Ординатура / Офтальмология / Английские материалы / Textbook of Vitreoretinal Diseases and Surgery_Natarajan, Hussain_2008

Textbook of Vitreoretinal Diseases and Surgery

the retinal blood vessels unlike in laser photocoagulation where the feeder vessels are treated. The scar produced is almost equal to the size of the tumor itself and there is minimal collateral damage to the surrounding retina. Thermotherapy is commonly applied through the indirect ophthalmoscope, operating microscope or the transcleral route. This is used for relatively small retinoblastomas without associated vitreous or subretinal seeds. This treatment provides satisfactory control for tumors measuring upto 4 mm in basal diameter and 2 mm in thickness. Tumor regression can be achieved in 86% of cases with multiple cycles of thermotherapy. The common complications are focal iris atrophy, focal paraxial lens opacity, retinal traction and serous retinal detachment. Thermotherapy can also be used synergistically with chemoreduction as heat amplifies the cytotoxic effect of platinum analogues.10

Plaque Brachytherapy

Plaque brachytherapy involves the placement of a radioactive implant on the sclera over the base of the tumor to irradiate the tumor transclerally.11 Commonly used materials include Ruthenium106 and Iodine125.

Plaque brachytherapy is now sparingly used as one of the primary treatment modalities for retinoblastoma. Tumor recurrence rate of 12% at one year follow-up has been reported when plaque is used as the primary treatment.12 It is used in situations where chemotherapy is contraindicated or in cases of recurrence or no response to chemoreduction or external beam radiotherapy. It can be done for tumors with basal dimension upto 16mm and height upto 8 mm and located more than 3mm from optic nerve or macula. Plaque brachytherapy delivers focal radiation to the tumor with minimal collateral damage; hence there are fewer chances of radiation optic neuropathy and retinopathy.13 Unlike with external beam radiotherapy, it minimizes the problems of bony orbital growth retardation and the risk of second malignant neoplasm.

Plaque brachytherapy requires precise localization of the tumor and measurement of its basal dimensions. The tumor thickness is measured by ultrasonography. This data is used for dosimetry on a three-dimensional computerized tumor modeling system. The plaque design is chosen depending on the basal tumor dimensions, its location, and configuration. The dose to the tumor apex ranges from 4000-5000 cGy. The radiation exposure time thus calculated guides the time of plaque implantation and removal. The surgery is performed under radiation safety precautions. The plaque is sutured to the sclera after confirming tumor centration with a dummy plaque and left in situ for the duration of exposure, generally ranging from 36 to 72 hours. The patient is hospitalized with radiation safety precautions for the duration of exposure. The results of plaque brachytherapy are gratifying. Shields et al reported in their series that 90% of the eyes destined for enucleation could be salvaged with plaque brachytherapy.11

The common complications are radiation optic neuropathy and radiation retinopathy. Special designs of plaques have reduced the incidence of radiation-induced complications especially to the optic nerve.4

External Beam Radiotherapy (EBRT)

External beam radiotherapy is no longer the first line management of retinoblastoma. Its use has fallen out of favor in view of the potential complications associated with it and reports demonstrating its definite potential to give rise to second nonocular neoplasms in germline retinoblastoma

248 survivors.13,14 It is used in cases where there is no response to chemoreduction or where chemotherapy

Pediatric Intraocular Tumors–I

is contraindicated. It is also used as an adjuvant therapy in cases of orbital retinoblastoma after local tumor control with chemoreduction and enucleation or exenteration. It is also used following enucleation in patients with involvement of the optic nerve transection, scleral infiltration and orbital extension.4 With EBRT, Reese Ellsworth stage I tumors have nearly 100% globe salvage rate while Reese Ellsworth stage V tumors have only about 30 % chance of globe salvage (Table 20-2).15,16

The major problems with EBRT are the stunting of the orbital growth, dry eye, cataract, radiation retinopathy and optic neuropathy. EBRT can induce second malignant neoplasms especially in patients with the hereditary form of retinoblastoma. There is a 30% chance of developing another malignancy by the age of 30 years in such patients.14 The risk of developing second malignant neoplasm is higher

Textbook of Vitreoretinal Diseases and Surgery

TABLE 20-3: Chemoreduction regimen and doses for intraocular retinoblastoma

Day 1: Vincristine + Etoposide + Carboplatin

Day 2: Etoposide

Standard dose: (3 weekly, 6 cycles):

