Graefe's Archive Ophthalmology for Clinical and Experimental
Clinical investigations
© Springer-Verlag 1991 Graefe's Arch Clin Exp Ophthalmol (1991) 229:309-314
Long-term treatment effects in patients with bilateral retinoblastoma: ocular and mid-facial findings* Elmar P. Messmer 1 **, Henning Fritze 1, Christopher Mohr 4, Thomas Heinrich 1, Wolfgang Sauerwein 2, Werner Havers 3, Bernhard Horsthemke s, and Wolfgang H6pping 1 1 Abteilung ffir Augenheilkunde, 2 Radiologie, 3 Kinderheilkunde, 4 Gesichtskieferchirurgie, and s Genetik, Universitfitsklinikum, W-4300 Essen, Federal Republic of Germany Received November 2, 1990 / Accepted January 21, 1991
Abstract. A total of 99 patients with bilateral retinoblastoma who had been treated between 1965 and 1982 were reexamined in April 1988 to study the late effects of treatment. Their median age at the follow-up visit in 1988 was 16 years (range, 6-27 years), and the median follow-up was 15 years (range, 6-26 years). All patients underwent a full eye examination, morphometric measurements of the mid-face and genetic counselling. Each eye or orbit and the corresponding side of the patient's mid-face were evaluated separately, resulting in 198 data sets from 99 individuals. Subjects were divided into four treatment groups according to whether photo- and cryocoagulation, enucleation, radiation therapy or various combinations thereof were used. In all, 81 eyes had a visual acuity of > 0 . 4 (in 23 of these, however, only with low-vision aids). Within a dose range of 36.51 Gy, the location of the tumor (36%) or cataract (15%) were the main factors responsible for poor visual acuity, whereas radiation retinopathy and/or optic neuropathy occurred in only three cases. Cataracts were more frequently observed following orthovoltage as compared with megavoltage therapy ( P = 0.012). A total of 72 eyes had been enucleated and had not received radiation therapy at any time. Cosmetic results (as measured by several parameters) in these cases were significantly better then those in 28 subjects who underwent combined radiation therapy and enucleation. As defined by various subjective as well as objective findings, mid-facial hypoplasia occurred significantly more often following orthovoltage as compared with megavoltage therapy.
tients develop metastatic disease, and in about 80% of bilateral cases at least one of the affected eyes can be retained [1, 13, 14, 19, 33]. Current emphasis should therefore be placed on reducing treatment morbidity, e.g. lowering the incidence of secondary non-ocular tumors and avoiding damage to ocular as well as midfacial structures. Secondary non-ocular tumors are almost exclusively observed in patients with bilateral retinoblastoma and, therefore, must be related to the gene defect [2, 7, 8, 26, 30]. However, the incidence seems to be higher in children who have been treated with radiation and/or chemotherapy. Although the indication for these treatment modalities thus requires careful consideration, the issue of secondary non-ocular tumors is too complex and multifactorial to be addressed in this retrospective report. Damage to ocular and mid-facial structures due to various combinations of treatment modalities such as radiation therapy, enucleation and cryo- or photocoagulation has repeatedly been reported [4, 24, 34, 35]. Many authors feel that considerable progress in limiting the total radiation dose has been made by the introduction of megavoltage therapy as well as by refinement of alignment techniques that enable the administration of smaller volumes of radiation [1, 12, 17-19, 22, 24, 32, 33]. However, rarely have larger series using long-term follow-ups been reported. In an attempt to contribute to the task of lowering morbidity in children with bilateral retinoblastoma, we retrospectively analyzed the longterm results of various treatment techniques with regard to visual acuity and ocular as well as mid-facial findings.
Introduction Treatment of retinoblastoma has become very effective during recent decades. Presently, < 1 0 % of these pa* Presented at the 17th meeting of the Club Jules Gonin, Lausanne, September ~6, 1990 ** Present address and address for offprint requests." Augenklinik des Universitfitsspitals, Rfimistrasse 100, CH-8091 Ziirich, Switzerland
Patients and methods To ensure sufficient follow-up, only patients who had been treated up to 1982 were included in the study. Of 273 patients who were treated for bilateral retinoblastoma between 1965 and 1982, 160 could be contacted; 43 had developed metastases or secondary non-ocular tumors, whereas others had moved to unknown cities or had been referred from other countries. Finally, 99 subjects agreed to be reexamined at the University Eye Hospital in Essen.
