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Ophthalmology / Paediatric ophthalmology

Trends in the Management of Retinoblastoma: Evaluation of 1,196 Consecutive Eyes During 1974 to 2001

John A. Epstein, MD Carol L. Shields, MD Jerry A. Shields, MD Reprinted from Epstein, JA, Shields, CL, Shields, JA. Trends in the Management of Retinoblastoma: Evaluation of 1,196 Consecutive Eyes During 1974 to 2001. J Pediatr Ophthalmol Strabismus. 2003;40(4):196-203.
Article


Introduction

Retinoblastoma is the most common malignant intraocular tumor in children,1 occurring in approximately 1 of 23,000 live births.2 For many years, the conventional treatment of retinoblastoma was primary enucleation.3 More recently, several authors have reported a trend toward the decreasing frequency of enucleation in the management of retinoblastoma.2-6 This has been largely attributed to earlier diagnosis and previous success with conservative management7,8 such as external beam radiotherapy,9,10 photocoagulation,11 cryotherapy,12 and plaque irradiation.13 Recent advancements in the use of chemoreduction combined with local therapy14-16 have greatly expanded clinical options and the effect on the overall enucleation rate for retinoblastoma has not yet been explored. In this article, we examine our experience with the management of retinoblastoma during 12 years (1989 to 2001) and compare treatment strategies, especially the need for enucleation, of this period with those of the period 1974 to 1988.

Patients and Methods

Data were retrospectively collected from all patients diagnosed as having retinoblastoma who received initial and follow-up treatment in the Ocular Oncology Service at Wills Eye Hospital, Philadelphia, Pennsylvania, between January 1989 and May 2001. The features of the patient and tumor, as well as the various treatments performed and the ultimate outcome, were recorded.

The patient data included features on initial examination such as age, gender, race (white, African American, Hispanic, or Asian), laterality of the disease, affected eye (right, left, or both), family history of the disease, the date first seen, and the date last seen.

The tumor data included the number of tumors, the Reese-Ellsworth classification (Ia, Ib, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, or Vb), and the presence of associated vitreous seeds, subretinal seeds, or both.

Treatment data included both primary and secondary treatments as classified into one of four major groups: enucleation, chemoreduction with consolidative therapy, external beam radiotherapy, and focal treatment only. Focal treatment included laser photocoagulation, cryotherapy, thermotherapy, or plaque radiotherapy without previous chemotherapy or radiotherapy. The indications for the various treatment options have been published elsewhere.7

Results

The general information regarding patient demographics is listed in Table 1, and tumor characteristics in Table 2. Treatment data were assessed based on unilateral or bilateral disease. Results for the management of unilateral retinoblastoma are listed by Reese-Ellsworth classification (Table 3) and by tumor seeding (Table 4). Data regarding enucleation for unilateral retinoblastoma are presented by year in Table 5, and are grouped into six periods dating from 1974 in Table 6. Of those eyes initially treated with non-enucleation methods, 17% in Reese-Ellsworth groups I to III and 44% in groups IV and V required secondary enucleation. Results for the management of bilateral retinoblastoma are listed by Reese-Ellsworth classification (Table 7) and by tumor seeding (Table 8). Data regarding enucleation of bilateral retinoblastoma are presented by year in Table 9, and are grouped into six periods dating from 1974 in Table 10.

Discussion

Retinoblastoma is a rare cancer that affects not only globe and vision outcome, but also life prognosis. Current treatment options for retinoblastoma include enucleation, focal therapy (such as laser photocoagulation,11 cryotherapy,12 transpupillary thermotherapy,17 and plaque radiotherapy13), chemoreduction with focal therapy,14 and external beam radiotherapy.9,10 Enucleation continues to be an excellent therapeutic modality in more advanced cases, but earlier detection and improved conservative measures have allowed improved globe salvage in recent years.7 In this study, we investigated the effects of newer treatment alternatives on enucleation rates during recent years and noted that enucleation (for one eye) had stabilized in both unilateral and bilateral cases at 75% and 64%, respectively, during 1989 to 2001.