•Vincristine 1.5 mg/m2 (0.05 mg/kg for children < 36 months of age and maximum dose < 2 mg)

•Etoposide 150 mg/m2 (5 mg/kg for children < 36 months of age)

•Carboplatin 560 mg/m2 (18.6 mg/kg for children < 36 months of age)

High-dose (3 weekly, 6-12 cycles):

•Vincristine 0.025 mg/kg

•Etoposide 12 mg/kg

•Carboplatin 28 mg/kg

Enucleation

Until recently enucleation was the standard management of advanced unilateral retinoblastoma and the advanced eye of bilateral retinoblastoma. This radical modality has been relegated to the second or third line of management with recent refinements in globe and vision salvaging management options.24 Enucleation is presently indicated as the primary management modality in eyes with International Classification of intraocular Retinoblastoma Group E eyes, that is, eyes with neovascularization of the iris, secondary glaucoma, anterior chamber tumor invasion, and tumors occupying >75% of the vitreous volume. Tumors associated with hyphema or vitreous hemorrhage where the tumor characteristics can not be visualized are also indications for primary enucleation. It is also indicated in those who fail focal therapy, chemotherapy or external beam radiotherapy.

The surgical technique of enucleation has to be meticulous and it is important to take adequate precautions not to accidentally perforate the eye. The rectus muscles have to be hooked carefully as the sclera is thin at the site of the muscle insertions. Gentle traction with the recti muscle traction sutures helps in prolapsing the globe out of the orbit and in getting a long optic nerve stump. The optic nerve stump should be at least 10 mm long, 15 mm being optimal. It would be easier to cut the optic nerve with a blunt tip tenotomy scissors. If the nerve is cut from the medial approach, a straight tenotomy scissors is useful as the medial orbital wall is straight. The lateral orbital wall being angulated at 45 degrees entails the use of a semi-curved scissor to obtain a long stump of optic nerve. The optic nerve should be cut a little above the apex so as to preserve the structures passing through the superior orbital fissure, which would help in retaining motility of the prosthesis and prevent post operative ptosis. The enucleated eye should be routinely inspected to look for any extraocular extension and optic nerve thickening.

Patients with tumor necrosis and sterile orbital inflammation present a special challenge in enucleation. Imaging should be done routinely for them to rule out any extraocular extension. In cases with no extraocular extension, a short course of systemic and topical steroid given before the surgery helps to control the inflammation and decreases the chance of intraoperative bleeding. Enucleation is also more difficult in these patients because of the scarring of the orbital tissues following inflammation.5

Orbital implants are not contraindicated in retinoblastoma and are routinely used. The common materials used to make implants are PMMA, silicon, hydroxy apatite and porous polyethylene. Porous implants are commonly used today because of their unique property of orbital integration, thus providing good centration and better prosthesis motility. Integrated implants, however, are

250 better avoided in situations where post-operative radiotherapy might be required (suspected

Textbook of Vitreoretinal Diseases and Surgery

FIGURE 20-5B: Massive choroidal infiltration (H & E stain; 40x)

FIGURE 20-5C: Retrolaminar optic nerve invasion (H & E stain;40x)

MANAGEMENT OF ORBITAL RETINOBLASTOMA

Orbital retinoblastoma can be primary (orbital extension of an intraocular tumor at initial presentation), secondary (orbital recurrence following uncomplicated enucleation), accidental (inadvertent globe perforation or intraocular surgery in eyes with unsuspected retinoblastoma), overt (extraocular or optic nerve extension recognized during surgery) and microscopic (extraocular or optic nerve invasion detected on histopathology).4

All cases of suspected orbital retinoblastoma require CT scan or MRI imaging to confirm orbital extension and to look for any associated intracranial extension. A through clinical evaluation should 252 be done in all cases, specifically looking for any regional lymph nodes. A metastatic workup should

Pediatric Intraocular Tumors–I

Textbook of Vitreoretinal Diseases and Surgery

GENETIC COUNSELING

Genetics of retinoblastoma is complex and the genetic counseling is often challenging. However, current understanding of the molecular mechanism of the disease suggests that a parent with bilateral retinoblastoma has 45% chance of having an affected child, 85% of whom will have bilateral disease and 15 % will be unilateral.31 Since all the children of parents with unilateral disease carry the germ line mutation, 45% of their children will also develop retinoblastoma. In patients with no family history of retinoblastoma, if the affected child has unilateral retinoblastoma, 1% of the siblings are at risk and 8% of the offspring may develop retinoblastoma. In cases of bilateral retinoblastoma with no positive family history, 6% of the siblings and 40% of the offspring have a chance of developing retinoblastoma.

