Abstract
Purpose
The aim of this study was to report the efficacy of combined intravitreal chemotherapy (IVC) and ruthenium-106 brachytherapy in retinoblastoma, either as first-line or second-line treatment, following systemic chemoreduction or intra-arterial chemotherapy.
Methods
Retrospective data of 18 eyes from 18 patients treated with IVC and brachytherapy from August 2014 to December 2019 were collected.
Results
The method described was our first-line therapy in 6 patients, whereas it was used as second-line treatment after chemoreduction in the remaining 12 patients. The eyes showed the following classification at initial presentation: 2 group B eyes, 3 group C eyes, and 13 group D eyes. The mean follow-up was 19.5 months (range 2–53 months). The mean patient age at brachytherapy was 34.0 months (range 15–83 months). The median prescribed dose at the tumour base and apex was 574.5 ± 306.7 Gy and 88.5 ± 12.2 Gy, respectively. The ocular retention rate was 66.7%. Six eyes had to be enucleated due to uncontrollable subretinal and recurrent vitreous seeding, tumour relapse, recurrence of a solid tumour elsewhere in the eye, and persistent vitreous bleeding with loss of tumour control. The mean number of intravitreal injections of melphalan was 5.0. Two patients received a simultaneous injection of topotecan for insufficient therapeutic response. With regard to radiogenic complications, we could observe temporary retinal and vitreous bleeding (27.8%), serous retinal detachment (44.4%), and radiogenic maculopathy and retinopathy (11.1%). None of the children showed metastatic disease during follow-up.
Conclusion
Ruthenium-106 plaque therapy in combination with IVC is an effective local therapy with good tumour control rates even in advanced eyes. Overall, the analysed therapeutic approach shows an acceptable side-effect profile, especially when considering that external-beam radiation therapy and systemic polychemotherapy or at least the number of cycles needed, with their increased incidence of adverse events, can thus be avoided.
Keywords: Optic neuropathy, Radiation maculopathy, Chemoreduction, External-beam radiation therapy, Intravitreal therapy
Introduction
Brachytherapy is an established method in the treatment of unilateral or bilateral retinoblastoma as they are known to be highly radiosensitive [1, 2]. Initially, brachytherapy was used in the primary management of solitary retinoblastomas. Later, it was also used in the treatment of relapses after external-beam radiation therapy (EBRT) or as a consolidation therapy after systemic chemotherapy, once EBRT was placed back due to the increased occurrence of radiation-induced subsequent second cancers [3] as long as the proton beam radiation therapy was not yet established [4]. There are different local brachytherapy approaches in the management of solid circumscribed retinoblastomas. Depending on availability, ruthenium-106 or iodine-125 plaques are used. The main advantage of brachytherapy is the lower risk of irradiation-induced tumours as the irradiation of extraocular structures can be reliably avoided, especially when using ruthenium-106 plaques [5]. It is well known that apart from tumour prominence or largest basal diameter, an initially present vitreous seeding or a concomitant or progressive seeding in the course of the disease is known to play a decisive role for the success of brachytherapy [6, 7]. With the introduction of intravitreal chemotherapy (IVC) for vitreous seeding, an effective treatment modality for this particular and serious complication is now available [8]. Therefore, this study is the first to discuss the combined approach of ruthenium-106 plaque brachytherapy and IVC in the treatment of retinoblastoma eyes, either as first-line or second-line therapy after chemoreduction.
Patients and Methods
We retrospectively reviewed the clinical records of all retinoblastoma patients treated with ruthenium-106 brachytherapy and IVC from August 2014 to December 2019. If the combination of brachytherapy and IVC was the initial therapy approach, the patients were classified as first-line therapy group, whereas patients treated with brachytherapy after chemoreduction were classified as second-line therapy group. Previous therapy was not considered an exclusion criterion. All eyes were classified according to the International Classification of Retinoblastoma (ICRB) (Philadelphia version) [9].
