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External beam radiation therapy and retinoblastoma: Long-term results in the comparison of two techniques
Int. J. Radiation
Oncology
Biol. Phys.. Vol 35, No. I. pp. 45-51, 1996 Copyright 0 1996 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-X)16/96 $15.00 + .OO
SSDI: 0360-3016( 95 )02204-X
ELSEVIER
l Clinical
Original Contribution
EXTERNAL BEAM RADIATION THERAPY AND RETINOBLASTOMA: LONG-TERM RESULTS IN THE COMPARISON OF TWO TECHNIQUES LAURIE E. BLACH, M.D.,* BERYL MCCORMICK, M.D.*
AND
*Memorial Sloan-Kettering Cancer Center and the ‘New York Hospital-Cornell
DAVID H. ABRAMSON, M.D.+ Medical
Center,
New York, NY
Purpose: This study compares the long-term actuarial local control, eye conservation rate, survival, and ocular complications in children with retinoblastoma treated with two different external beam treatment techniques. Methods and Materials: From 1979-1991,182 eyes in 123 children (104 bilateral) received primary external beam radiation therapy. An anterior lens-sparing electron beam technique delivering 38 to 50 Gy in 2.5 Gy fractions was used in 67 eyes from 1979-1984 and a modified lateral beam technique, delivering 42 to 46 Gy in 2 Gy fractions, was used in 113 eyes from 1984-1991. These groups were balanced with respect to known prognostic variables. Results: For Group I-III eyes, the 5- and S-year local control was significantly improved using the modified lateral beam technique (84% ) compared to (38% ) using the anterior lens sparing technique (p p 5 0.0001). For Group IV-V eyes, the 5 and I-year local control rates were not statistically different, despite a trend favoring the modified lateral beam technique. Survival endpoints including eye survival (no enucleation), cause-specific survival, and overall survival comparing the two treatment techniques were not significantly different. Overall, 22% of eyes developed cataracts. There was no difference between the two treatment groups in terms of cataract development. No eyes required enucleation for ocular complications. Conclusion: There is a significant improvement in local control using the modified lateral beam technique compared to an anterior lens-sparing approach for Group I-III eyes. However, there was no difference in survival end points between the two treatment techniques. The incidence of ocular complications using these two external beam techniques is acceptable. Retinoblastoma,
Radiation
therapy,
External
beam radiation.
INTRODUCTION
the lens, our group developed an anterior lens-sparing technique (ALS) in 1979. This technique has been previously described in detail (4, 20, 2 1). This technique produced isodose distributions, thought acceptable, but at initial analysis of our results, we discovered that there was an unacceptable number of local relapses requiring additional therapy. Therefore, in 1984 we returned to the use of a traditional lateral “D”-shaped field but with a few significant modifications as previously described (20, 21). This modified lateral beam technique (MLB) resulted in a significant advantage for Group I-III eyes in terms of local relapse, but this did not translate into a significant improvement in eye survival (20, 21). Follow-up, however, was too short to accurately compare ultimate need for enucleation, cataract formation, and survival.
Historically, children with retinoblastoma were treated with enucleation. However, as the successful use of radiation therapy in the treatment of this disease was documented (6, 7, 10, 23), external beam radiation therapy (EBRT) evolved into a standard eye-conserving treatment for children with intraocular bilateral disease ( 10, 11, 12, 18). Traditionally, a single “D”-shaped lateral field with the anterior border placed at the outer canthus was used ( 10). This method left the anterior portion of the retina untreated and resulted in recurrence in this region. The difficulty in treating the entire retina without delivering a significant dose to the lens continues to present a challenge to the radiation oncologist. In an attempt to treat the anterior retina while sparing
Presented at the 36th Annual Meeting of American Society Therapeutic Radiology and Oncology, San Francisco, CA, October 2-6, 1994. Reprint requests to: Beryl McCormick, M.D., Department of
Radiation Oncology, H-208, Memorial Sloan-Kettering Center, 1275 York Ave., New York, NY 10021. Accepted for publication 1 November 1995.
45
Cancer
46
1. .I. Radiation
Oncology
l
Biology 0 Physics
Volume
35, Number
I. 1996
Table 1. Reese-Ellsworth classification (%) Group Group Group Group Group Group
I II III IV V
ALS 16 (24) 10 (15) 9 (13) 5 (7) 27 (40)
MLB 25 22 13 8 45
(22) (19) (12) (7) (40)
ALS = anterior lens-sparing technique. MLB = modified lateral beam technique.
This report presents the long-term follow-up results in the comparison of these two external beam radiation therapy (EBRT) techniques in children treated for retinoblastoma (RB). This series also represents the largest cohort of children treated for retinoblastoma (RB). This series also represents the largest cohort of children consecutively irradiated for RB in a single institution in the modem radiotherapy era (5, 13, 16, 26-28).
METHODS
AND
MATERIALS
From 1979- 199 1 395 children with RB were evaluated at the New York Hospital-Cornell Medical Center Ophthalmic Oncology Clinic. Of these, 123 children were referred for radiation therapy to Memorial Sloan-Kettering Cancer Center. The others either underwent enucleation for unilateral disease or were referred for radiation therapy to institutions closer to their homes. During this time period, all children who had bilateral RB were treated with radiation therapy and/or other eye-sparing methods to one or both eyes. No child underwent bilateral enucleations as initial treatment. A total of 180 eyes in 123 children ( 104 bilateral, 19 unilateral) was primarily irradiated for RB. An anterior lens sparing technique (ALS) was used in 67 eyes from 1979- 1984 and a modified lateral beam (MLB) technique in 113 eyes from 1984- 199 1. There were approximately equal numbers of males and females, and (30%) had a family history of RB. The two EBRT treatment groups were balanced with regard to prognostic variables including Reese-Ellsworth classification group, number of unilateral eyes, initial age at diagnosis of RB, administration of chemotherapy, and family history of RB. All children who underwent radiation therapy were initially evaluated with ophthalmic examination under anesthesia, routine blood work (including CBC, screening profile, and electrolytes), cerebrospinal fluid cytology, bone marrow biopsy, and a head computerized tomography scan (CT) or magnetic resonance image (MRI) to rule out extra ocular extension and/or metastatic disease. All diagnoses were made clinically. All eyes were classi-
’ Olympic Medical Supply, Seattle, WA.
Fig. 1. Isodose distribution for patients wiht bilateral disease, using anterior lens-sparing technique.
fied using the Reese-Ellsworth classification system. Approximately half were Group I-III eyes and the other half were Group IV-V eyes (Table 1). Fifteen percent received chemotherapy for evidence of extra ocular disease at the time of salvage enucleation, but none received initial systemic treatment. Eyes that relapsed after irradiation were treated by other eye-sparing methods including cryotherapy, photocoagulation, reirradiation, or plaque therapy. Eyes were enucleated for failure of salvage therapy or if the initial relapse was of such an advanced nature that focal methods would not be of use. Simulation and treatment-planning details have been previously published (4, 20, 21). Briefly, prior to simulation, a tight-fitting plaster cast was fabricated to the child’s head and neck and molded onto a “papoose board” ’ for immobilization. Sedation was used when necessary. For the ALS technique, a lateral “D”-shaped photon field was placed with the anterior border at the lateral bony rim of the orbit. This field was irradiated 4 days per week. On the fifth day, an anterior electron beam field was used with a circular contact lens inserted in the eye as a lens shield. Children were anesthetized with ketamine for this treatment. Figure 1 shows the composite isodose distribution of this approach. The dose prescribed to the
External
beam radiation
therapy
and retinoplastoma
l
L. E.
BLACH
et nl.
