Episcleral brachytherapy for intraocular retinoblastoma with 106Ruthenium plaque: analysis of 13 procedures

INTRODUCTION

Brachytherapy (plaque radiotherapy) is a method of treatment that involves delivering radiation directly to lesions, by placing a source of radiation in a tumor (or other lesion) or in its immediate proximity. It enables the irradiation of the tumor with minimum damage to the surrounding healthy tissues. In ophthalmology, brachytherapy is most often used for intraocular tumors such as choroidal melanoma in adults and retinoblastoma in children [1].
Brachytherapy, in contrast to external beam radiation therapy (EBRT), due to the possibility of more precise and local irradiation of the tumor, does not induce orbital bone deformities in infants and carries much smaller risk of induction of second cancers in the treated orbit. Moreover, brachytherapy is in selected cases more effective in treatment of retinoblastoma than EBRT [2].
The use of brachytherapy to treat intraocular tumors was introduced by Moore at the beginning of the 20th century and then modified and further popularized in retinoblastoma treatment by Stallard [3, 4]. In the 1970s, Lommatzsch utilized the β-emitting isotope 106Ru in a shell-shaped applicator with silver casing which provided effective protection of nearby tissues [5].
In Poland, the pioneer of brachytherapy (cobalt-60 – 60Co) in the 1960s in the treatment of eye tumors was Professor Helena Żygulska-Mach in Cracow. The Department of Ophthalmology in Kraków was among the first centers in the world to use brachytherapy to treat ocular tumors [6]. Brachytherapy in the treatment of children with retinoblastoma has been used in the Department of Ophthalmology of the University Hospital in Kraków since 1968, initially with the use of Co-60 applicators, and since 1995 with Ru-106 applicators, while very large tumors are irradiated with I-125. Both methods of brachytherapy are still used today in the treatment of retinoblastoma [7]. At present, ruthenium-106 (106Ru) is the most popular isotope used in Europe, while iodine-125 (125I) is preferred in the USA [8, 9].
106Ru emits β-particles with penetration of 10% of the surface dose to 5–6 mm through water or tissue. 106Ru plaques are suitable for tumors up to 6 mm thick, because of the steep dose gradient in tissue [10]. Applicators with 125I can be used for larger tumors, with a greater radiation range (also useful in cases of tumor dissemination into the vitreous), which allows the eyeball to be preserved, often with useful vision [7]. Treatment with 106Ru plaques, compared with 125I ones, reduces the radiation dose delivered to sensitive structures of the eye: lens, macula and optic disc. Major adverse effects such as cataract formation or optic nerve atrophy are less common after 106Ru brachytherapy in comparison with 125I [10, 11]. Another advantage of 106Ru brachytherapy over 125I is smaller thickness of the former (1 mm vs. 3 mm), which has great importance particularly in infants [12].
In Poland, the total number of children undergoing chemotherapy combined with focal treatment (brachytherapy, cryotherapy, transpupillary thermotherapy (TTT)) increased significantly from 2010 to 2017. In the same period, the number of enucleations and external beam radiotherapies decreased [13]. Brachytherapy with 106Ru has been used in the treatment of retinoblastoma in the Department of Ophthalmology of the Children’s Memorial Health Institute in Warsaw, Poland for more than 15 years.

AIM OF THE STUDY

The purpose of this study is to evaluate the efficacy of 106Ru brachytherapy for the treatment of retinoblastoma, in the era of modern treatment modalities: intra-arterial and intravitreal chemotherapy.

MATERIAL AND METHODS

Patients

This study included 13 eyes of 13 patients (9 male, 4 female) – all patients treated with 106Ru brachytherapy in the Department of Ophthalmology of the Children’s Memorial Health Institute in Warsaw, Poland from 01.01.2015 to 1.11.2020. The mean time between the initial diagnosis of retinoblastoma and brachytherapy was 19.92 months (median 19; range 10-41). The mean follow-up time from brachytherapy to the last visit was 24.33 months (median 22; range 7-54).

