near the ora serrata and probably are attributable to incomplete irradiation of the most anterior portions of the retina. We believe that cryotherapy is generally contraindicated if vitreous seeding of tumor cells is present. Cryotherapy for retinoblastoma should be administered by the triple freeze-thaw technique. With use of careful
Z.
Fig. 4. Response of endophytic retinoblastoma to plaque radiotherapy. A, Appearance of tumor before treatment. B, Appearance approximately 1 year after plaque radiotherapy, showing complete regression of tumor and disappearance of vitreous seeds.
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indirect ophthalmoscopy and the cryoprobe as a scierai depressor, the tumor is elevated and freezing is applied until the surrounding retina turns white and ice crystals appear in the overlying vitreous. After freezing for 10 to 15 seconds, the tumor is allowed to thaw. Then, it is immediately refrozen and the sequence is repeated. Three successive freezethaw applications are usually adequate to attain tumor control. The treatment may need to be repeated in 3 to 4 weeks if viable tumor remains evident ophthalmoscopically. Cryotherapy for retinoblastoma is associated with few major complications. Local vitreous hemorrhage and transient localized retinal detachment (ablatio fugax) are the most frequent complications. A recent report described results of triple freeze-thaw cryotherapy for 67 retinoblastomas in 47 eyes of 45 patients.12 Tumor destruction was achieved with one or more cryotherapy applications in all cases in which the tumor was no larger than 2.5 mm in diameter and 1.0 mm thick and in which the tumor was confined to the sensory retina without seeding into the adjacent vitreous. In general, cryotherapy is effective for tumors up to 3.5 mm in diameter and 2.0 mm thick, but more than one treatment may be necessary. PHOTOCOAGULATION Photocoagulation can be used for selected small retinoblastomas.14 It is beneficial for small retinal tumors that do not involve the optic disk or the macula. If ophthalmoscopy shows evidence of vitreous seeding, choroidal invasion, or involvement of the fovea, optic disk, or pars plana, photocoagulation is probably contraindicated. This technique does not eliminate tumor cells in the vitreous. It probably would not destroy "tumor cells in the choroid and possibly could promote dissemination of the tumor in such cases. If photocoagulation is used on the optic disk or fovea, it will result in severe visual loss. In such cases, radiotherapy is usually preferable. One or two rows of confluent burns are placed around the tumor by using enough power to cause whitening of the surrounding retina and closure of the retinal vessels that supply the tumor (Fig. 5). The treatment should be sufficient enough only to obliterate the retinal vessels. Within a few weeks, the tumor should regress into a flat or excavated scar. In some cases, applying a second and a third treatment may be necessary. Properly administered photocoagulation for retinoblastoma is associated with few complications.
Fig. 5. Laser photocoagulation of small retinoblastoma. A, Pretreatment appearance, showing small tumor inferior to optic disk (arrows). B, Appearance immediately after application of laser, showing laser burns around tumor. C, Appearance 1 month after treatment, showing complete resolution of tumor.
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Mayo Clin Proc, January 1994, Vol 69
A recent report described the results of photocoagulation of 45 retinoblastomas.'4 Overall, photocoagulation alone successfully eradicated 76% of the tumors, whereas in 24% of the tumors, supplemental treatment with other modalities was necessary. In cases in which the tumor was less than or equal to 3.0 mm in diameter and 2.0 mm in thickness and was confined to the sensory retina without vitreous seeding, tumor destruction was generally achieved with photocoagulation. CHEMOTHERAPY In patients with retinoblastoma, the indications for chemotherapy are not clearly established, and some controversy still exists about its value. Some clinicians recommend chemotherapy for all patients who are treated conservatively rather than with enucleation.15 Our colleagues in pediatrie oncology are less inclined to use chemotherapy except in certain circumstances. For example, most authorities agree that if a child with retinoblastoma has known metastatic disease, chemotherapy should be part of the treatment regimen. If orbital involvement or extensive optic nerve involvement is evident after enucleation or if the tumor recurs in the surgically anophthalmic socket, chemotherapy should be initiated along with a course of orbital irradiation. Chemotherapy also may be indicated for children with bilateral retinoblastoma, particularly if one or both eyes are being treated by methods other than enucleation. Chemotherapy for retinoblastoma should be administered by physicians experienced in the use of these drugs. The chemotherapeutic regimen used varies from center to center. Meaningful published information on the results of chemotherapy for retinoblastoma has been scarce. Many cases associated with metastatic disease are fatal. A few reports have described survival of patients with retinoblastoma and metastatic disease after vigorous chemotherapy.15·16