41
Freedom from relapse (local control ) , need for enucleation (eye survival), cause-specific survival, and overall survival were analyzed using Kaplan-Meier survival curves. Relapse or local failure was defined as the need for any additional treatment to the irradiated eye. A true failure of irradiation was defined as the need for enucleation. The development of cataracts between the two treatment techniques was compared using the chi-square statistic.
RESULTS
Fig. 2. Isodose distribution for child with bilateral disease, using the modified lateral beam technique.
90% isodose contour ranged from 38.5 to 50 Gy in daily fractions of 2.50 Gy. For the MLB technique, a lateral “D”-shaped field was designed, which placed the anterior border at 2 to 3 mm posterior to the surgical limbus. The isocenter was placed at the anterior border to avoid divergence into the lens. For the period in which the MLB technique was used, a dose of 42 to 46 Gy was prescribed to the 90% isodose curve and a lower daily fraction of 2 Gy was used. For patients with bilateral eye disease, two lateral parallel opposed “D”-shaped photon fields were used. Figure 2 shows the composite isodose distribution of this technique. For patients with bilateral disease who had previously undergone unilateral enucleation, a single lateral “D”-shaped photon tield was treated exiting through the fellow socket. For patients with unilateral disease, the single oblique held described by Schipper (25) was modified in several ways (20, 21). A composite arrangement using three fields was produced that avoided the uninvolved eye and whose composite isodose curves are shown in Fig. 3. For the first two-thirds of treatment, a pair of superior and anterior wedged oblique “D”-shaped fields were used, weighting up the superior oblique field to avoid a significant exit dose to the frontal lobe. For the last one-third of the treatment, a “D”-shaped lateral electron beam field was used with the anterior border placed 2-3 mm behind the limbus.
A detailed comparison between the two techniques is presented in Table 2. With a median follow-up of 52 months for the MLB group (range 4 to 108 months) and 101 months for the ALS group (range 13 to 159 months) the S- and 8-year actuarial local control or freedom from relapse (FFR) was improved using the MLB technique overall (38 vs. 65%) (p = 0.0001) and for Group I-III eyes (37 vs. 84%) (p < 0.0001) (Fig. 4). For Group IV-V eyes the difference (34 vs. 50%) was not significant (Fig. 5). A comparison of eye survival (no enucleation) for the two techniques is presented in Table 2. Despite a trend favoring the MLB technique for Group I-III eyes (94 vs. 8 l%), this difference was not significant (Fig. 6). There was no significant difference in eye survival overall and for Group IV-V eyes (Fig. 7). Many relapses,
Fig. 3. Isodose distribution for a child with unilateral disease, using the modified lateral beam technique with three separate fields.
1. J. Radiation Oncology
48
Table 2. Actuarial
0 Biology
0 Physics
Volume 35, Number 1, 1996
local control and eye survival
Local control
%
Local
Eye survival
%
Control
Group
IV-V Eyes
100 90
No. eyes
Group
5 years
8 years
5 years
8 years
80
I-III ALL ALS MLB
96 35 61
67 37 84
67 37 84
p < 0.0001
90 85 94
88 81 94
p = NS
IV-V ALL ALS MLB
84 32 52
44 38 50
44 34 50
p = NS
60 60 61
60 60 61
p = NS
I-V ALS MLB
180 67 113
56 38 65
56 38 65
p < 0.0001
76 73 78
75 71 78
p = NS
-
MLB Tcchnape
______.
ALS Tcchnqur
10
p =
Group
I-III
Eyes
90
7
70
E s 7
60
-1 g
40
8
30
50
iI : i
84%
!. ‘I
-I__, :. :___,
--~~~~-~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.
37% -
MLB Technques
20 10 0 I2
24
36
48
60
72
84
96
108
120
Months
Fig. 4. Comparison
I
24
36
Fig. 5. Comparison
100
80
I
NS
4'8 6'0 7'2 8'4 9'6 It;8I;0 I;2 I;4
6
Months
defined as the need for any additional treatment, could be successfully treated using other eye-sparing methods including cryotherapy, photocoagulation, and plaque therapy. Twenty-two percent of eyes developed cataracts overall. There was no difference in cataract development between the two treatment techniques. All enucleations were performed for failure of salvage therapy or for initial treatment failure for very advanced disease in which there appeared to be no hope of successful salvage by focal eye sparing methods. No eyes were enucleated for complications of therapy. Actuarial cause-specific survival for RB was 94% at 5 and 8 years. Six children out of the 123 treated with radiation therapy died due to metastatic RB. All of these six had the bilateral form of RB and all were diagnosed
Control
8 12
ALS = anterior lens sparing. MLB = modified lateral beam. NS = not significant.
Local
0
of local control for Group I-III
eyes.
of local control for Group IV-V
eyes.
with Group V RB after the age of 8 months. Actuarial overall survival at 5 and 8 years was 87%. Overall and cause-specific survival was not influenced by the treatment technique. Eight children have died from a second primary malignancy, seven of these from “Trilateral Retinoblastoma” (8) and only one from the development of a malignancy within the radiation field.
DISCUSSION Radiation therapy has been widely used in the treatment of RB. However, the EBRT technique used in the treatment of RB has varied and evolved over the years. This study compares the results of two different EBRT treatment techniques that were used at our institution over the last decade. Table 2 provides a detailed comparison between the two EBRT techniques. This study confirms our initial results in the comparison of the ALS and MLB EBRT treatment techniques (20, 21). For Group I-III eyes, the MLB technique was found to be superior to the ALS technique in terms of local control (p 5 0.0001). Although there was a trend favoring the MLB technique for Group IV-V eyes, this trend did not attain statistical significance, even with longer follow-up. The difference in local control between the two treatment techniques is potentially attributable to a shift of the contact lens block, to the isodose distribution of the anterior lens-sparing technique, and the shadow under the lens block. Despite the improved local control using the MLB technique, survival end points including eye survival, and cause-specific and overall survival were similar using the two treatment techniques. This is due to the successful use of salvage eye-sparing methods including cryotherapy, photocoagulation, and radiation plaque therapy.
External beam radiation therapy and retinoplastoma l L. E. BLACH et al.