Inclusion criteria

Tumors qualified for brachytherapy were active, repeatedly recurring, not amenable to other methods of local treatment such as cryotherapy, transpupillary thermotherapy (TTT) or indocyanine green enhanced transpupillary thermotherapy (ICG-TTT). Tumors qualified for treatment were less than 6 mm in height, located at a distance not smaller than 2 DD from the optic disc or fovea.

Tumor classification

Bilateral retinoblastoma was diagnosed in 7 patients (53.85%), unilateral in 6 (46.15%). During the initial examination of the child, at the time of retinoblastoma diagnosis, tumors in eyes, that were later treated with brachytherapy, were classified according to the International Classification of Retinoblastoma (ICRB) [14] (Table I).
Three tumors were classified as group A (23.08%), two tumors as group B (15.38%), three tumors as group C (23.08%), one tumor as group D (7.69%) and four tumors as group E (30.77%). The mean tumor height (with sclera) immediately before brachytherapy was 3.7 mm (median 3.74; range 2.66-4.87). Immediately before brachytherapy, tumors were located on white scar in 12 cases (92.3%) and on calcification in one case (7.7%).
h3>Previous treatment In all cases brachytherapy was used as salvage therapy on the active tumor, after inefficacy of other treatment modalities. The mean number of tumor recurrences before brachytherapy was 3.15 (median 3; range 2-7). All eyes received systemic or intra-arterial chemotherapy before the final relapse which was the indication for brachytherapy. Every tumor before brachytherapy had already received in the past other forms of local treatment (Table II).
h3>Plaque 106Ru plaque, made by Eckert & Ziegler BEBIG GmbH, model CCA 15.3 mm diameter, was used. The plaque was round, shaped correspondingly to the globe curvature, designated for tumors not adjacent to the optic nerve or cornea.
h3>Dosimetry The aimed prescription dose at the tumor apex was 40 Gy. Tumor apex dose calculation was based on the one-dimensional depth dose curve given by the manufacturer on fact sheets for each individual plaque.
h3>Surgical procedure The episcleral plaques were inserted under general anesthesia after precise tumor localization using indirect ophthalmoscopy and scleral depression. A temporary disinsertion of one extraocular muscle was performed if required. Plaques were affixed to the globe with nonabsorbable sutures. We did not use additional mattress suture to prevent the plaque from possibly tilting away from the globe. Plaques were removed under general anesthesia, after the calculated treatment time corresponding to the delivery of the prescribed radiation dose.

RESULTS

Brachytherapy as the only treatment on active recurrence of retinoblastoma was effective in 12 cases (92.3%). Tumor relapse occurred in one case (7.7%) – 8 months after brachytherapy. Initially, the tumor in this eye was classified as group E. Prior to brachytherapy this eye received: 6 cycles of systemic chemotherapy, 7 cycles of intra-arterial chemotherapy, 5 cryotherapy procedures, 1 TTT procedure, and 3 intravitreal injections of melphalan. The tumor was located on white scar and its height before brachytherapy was 4.13 mm with sclera. In this case, enucleation was suggested to parents at an earlier stage before brachytherapy, but the parents did not give their consent.
In two cases, after brachytherapy, an additional method of treatment was applied, which could have an influence also on the tumor treated with brachytherapy. In both cases, intravitreal injections of melphalan were administered. In the first case, adjuvant treatment was planned at the moment of qualification for brachytherapy. In the second case, it became necessary to treat recurrence in the vitreous 7 months after brachytherapy (recurrence in another part of the vitreous, probably not related to the tumor treated with brachytherapy). In both cases, all intraocular tumors remained in regression.

Ocular survival

Enucleation was performed in one case (7.7%) out of all 13 brachytherapy procedures.

Overall survival

None of the patients died from retinoblastoma. There were no metastases or second cancers in any patient.