Before starting therapy, a detailed examination with RetCam® photo documentation and precise measurement of the tumour volume were performed. The target volume and the radiation dose, as well as the chemotherapy dosage (local or systemic), were then individually determined in an interdisciplinary tumour board in cooperation with ophthalmologists, radiation therapists, paediatric oncologists, and neuroradiologists. The radiation dosage was calculated in accordance to the National Institute of Standards and Technology (NIST) traceability with 88 Gy at the tumour apex. If a tumour showed a focal vitreous seed floating above the tumour intended to treat, this was added to the initial tumour height as a positive effect on local vitreous seeding was expected. Nevertheless, IVC was performed in all of these cases.
According to these values, it was decided whether chemoreduction was reasonable or not, whereby the risk of radiogenic complications by treating a naive and larger tumour was therefore individually weighed against the side effects of intravenous or intra-arterial chemotherapy (IAC). Systemic polychemotherapy was done in accordance with the vincristine, etoposide, and carboplatin protocol. IAC was initially carried out as a routine procedure with melphalan only as it appears to be the most potent and most commonly used drug for retinoblastoma. As long as a standardized protocol specifying drugs and dosage for IAC has not been established yet, this therapy approach might be less aggressive compared to other centres but shows good results in our cohort [10]. Combined therapy with topotecan and carboplatin was reserved for complicated courses with a lack of response to initial melphalan therapy.
Brachytherapy and intravitreal injections of melphalan/topotecan were conducted under general anaesthesia. Brachytherapy was performed exclusively with ruthenium-106 plaques (commercially available by BEBIG Isotopen und Medizintechnik GmbH, Berlin, Germany). At the beginning of surgery, maximum tumour height and diameter were sonographically re-examined, and the corresponding plaque provided. Localization and tumour borders were identified by intraoperative ophthalmoscopy. The plaque was positioned and fixed to the sclera with non-absorbable sutures. After confirming the correct positioning of the plaque, it was thoroughly fixed by adding a mattress suture. The plaque was removed once the required 88 Gy at the tumour apex was obtained, mostly in combination with the first intravitreal injection. If 2 drugs had to be injected, melphalan was injected first. Follow-up injections were applied within 7–10 days.
Results
Eighteen eyes of 18 patients (male n = 14, female n = 4) could be analysed in this study shown in Table 1. In 2 cases, the diagnosis of retinoblastoma was bilateral, whereas 88.9% showed unilateral disease. Three children had a family history of retinoblastoma. The mean patient age at brachytherapy was 34.0 months (range 15 months to 83 months). The mean follow-up time was 19.5 months (range 2–53 months). In 2 children, pretreated with either systemic chemotherapy or a plaque elsewhere in the eye, a tumour relapse was treated with the therapeutic approach discussed here.
Table 1.
Patient demographics and tumour characteristics
| Treated eyes | 18 |
| Patients, N | 18 |
| Gender, n (%) | |
| Male | 14 (77.8) |
| Female | 4 (22.2) |
| Patient age at brachytherapy in months | |
| Median (range) | 34.0 (15–83) |
| Laterality, n (%) | |
| Bilateral | 2 (11.1) |
| Unilateral | 16 (88.9) |
| Family history, n (%) | |
| Positive | 3 (16.7) |
| Negative | 15 (83.3) |
| Follow-up time in months | |
| Median (range) | 19.5 (2–53) |
| ICRB* (first-/second-line treatment) | |
| A | 0 |
| B | 2** (1/1) |
| C | 3 (2/1) |
| D | 13 (3/10) |
| E | 0 |
| Tumour height, mm | |
| First-line therapy | 6.0±2.5 (range 2.0–8.0) |
| Second-line therapy | |
| Initial tumour height | 9.0±1.3 (range 7.0–11.0) |
| Following chemoreduction | 5.0±0.8 (range 3.8–6.0) |
| All patients | |
| Tumour height before brachytherapy | 5.0±1.5 (range 2.0–8.0) |
| Classification of intravitreal seeds, n (%) | |
| Dust | 2 (11.1) |
| Spheres | 7 (38.9) |
| Clouds | 9 (50.0) |
International Classification of Retinoblastoma.
Worsening of the findings during course of disease.