49
Table 3. Comparison of crude external beam treatment results
Institut. Stanford
(13)
Eyes 38
Year
RT (Gy) dose
Technique
1956-74
35-60
Lateral Group I-III Group IV-V Lateral Lateral Anterior wedged pair Combined Anterior Group I-III Group IV-V Lateral Group I-III Group IV Lateral Group I-III Group IV-V Lateral Group I-III Group IV-VA Combined Anterior-ALS Group I-III Group IV-V Lateral-MLB Group I-III Group IV-V
U Oregon (16) U Indiana (28) Wills Eye (5)
22 12 13
1958-78 1967-72 1975-88
45-50 35-40 40-45
Mayo (27)
30
1977-89
39-51
New York (3)
74
1955-80
New York (2) Utrecht (26)
64 54
1955-80 1971-82
MSKC
180 67
113
1979-91 1979-84
1984-91
35-60#
45
38.5-50
42-44
% Eye surv (number) 58
% Cataract (number)
% css
66 (25)
96
5 (1) 25 (3) 31 (4)
86 100 100
(17/21) (5117) 83 83 77
100
(“90/l 1)
(5/5) (4/6) (1 l/14) (8/10) (3/4) 85 (63/74) 0 (19/64)
65
NA
29
NA
NA NA 33 (18)
92 88 100
94 (33135) 58 (11/19) 79
22 23.5
94
81 60 20.5 94 61
Orthovoltage era treatments excluded; enucleation results from Foote et al. (15); # includes betatron and Cobalt; enucleated worst eye, Group 5b eyes excluded & no Group 5a successes; some children received TEM initially; primary treatment with external beam only. ALS = Anterior lens sparing. MLB = Modified lateral beam. NA = Not available. CSS = Cause-specific survival. RT = Radiation therapy.
There was no significant difference in the development of cataracts in comparison of the two EBRT techniques. Only 22% of eyes developed cataracts in this series overall, which compares favorably to the incidence of cataract development in the literature, which ranges from 8 to 66% (median 31%) (5, 13, 16, 26-28). Ocular complications using these two external beam techniques were acceptable, as no eyes developed radiation retinopathy and none required enucleation for complications of treatment. This is comparable to the megavoltage external beam radiation therapy results reported by Sauerwein et al. (24) with the use of doses between 40 to 50 Gy. The Mayo clinic ( 15, 27) is the only other series that compares two different EBRT treatment techniques for RB. However, they concluded that an anterior technique is superior to a lateral technique. This is in direct contrast to our results. A possible explanation for this difference is the small number of patients in their series with a proportionally large percentage of Group III eyes and a
large number of the lateral technique failures occurring in the Group III eyes. After the ALS technique appeared to produce an increase in local relapse in our series, the decision was made to return to a lateral technique with a number of significant modifications as described above rather than use an anterior technique without lens blocking. The use of an anterior approach produces excellent lc,;l control; however, it introduces the inherent problems of lacrimal gland irradiation, exit of the beam through the brain, and cataracts in most patients (9, 18, 27). Although many have negated the importance of cataract development, we believe that the development of cataracts, although surgically treatable, can interfere with vision and result in disuse amblyopia. Occasionally, cataract removal can cause recurrence or extraorbital extension of disease (9). As the ultimate goal of RT is successful preservation of useful vision, the development of cataracts cannot be negated from the equation.
1. J. Radiation Oncology 0 Biology 0 Physics
50
Eye Survival
Group
I-III Eyes
100 90 80 -i
70
zt
60
cz
50
x w
40
$?
30
to-
MLD Tcchnquc
.
ALS Tachnqur
1.1-m-.
lo-
,> = NS
0 II
I 12
I 24
I 36
I 48
I 60
I 72
8 84
I 96
I I II 3081201321441561
1
Months
Fig. 6. Comparison of eye survival for Group I-III eyes.
Table 3 presents a comparison of crude eye survival between the different centers in the U.S. and from Utrecht (2, 3, 5, 13, 15, 16, 26-28). Local control or FFR could not be compared due to the differing definitions used to define relapse between papers, the difficulty in extracting this information from the data given, and the differences in reporting recurrent vs. new tumors. Of the 180 eyes irradiated in this report, 79% were conserved. Using the MLB technique, 19% (22 out of 113) underwent enucleation overall and only 5% with Group I-III eyes. This is comparable to the results of other series (2, 3, 5, 13, 16, 26-28) reported in the literature despite the fact that almost half of the eyes in this series had advanced disease at diagnosis. When stratified by early and late classification groups, the results of the MLB technique in terms of eye survival rate appear superior to some of the previously reported series, particularly for Group IV-V eyes (2, 3, 13. 26) (Table 3). This is despite the fact that some of these series selected cases for eye conservation, enucleated the worst eye in bilateral cases, and in some, excluded Group Vb eyes (3, 15, 16, 26-28). The cause-specific survival for this series is 94% at 5 and 8 years and 100% for children without a Group V eye. These results are comparable to those in the literature that report cause-specific survivals between 86 and 100% (2, 3, 5, 13, 16, 26-28) (Table 3). The actuarial overall survival of this cohort of 123 consecutively treated children for RB is 87% at 5 and 8 years. This is comparable to other EBRT series (2, 3, 13, 15, 16, 26). Overall survival of RB patients however, becomes increasingly dependent upon the development of second primary malignancies with longer follow-up. With a median follow-up of 68 months, trilateral retinoblastoma was the cause of death in seven, and an extracranial second malignancy in one. The inci-
Volume 35, Number 1, 1996
dence, outcome, and treatment approaches to “trilateral retinoblastoma” have been previously described (8). The increased incidence of second malignancies in children irradiated for RB has been studied in detail by Eng et al. (14). An attempt to avoid the induction of second tumors by EBRT in this genetically susceptible subset children has prompted some institutions to attempt to avoid the use of external beam radiation therapy in favor of other eye sparing modalities ( 1, 17, 19, 22, 29). These methods include the use of other visionsparing treatments such as cryotherapy. photocoagulation, and chemotherapy. Using this approach, EBRT or enucleation is reserved for failures ( 17, 22). However, when comparing results of alternate treatment strategies to primary external beam radiation therapy, the definition of “local control” must be universally applied. In this series, local failure was defined as the need for any additional treatment modality after primary external beam radiation therapy, including other focal eye-sparing methods. A true failure of irradiation was defined as the need for enucleation, and comparisons should be made accordingly.
CONCLUSION There is a significant improvement in local control of the irradiated eyes when a modified lateral beam technique is used as compared to an anterior lens-sparing technique. Survival end points and complications of the two techniques are similar. Due to an increase in cataract development and other potential complications using an anterior approach without lens blocking, we recommend the use of a modified lateral beam approach for the treatment of intraocular RB with EBRT.
Eye Survival
Group
IV-V Eyes
100. 90. 80. F
7 0.
.?;
6n.
2
50.
2 0
w^
40.
@
3
0. MLB Tecimque
20. 10.
-_____.
ALS Techn,qus p = NS
0. 12
2’4
3’6
4’8
6’0
7’2
8’4
9’6
lb81;~~,~2,~4,;,
x
Months
Fig. 7. Comparison
of eye survival
for Group IV-V
eyes.
External beam radiation therapy and retinoplastoma l L. E.
BLACH
et al.