Recent Advances

The recent work on genetics of retinoblastoma is focused on identification of new mutations and preimplantation genetic testing for families who have children affected with germinal retinoblastoma.32 Identification of more mutations will help in designing a screening test panel for individuals at risk.33

Direct intra-arterial chemotherapy with melphalan has been tried recently in Phase I/II studies in patients with Reese-Ellsworth V eyes and has shown promising results in terms of globe salvage. Further studies are required in this direction to establish the feasibility and efficacy of this procedure.

In summary, the current trend is to provide an individualized (Table 20-5) multispecialty management for patients with retinoblastoma. The recent advances in the management of retinoblastoma have yielded gratifying outcome in terms of preservation of life, salvage of the eye, and optimal residual vision.

TABLE 20-5: Current suggested protocol

A.Intraocular tumor, Reese-Ellsworth Groups 1 to 4, Unilateral or Bilateral

1.Focal therapy alone for smaller tumors if the standard tumor size indications are satisfied.

2.Standard 6 cycle Chemoreduction and sequential aggressive focal therapy for larger tumors and all tumors located in the macular area.

3.Consider focal therapy for small residual tumor, and plaque brachytherapy/EBRT for large residual tumor if bilateral, and enucleation if unilateral.

B.Intraocular tumor, Reese-Ellsworth Groups 5A and 5B, Unilateral

Primary enucleation

C.Intraocular tumor, Reese-Ellsworth Groups 5A and 5B, Bilateral

1.High dose chemotherapy and sequential aggressive focal therapy

2.Consider focal therapy for small residual tumor, and plaque brachytherapy/EBRT for large residual tumor.

D.Advanced intraocular tumor, unilateral or bilateral, with neovascularization of iris, anterior segment seeds, iris infiltration, necrotic retinoblastoma with orbital inflammation, media opacity precluding tumor visualization, and eyes with no visual potential.

Primary enucleation

E.Extraocular tumor

1.Baseline CT scan / MRI, bone marrow and cerebrospinal fluid cytology

2.Intrathecal methotrexate if cerebrospinal fluid is positive for tumor cells

3.High dose Chemotherapy for 6 cycles, followed by enucleation or exenteration, external beam radiotherapy, and continued chemotherapy for 12 cycles

F.High-risk factors on histopathology

1.Standard 6 cycle adjuvant chemotherapy

2.High dose adjuvant chemotherapy and orbital external beam radiotherapy in patients with scleral infiltration,

Pediatric Intraocular Tumors–I

References

1.Bishop JO, Madsen EC. Retinoblastoma. Review of current status. Surv Ophthalmol 1975;19: 342-66.

2.Shields JA, Shields CL. Intraocular tumors – A text and Atlas. Philadelphia, PA, USA, WB Saunders Company,1992.

3.Abramson DH, Frank CM, Susman M, Whalen MP, Dunkel IJ, Boyd NW III. Presenting signs of retinoblastoma. J Pediatr 1998; 132:505-8.

4.Murthy R, Honavar SG, Naik MN, Reddy VA. Retinoblastoma. In Dutta LC (Ed): Modern Ophthalmology. New Delhi, India, Jaypee Brothers 2004;849-59.

5.Honavar SG, Singh AD. Management of advanced retinoblastoma. Ophthalmol Clin North Am 2005;18:65-73.

6.Ellsworth RM. The practical management of retinoblastoma. Trans Am Ophthalmol Soc 1969; 67: 462-534.

7.Linn Murphree A. Intraocular retinoblastoma: the case for a new group classification. Ophthalmol Clin North Am. 2005;18:41-53.

8.Shields CL, Shields JA. Basic understanding of current classification and management of retinoblastoma. Curr Opin Ophthalmol.2006;17:228-34.

9.Shields CL, Santos MC, Diniz W, et al. Thermotherapy for retinoblastoma. Arch Ophthalmol 1999; 117: 885-93.