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socket should be inspected and palpated for recurrent orbital tumor. For eyes treated conservatively, indirect ophthalmoscopy is the best method for determining the status of the residual tumor tissue and for detecting radiationrelated retinopathy or other complications. GENETIC COUNSELING Genetic counseling is an extremely important component of the overall management of patients with retinoblastoma. Karyotype studies and DNA analysis of fresh tumor tissue after enucleation and assessment of blood specimens from family members are helpful in that regard. Some patients with retinoblastoma have a deletion in the long arm of chromosome 13—specifically, in the 13ql4 segment. Certain tumors that are genetically related to retinoblastoma, particularly osteosarcoma17 and pinealoblastoma,18 commonly occur in children with inherited retinoblastoma. Hence, children with retinoblastoma and their family members should undergo assessment and counseling accordingly. Children born to parents with a family history of retinoblastoma should be examined by a qualified ophthalmologist immediately after birth in order to detect retinoblastoma as early as possible.
COMBINED THERAPEUTIC MODALITIES The management of retinoblastoma can be extremely difficult, and physicians must often make difficult decisions about the use of various treatment modalities. They must be able to recognize residual tumor or recurrent tumor and be able to select the most appropriate supplemental treatment method. Considerable training and experience are necessary for optimal management. If one method does not achieve tumor control, combinations of other methods may be used, depending on the clinical circumstances.
FOLLOW-UP PROCEDURES After the initial treatment, a follow-up plan should be devised for each patient, depending on the clinical and pathologic findings. In general, if an adequate office examination cannot be performed on a child with unilateral sporadic retinoblastoma who has undergone enucleation, examinations with use of anesthesia should be performed every 4 months until the child is 2 years of age and every 6 months from age 2 to 5 years. An annual examination without anesthesia should be performed after age 5 years. Children being treated by methods other than enucleation, whether they have unilateral or bilateral retinoblastoma, should undergo closer follow-up. Such children should be examined while under anesthesia within 3 to 4 weeks after photocoagulation, cryotherapy, or termination of a course of irradiation. The frequency of subsequent examinations depends on the response to previous treatment and varies from patient to patient. For each subsequent examination, the anophthalmic socket should be inspected and palpated, and indirect ophthalmoscopy should be performed on conservatively treated eyes to evaluate the effect of treatment on known tumors and to detect any new tumors.
ASSESSMENT OF TREATMENT RESPONSE The ability to determine the response to treatment by using the methods previously outlined is important. In children who have undergone enucleation, the prosthesis should be removed on each subsequent visit, and the anophthalmic
CONCLUSION Prompt diagnosis of retinoblastoma by pediatricians, ophthalmologists, and other practitioners has enabled ocular oncologists to see affected children earlier. Improvements in therapeutic modalities, such as techniques of radiotherapy,
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laser photocoagulation, cryotherapy, or combinations of these methods, have allowed conservative treatment of many children who would have required enucleation in the past. The visual results, as well as the systemic prognosis, are expected to continue to improve for children with this important intraocular malignant tumor. REFERENCES 1. Shields JA, Shields CL. Intraocular Tumors: A Text and Atlas. Philadelphia: Saunders, 1992: (a) 305-332; (b) 333339; (c) 341-362; (d) 363-376; (e) 377-391; (f) 25-43 2. Ellsworth RM. The practical management of retinoblastoma. Trans Am Ophthalmol Soc 1969; 67:462-534 3. Shields JA, Shields CL, Donoso LA, Lieb WE. Changing concepts in the management of retinoblastoma. Ophthalmic Surg 1990;21:72-76 4. Shields JA, Shields CL, Sivalingam V. Decreasing frequency of enucleation in patients with retinoblastoma. Am J Ophthalmol 1989;108:185-188 5. Abramson DH, Marks RF, Ellsworth RM, Tretter P, Kitchin FD. The management of unilateral retinoblastoma without primary enucleation. Arch Ophthalmol 1982; 100:12491252 6. Brooks HL, Meyer D, Shields JA, Balas AG, Nelson LB, Fontanesi J. Removal of radiation-induced cataracts in patients treated for retinoblastoma. Arch Ophthalmol 1990; 108:1701-1708 7. Abramson DH, Ronner HJ, Ellsworth RM. Second tumors in nonirradiated bilateral retinoblastoma. Am J Ophthalmol 1979; 87:624-627
8.
