A C T A O P H T H A L M O L O G I C A VOL. 5 3 1 9 7 5
The Department of Ophthalmology (Heads: Niels Ehlers and Viggo A . /ensen) and the Radium Centre (Head: Sigvard Kaae), Arhus Kommunehospital, University of Aarhus, Denmark
RADIATION TREATMENT OF RETlNOBLASTOMA BY
NIELS EHLERS and SIGVARD KAAE
In a series of 45 children with retinoblastoma, from the period 1953-1973, comprising 27 bilateral cases, 32 eyes were treated by irradiation. The different techniques of radiation are reviewed. In the present series small tumours were irradiated by local application of Stallard discs or Rosengren balls, while advanced cases were treated by external radiation. The results are discussed, and it is emphasized that the major factor of importance for the success of the treatment is the size of the tumour. Small tumours are cured, large ones are not. Future efforts must be directed towards early diagnosis. The treatment should be centralized in order to secure sufficient experience for the ophthalmologist and radiotherapist, as evaluation of the post- radiation fundus findings may present difficulties.
Key words: retinoblastoma balls - external radiation.
- radiation - SOCo - Stallard discs - Rosengren
For several years the treatment of bilateral retinoblastoma in Denmark has been centralized at the University of Aarhus. It is the purpose of this publication to present the results and the experiences obtained from radiation treatment of these cases. Received May 9, 1975.
Niels Ehlers and Sigvard Kaae With about 5 mill. inhabitants and a birth rate of less than 1 5 0 only a few cases of retinoblastoma can be expected every year in Denmark. Despite this numerical paucity the retinoblastoma has been extensively studied. The natural history was discussed by Bech & Jensen (1961) and Jensen (1965). In the latter publication the histopathological aspects were particularly emphasized. The prognosis was studied by Kindt (1939) and the occurrence in a 48-year-old man was reported by Rasmussen (1944). Spontaneous regression was discussed by Nehen (1975), while a partial spontaneous regression and necrosis of the central retinal artery was reported by Andersen & Jensen (1974). The treatment by irradiation was discussed by Boberg-Ans (1958) and its organizational aspects by Ry Andersen (1971), while hereditary aspects of retinoblastoma were evaluated by Nielsen & Goldschmidt (1968) and Warburg (1974). Recent papers from the other Scandinavian countries were published by Jerndal, Lindstedt, Svensson & Akerskog (1973), Jerndal & Tengroth (1974), Herven (1974), Tarkkanen 8r Tuovinen (1971).
Material In the period 1953-1973 a total of 45 children with retinoblastoma were treated at the Uepartment of Ophthalmology and the Radium Centre, Arhus Kommunehospital, University of Aarhus. This series comprised 27 bilateral and 18 unilateral cases. T h e relatively high number of bilateral cases is caused by the centralization of these cases from the whole of Denmark, while the unilateral cases all originated from the local area of the hospital. Ten of the 27 bilateral cases were girls, while among the 18 unilateral cases seven were girls. Among the unilateral cases eight occurred in the right and ten in the left eye. Among the bilateral cases the right eye was primarily affected in 14 cases, the left in 13 cases. The localization in the eye could be determined in 53 tumours, 13 of which occurred in the posterior pole, the remainder in the periphery. There was no tendency to concentration of the tumours in any particular quadrant. The average age at the time of the first symptom was for the bilateral cases 8.7 months, as compared to 24.3 months in the unilateral cases. The distribution of the series according to age at first symptom, and at first admission is shown in Table I. The range of ages at first symptom was for the bilateral cases 0.5-36 months, for the unilateral cases 3-53 months. In eight cases multiple tumours occurred in one eye.