51
REFERENCES I. Abramson, D. H.; Ellsworth, R. M.; Rozakis, G. W. Cyrotherapy for Retinoblastoma. Arch. Opthalmol. 100: 12531256; 1982. 2. Abramson, D. H.; Ellsworth, R. M.; Tretter, P.; Adams, K.; Kitchin, F. D. Simultaneous bilateral radiation for advanced bilateral retinoblastoma. Arch. Ophthalmol. 99: 17631766; 1981. 3. Abramson, D. H.; Ellsworth, R. M.; Tretter, P.; Javitt, J.; Kitchin. F. D. Treatment of bilateral groups I-III retinoblastoma with bilateral radiation. Arch. Opthalmol. 99:1761-1762; 1981. 4. Abramson, D. H.; Jereb, B; Ellsworth, R. M. External beam radiation for retinoblastoma. Bull. NY Acad. Med. .57:787803; 1981. 5. Amendola, B. E.; Lamm, F. R.; Markoe, A. M.: Karlsson, U. L.; Shields, J.; Shields, C. L.; Augsburger, J.; Brady, L. W.; Woodleigh, R.; Miller, C. Radiotherapy of retinoblastoma. A review of 63 children treated with different irradiation techniques. Cancer 66:21-26; 1990. 6. Bagshaw, M. A.; Kaplan, H. S. Supervoltage linear accelerator radiation therapy VIII. Retinoblastoma. Radiology 86:242-246; 1966. 7. Bedford, M. D.; Bedotto, C.; MacFaul P. A. Retinoblastoma: A study of 139 cases. Br. J. Ophthalmol. 55: 19-27; 1971. 8. Blach, L. E.; McCormick, B.: Abramson, D. H.; Ellsworth, R. M. Trilateral retinoblastoma-Incidence and outcome: A decade of experience. Int. J. Radiat. Oncol. Biol. Phys. 291729-733; 1994. 9. Brooks, H. L., Jr.; Meyer, D.; Shields, J. A.; Balas, A. G.; Nelson. L. B.; Fontanesi, J. Removal of radiation-induced cataracts in patients treated for retinoblastoma. Arch. Ophthalmol. 108:1701-1708; 1990. 10. Cassady, J. R.; Sagerman. R. H.; Tretter, P.; Ellsworth, R. M. Radiation therapy in retinoblastoma. Radiology 93:405-409; 1969. Il. Donaldson, S. S.; Egbert, P. R.; Lee, W.-H. Retinoblastoma. In: Pizzo, P. A., ed. Principles and practice of pediatric oncology, 2nd ed. Philadelphia: J. B. Lippincott Company; 1993:683-696. Biology, 12. Donaldson, S. S.; Smith, L. M. Retinoblastoma: presentation, aning tl. Cancer Inst. 85: 112 I - 1128; 1993. 13. Egbert, P. R.; Donaldson, S. S.; Moazed K.; Rosenthal, A. R. Visual results and ocular complications following radiotherapy for retinoblastoma. Arch. Ophthalmol. 96:1826-1830;1978. 14. Eng, C.; Li, F. P.; Abramson, D. H.; Ellsworth, R. M.; Wong, F. L.; Goldman, M. B.; Seddon, J.; Tarbell, N.: Boice, J. D., Jr. Mortality from second tumors among longterm survivors of retinoblastoma. J. Natl. Cancer Inst. 85:1121-l 128: 1993. 15. Foote, R. L.; Garretson, B. R.; Schomberg, P. J.; Buskirk, S. J.; Robertson, D. M.; Earle, J. D. External beam irradiation for retinoblastoma: Patterns of failure and dose-response analysis. Int. J. Radiat. Oncol. Biol. Phys. 16:823830; 1989.
16. Gagnon, J. D.; Ware, C. M.; Moss, W. T.; Stevens, K. R. Radiation Management of bilateral retinoblastoma: The need to preserve vision. Int. J. Radiat. Oncol. Biol. Phys. 6:669-673; 1980. chemotherapy use with 17. Gallie, B. Cyclosporin-modulated focal therapy: A new approach to retinoblastoma. Presented at the 10th symposium of the International Society of Genetic Eye Diseases. Niagara on the Lake, Ontario, Canada, June 24, 1994. 18. Halperin, E. C.; Constine, L. S.; Tarbell, N. J.; Kun, L. E. Retinoblastoma In: Pediatric radiation oncology, 2nd ed. New York: Raven Press; 1994. in the manage19. Kingston. J. Is there a role for chemotherapy ment of intraocular retinoblastoma? Presented at the 10th symposium of the International Society of Genetic Eye Diseases. Niagara on the Lake, Ontario, Canada, June 24, 1994. B.; Ellsworth, R.; Abramson, D.; Haik, B.; 20. McCormick, Tome, M.; Grabowski, E; LoSasso, T. Radiation therapy for retinoblastoma; Comparison of results with lens-sparing vs. lateral beam techniques. Int. J. Radiat. Oncol. Biol. Phys. l5:567-574; 1988. 21. McCormick, B.; Ellsworth, R.; Abramson, D.; loSasso, T; Grabowski, E. Results of external beam radiation for children with retinoblastoma: A comparison of two techniques. J. Pediatr. Ophthalmol. Strabismus 26:239-243; 1989. 22. Murphree, L. Chemoreduction of intraocular retinoblastoma. Presented at the 10th symposium of the InternationaI Society of Genetic Eye Diseases. Niagara on the Lake, Ontario, Canada, June 24, 1994. 23. Reese, A. B.; Ellsworth, R. M. The evaluation and current concept of retinoblastoma therapy. Trans. Am. Acad. Ophth. Otolaryng. 67: l64- 172; 1963. 24. Sauerwein, W.: Messmer, E.; Fitze, H.; Hopping, W.; Mohr, C.; Havers, W.; Sack, H. Late effects following treatment of Retinoblastoma (Meeting Abstract). Ninth Annual Meeting of the European Society for Therapeutic Radiology and Oncology. Montecatini, Terme, Italy, September 1215, 1990, p. 174. 25. Schipper, J. An accurate and simple method for megavoltage radiation therapy of retinoblastoma. Radiother. Oncol. l:31-41: 1983. 26. Schipper, J.; Tan, K. E. W. P.; van Peperzeel, H. A. Treatment of retinoblastoma by precision megavoltage radiation therapy. Radiother. Oncol. 3:117-132; 1985. 27. Schomberg P.; Foote, R.; Robertson, D.; Earle, J. External beam irradiation for retinoblastoma: A comparison of two treatment techniques. Proc. Annu. Meet. Am. Sot. Clin. Oncol. 1 l:A1286; 1992. 28. Shidnia, H.; Homback, N. B.; Helveston, E. M.; Gettlefinger. T.; Biglan, A. W. Treatment results of retinoblastoma at Indiana University Hospitals. Cancer 40:29172922; 1977. 29. Shields, J. A.; Giblin, M. E.; Shields, C. L.; Markoe, A. M.; Karlsson, U.; Brady, L. W.; Amendola, B. E.; Woodleigh, R. Episcleral plaque radiotherapy for retinoblastoma. Ophthalmology 96:530-537; 1989.