Roarty JD, McLean IW, Zimmerman LE. Incidence of second neoplasms in patients with bilateral retinoblastoma. Ophthalmology 1988;95:1583-1587 9. Forrest AW. Tumors following radiation about the eye. Int Ophthalmol Clin 1962 Jun; 2:543-553 10. Sagerman RH, Cassady JR, Tretter P, Ellsworth RM. Radiation induced neoplasia following external beam therapy for children with retinoblastoma. AJR Am J Roentgenol 1969; 105:529-535 11. Shields JA, Giblin ME, Shields CL, Markoe AM, Karlsson U, Brady LW, et al. Episcleral plaque radiotherapy for retinoblastoma. Ophthalmology 1989; 96:530-537 12. Shields JA, Parsons H, Shields CL, Giblin ME. The role of cryotherapy in the management of retinoblastoma. Am J Ophthalmol 1989; 108:260-264 13. Tolentino FI Jr, Tablante RT. Cryotherapy of retinoblastoma. Arch Ophthalmol 1972; 87:52-55 14. Shields JA, Shields CL, Parsons H, Giblin ME. The role of photocoagulation in the management of retinoblastoma. Arch Ophthalmol 1990; 108:205-208 15. Zelter M, Gonzalez G, Schwartz L, Gallo G, Schvartzman E, Darnel A, et al. Treatment of retinoblastoma: results obtained from a prospective study of 51 patients. Cancer 1988; 61:153-160 16. Judisch GF, Apple DJ, Fratkin JD. Retinoblastoma: a survivor 12 years after treatment for metastatic disease. Arch Ophthalmol 1980;98:711-713 17. Petersen RA, Friend SH, Albert DM. Prolonged survival of a child with metastatic retinoblastoma. J Pediatr Ophthalmol Strabismus 1987;24:247-248 18. Pesin SR, Shields JA. Seven cases of trilateral retinoblastoma. Am J Ophthalmol 1989;107:121-126
End of Symposium on Ocular Tumors, Part IV. Part V will appear in the February issue.
Current Management of Retinoblastoma JERRY A. SHIELDS, M.D.,
AND CAROL L. SHIELDS, M.D.
Objective: The recommended management of retinoblastoma based on personal experience with the assessment and treatment of more than 450 children with this intraocular malignant lesion is presented. Recommendations: Although retinoblastoma is usually managed by enucleation, the treatment of each case must be individualized; in an increasing number of children, the techniques of irradiation, photocoagulation, or cryotherapy are being used. In some patients, a combination of these techniques is necessary. Chemotherapy is often used to prevent distant metastatic involvement, although its effectiveness as a prophylactic treatment has
not been clearly established. Because metastatic retinoblastoma is often fatal, intense chemotherapy is recommended in this setting. Conclusion: The prognosis for vision and life in patients with retinoblastoma has improved considerably during the past century, primarily because of earlier recognition of the tumor and use of modern therapeutic methods. All children of parents with a family history of retinoblastoma should be examined by a qualified ophthalmologist immediately after birth in order to detect and treat this condition as early as possible. (Mayo Clin Proc 1994; 69:50-56)
Retinoblastoma is the most important intraocular malignant tumor of childhood, with an incidence of about 1 in 15,000 live births in the United States. The heritable variant of this tumor is usually bilateral and multifocal, whereas nonheritable retinoblastoma is invariably unilateral and solitary.1" The affected child usually has a white pupillary reflex (leukokoria) (Fig. 1). The diagnosis is established by recognition of the typical clinical features of the tumor in combination with judicious use of ancillary diagnostic studies, particularly ultrasonography and computed tomography. In the recent literature on retinoblastoma, the clinical features,13 genetics,lb differential diagnosis,lc and diagnostic approachesld have been discussed. This review provides an update on the current clinical management of this childhood tumor based on personal experience with more than 450 affected children. The management of retinoblastoma can be extremely complex, and establishing firm treatment guidelines is impossible. For each case, therapy should be individualized on the basis of the overall clinical situation. Proper management necessitates the ability to use the various instruments,