10.Murray TG, Ciccearelli N, McCabe CM, et al. In vitro efficacy of carboplatin and hyperthermia in a murine retinoblastoma cell line. Invest Ophthalmol Vis Sci 1997;38(12): 2516-22.

11.Shields CL, Shields JA, Cater J, et al. Plaque radiotherapy for retinoblastoma, long term tumor control and treatment complications in 208 tumors. Ophthalmology 2001;108: 2116-21.

12.Imhof SM, Mourits MP, Hofman P, et al. Quantification of orbital and midfacial growth retardation after megavoltage external beam irradiation in children with retinoblastoma. Ophthalmology 1996;103(2): 263-8.

13.Abramson DH, Melson MR, Dunkel IJ, Frank CM. Third ( fourth and fifth) nonocular tumors in survivors of retinoblastoma. Ophthalmology 2001;108(10):1868-76.

14.Abramson DH, Frank CM. Second nonocular tumor in survivors of bilateral retinoblastoma: a possible age effect on radiation related risk. Ophthalmology 1998;105(4):573-9, discussion 79-80.

15.Ellsworth RM. Retinoblastoma. Modern problems in ophthalmology. 1977; 96:1826-30.

16.Hungerford JL, Toma NMG, Plowman PN, Kingston JE. External beam radiotherapy for retinoblastoma: I, whole eye technique. Br J Ophthalmol 1995;79:112-7.

17.Ferris FL, Chew EY. A new era for the treatment of retinoblastoma. Arch Ophthalmol 1996; 114:1412.

18.Gallie BL, Budning A, DeBoer G, Thiessen JJ, Koren G, Verjee Z, et al. Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy. Arch Ophthalmol 1996;114:1321-8.

19.Murphree AL, Villablanca JG, Deegan WF, 3rd, Sato JK, Malogolowkin M, Fisher A, et al. Chemotherapy plus local treatment in the management of intraocular retinoblastoma. Arch Ophthalmol 1996; 114:1348-56.

20.Shields CL, De Potter P, Himelstein BP, Shields JA, Meadows AT, Maris JM. Chemoreduction in the initial management of intraocular retinoblastoma. Arch Ophthalmol 1996; 114:1330-8.

21.Shields CL, Mashayekhi A, Demirci H, Meadows AT, Shields JA. Practical approach to management of retinoblastoma. Arch Ophthalmol 2004 May;122(5):729-35.

22.Honavar SG, Shome D, Reddy VAP. Periocular carboplatin in the management of advanced intraocular retinoblastoma. Proceedings of the XII International Congress of Ocular Oncology, Vancouver, Canada, 2005.

23.Mendelsohn ME, Abramson DH, Madden T, Tong W, Tran HT, Dunkel IJ. Intraocular concentration of chemotherapeutic agents after systemic and local administration. Arch Ophthalmol 1998; 116(9):1209-12.

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

25.Singh AD, Shields CL, Shields JA. Prognostic factors in retinoblastoma. J Pediatr Ophthalmol Strab 2000; 37:13441.

26.Kopelman JE, McLean IW, Rosenberg SH. Multivariate analysis of risk factors for metastasis in retinoblastoma treated by enucleation. Ophthalmology 1987; 94:371-7.

27.Shields CL, Shields JA, Baez KA, et a. Choroidal invasion of retinoblastoma: Metastatic potential and clinical risk factors. Br J Ophthalmol 1993; 77:544- 8.

28.Shields CL, Shields JA, Baez K, Cater JR, De Potter P. Optic nerve invasion of retinoblastoma. Metastatic potential and clinical risk factors. Cancer 1994; 73:692-8.

29.Honavar SG, Singh AD, Shields CL, Demirci H, Smith AF, Shields JA. Postenucleation prophylactic chemotherapy in highrisk retinoblastoma. Arch Ophthalmol 2002; 120:923-31.

30.Dunket IJ, Aledo A, Kerman NA, Kushner B, Bayer L, Gollamundi SV, et al. Successful treatment of metastatic retinoblastoma. Cancer 2000; 89:2117-21.

31.Abramson DH, Schefler AC. Update on retinoblastoma. Retina 2004; 24(6):828-45.

32.Xu K, Rosenwaks Z, Beaverson K, Cholst I, Veeck L, Abramson DH. Preimplantation genetic diagnosis for 255 retinoblastoma: the first reported liveborn. Am J Ophthalmol 2004; 137(1): 18-23.