Enucleation continues to be necessary for advanced retinoblastoma, particularly if there is no hope for useful vision in the affected eye or if invasion of the tumor into the optic nerve, choroid, or orbit is suspected.7 External beam radiotherapy is also employed for advanced disease with vitreous seeding, but recurrence is problematic. Hungerford et al. found that external beam radiotherapy using a whole eye technique provided an overall ocular cure rate of 57% for Reese-Ellsworth groups I to V.9 When combined with additional salvage therapy, the cure rate increased to 80%.9 The use of external beam radiotherapy is limited by tumor recurrence,18 local side effects,19 and, importantly, risks for secondary neoplasms.20-22 Chemoreduction can be a valuable adjunctive measure for the management of retinoblastoma. Dramatic reduction of tumor thickness by a mean of 50% and impressive resolution of associated subretinal fluid has fueled the popularity of chemoreduction.23 Chemoreduction led to a temporary decrease in the enucleation rate for retinoblastoma in the mid-1990s, but once experience was gained with the limitations of this technique, the enucleation rate rebounded to previous levels (Table 5 and Table 9).

In 1982, Abramson et al. reported on the conservative management (non-enucleation strategies) of unilateral retinoblastoma.6 Of 586 patients initially diagnosed between 1914 and 1982 as having unilateral retinoblastoma, 520 (89%) were treated with primary enucleation and 57 (10%) were primarily treated with conservative methods. Our study contributes more recent information on enucleation for retinoblastoma. Of the 282 children with unilateral retinoblastoma we evaluated from 1989 to 2001, 183 (65%) were treated with enucleation and 99 (35%) were treated conservatively (Table 4). When analyzing primary enucleation per Reese-Ellsworth classification, it is evident that more patients in groups IV and V (178 of 225, 79%) undergo enucleation than those in groups I to III (5 of 59, 8%). During the period of 1989 to 2001, the overall enucleation rate was 75%, whereas during the period of 1914 to 1982, the rate was 92%.6

From 1989 to 2001, enucleation remained the most common primary therapy for children with unilateral retinoblastoma (Table 3). However, conservative measures have been and continue to be effective for selected cases. Abramson et al. commented on specific conservative management for unilateral retinoblastoma in their analysis of 57 such patients treated between 1914 and 1982.6 They reported that 48 (84%) of the patients were treated with external beam radiotherapy, 8 (14%) of the patients received focal treatment with laser photocoagulation or cryotherapy, and 1 (2%) of the patients was treated with a cobalt plaque. They observed that of 39 patients in Reese-Ellsworth groups I to III, 5 (13%) ultimately required enucleation, and of 14 patients in groups IV and V, 12 (86%) eventually required enucleation. Four eyes were unclassifiable in terms of a Reese-Ellsworth group, having received prior treatment elsewhere, and all of these patients required enucleation. They concluded that conservative treatment was appropriate for retinoblastoma, mostly for patients in groups I to III. In our study of 99 patients with unilateral retinoblastoma who received conservative treatment, 21 (21%) were treated with external beam radiotherapy, 34 (34%) received focal treatment, and 44 (44%) received chemoreduction. For patients in Reese-Ellsworth groups I to III treated conservatively, 9 (17%) of 53 ultimately required enucleation. For patients in groups IV and V, 20 (44%) of 45 required secondary enucleation. Conservative management with non-enucleation measures appears feasible in Reese-Ellsworth groups I to III, with 83% success during the 12-year period, similar to that noted in the early 1980s.6 For eyes in Reese-Ellsworth groups IV and V, improvement in ocular salvage has been achieved with 66% globe salvage currently compared with 14% previously.6