familiarity with the disease, and, of foremost importance, experience in dealing with retinoblastoma. Several options are available for treating retinoblastoma, and the method selected should depend on the size and extent of the tumor (or tumors), the site of involvement (unilateral or bilateral), and the patient's systemic status. The currently used methods include enucleation, external beam irradiation, scierai plaque irradiation, cryotherapy, photocoagulation, chemotherapy, and, occasionally, other modalities.le·2·3 In many cases, various combinations of treatment may be needed to achieve a satisfactory result. ENUCLEATION Although enucleation is still the most commonly used treatment of retinoblastoma, earlier recognition of the tumor has allowed the use of more conservative eye-saving therapeutic methods in recent years than in the past.4 Enucleation is probably indicated for all unilateral tumors that fill most of the globe and for which little hope exists of salvaging any viable retina or useful vision (Fig. 1). If half the retina is free of tumor, other methods of treatment can be considered.le In bilateral cases, the eye with the more advanced tumor has traditionally been enucleated, and the less involved eye is managed with irradiation or other methods. If the eye with more advanced tumor has sparing of more than half the retina, salvage of both eyes with treatment can be attempted.
From the Ocular Oncology Service, Wills Eye Hospital, Philadelphia, Pennsylvania. This study was supported in part by the Eye Tumor Research Foundation, Inc., Philadelphia. Individual reprints of this article are not available. Mayo Clin Proc 1994; 69:50-56
50
© / 994 Mayo Foundation for Medical Education and Research
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and their families, the globe should be opened immediately after enucleation to harvest fresh tissue. The specific method for harvesting such tissue is too detailed for inclusion in this review but has been outlined in the recent literature.16 Few major complications are associated with enucleation. Hemorrhage at the time of operation may be controlled with orbital compression and sterile thrombin solution. Ecchymoses of the eyelids usually subside with use of a pressure patch and ice compresses postoperatively. In patients who are receiving chemotherapy, recurrent infections of the socket often develop but can be managed with appropriate antibiotic therapy. The results of enucleation for retinoblastoma are generally excellent. If the child had external radiotherapy in addition to enucleation, the cosmetic result is often less satisfactory because of a sunken orbit and temporal fossa. Use of the integrated hydroxyapatite implant improves the motility of the prosthesis.
Fig. 1. A, Infant with leukokoria attributable to advanced retinoblastoma in left eye. (Patient also had coincidental cleft lip and palate.) B, Photograph of sectioned eye after enucleation, showing extensive retinoblastoma. Enucleation is the preferred treatment for such advanced tumors.
If both eyes have far advanced tumors and no hope exists for any vision, bilateral enucleation may rarely be necessary. The technique of enucleation for retinoblastoma differs slightly from the standard enucleation performed by most ophthalmic surgeons. Because retinoblastoma is a loosely cohesive malignant tumor, precautions should be taken to be extremely gentle during the procedure and, of utmost importance, to prevent perforation of the globe at the time of surgical intervention. As long a section of optic nerve as possible should be obtained (Fig. 2), a result that can be accomplished better with long enucleation scissors that have a lesser curve than with short scissors that have a steeper curve. We do not recommend using snares or clamps on the optic nerve because they induce more trauma and can produce crush artifact in the optic nerve. Such damage can lead to difficulty for the pathologist in distinguishing meningothelial cells from crushed retinoblastoma cells. We use the integrated hydroxyapatite implant to provide optimal ocular motility for the patient.3 Because DNA analysis of fresh tumor tissue is important for research and future genetic counseling of patients
EXTERNAL BEAM RADIOTHERAPY In general, retinoblastoma is an extremely radiosensitive tumor; thus, irradiation can be effective.16-2·5 The treatment should be administered by physicians experienced in childhood ocular radiotherapy in close cooperation with an ophthalmologist. Most often, external beam irradiation is used to treat the second eye in patients with bilateral retinoblastoma after the eye with the more advanced tumor has been enucleated. This therapeutic modality is generally preferred if the second eye has a tumor larger than 15 mm in diameter, a tumor adjacent to the optic disk or fovea, or multiple tumors or if extensive vitreous seeding of tumor cells is present. If both
Fig. 2. Photograph of eye with retinoblastoma immediately after enucleation, showing long section of optic nerve. (From Shields and Shields.1' By permission of Saunders.)