Techniques of radiation treatment
The radiosensitivity of the retinoblastoma was observed in 1903 by Hilgartner, and subsequently, Moore (1929) and Martin PC Reese (1936) succeeded in destroying the tumour by irradiation. Since then radiotherapy has improved and today several possibilities are available, either the application of radioactive material adjacent to the tumour, or external radiation can be used alone or in combination with cytostatics. Additional therapeutic measures comprise coagulation of the tumour by light, by cold or by diathermy. Radiotherapy and cytostatics both depend upon a persistent vascularization. 592
Radiation of Retinoblastoma Table I . Age distribution for 45 cases of retinoblastoma at onset of symptoms and at first admission
at symptoms fonset tof
admission r a l
at asymptoms onset t of
admission first no.
5 4 2
5 9 4 -
1-2 2-3 3-4 4-5
years years years years
4 2 3 7
3 2 1 10
The large number of bilateral cases is caused by the centralized treatment of these during the last 20 years.
Radioactive applicators. This treatment was initiated by Moore (1929) who inserted radon needles into the tumour. Modifications of this technique were in use until Stallard (1948) introduced his shell-formed radium applicators, which have the same curvature as the sclera and are sutured to the sclera outside the tumour. The construction of these applicators was discussed by Williams (1957) and the calculation of isodose curves by Raimondi (1971). The applicator was modified by substituting 6OCo for the original radium preparation. A slightly different technique was introduced by Rosengren & Tengroth (1963). The 6OCo was placed in a platinum ball fixed by an arm to a ring sutured around the cornea. The ball is pressed against and into the base of the tumour. T he position of both types of applicators are checked by ophthalmoscopy using diathermy marks for the discs and the visible indentation for the ball. The isodose curves are different for the two applicators, as illustrated in Fig. 1. From histological studies of irradiated eyes Moore, Stallard & Milner (1931) and Stallard (1955) determined that 3500 rads were lethal to retinoblastoma cells. A dose of 3500-4000 rads to the summit of the tumour is recommended (Stallard 1962). Disc shaped applicators containing the ,%emitter 106Rd”J‘JRhhave been introduced by Lommatzsch (1970), who reported a curative effect on small tumours. The limited penetration into the tissue prevented the treatment of tumours with 593 Acta ophthal. 53, 4
Niels Ehlers and Sigvard Kaae
Fig. 1. Isodose curves for WOapplicators. Left: disc-shaped applicator of the Stallard type, right: ball-shaped applicator of the Rosengren type (Amersham, England).
a prominence of more than a few millimeters. The advantage is the possibility of avoiding radiation complications. Exlernal irradiation. Martin & Reese (1936) described a technique for treating retinoblastoma by X-rays employing special cones and a temporal and nasal port in an effort to deliver an adequate dose to the posterior segment of the eye, avoiding the vulnerable anterior segment. These radiation damages may be significantly reduced by careful adjustment, which unfortunately also spares the anterior retina and vitreous from getting the full therapeutic dose. The initially used doses of 8-10,000 R gave rise to severe complications (Reese, Merriam & Martin 1949), particularly vitreous haemorrhages, and a few patients several years later developed osteosarcoma or rhabdomyosarcoma in the exposed area. The currently recommended dose is 3500 R delivered over a three-week period, (Reese, Hyman, Tapley & Forest 1949, Reese 1963), which, however, still gives rise to radiation dermatitis and retardation of cranial growth on the exposed side. Many of the disadvantages of the external radiation were eliminated by the use of megavolt X-rays, 6"Co beams or the linear accelerator whose much more sharply delimited bundle can more easily be directed to bypass the anterior segment of the eye, and at the same time the absence of excessive bone absorption and a low skin dose prevent cranial deformities and skin lesions. Skeggs & Williams (1966) developed a method with the 6OCo beam using a direct anterior field. It has the advantage of treating the whole retina and vitreous, while the other eye can be effectively shielded, but all ocular structures and the brain are irradiated, and a cataract inevitably develops within about 18 months (McFaul & Bedford 1970). This latter complication may today be amenable to surgical treatment. Radiomimetic and cytostatic agrnts have been recommended as a supplement 594