310 All patients underwent a full eye examination with photographic documentation of facial and ocular structures. Eight subjects agreed to have fluorescein angiograms performed. All patients were also seen by a dental surgeon, who obtained objective measurements and subjective gradings of mid-facial structures. Furthermore, pediatric examination as well as genetic counselling and DNA studies were performed and will be reported elsewhere. Of the 99 patients examined, left and right eyes or periorbital structures were evaluated separately such that 198 data sets from 99 individuals could be analyzed; these data sets consisted of 102 postenucleation sockets and 96 eyes that had been preserved. Univariant analyses for binomial data were carried out with the chi-square test. For small samples, Fisher's exact test was used. Rank statistics were performed using the Wilcoxon-Mann-Whitney U-test. For multivariate analyses the Cat-mod model was applied.
Results
In all, 55 of the patients were w o m e n and 44 were men. The median age at diagnosis was 10 months, and the median age at the last follow-up examination was 16 years. The median follow-up was therefore 15 years, with 90% of patients being followed for > 10 years. Four different treatment groups were evaluated (Table 1). Overall, 15 eyes had received only photo- or cryocoagulation, 74 had been enucleated without prior or subsequent radiation, 81 had undergone radiation therapy without enucleation and 28 had been subjected to radiation therapy either prior to or following enucleation. In 107 of 109 cases that had received radiation therapy, exact treatment data could be reviewed; 49 patients had undergone orthovoltage therapy and 43, megavoltage treatment. The median dose was 44 Gy (range, 11130 Gy; Fig. 1). Cases treated with either orthovoltage or megavoltage therapy had received about the same median doses. We evaluated only subjects who had been given a total dose of 36-51 Gy, which approximately represents the currently used dose range.
100-
8 o-
,.-
u.
6 o-
N=30
N=6
~\\\\~ "-.'-.'-.'-.',.',.'-2
N=28
4 O-
,',',,',',',,'-.,
2 O-
2 . 2 . 2 . - . 2 . - . - . .
0
Table 1. Treatment groups
Group I Group II Group III Group IV
O f 64 eyes treated with photocoagutation, 3 exhibited iridic atrophy due to accidental irradiation of the iris. O f the 96 preserved eyes, 57 had developed cataracts. Generally, circumscribed posterior subcapsular cataracts were noted and 14 of these were found to be visually significant. In 7 additional eyes (of 57), cataract surgery had previously been performed. Therefore, although 70% of all irradiated eyes had developed cataracts, only 26% were graded as being clinically significant. Cataracts were observed significantly more often following orthovoltage therapy as compared with megavoltage treatment (Fig. 2). There was no relationship between the radiation dose applied (within the studied dose range of 36-51 Gy) and the incidence of cataract. All types of t u m o r regression were observed in the 96 eyes examined (Table 2). A cottage-cheese regression pattern (Type I) as well as flat chorioretinal scars (Type IV), generally occurring after combined radiation and photo- or cryocoagulation therapy, were noted most frequently. A m o n g other ophthalmoscopic findings, granular retinal pigment epithelial changes were most often observed (Table 3). Usually these findings were manifest in the immediate vicinity of the original t u m o r or in the inferior half of the retina, indicating that they are related to a transitory retinal detachment that follows radiation-induced t u m o r necrosis. Retracting scars following photocoagulation were seen in five cases, two
~
i
p=0,012 p=0,231 I p=0,829 ~ = O r t h o v o l t a g e E~=Megavoltage~ =Telecurie I
Photo- or cryocoagulation only Enucleation without radiation Enucleation with radiation Radiation without enucleation
(n = 15) (n = 74) (n = 28) (n = 81)
Fig. 2. Percentage of cases developing cataracts according to the radiation source involved (dose range, 36-51 Gy) Table 2. Tumor regression
32 28
Type I Type I[ Type III Type IV
24 >,20 o
§16
42 eyes 1 eye 9 eyes 73 eyes
g12 kL.