Oncology
Biol. Phys.. Vol 35, No. I. pp. 45-51, 1996 Copyright 0 1996 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-X)16/96 $15.00 + .OO
SSDI: 0360-3016( 95 )02204-X
ELSEVIER
l Clinical
Original Contribution
EXTERNAL BEAM RADIATION THERAPY AND RETINOBLASTOMA: LONG-TERM RESULTS IN THE COMPARISON OF TWO TECHNIQUES LAURIE E. BLACH, M.D.,* BERYL MCCORMICK, M.D.*
AND
*Memorial Sloan-Kettering Cancer Center and the ‘New York Hospital-Cornell
DAVID H. ABRAMSON, M.D.+ Medical
Center,
New York, NY
Purpose: This study compares the long-term actuarial local control, eye conservation rate, survival, and ocular complications in children with retinoblastoma treated with two different external beam treatment techniques. Methods and Materials: From 1979-1991,182 eyes in 123 children (104 bilateral) received primary external beam radiation therapy. An anterior lens-sparing electron beam technique delivering 38 to 50 Gy in 2.5 Gy fractions was used in 67 eyes from 1979-1984 and a modified lateral beam technique, delivering 42 to 46 Gy in 2 Gy fractions, was used in 113 eyes from 1984-1991. These groups were balanced with respect to known prognostic variables. Results: For Group I-III eyes, the 5- and S-year local control was significantly improved using the modified lateral beam technique (84% ) compared to (38% ) using the anterior lens sparing technique (p p 5 0.0001). For Group IV-V eyes, the 5 and I-year local control rates were not statistically different, despite a trend favoring the modified lateral beam technique. Survival endpoints including eye survival (no enucleation), cause-specific survival, and overall survival comparing the two treatment techniques were not significantly different. Overall, 22% of eyes developed cataracts. There was no difference between the two treatment groups in terms of cataract development. No eyes required enucleation for ocular complications. Conclusion: There is a significant improvement in local control using the modified lateral beam technique compared to an anterior lens-sparing approach for Group I-III eyes. However, there was no difference in survival end points between the two treatment techniques. The incidence of ocular complications using these two external beam techniques is acceptable. Retinoblastoma,
Radiation
therapy,
External
beam radiation.
INTRODUCTION
the lens, our group developed an anterior lens-sparing technique (ALS) in 1979. This technique has been previously described in detail (4, 20, 2 1). This technique produced isodose distributions, thought acceptable, but at initial analysis of our results, we discovered that there was an unacceptable number of local relapses requiring additional therapy. Therefore, in 1984 we returned to the use of a traditional lateral “D”-shaped field but with a few significant modifications as previously described (20, 21). This modified lateral beam technique (MLB) resulted in a significant advantage for Group I-III eyes in terms of local relapse, but this did not translate into a significant improvement in eye survival (20, 21). Follow-up, however, was too short to accurately compare ultimate need for enucleation, cataract formation, and survival.
Historically, children with retinoblastoma were treated with enucleation. However, as the successful use of radiation therapy in the treatment of this disease was documented (6, 7, 10, 23), external beam radiation therapy (EBRT) evolved into a standard eye-conserving treatment for children with intraocular bilateral disease ( 10, 11, 12, 18). Traditionally, a single “D”-shaped lateral field with the anterior border placed at the outer canthus was used ( 10). This method left the anterior portion of the retina untreated and resulted in recurrence in this region. The difficulty in treating the entire retina without delivering a significant dose to the lens continues to present a challenge to the radiation oncologist. In an attempt to treat the anterior retina while sparing
Presented at the 36th Annual Meeting of American Society Therapeutic Radiology and Oncology, San Francisco, CA, October 2-6, 1994. Reprint requests to: Beryl McCormick, M.D., Department of
Radiation Oncology, H-208, Memorial Sloan-Kettering Center, 1275 York Ave., New York, NY 10021. Accepted for publication 1 November 1995.
45
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Oncology
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Volume
35, Number
I. 1996
Table 1. Reese-Ellsworth classification (%) Group Group Group Group Group Group
I II III IV V
ALS 16 (24) 10 (15) 9 (13) 5 (7) 27 (40)
MLB 25 22 13 8 45
(22) (19) (12) (7) (40)
ALS = anterior lens-sparing technique. MLB = modified lateral beam technique.
This report presents the long-term follow-up results in the comparison of these two external beam radiation therapy (EBRT) techniques in children treated for retinoblastoma (RB). This series also represents the largest cohort of children treated for retinoblastoma (RB). This series also represents the largest cohort of children consecutively irradiated for RB in a single institution in the modem radiotherapy era (5, 13, 16, 26-28).
METHODS
AND
MATERIALS
From 1979- 199 1 395 children with RB were evaluated at the New York Hospital-Cornell Medical Center Ophthalmic Oncology Clinic. Of these, 123 children were referred for radiation therapy to Memorial Sloan-Kettering Cancer Center. The others either underwent enucleation for unilateral disease or were referred for radiation therapy to institutions closer to their homes. During this time period, all children who had bilateral RB were treated with radiation therapy and/or other eye-sparing methods to one or both eyes. No child underwent bilateral enucleations as initial treatment. A total of 180 eyes in 123 children ( 104 bilateral, 19 unilateral) was primarily irradiated for RB. An anterior lens sparing technique (ALS) was used in 67 eyes from 1979- 1984 and a modified lateral beam (MLB) technique in 113 eyes from 1984- 199 1. There were approximately equal numbers of males and females, and (30%) had a family history of RB. The two EBRT treatment groups were balanced with regard to prognostic variables including Reese-Ellsworth classification group, number of unilateral eyes, initial age at diagnosis of RB, administration of chemotherapy, and family history of RB. All children who underwent radiation therapy were initially evaluated with ophthalmic examination under anesthesia, routine blood work (including CBC, screening profile, and electrolytes), cerebrospinal fluid cytology, bone marrow biopsy, and a head computerized tomography scan (CT) or magnetic resonance image (MRI) to rule out extra ocular extension and/or metastatic disease. All diagnoses were made clinically. All eyes were classi-
’ Olympic Medical Supply, Seattle, WA.
Fig. 1. Isodose distribution for patients wiht bilateral disease, using anterior lens-sparing technique.
fied using the Reese-Ellsworth classification system. Approximately half were Group I-III eyes and the other half were Group IV-V eyes (Table 1). Fifteen percent received chemotherapy for evidence of extra ocular disease at the time of salvage enucleation, but none received initial systemic treatment. Eyes that relapsed after irradiation were treated by other eye-sparing methods including cryotherapy, photocoagulation, reirradiation, or plaque therapy. Eyes were enucleated for failure of salvage therapy or if the initial relapse was of such an advanced nature that focal methods would not be of use. Simulation and treatment-planning details have been previously published (4, 20, 21). Briefly, prior to simulation, a tight-fitting plaster cast was fabricated to the child’s head and neck and molded onto a “papoose board” ’ for immobilization. Sedation was used when necessary. For the ALS technique, a lateral “D”-shaped photon field was placed with the anterior border at the lateral bony rim of the orbit. This field was irradiated 4 days per week. On the fifth day, an anterior electron beam field was used with a circular contact lens inserted in the eye as a lens shield. Children were anesthetized with ketamine for this treatment. Figure 1 shows the composite isodose distribution of this approach. The dose prescribed to the
External
beam radiation
therapy
and retinoplastoma
l
L. E.
BLACH
et nl.