to radiotherapy. Triethylene melamine (TEM) was used by Reese et al. (1958), others have employed cyclophosphamide (Stallard 1968), and the more recent drug, vincristine sulphate. The effect of these toxic agents has recently been doubted (Hopping 1968, T a n & Moller 1973) and they are today used only in the gravest cases. Techniques employed in treatment of present series. All patients have been treated solely by irradiation, without a supplement of cytostatic agents. Light-, cryo- or diathermy-coagulations have not been used. Radiation treatment was given with applicators of the Stallard- (Amersham. England) or Rosengren-type. The surgical directions given by Stallard (1968) have been followed, whereas the Rosengren applicators have been applied only once, occasionally twice, over a tumour area, as it was found difficult to secure the position accurately enough for the several applications recommended by Rosengren & Tengroth (1963). Accordingly only small tumours were treated by the Rosengren applicator. External irradiation was given in early cases by X-rays, later as 6OCo beams. Some of the early cases were given doses now known to be inadequate, later cases were given GOCo treatments 3-5 per week, in a total dose of 4400-6700 rads in 23-79 days. The calculated dose in the eye corresponds to a TSD factor of maximally 116-92 and minimally 100-79 (Orton & Ellis 1973). With the GOCo applicators a minimal tumour dose of 3500-4000 rads was aimed at, given with the Stallard discs over a period of approximately 6 days, with the Rosengren balls in about 24 hours. I n using the Stallard discs the doses were calculated from a supposed prominence of the tumour of 7/10 of its base width (Stallard 1968) not taking the actual ophthalmoscopically measured prominence into account. I n the later evaluation of these cases it became evident that some of the tumours were rather heavily overdosed.
It has been the experience of the authors that the most difficult aspect of the radiation treatment is not the surgical localization and fixation of the cobolt disc or ball but rather the interpretation of the postirradiation ophthalmoscopic findings at the follow-up examinations. For this reason a few cases illustrating the particular problems are reported in detail. N o . 180368. A boy, whose twin brother ultimately had both eyes removed because of retinoblastoma; otherwise no family history of retinoblastoma. Ophthalmoscopy at the age of 2 months showed nothing abnormal. Three months later a tumour was seen above and temporal to the left macula, measuring 2-3 PD, (papil diameters) with a prominence of 3-4 D.
Niels Ehlers and Sigvard Kaae Treatment and course. The tumour in the left eye was treated by a Rosengren ball with a calculated dose of 12,000 rads at a depth of 1 mm. The tumour regressed and after 6 months appeared as a ring of calcifications (Fig. 2). Seven months later a 2 PD tumour was seen in the right eye in the 10 o’clock meridian in the peripheral retina. This tumour was treated in the same manner as the one in the left eye, and disappeared leaving a white atrophic scar. Twenty months later (i.e. 27 months after the first treatment) a new tumour appeared in the left eye, in the periphery in the 6 o’clock meridian. This tumour was also healed by irradiation with a Rosengren ball, again giving a dose of 12,000 rads at a depth of 1 mm. Ophthalmoscopy under general anaesthesia was performed at regular intervals. For more than 4 years (age 6 years) no tumour growths have appeared. The fundus was as illustrated in Fig. 3. Visual acuity was 0.3 OD, and 0.5 0s. T h i s case shows t h e multifocal n a t u r e of t h e tumour. It is often stated in t h e literature that multiple tumours are an indication for external irradiation of the entire retina. In the eight eyes in the present series with multiple tumours these were most often not simultaneously manifest. A 6OCo applicator is used for the first tumour which m a y be cured by t h e time the second tumour appears. In this situation another 6OCo disc is preferable.
Fig. 2. Small ring-shaped white scar, surrounded by faint retinal oedema. Retinoblastonia measuring 2-3 PD, with a prominence of 3-4 D, treated 6 months earlier by a Rosengren ball. Design dose 12,000 rads at a depth of 1 mni (case 180368, left eye).