Table 3. Other ophthalmoscopic findings
8
I
i
I
10
20
30
40
I
|
50
60
I
70
80
I
90 110 120130
Total dosis in Gy
Fig. 1. Spectrum of total doses given in 107 subjects who had undergone radiation therapy
Granular RPE Retracting scar Sectorial optic atrophy Diffuse optic atrophy Radiation retinopathy RPE, retinal pigment epithelium
21/96 eyes 5/96 eyes 33/96 eyes 3/96 eyes 3/96 eyes
311
Fig. 5. Severe anophthalmic socket syndrome following enucleation and radiation therapy to the involved orbit
100-
incomplete lid c l o s u r e
shrunken fornix
p r o t h e s i s not fitting well
p
Clinical investigations
© Springer-Verlag 1991 Graefe's Arch Clin Exp Ophthalmol (1991) 229:309-314
Long-term treatment effects in patients with bilateral retinoblastoma: ocular and mid-facial findings* Elmar P. Messmer 1 **, Henning Fritze 1, Christopher Mohr 4, Thomas Heinrich 1, Wolfgang Sauerwein 2, Werner Havers 3, Bernhard Horsthemke s, and Wolfgang H6pping 1 1 Abteilung ffir Augenheilkunde, 2 Radiologie, 3 Kinderheilkunde, 4 Gesichtskieferchirurgie, and s Genetik, Universitfitsklinikum, W-4300 Essen, Federal Republic of Germany Received November 2, 1990 / Accepted January 21, 1991
Abstract. A total of 99 patients with bilateral retinoblastoma who had been treated between 1965 and 1982 were reexamined in April 1988 to study the late effects of treatment. Their median age at the follow-up visit in 1988 was 16 years (range, 6-27 years), and the median follow-up was 15 years (range, 6-26 years). All patients underwent a full eye examination, morphometric measurements of the mid-face and genetic counselling. Each eye or orbit and the corresponding side of the patient's mid-face were evaluated separately, resulting in 198 data sets from 99 individuals. Subjects were divided into four treatment groups according to whether photo- and cryocoagulation, enucleation, radiation therapy or various combinations thereof were used. In all, 81 eyes had a visual acuity of > 0 . 4 (in 23 of these, however, only with low-vision aids). Within a dose range of 36.51 Gy, the location of the tumor (36%) or cataract (15%) were the main factors responsible for poor visual acuity, whereas radiation retinopathy and/or optic neuropathy occurred in only three cases. Cataracts were more frequently observed following orthovoltage as compared with megavoltage therapy ( P = 0.012). A total of 72 eyes had been enucleated and had not received radiation therapy at any time. Cosmetic results (as measured by several parameters) in these cases were significantly better then those in 28 subjects who underwent combined radiation therapy and enucleation. As defined by various subjective as well as objective findings, mid-facial hypoplasia occurred significantly more often following orthovoltage as compared with megavoltage therapy.
tients develop metastatic disease, and in about 80% of bilateral cases at least one of the affected eyes can be retained [1, 13, 14, 19, 33]. Current emphasis should therefore be placed on reducing treatment morbidity, e.g. lowering the incidence of secondary non-ocular tumors and avoiding damage to ocular as well as midfacial structures. Secondary non-ocular tumors are almost exclusively observed in patients with bilateral retinoblastoma and, therefore, must be related to the gene defect [2, 7, 8, 26, 30]. However, the incidence seems to be higher in children who have been treated with radiation and/or chemotherapy. Although the indication for these treatment modalities thus requires careful consideration, the issue of secondary non-ocular tumors is too complex and multifactorial to be addressed in this retrospective report. Damage to ocular and mid-facial structures due to various combinations of treatment modalities such as radiation therapy, enucleation and cryo- or photocoagulation has repeatedly been reported [4, 24, 34, 35]. Many authors feel that considerable progress in limiting the total radiation dose has been made by the introduction of megavoltage therapy as well as by refinement of alignment techniques that enable the administration of smaller volumes of radiation [1, 12, 17-19, 22, 24, 32, 33]. However, rarely have larger series using long-term follow-ups been reported. In an attempt to contribute to the task of lowering morbidity in children with bilateral retinoblastoma, we retrospectively analyzed the longterm results of various treatment techniques with regard to visual acuity and ocular as well as mid-facial findings.
Introduction Treatment of retinoblastoma has become very effective during recent decades. Presently, < 1 0 % of these pa* Presented at the 17th meeting of the Club Jules Gonin, Lausanne, September ~6, 1990 ** Present address and address for offprint requests." Augenklinik des Universitfitsspitals, Rfimistrasse 100, CH-8091 Ziirich, Switzerland
Patients and methods To ensure sufficient follow-up, only patients who had been treated up to 1982 were included in the study. Of 273 patients who were treated for bilateral retinoblastoma between 1965 and 1982, 160 could be contacted; 43 had developed metastases or secondary non-ocular tumors, whereas others had moved to unknown cities or had been referred from other countries. Finally, 99 subjects agreed to be reexamined at the University Eye Hospital in Essen.