41
Freedom from relapse (local control ) , need for enucleation (eye survival), cause-specific survival, and overall survival were analyzed using Kaplan-Meier survival curves. Relapse or local failure was defined as the need for any additional treatment to the irradiated eye. A true failure of irradiation was defined as the need for enucleation. The development of cataracts between the two treatment techniques was compared using the chi-square statistic.
RESULTS
Fig. 2. Isodose distribution for child with bilateral disease, using the modified lateral beam technique.
90% isodose contour ranged from 38.5 to 50 Gy in daily fractions of 2.50 Gy. For the MLB technique, a lateral “D”-shaped field was designed, which placed the anterior border at 2 to 3 mm posterior to the surgical limbus. The isocenter was placed at the anterior border to avoid divergence into the lens. For the period in which the MLB technique was used, a dose of 42 to 46 Gy was prescribed to the 90% isodose curve and a lower daily fraction of 2 Gy was used. For patients with bilateral eye disease, two lateral parallel opposed “D”-shaped photon fields were used. Figure 2 shows the composite isodose distribution of this technique. For patients with bilateral disease who had previously undergone unilateral enucleation, a single lateral “D”-shaped photon tield was treated exiting through the fellow socket. For patients with unilateral disease, the single oblique held described by Schipper (25) was modified in several ways (20, 21). A composite arrangement using three fields was produced that avoided the uninvolved eye and whose composite isodose curves are shown in Fig. 3. For the first two-thirds of treatment, a pair of superior and anterior wedged oblique “D”-shaped fields were used, weighting up the superior oblique field to avoid a significant exit dose to the frontal lobe. For the last one-third of the treatment, a “D”-shaped lateral electron beam field was used with the anterior border placed 2-3 mm behind the limbus.
A detailed comparison between the two techniques is presented in Table 2. With a median follow-up of 52 months for the MLB group (range 4 to 108 months) and 101 months for the ALS group (range 13 to 159 months) the S- and 8-year actuarial local control or freedom from relapse (FFR) was improved using the MLB technique overall (38 vs. 65%) (p = 0.0001) and for Group I-III eyes (37 vs. 84%) (p < 0.0001) (Fig. 4). For Group IV-V eyes the difference (34 vs. 50%) was not significant (Fig. 5). A comparison of eye survival (no enucleation) for the two techniques is presented in Table 2. Despite a trend favoring the MLB technique for Group I-III eyes (94 vs. 8 l%), this difference was not significant (Fig. 6). There was no significant difference in eye survival overall and for Group IV-V eyes (Fig. 7). Many relapses,
Fig. 3. Isodose distribution for a child with unilateral disease, using the modified lateral beam technique with three separate fields.
1. J. Radiation Oncology
48
Table 2. Actuarial
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0 Physics
Volume 35, Number 1, 1996
local control and eye survival
Local control
%
Local
Eye survival
%
Control
Group
IV-V Eyes
100 90
No. eyes
Group
5 years
8 years
5 years
8 years
80
I-III ALL ALS MLB
96 35 61
67 37 84
67 37 84
p < 0.0001
90 85 94
88 81 94
p = NS
IV-V ALL ALS MLB
84 32 52
44 38 50
44 34 50
p = NS
60 60 61
60 60 61
p = NS
I-V ALS MLB
180 67 113
56 38 65
56 38 65
p < 0.0001
76 73 78
75 71 78
p = NS
-
MLB Tcchnape
______.
ALS Tcchnqur
10
p =
Group
I-III
Eyes
90
7
70
E s 7
60
-1 g
40
8
30
50
iI : i
84%
!. ‘I
-I__, :. :___,
--~~~~-~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.
37% -
MLB Technques
20 10 0 I2
24
36
48
60
72
84
96
108
120
Months
Fig. 4. Comparison
I
24
36
Fig. 5. Comparison
100
80
I
NS
4'8 6'0 7'2 8'4 9'6 It;8I;0 I;2 I;4
6
Months
defined as the need for any additional treatment, could be successfully treated using other eye-sparing methods including cryotherapy, photocoagulation, and plaque therapy. Twenty-two percent of eyes developed cataracts overall. There was no difference in cataract development between the two treatment techniques. All enucleations were performed for failure of salvage therapy or for initial treatment failure for very advanced disease in which there appeared to be no hope of successful salvage by focal eye sparing methods. No eyes were enucleated for complications of therapy. Actuarial cause-specific survival for RB was 94% at 5 and 8 years. Six children out of the 123 treated with radiation therapy died due to metastatic RB. All of these six had the bilateral form of RB and all were diagnosed
Control
8 12
ALS = anterior lens sparing. MLB = modified lateral beam. NS = not significant.
Local
0
of local control for Group I-III
eyes.
of local control for Group IV-V
eyes.
with Group V RB after the age of 8 months. Actuarial overall survival at 5 and 8 years was 87%. Overall and cause-specific survival was not influenced by the treatment technique. Eight children have died from a second primary malignancy, seven of these from “Trilateral Retinoblastoma” (8) and only one from the development of a malignancy within the radiation field.
DISCUSSION Radiation therapy has been widely used in the treatment of RB. However, the EBRT technique used in the treatment of RB has varied and evolved over the years. This study compares the results of two different EBRT treatment techniques that were used at our institution over the last decade. Table 2 provides a detailed comparison between the two EBRT techniques. This study confirms our initial results in the comparison of the ALS and MLB EBRT treatment techniques (20, 21). For Group I-III eyes, the MLB technique was found to be superior to the ALS technique in terms of local control (p 5 0.0001). Although there was a trend favoring the MLB technique for Group IV-V eyes, this trend did not attain statistical significance, even with longer follow-up. The difference in local control between the two treatment techniques is potentially attributable to a shift of the contact lens block, to the isodose distribution of the anterior lens-sparing technique, and the shadow under the lens block. Despite the improved local control using the MLB technique, survival end points including eye survival, and cause-specific and overall survival were similar using the two treatment techniques. This is due to the successful use of salvage eye-sparing methods including cryotherapy, photocoagulation, and radiation plaque therapy.
External beam radiation therapy and retinoplastoma l L. E. BLACH et al.