Complications

Neovascularisation that caused recurrent retinal and preretinal hemorrhages was found in 4 eyes (30.8%). Abnormal blood vessels were usually located on the tumor apex. Recurrent vitreous hemorrhages from these blood vessels occurred at the mean time of 7.75 months after brachytherapy (median 8.5; range 3-11). Exudate in the area of the tumor was found in 1 eye (7.69%). No cases of optic neuropathy or cataract were observed.

DISCUSSION

In the literature, there is a very limited number of publications concerning the efficacy of brachytherapy for the treatment of retinoblastoma (particularly using 106Ru) after the introduction of both important modern chemotherapy techniques: OAC (ophthalmic artery chemosurgery) and IVIM. In 2013, Francis et al. assessed the efficacy of 125I brachytherapy after OAC (only in one case 106Ru plaque). At that time, administering IVIM was not yet widespread [15]. Introduction of IVIM in treatment of retinoblastoma has a major impact on the brachytherapy regimen. At present it is not necessary to consider the vitreous seeds, during treatment field planning, which are often present near the main mass of the treated tumor. Therefore, IVIM administration enables, in selected cases, significant reduction of the radiation dose – which has an influence on reducing the number of complications, particularly involving sensitive structures such as lens and optic nerve. On the other hand, introduction of OAC significantly reduces the risk of subretinal recurrence.
In our work, in all cases, we used brachytherapy for treatment of active tumors. We do not use brachytherapy as consolidation treatment, because after OAC usually there is no need for consolidation, and brachytherapy is associated with complications (recurrent vitreal hemorrhages in 30.8% of patients in our study) too serious to use it as a method to prevent possible recurrences.
In our material, we used brachytherapy as a treatment to save the eye – salvage therapy. Tumors had already received comprehensive systemic and local treatment. All tumors had multiple recurrences before brachytherapy (mean: over 3 recurrences). Almost all tumors were located on white scar, except for one tumor located on calcification (Figures 1-3). At this location of the tumor other local treatment modalities are usually ineffective [16]. Despite these conditions, very high efficacy of brachytherapy draws attention in our data (92.3%).
In our study, the aimed prescription dose at the tumor apex was 40 Gy. Using 106Ru plaque, different centers calculate different doses at the tumor apex: 40 Gy, 55 Gy, 88 Gy [9, 11, 15]. In our study, the dose at the tumor apex of 40 Gy seems to be sufficient. We also did not apply an additional safety margin during dose calculation, adding e.g. 1 mm to the height of the tumor [12].
Notably, there is a small number of complications in our study. Particularly, we did not observe any case of cataract or optic neuropathy. The cause of a small percentage of radiation-related complications might be the use of plaques, in which the source of radiation is the 106Ru isotope. It emits β-radiation of a very short range (penetration of 10% of the surface dose to 5–6 mm through water or tissue) [10, 11]. Other reasons for the small number of complications in our study are: margin of 2 DD from plaque to optic disc or fovea, no cases of double use of plaque in the same eye, not using EBRT in treatment of intraocular retinoblastoma (method not used for 15 years in our center), average dose of 40 Gy at the tumor apex. The mean follow-up time in our study was 24.33 months (median 22; range 7-54), and occurrence of late complications cannot be excluded [17]. It is worth emphasizing that apart from the greater safety for patient, 106Ru plaque, because of the shorter range of β-radiation, is safer than 125I plaque for medical staff in the operating room and for parents (who could have a mutation of the Rb1 gene) who stay with the child in close proximity in the postoperative period [10, 18, 19].

CONCLUSIONS

106Ru plaque brachytherapy is a highly effective method of treatment for retinoblastoma recurrence even in patients with relapses after OAC. Brachytherapy is associated with adverse effects which have to be taken into account, but are acceptable considering the alternative of enucleation in patients with recurrence after previous treatment.

DISCLOSURE

The authors declare no conflict of interest.

References