Radiation of Retinoblastoma
Fig. 3. Right (upper) and left (lower) eye of the same patient as in Fig. 2, 6 years after 6OCo irradiation (case 180368).
Niels Ehlers and Sigvard Kaae
Fig. 4. Composite fundusphotograph 1 year after W o irradiation (case 29037 1). Irradiation changes in tumour area. Greyish-white processes towards the disc.
No. 2.90371. A girl with no family history of retinoblastoma. At the age of 8 months the mother noticed a yellow reflex in the left pupil, and shortly afterwards divergent squint of this eye. Ophthalmoscopy of the right eye disclosed a large tumour temporal to the macula, measuring 5-6 PD, and with a prominence of about 5 D. T h e left fundus was completely filled with tumour, most prominent in the temporal half. Satellites were seen in the vitreous. Treatment and course. T h e left eye was enucleated as no normal retina was left. Microscopy confirmed the diagnosis of retinoblastoma. A Stallard 6OCo disc (CKA 4) was applied to the right eye, until a dose of 4000 rads at a depth of 11.5 mm had been given as recommended by the manufacturer. Regression occurred, with flattening,, marginal pigmentation and a central white fragmented area. At examinations 2 and 3 months after radiotherapy the tumour still had a prominence of 3 D. The white tumour was surrounded by oedematous retina and pigmentation. After 5 and 7 months conditions were unchanged. Nine months after the treatment small haemorrhages together with oedema were seen in the tumour area.
Fig. 5. Composite fundusphotograph, same eye as Fig. 4, 3 months later. Progression in the processes towards the disc, now showing haemorrhages (case 29037 1).
Six weeks later conditions were similar, except for exudate-like areas above and below the macula. A further 6 weeks later, which was almost 1 year after the initial treatment. the findings were as shown in Fig. 4. The areas above and below the macula progressed during the next months (Fig. 5 ) and finally reached the lower disc margin. As the nature of the process, which now contained some haemorrhages at the disc margin, was uncertain, and as tumour could not definitely be ruled out, it was decided the safest procedure would be to enucleate the eye. This was done 1 year and 7 months after the radiation treatment. Examination of the eye. Histological examination showed the processes above and below the disc to be subretinal, acellular exudates (Fig. 6). The retina showed moderate oedema with cystic degeneration, and in all layers, large swollen hydropic cells with a light and finely granular cytoplasm. No inflammatory cell infiltration. The tumour area revealed a glial scar with granular calcifications. The glial cells were enlarged and hyperchromatic. Around the calcifications were remnants of tumour tissue, appearing as regular, hyperchromatic cells showing in some places rosettes but no proliferation (Fig. 7). Oedema and small haemorrhages were present. Some of the vessels were thrombosed, with swollen endothelium and perivascular fibrosis. There was no invasion of tumour in the optic nerve.
Niels Ehlers and Sigvard Kaae No. 250472. The younger brother of a girl with bilateral retinoblastoma; otherwise no family history of retinoblastoma. Examined at the age of 4 months. In the right eye a 4 PD tumour was seen in and below the macula ending less than 1 PD from the disc. The left eye was normal. Treatment and course. A Stallard disc (CKA 10) with a n excavation for the optic nerve was placed over the tumour. Design dose 4000 rads at a depth of 11.5 mm. After 1 month the tumour base appeared greyish and oedematous, there were calcifications on the top of the tumour. The eye was examined at 1 month intervals and remained unchanged for the next 3 months. Six months after irradiation the tumour was described as being chalk-white and a delicate veil towards the disc was noted. Two months later the disc was oedematous with large newformed vessels. The tumour was surrounded by a finely pigmented area and the white calcifications were somewhat diminished. Below the tumour and reaching the margin of the disc was an area of greyish oedema with haemorrhages. As the other eye was tumour-free, and as the findings in the right fundus were difficult to interpret, an enucleation was decided upon. The left eye has been followed regularly, and after 9 months still shows no tumour. Examination of the eye. In the macula the 2 x 1 mm yellowish remnants of the treated tumour were found. The tissue around the disc was whitish and oedematous. Microscopic examination in the tumour area showed cicatriceated calcified necrobiotic tumour. In
Fig. 6. Photomicrograph showing the greyish-white process below the disc seen in Fig. 5 to be a subretinal, acellular exudate. The retina is oedematous with swollen hydropic cells. No tumour infiltration. Case 29037 1, magnification x 60.