310 All patients underwent a full eye examination with photographic documentation of facial and ocular structures. Eight subjects agreed to have fluorescein angiograms performed. All patients were also seen by a dental surgeon, who obtained objective measurements and subjective gradings of mid-facial structures. Furthermore, pediatric examination as well as genetic counselling and DNA studies were performed and will be reported elsewhere. Of the 99 patients examined, left and right eyes or periorbital structures were evaluated separately such that 198 data sets from 99 individuals could be analyzed; these data sets consisted of 102 postenucleation sockets and 96 eyes that had been preserved. Univariant analyses for binomial data were carried out with the chi-square test. For small samples, Fisher's exact test was used. Rank statistics were performed using the Wilcoxon-Mann-Whitney U-test. For multivariate analyses the Cat-mod model was applied.
Results
In all, 55 of the patients were w o m e n and 44 were men. The median age at diagnosis was 10 months, and the median age at the last follow-up examination was 16 years. The median follow-up was therefore 15 years, with 90% of patients being followed for > 10 years. Four different treatment groups were evaluated (Table 1). Overall, 15 eyes had received only photo- or cryocoagulation, 74 had been enucleated without prior or subsequent radiation, 81 had undergone radiation therapy without enucleation and 28 had been subjected to radiation therapy either prior to or following enucleation. In 107 of 109 cases that had received radiation therapy, exact treatment data could be reviewed; 49 patients had undergone orthovoltage therapy and 43, megavoltage treatment. The median dose was 44 Gy (range, 11130 Gy; Fig. 1). Cases treated with either orthovoltage or megavoltage therapy had received about the same median doses. We evaluated only subjects who had been given a total dose of 36-51 Gy, which approximately represents the currently used dose range.
100-
8 o-
,.-
u.
6 o-
N=30
N=6
~\\\\~ "-.'-.'-.'-.',.',.'-2
N=28
4 O-
,',',,',',',,'-.,
2 O-
2 . 2 . 2 . - . 2 . - . - . .
0
Table 1. Treatment groups
Group I Group II Group III Group IV
O f 64 eyes treated with photocoagutation, 3 exhibited iridic atrophy due to accidental irradiation of the iris. O f the 96 preserved eyes, 57 had developed cataracts. Generally, circumscribed posterior subcapsular cataracts were noted and 14 of these were found to be visually significant. In 7 additional eyes (of 57), cataract surgery had previously been performed. Therefore, although 70% of all irradiated eyes had developed cataracts, only 26% were graded as being clinically significant. Cataracts were observed significantly more often following orthovoltage therapy as compared with megavoltage treatment (Fig. 2). There was no relationship between the radiation dose applied (within the studied dose range of 36-51 Gy) and the incidence of cataract. All types of t u m o r regression were observed in the 96 eyes examined (Table 2). A cottage-cheese regression pattern (Type I) as well as flat chorioretinal scars (Type IV), generally occurring after combined radiation and photo- or cryocoagulation therapy, were noted most frequently. A m o n g other ophthalmoscopic findings, granular retinal pigment epithelial changes were most often observed (Table 3). Usually these findings were manifest in the immediate vicinity of the original t u m o r or in the inferior half of the retina, indicating that they are related to a transitory retinal detachment that follows radiation-induced t u m o r necrosis. Retracting scars following photocoagulation were seen in five cases, two
~
i
p=0,012 p=0,231 I p=0,829 ~ = O r t h o v o l t a g e E~=Megavoltage~ =Telecurie I
Photo- or cryocoagulation only Enucleation without radiation Enucleation with radiation Radiation without enucleation
(n = 15) (n = 74) (n = 28) (n = 81)
Fig. 2. Percentage of cases developing cataracts according to the radiation source involved (dose range, 36-51 Gy) Table 2. Tumor regression
32 28
Type I Type I[ Type III Type IV
24 >,20 o
§16
42 eyes 1 eye 9 eyes 73 eyes
g12 kL.
Table 3. Other ophthalmoscopic findings
8
I
i
I
10
20
30
40
I
|
50
60
I
70
80
I
90 110 120130
Total dosis in Gy
Fig. 1. Spectrum of total doses given in 107 subjects who had undergone radiation therapy
Granular RPE Retracting scar Sectorial optic atrophy Diffuse optic atrophy Radiation retinopathy RPE, retinal pigment epithelium
21/96 eyes 5/96 eyes 33/96 eyes 3/96 eyes 3/96 eyes
311
Fig. 5. Severe anophthalmic socket syndrome following enucleation and radiation therapy to the involved orbit
100-
incomplete lid c l o s u r e
shrunken fornix
p r o t h e s i s not fitting well
p