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eyes have moderately advanced tumors with sparing of half the retina, bilateral external beam irradiation may be justified. Solitary tumors smaller than 15 mm in diameter can often be managed by scierai plaque radiotherapy without subjecting the entire eye to radiotherapy. External beam irradiation to the anophthalmic orbit is indicated when the tumor is found histopathologically after enucleation to extend into the optic nerve posterior to the lamina cribrosa or to the line of surgical transection. It is also indicated for orbital recurrence of the tumor after enucleation and possibly for cases with extensive choroidal invasion of tumor. Irradiation probably is contraindicated in cases in which the tumor fills the entire globe and is producing secondary glaucoma. Such eyes should usually be enucleated. For retinoblastoma, the method of external beam irradiation most commonly used in the United States is irradiation by a combination of anterior and lateral portals, as directed by experienced radiation oncologists. Although 7,000 to 8,000 cGy previously was used, 3,500 to 4,000 cGy delivered in divided doses during a 4- to 5-week period currently is the treatment of choice. In comparison with the lateral portal, the anterior portal technique involves a greater risk of producing a radiation-induced cataract but provides irradiation to the ora serrata region. In contrast, the temporal portal approach is less likely to produce a cataract but may miss the anterior aspects of the retina, especially on the nasal side. Our radiation oncologists generally use combined lateral and anterior portals, in conjunction with shielding of the lens in hopes of preventing development of a cataract. If a cataract does develop, it can be removed surgically. For radiation-induced cataract in eyes with retinoblastoma, surgical removal is often successful.6
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The main complications of external beam irradiation are cataract, radiation-induced retinopathy, and optic neuropathy. Less severe but still important complications include a dry eye, a sunken orbit, and atrophy of muscle and subcutaneous tissues. Perhaps the most important long-term complication of external beam irradiation is the development of radiation-induced tumors.7·8 Radiation-induced orbital sarcomas in the field of irradiation are the most common, but other malignant lesions such as lymphomas and leukemias also have been recognized. The incidence of such tumors has diminished substantially since the total radiation doses were decreased from 8,000 to 4,000 cGy.910 Recently, new tumors distant from the site of irradiation have been detected. Furthermore, many second tumors have been detected in patients who had undergone no radiation therapy.7 The results of external beam irradiation are generally good. In most cases, the tumors can be controlled with this method (Fig. 3). In some treated cases, supplemental therapy with other modalities may be necessary. Some patients have atrophy of the temporal fossa and orbit, which causes the affected eye to appear sunken. Cosmetic repair can be undertaken when the child's head and face are fully developed. SCLERAL PLAQUE BRACHYTHERAPY An increasingly used alternative method of irradiation for retinoblastoma is the application of a radioactive plaque. Although we have used ^Co, 192Ir, and 106Ru in the past, currently we usually use 125I. In appropriately selected cases, fewer complications are associated with this technique than with external beam irradiation.
Fig. 3. A, Fundus photograph of retinoblastoma in macular area of right eye, showing superior position of retinoblastoma. B, Photograph taken 4 months after external beam irradiation, showing notable regression of tumor. (From Shields and Shields.1' By permission of Saunders.)
Mayo Clin Proc, January 1994, Vol 69
Relative indications for use of a radioactive plaque include a retinoblastoma that is smaller than 15 mm in diameter and less than 9 mm thick. Although investigators previously believed that tumors within 2 mm of the optic disk or the foveola could not be treated with a plaque, recent experience suggests that many such cases can be successfully treated with this technique. Custom-designed plaques and use of proper shielding are essential for tumors near the optic disk. This treatment can be used for unilateral retinoblastoma or for one or both eyes in patients with bilateral tumors. It can be used when mild to moderate vitreous seeding is present. Recurrent or residual tumors that have been uncontrolled with external beam irradiation, photocoagulation, or cryotherapy may be managed by plaque therapy. The surgical technique for plaque radiotherapy has been described in the literature.lf For retinoblastoma, approximately 3,500 to 4,000 cGy is delivered to the tumor apex. Most tumors show a dramatic response to irradiation within the first 3 weeks after removal of the plaque (Fig. 4). The regression patterns noted are similar to those seen after external beam irradiation. The potential complications of plaque therapy, such as cataract and radiation-related retinopathy, are the same as those associated with external beam irradiation. Whether radiation-induced sarcomas occur after plaque therapy, however, is uncertain. The calculated radiation dose to the orbit is considerably less with shielded plaques than with external beam radiation. As more follow-up data become available, such complications may be-evident.