49
Table 3. Comparison of crude external beam treatment results
Institut. Stanford
(13)
Eyes 38
Year
RT (Gy) dose
Technique
1956-74
35-60
Lateral Group I-III Group IV-V Lateral Lateral Anterior wedged pair Combined Anterior Group I-III Group IV-V Lateral Group I-III Group IV Lateral Group I-III Group IV-V Lateral Group I-III Group IV-VA Combined Anterior-ALS Group I-III Group IV-V Lateral-MLB Group I-III Group IV-V
U Oregon (16) U Indiana (28) Wills Eye (5)
22 12 13
1958-78 1967-72 1975-88
45-50 35-40 40-45
Mayo (27)
30
1977-89
39-51
New York (3)
74
1955-80
New York (2) Utrecht (26)
64 54
1955-80 1971-82
MSKC
180 67
113
1979-91 1979-84
1984-91
35-60#
45
38.5-50
42-44
% Eye surv (number) 58
% Cataract (number)
% css
66 (25)
96
5 (1) 25 (3) 31 (4)
86 100 100
(17/21) (5117) 83 83 77
100
(“90/l 1)
(5/5) (4/6) (1 l/14) (8/10) (3/4) 85 (63/74) 0 (19/64)
65
NA
29
NA
NA NA 33 (18)
92 88 100
94 (33135) 58 (11/19) 79
22 23.5
94
81 60 20.5 94 61
Orthovoltage era treatments excluded; enucleation results from Foote et al. (15); # includes betatron and Cobalt; enucleated worst eye, Group 5b eyes excluded & no Group 5a successes; some children received TEM initially; primary treatment with external beam only. ALS = Anterior lens sparing. MLB = Modified lateral beam. NA = Not available. CSS = Cause-specific survival. RT = Radiation therapy.
There was no significant difference in the development of cataracts in comparison of the two EBRT techniques. Only 22% of eyes developed cataracts in this series overall, which compares favorably to the incidence of cataract development in the literature, which ranges from 8 to 66% (median 31%) (5, 13, 16, 26-28). Ocular complications using these two external beam techniques were acceptable, as no eyes developed radiation retinopathy and none required enucleation for complications of treatment. This is comparable to the megavoltage external beam radiation therapy results reported by Sauerwein et al. (24) with the use of doses between 40 to 50 Gy. The Mayo clinic ( 15, 27) is the only other series that compares two different EBRT treatment techniques for RB. However, they concluded that an anterior technique is superior to a lateral technique. This is in direct contrast to our results. A possible explanation for this difference is the small number of patients in their series with a proportionally large percentage of Group III eyes and a
large number of the lateral technique failures occurring in the Group III eyes. After the ALS technique appeared to produce an increase in local relapse in our series, the decision was made to return to a lateral technique with a number of significant modifications as described above rather than use an anterior technique without lens blocking. The use of an anterior approach produces excellent lc,;l control; however, it introduces the inherent problems of lacrimal gland irradiation, exit of the beam through the brain, and cataracts in most patients (9, 18, 27). Although many have negated the importance of cataract development, we believe that the development of cataracts, although surgically treatable, can interfere with vision and result in disuse amblyopia. Occasionally, cataract removal can cause recurrence or extraorbital extension of disease (9). As the ultimate goal of RT is successful preservation of useful vision, the development of cataracts cannot be negated from the equation.
1. J. Radiation Oncology 0 Biology 0 Physics
50
Eye Survival
Group
I-III Eyes
100 90 80 -i
70
zt
60
cz
50
x w
40
$?
30
to-
MLD Tcchnquc
.
ALS Tachnqur
1.1-m-.
lo-
,> = NS
0 II
I 12
I 24
I 36
I 48
I 60
I 72
8 84
I 96
I I II 3081201321441561
1
Months
Fig. 6. Comparison of eye survival for Group I-III eyes.
Table 3 presents a comparison of crude eye survival between the different centers in the U.S. and from Utrecht (2, 3, 5, 13, 15, 16, 26-28). Local control or FFR could not be compared due to the differing definitions used to define relapse between papers, the difficulty in extracting this information from the data given, and the differences in reporting recurrent vs. new tumors. Of the 180 eyes irradiated in this report, 79% were conserved. Using the MLB technique, 19% (22 out of 113) underwent enucleation overall and only 5% with Group I-III eyes. This is comparable to the results of other series (2, 3, 5, 13, 16, 26-28) reported in the literature despite the fact that almost half of the eyes in this series had advanced disease at diagnosis. When stratified by early and late classification groups, the results of the MLB technique in terms of eye survival rate appear superior to some of the previously reported series, particularly for Group IV-V eyes (2, 3, 13. 26) (Table 3). This is despite the fact that some of these series selected cases for eye conservation, enucleated the worst eye in bilateral cases, and in some, excluded Group Vb eyes (3, 15, 16, 26-28). The cause-specific survival for this series is 94% at 5 and 8 years and 100% for children without a Group V eye. These results are comparable to those in the literature that report cause-specific survivals between 86 and 100% (2, 3, 5, 13, 16, 26-28) (Table 3). The actuarial overall survival of this cohort of 123 consecutively treated children for RB is 87% at 5 and 8 years. This is comparable to other EBRT series (2, 3, 13, 15, 16, 26). Overall survival of RB patients however, becomes increasingly dependent upon the development of second primary malignancies with longer follow-up. With a median follow-up of 68 months, trilateral retinoblastoma was the cause of death in seven, and an extracranial second malignancy in one. The inci-
Volume 35, Number 1, 1996
dence, outcome, and treatment approaches to “trilateral retinoblastoma” have been previously described (8). The increased incidence of second malignancies in children irradiated for RB has been studied in detail by Eng et al. (14). An attempt to avoid the induction of second tumors by EBRT in this genetically susceptible subset children has prompted some institutions to attempt to avoid the use of external beam radiation therapy in favor of other eye sparing modalities ( 1, 17, 19, 22, 29). These methods include the use of other visionsparing treatments such as cryotherapy. photocoagulation, and chemotherapy. Using this approach, EBRT or enucleation is reserved for failures ( 17, 22). However, when comparing results of alternate treatment strategies to primary external beam radiation therapy, the definition of “local control” must be universally applied. In this series, local failure was defined as the need for any additional treatment modality after primary external beam radiation therapy, including other focal eye-sparing methods. A true failure of irradiation was defined as the need for enucleation, and comparisons should be made accordingly.
CONCLUSION There is a significant improvement in local control of the irradiated eyes when a modified lateral beam technique is used as compared to an anterior lens-sparing technique. Survival end points and complications of the two techniques are similar. Due to an increase in cataract development and other potential complications using an anterior approach without lens blocking, we recommend the use of a modified lateral beam approach for the treatment of intraocular RB with EBRT.
Eye Survival
Group
IV-V Eyes
100. 90. 80. F
7 0.
.?;
6n.
2
50.
2 0
w^
40.
@
3
0. MLB Tecimque
20. 10.
-_____.
ALS Techn,qus p = NS
0. 12
2’4
3’6
4’8
6’0
7’2
8’4
9’6
lb81;~~,~2,~4,;,
x
Months
Fig. 7. Comparison
of eye survival
for Group IV-V
eyes.
External beam radiation therapy and retinoplastoma l L. E.
BLACH
et al.