Radiation of Retinoblastoma the internal nuclear layer a considerable hyperplasia was seen, in a few places with attempted formation of rosettes. T h e tumour cells were homogeneously hyperchromatic, without mitoses and malignant structures. T h e whitish area with haemorrhages around the disc was composed of connective tissue, lipid infiltration and oedema, but did not contain tumour. There was some haemorrhage and fibrosis in the optic nerve sheets, but no tumour infiltration. No. 070867. A boy with no family history of retinoblastoma. At the age of 1 month a white-yellow pupil was noted. On admission, at the age of 3 months, the left eye was filled by tumour, seen immediately behind the lens. In the right eye there was a 4 PD tumour situated in the upper nasal quadrant, with a n 8 D prominence. In the 12 o’clock meridian another small, white tumour with no measurable prominence was seen. Treatment and course. The left eye was enucleated. Microscopy showed retinoblastoma with rosettes. T h e large tumour in the right eye was treated by a Rosengren ball with a calculated dose of 12,000 rads at a depth of 1 mm. Three weeks later the upper smaller tumour was similarly treated, the dose being 12,000 rads at a depth of 1 mm. After 1 month the large tumour showed a definite regression with chalk-white nodules, now with only a 4 D prominence. T h e upper, smaller tumour had almost disappeared. One year later the large tumour consisted of a grey area with a small central whitish scar. The prominence was less than 2 D. Eighteen months after the radiation treatment a new
Fig. 7. The tumour area of the same eye as shown in Figs. 4-6. A glial scar with calcification and remnants of tumour tissue appearing as regular, hyperchromatic cells showing in some places rosettes but no proliferation. Magnification x 120.
Niels Ehlers and Sigvard Kaae
Fig. 8. Preretinal cyst appearing after local W o irradiation (case 070867)
tumour appeared at the 6.30 meridian in the peripheral retina, with a n estimated size of 1 PD. This tumour was treated with a Rosengren ball. Design dose 12,000 rads at a depth of 1 mm. The tumour had disappeared after 1 month. During the following month the large central tumour showed no further regression. At the site of the upper tumour a large "cyst" appeared (Fig. 8). Later it descended towards the lower tumour, where a large scleral necrosis developed. A biopsy from this area showed no tumour. Twenty-six months after irradiation the large central tumour was seen to be inrreasing, it vaulted over the margin of the disc. As recurrence of the tumour was suspected, another radiation treatment was given with a crescentic Stallard disc (CKA 19). Design dose 4000 rads at a depth of 7.9 mm. After 1 month a vitreous haze had appeared, the tumour had definitely grown, now extending over the disc. There were haemorrhages in the tumour. The peripheral irradiated areas were unaltered without signs of recurrence. An enucleation was decided upon. Examination of the eye. The retina showed atrophic changes, gliosis and necrobiotic areas containing histiocytes but no calcification and no surviving tumour cells. The findings can be interpreted as being due to irradiation. There was no tumour growth in the optic nerve.
Radiation effects and complications
Following irradiation the tumour mass changes its appearance becoming a dense white flocculent mass, probably due to necrosis and calcification (Stallard 1955).
In the first weeks after irradiation the tumour is surrounded by greyish-white oedema. Then regression begins and during the next month the chalk-white areas make their appearance, until the tumour is finally made up of small avascular nodules (Fig. 9). Fragments may spread into the vitreous, where they appear white, refractile and crystalline, and should not be mistaken for intravitreal seeding or recurrence (Haye & Calle 1970). Small tumours (