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We reported our preliminary results with episcleral plaque radiotherapy for retinoblastoma in a study of 97 plaque applications to 51 eyes in 50 patients." After treatment of almost 200 patients with this technique, we believe that plaque radiotherapy can be used successfully as a primary treatment in selected cases of unilateral or bilateral retinoblastoma or as a supplemental treatment after other therapeutic modalities have failed. Three patterns of regression are seen after irradiation for retinoblastoma.2 Type 1 is characterized by a white calcified mass that resembles cottage cheese (Fig. 3). Type 2 is characterized by a pink translucent mass that lacks calcium and resembles fish flesh. Distinguishing type 2 regression ophthalmoscopically from residual viable tumor may be extremely difficult. In general, however, viable tumor has a more opaque appearance and has larger dilated tortuous feeder and drainer vessels. Type 3, a combination of types 1 and 2, typically shows areas of cottage cheese calcification and areas that resemble fish flesh. CRYOTHERAPY Cryotherapy may be used as the primary management modality for small peripheral retinoblastomas located near the ora serrata.12·13 It is also used for residual or recurrent tumors in the peripheral fundus after incomplete eradication with external beam irradiation. Usually, such recurrent lesions are near the ora serrata and probably are attributable to incomplete irradiation of the most anterior portions of the retina. We believe that cryotherapy is generally contraindicated if vitreous seeding of tumor cells is present. Cryotherapy for retinoblastoma should be administered by the triple freeze-thaw technique. With use of careful
Z.
Fig. 4. Response of endophytic retinoblastoma to plaque radiotherapy. A, Appearance of tumor before treatment. B, Appearance approximately 1 year after plaque radiotherapy, showing complete regression of tumor and disappearance of vitreous seeds.
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indirect ophthalmoscopy and the cryoprobe as a scierai depressor, the tumor is elevated and freezing is applied until the surrounding retina turns white and ice crystals appear in the overlying vitreous. After freezing for 10 to 15 seconds, the tumor is allowed to thaw. Then, it is immediately refrozen and the sequence is repeated. Three successive freezethaw applications are usually adequate to attain tumor control. The treatment may need to be repeated in 3 to 4 weeks if viable tumor remains evident ophthalmoscopically. Cryotherapy for retinoblastoma is associated with few major complications. Local vitreous hemorrhage and transient localized retinal detachment (ablatio fugax) are the most frequent complications. A recent report described results of triple freeze-thaw cryotherapy for 67 retinoblastomas in 47 eyes of 45 patients.12 Tumor destruction was achieved with one or more cryotherapy applications in all cases in which the tumor was no larger than 2.5 mm in diameter and 1.0 mm thick and in which the tumor was confined to the sensory retina without seeding into the adjacent vitreous. In general, cryotherapy is effective for tumors up to 3.5 mm in diameter and 2.0 mm thick, but more than one treatment may be necessary. PHOTOCOAGULATION Photocoagulation can be used for selected small retinoblastomas.14 It is beneficial for small retinal tumors that do not involve the optic disk or the macula. If ophthalmoscopy shows evidence of vitreous seeding, choroidal invasion, or involvement of the fovea, optic disk, or pars plana, photocoagulation is probably contraindicated. This technique does not eliminate tumor cells in the vitreous. It probably would not destroy "tumor cells in the choroid and possibly could promote dissemination of the tumor in such cases. If photocoagulation is used on the optic disk or fovea, it will result in severe visual loss. In such cases, radiotherapy is usually preferable. One or two rows of confluent burns are placed around the tumor by using enough power to cause whitening of the surrounding retina and closure of the retinal vessels that supply the tumor (Fig. 5). The treatment should be sufficient enough only to obliterate the retinal vessels. Within a few weeks, the tumor should regress into a flat or excavated scar. In some cases, applying a second and a third treatment may be necessary. Properly administered photocoagulation for retinoblastoma is associated with few complications.