For the management of bilateral disease, we noted a high rate of conservative treatment in all Reese-Ellsworth groups. Only 17% of eyes were primarily enucleated, compared with 65% of eyes of patients with unilateral retinoblastoma. When assessing both eyes (n = 445) in bilateral cases, the primary treatment for Reese-Ellsworth groups I to III included enucleation (0%), chemoreduction (35%), external beam radiotherapy (20%), focal therapy (37%), and no treatment (8%). In contrast, Reese-Ellsworth group V was managed primarily with enucleation (37%), chemoreduction (32%), external beam radiotherapy (17%), and focal treatment (14%). There are numerous factors that enter into the choice of treatment, such as the size and extent of the tumor(s) and the status of the opposite eye. Thus, chemoreduction might be a therapeutic choice for Reese-Ellsworth group V, especially if the opposite eye required chemoreduction. Those eyes with vitreous seeding were more likely enucleated in unilateral (76%) as opposed to bilateral (13%) cases. Similarly, those eyes with subretinal seeds were more likely enucleated in unilateral (49%) as opposed to bilateral (14%) cases. The overall rate of enucleation of one eye in bilateral cases remained stable at approximately 64%. The only exception to this rate was the period from 1994 to 1998, when it decreased to 44% after chemoreduction was introduced.

In a previous study from our department, the rate of enucleation for unilateral retinoblastoma decreased from 96% (from 1974 to 1978) to 75% (from 1984 to 1988).3 Additionally, the rate of enucleation for bilateral retinoblastoma remained stable (67% from 1974 to 1978 and 65% from 1984 to 1988).3 Other authors have noted similar decreasing rates of enucleation for unilateral retinoblastoma (from 97% to 87%) and enucleation for bilateral retinoblastoma in one eye (from 67% to 58%) during the periods from 1951 to 1965 and from 1966 to 1980.4 Adding our new data to those of our previous study during the period from 1974 to 1988, we can now follow management trends during the past 27 years. Comparison of the enucleation trend for unilateral retinoblastoma from 1974 to 2001 shows a decrease from 96% (1974 to 1978) that has stabilized at approximately 75% (1989 to 2001), although the past few years seem to show an increase to 81% (1999 to 2001), again hinting at the limitations of chemoreduction. For bilateral retinoblastoma, cases with both eyes enucleated decreased from 24% (1974 to 1978) to 10% (1984 to 1988) to 2% (1999 to 2001). Bilateral cases that avoided enucleation in either eye increased from 4% (1974 to 1978) to 25% (1984 to 1988) to 36% (1989 to 2001).

There are several limitations to this study. First, the follow-up time for our more recent patients may be inadequate to fully appreciate the trends of enucleation, and may therefore underestimate the number of patients with secondary enucleation. Second, because our practice is a tertiary referral center, our sample may not be representative of all patients with retinoblastoma. Our population showed a predominance of advanced Reese-Ellsworth group V retinoblastoma and more patients with bilateral disease. This may indicate that more serious cases are referred to us, and also that there are still a substantial number of patients whose disease is detected at an advanced stage. Thus, continued emphasis on early screening and diagnosis is advised.

Our results show that the enucleation rate for unilateral retinoblastoma has stabilized during the past 27 years at approximately 75%. The enucleation rate for one eye in bilateral retinoblastoma has drifted depending on treatment strategies, but has generally stabilized at 64%. The enucleation rate for both eyes in bilateral retinoblastoma has continued to decrease from 29% in the 1970s to 2% currently. Patients with bilateral retinoblastoma who avoided enucleation altogether increased from 4% in the 1970s to approximately 36% currently. Much of this trend can be attributed to advancements in conservative therapy, and, importantly, earlier diagnosis.

References

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  2. Saunders BM, Draper GJ, Kingston JE. Retinoblastoma in Great Britain 1969-1980: incidence, treatment, and survival. Br J Ophthalmol. 1988;72:576-583.

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

  4. Abramson DH, Niksarli K, Ellsworth RM, Servodidio CA. Changing trends in the management of retinoblastoma: 1951-1965 vs 1966-1980. J Pediatr Ophthalmol Strabismus. 1994;31:32-37.

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Posted May 2004