51
REFERENCES I. Abramson, D. H.; Ellsworth, R. M.; Rozakis, G. W. Cyrotherapy for Retinoblastoma. Arch. Opthalmol. 100: 12531256; 1982. 2. Abramson, D. H.; Ellsworth, R. M.; Tretter, P.; Adams, K.; Kitchin, F. D. Simultaneous bilateral radiation for advanced bilateral retinoblastoma. Arch. Ophthalmol. 99: 17631766; 1981. 3. Abramson, D. H.; Ellsworth, R. M.; Tretter, P.; Javitt, J.; Kitchin. F. D. Treatment of bilateral groups I-III retinoblastoma with bilateral radiation. Arch. Opthalmol. 99:1761-1762; 1981. 4. Abramson, D. H.; Jereb, B; Ellsworth, R. M. External beam radiation for retinoblastoma. Bull. NY Acad. Med. .57:787803; 1981. 5. Amendola, B. E.; Lamm, F. R.; Markoe, A. M.: Karlsson, U. L.; Shields, J.; Shields, C. L.; Augsburger, J.; Brady, L. W.; Woodleigh, R.; Miller, C. Radiotherapy of retinoblastoma. A review of 63 children treated with different irradiation techniques. Cancer 66:21-26; 1990. 6. Bagshaw, M. A.; Kaplan, H. S. Supervoltage linear accelerator radiation therapy VIII. Retinoblastoma. Radiology 86:242-246; 1966. 7. Bedford, M. D.; Bedotto, C.; MacFaul P. A. Retinoblastoma: A study of 139 cases. Br. J. Ophthalmol. 55: 19-27; 1971. 8. Blach, L. E.; McCormick, B.: Abramson, D. H.; Ellsworth, R. M. Trilateral retinoblastoma-Incidence and outcome: A decade of experience. Int. J. Radiat. Oncol. Biol. Phys. 291729-733; 1994. 9. Brooks, H. L., Jr.; Meyer, D.; Shields, J. A.; Balas, A. G.; Nelson. L. B.; Fontanesi, J. Removal of radiation-induced cataracts in patients treated for retinoblastoma. Arch. Ophthalmol. 108:1701-1708; 1990. 10. Cassady, J. R.; Sagerman. R. H.; Tretter, P.; Ellsworth, R. M. Radiation therapy in retinoblastoma. Radiology 93:405-409; 1969. Il. Donaldson, S. S.; Egbert, P. R.; Lee, W.-H. Retinoblastoma. In: Pizzo, P. A., ed. Principles and practice of pediatric oncology, 2nd ed. Philadelphia: J. B. Lippincott Company; 1993:683-696. Biology, 12. Donaldson, S. S.; Smith, L. M. Retinoblastoma: presentation, aning tl. Cancer Inst. 85: 112 I - 1128; 1993. 13. Egbert, P. R.; Donaldson, S. S.; Moazed K.; Rosenthal, A. R. Visual results and ocular complications following radiotherapy for retinoblastoma. Arch. Ophthalmol. 96:1826-1830;1978. 14. Eng, C.; Li, F. P.; Abramson, D. H.; Ellsworth, R. M.; Wong, F. L.; Goldman, M. B.; Seddon, J.; Tarbell, N.: Boice, J. D., Jr. Mortality from second tumors among longterm survivors of retinoblastoma. J. Natl. Cancer Inst. 85:1121-l 128: 1993. 15. Foote, R. L.; Garretson, B. R.; Schomberg, P. J.; Buskirk, S. J.; Robertson, D. M.; Earle, J. D. External beam irradiation for retinoblastoma: Patterns of failure and dose-response analysis. Int. J. Radiat. Oncol. Biol. Phys. 16:823830; 1989.
16. Gagnon, J. D.; Ware, C. M.; Moss, W. T.; Stevens, K. R. Radiation Management of bilateral retinoblastoma: The need to preserve vision. Int. J. Radiat. Oncol. Biol. Phys. 6:669-673; 1980. chemotherapy use with 17. Gallie, B. Cyclosporin-modulated focal therapy: A new approach to retinoblastoma. Presented at the 10th symposium of the International Society of Genetic Eye Diseases. Niagara on the Lake, Ontario, Canada, June 24, 1994. 18. Halperin, E. C.; Constine, L. S.; Tarbell, N. J.; Kun, L. E. Retinoblastoma In: Pediatric radiation oncology, 2nd ed. New York: Raven Press; 1994. in the manage19. Kingston. J. Is there a role for chemotherapy ment of intraocular retinoblastoma? Presented at the 10th symposium of the International Society of Genetic Eye Diseases. Niagara on the Lake, Ontario, Canada, June 24, 1994. B.; Ellsworth, R.; Abramson, D.; Haik, B.; 20. McCormick, Tome, M.; Grabowski, E; LoSasso, T. Radiation therapy for retinoblastoma; Comparison of results with lens-sparing vs. lateral beam techniques. Int. J. Radiat. Oncol. Biol. Phys. l5:567-574; 1988. 21. McCormick, B.; Ellsworth, R.; Abramson, D.; loSasso, T; Grabowski, E. Results of external beam radiation for children with retinoblastoma: A comparison of two techniques. J. Pediatr. Ophthalmol. Strabismus 26:239-243; 1989. 22. Murphree, L. Chemoreduction of intraocular retinoblastoma. Presented at the 10th symposium of the InternationaI Society of Genetic Eye Diseases. Niagara on the Lake, Ontario, Canada, June 24, 1994. 23. Reese, A. B.; Ellsworth, R. M. The evaluation and current concept of retinoblastoma therapy. Trans. Am. Acad. Ophth. Otolaryng. 67: l64- 172; 1963. 24. Sauerwein, W.: Messmer, E.; Fitze, H.; Hopping, W.; Mohr, C.; Havers, W.; Sack, H. Late effects following treatment of Retinoblastoma (Meeting Abstract). Ninth Annual Meeting of the European Society for Therapeutic Radiology and Oncology. Montecatini, Terme, Italy, September 1215, 1990, p. 174. 25. Schipper, J. An accurate and simple method for megavoltage radiation therapy of retinoblastoma. Radiother. Oncol. l:31-41: 1983. 26. Schipper, J.; Tan, K. E. W. P.; van Peperzeel, H. A. Treatment of retinoblastoma by precision megavoltage radiation therapy. Radiother. Oncol. 3:117-132; 1985. 27. Schomberg P.; Foote, R.; Robertson, D.; Earle, J. External beam irradiation for retinoblastoma: A comparison of two treatment techniques. Proc. Annu. Meet. Am. Sot. Clin. Oncol. 1 l:A1286; 1992. 28. Shidnia, H.; Homback, N. B.; Helveston, E. M.; Gettlefinger. T.; Biglan, A. W. Treatment results of retinoblastoma at Indiana University Hospitals. Cancer 40:29172922; 1977. 29. Shields, J. A.; Giblin, M. E.; Shields, C. L.; Markoe, A. M.; Karlsson, U.; Brady, L. W.; Amendola, B. E.; Woodleigh, R. Episcleral plaque radiotherapy for retinoblastoma. Ophthalmology 96:530-537; 1989.