Fig. 5. Laser photocoagulation of small retinoblastoma. A, Pretreatment appearance, showing small tumor inferior to optic disk (arrows). B, Appearance immediately after application of laser, showing laser burns around tumor. C, Appearance 1 month after treatment, showing complete resolution of tumor.
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Mayo Clin Proc, January 1994, Vol 69
A recent report described the results of photocoagulation of 45 retinoblastomas.'4 Overall, photocoagulation alone successfully eradicated 76% of the tumors, whereas in 24% of the tumors, supplemental treatment with other modalities was necessary. In cases in which the tumor was less than or equal to 3.0 mm in diameter and 2.0 mm in thickness and was confined to the sensory retina without vitreous seeding, tumor destruction was generally achieved with photocoagulation. CHEMOTHERAPY In patients with retinoblastoma, the indications for chemotherapy are not clearly established, and some controversy still exists about its value. Some clinicians recommend chemotherapy for all patients who are treated conservatively rather than with enucleation.15 Our colleagues in pediatrie oncology are less inclined to use chemotherapy except in certain circumstances. For example, most authorities agree that if a child with retinoblastoma has known metastatic disease, chemotherapy should be part of the treatment regimen. If orbital involvement or extensive optic nerve involvement is evident after enucleation or if the tumor recurs in the surgically anophthalmic socket, chemotherapy should be initiated along with a course of orbital irradiation. Chemotherapy also may be indicated for children with bilateral retinoblastoma, particularly if one or both eyes are being treated by methods other than enucleation. Chemotherapy for retinoblastoma should be administered by physicians experienced in the use of these drugs. The chemotherapeutic regimen used varies from center to center. Meaningful published information on the results of chemotherapy for retinoblastoma has been scarce. Many cases associated with metastatic disease are fatal. A few reports have described survival of patients with retinoblastoma and metastatic disease after vigorous chemotherapy.15·16
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socket should be inspected and palpated for recurrent orbital tumor. For eyes treated conservatively, indirect ophthalmoscopy is the best method for determining the status of the residual tumor tissue and for detecting radiationrelated retinopathy or other complications. GENETIC COUNSELING Genetic counseling is an extremely important component of the overall management of patients with retinoblastoma. Karyotype studies and DNA analysis of fresh tumor tissue after enucleation and assessment of blood specimens from family members are helpful in that regard. Some patients with retinoblastoma have a deletion in the long arm of chromosome 13—specifically, in the 13ql4 segment. Certain tumors that are genetically related to retinoblastoma, particularly osteosarcoma17 and pinealoblastoma,18 commonly occur in children with inherited retinoblastoma. Hence, children with retinoblastoma and their family members should undergo assessment and counseling accordingly. Children born to parents with a family history of retinoblastoma should be examined by a qualified ophthalmologist immediately after birth in order to detect retinoblastoma as early as possible.
COMBINED THERAPEUTIC MODALITIES The management of retinoblastoma can be extremely difficult, and physicians must often make difficult decisions about the use of various treatment modalities. They must be able to recognize residual tumor or recurrent tumor and be able to select the most appropriate supplemental treatment method. Considerable training and experience are necessary for optimal management. If one method does not achieve tumor control, combinations of other methods may be used, depending on the clinical circumstances.
FOLLOW-UP PROCEDURES After the initial treatment, a follow-up plan should be devised for each patient, depending on the clinical and pathologic findings. In general, if an adequate office examination cannot be performed on a child with unilateral sporadic retinoblastoma who has undergone enucleation, examinations with use of anesthesia should be performed every 4 months until the child is 2 years of age and every 6 months from age 2 to 5 years. An annual examination without anesthesia should be performed after age 5 years. Children being treated by methods other than enucleation, whether they have unilateral or bilateral retinoblastoma, should undergo closer follow-up. Such children should be examined while under anesthesia within 3 to 4 weeks after photocoagulation, cryotherapy, or termination of a course of irradiation. The frequency of subsequent examinations depends on the response to previous treatment and varies from patient to patient. For each subsequent examination, the anophthalmic socket should be inspected and palpated, and indirect ophthalmoscopy should be performed on conservatively treated eyes to evaluate the effect of treatment on known tumors and to detect any new tumors.
ASSESSMENT OF TREATMENT RESPONSE The ability to determine the response to treatment by using the methods previously outlined is important. In children who have undergone enucleation, the prosthesis should be removed on each subsequent visit, and the anophthalmic
CONCLUSION Prompt diagnosis of retinoblastoma by pediatricians, ophthalmologists, and other practitioners has enabled ocular oncologists to see affected children earlier. Improvements in therapeutic modalities, such as techniques of radiotherapy,
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laser photocoagulation, cryotherapy, or combinations of these methods, have allowed conservative treatment of many children who would have required enucleation in the past. The visual results, as well as the systemic prognosis, are expected to continue to improve for children with this important intraocular malignant tumor. REFERENCES 1. Shields JA, Shields CL. Intraocular Tumors: A Text and Atlas. Philadelphia: Saunders, 1992: (a) 305-332; (b) 333339; (c) 341-362; (d) 363-376; (e) 377-391; (f) 25-43 2. Ellsworth RM. The practical management of retinoblastoma. Trans Am Ophthalmol Soc 1969; 67:462-534 3. Shields JA, Shields CL, Donoso LA, Lieb WE. Changing concepts in the management of retinoblastoma. Ophthalmic Surg 1990;21:72-76 4. Shields JA, Shields CL, Sivalingam V. Decreasing frequency of enucleation in patients with retinoblastoma. Am J Ophthalmol 1989;108:185-188 5. Abramson DH, Marks RF, Ellsworth RM, Tretter P, Kitchin FD. The management of unilateral retinoblastoma without primary enucleation. Arch Ophthalmol 1982; 100:12491252 6. Brooks HL, Meyer D, Shields JA, Balas AG, Nelson LB, Fontanesi J. Removal of radiation-induced cataracts in patients treated for retinoblastoma. Arch Ophthalmol 1990; 108:1701-1708 7. Abramson DH, Ronner HJ, Ellsworth RM. Second tumors in nonirradiated bilateral retinoblastoma. Am J Ophthalmol 1979; 87:624-627
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Roarty JD, McLean IW, Zimmerman LE. Incidence of second neoplasms in patients with bilateral retinoblastoma. Ophthalmology 1988;95:1583-1587 9. Forrest AW. Tumors following radiation about the eye. Int Ophthalmol Clin 1962 Jun; 2:543-553 10. Sagerman RH, Cassady JR, Tretter P, Ellsworth RM. Radiation induced neoplasia following external beam therapy for children with retinoblastoma. AJR Am J Roentgenol 1969; 105:529-535 11. Shields JA, Giblin ME, Shields CL, Markoe AM, Karlsson U, Brady LW, et al. Episcleral plaque radiotherapy for retinoblastoma. Ophthalmology 1989; 96:530-537 12. Shields JA, Parsons H, Shields CL, Giblin ME. The role of cryotherapy in the management of retinoblastoma. Am J Ophthalmol 1989; 108:260-264 13. Tolentino FI Jr, Tablante RT. Cryotherapy of retinoblastoma. Arch Ophthalmol 1972; 87:52-55 14. Shields JA, Shields CL, Parsons H, Giblin ME. The role of photocoagulation in the management of retinoblastoma. Arch Ophthalmol 1990; 108:205-208 15. Zelter M, Gonzalez G, Schwartz L, Gallo G, Schvartzman E, Darnel A, et al. Treatment of retinoblastoma: results obtained from a prospective study of 51 patients. Cancer 1988; 61:153-160 16. Judisch GF, Apple DJ, Fratkin JD. Retinoblastoma: a survivor 12 years after treatment for metastatic disease. Arch Ophthalmol 1980;98:711-713 17. Petersen RA, Friend SH, Albert DM. Prolonged survival of a child with metastatic retinoblastoma. J Pediatr Ophthalmol Strabismus 1987;24:247-248 18. Pesin SR, Shields JA. Seven cases of trilateral retinoblastoma. Am J Ophthalmol 1989;107:121-126
End of Symposium on Ocular Tumors, Part IV. Part V will appear in the February issue.