Six patients were assigned to the first-line therapy group. The treated eyes showed the following classification at initial presentation as shown in Table 1: 1 eye was grouped as ICRB B due to 1 solid tumour with impending vitreous seeding in the middle periphery which resulted in a proper vitreous seeding under the manipulation of plaque surgery. Two eyes were classified as ICRB C and 3 eyes as ICRB D. Four patients showed unilateral disease, and 3 cases had a familial retinoblastoma. Figure 1a–c shows a typical example of the first-line treatment group.
Fig. 1.
First-line treatment group: 2-year-old girl with bilateral retinoblastoma, right eye ICRB C and left eye ICRB E. Retinoblastoma at diagnosis (height 4.9 mm) with floating fluffy vitreous seeds (a), corresponding MRI scan showing the solid tumour with vitreous seeding (arrow) in the right eye and extensive retinoblastoma with complete retinal detachment in the left eye (b), type-I regression and radiation scar 2 months after termination of treatment with brachytherapy and intravitreal melphalan (c), typical salt-and-pepper-fundus after intravitreal injections as a local toxic reaction to melphalan (d).
Regarding the second-line treatment group (n = 12), 10 cases were classified as ICRB D eyes. The 2 remaining eyes were C and B eyes. The B eye developed vitreous seeding after chemoreduction. All patients in this group showed unilateral disease. Concerning chemoreduction, 7 children were treated with systemic chemotherapy and 4 children with intra-arterial melphalan. One child received both, due to insufficient response after 2 cycles of systemic chemotherapy. Figure 2 shows a typical example of the second-line therapy group. Table 1 summarizes the characteristics of both groups.
Fig. 2.
Second-line treatment group: case of a 3-year-old patient with unilateral retinoblastoma, height 5.5 mm. Fundus photography of the initial tumour in the left eye (a), tumour regression and diffuse vitreous seeding after 1 cycle of systemic polychemotherapy (b), serous retinal detachment, local intraretinal bleeding and beginning of a radiation scar (3 months later) (c), regressive disease during follow-up (d), and organized vitreous seeds after 9 injections of intravitreal melphalan.
All 18 eyes were treated with a ruthenium-106 plaque. The mean tumour height at initial presentation was 6.0 ± 2.5 mm (range 2.0–8.0 mm) in the first-line treatment group and 9.0 ± 1.3 mm (range 7.0–11.0 mm) in the second-line treatment group, as shown in Table 1. After chemoreduction, the tumour volume was reduced to a mean tumour height of 5.0 ± 0.8 mm (range 3.8–6.0 mm). The median radiation dose was 574.5 ± 306.7 Gy (range 187.0–1,504.0 Gy) at the sclera and 88.5 ± 12.2 Gy (range 61.0–102.0 Gy) at the apex. The treatment time added up to 80.1 ± 39.5 h as listed in Table 2.
Table 2.
Treatment characteristics
| First-line therapy | 6 |
| Second-line therapy | 12 |
| Systemic chemotherapy (VEC*) | |
| 1 cycle | 3 |
| 2 cycles | 4 |
| IAC (melphalan) | |
| 1 cycle | 0 |
| 2 cycles | 3 |
| 3 cycles | 1 |
| Systemic chemotherapy and IAC** | 1 |
| Radiation dosimetry in Gy (median) | |
| Sclera | 574.5±306.07 |
| Apex | 88.5±12.2 |
| Brachytherapy treatment time in hours | 80.1±39.5 |
| (median) | |
| Intravitreal therapy | 18 |
| Melphalan 25 μg | 16 |
| Melphalan 25 μg + topotecan 20 μg | 2 |
| Injections per eye, n (median) | 5.0±3.5 (range 1–12) |
| First-line group | 3.0±1.5 (range 1–6) |
| Second-line group | 6.0±3.6 (range 3–12) |
| Injections per eye, n (median) | |
| Dust | 2.0±1.41 (range 1–3) |
| Spheres | 3.0±2.24 (range 3–6) |
| Clouds | 6.0±3.14 (range 5–12) |
| Response to therapy, n (%) | |
| Brachytherapy | 18 (100) |
| Intravitreal melphalan/topotecan | 16 (88.9) |
| Globe salvage rate, n (%) | 12 (66.7) |
Vincristine, etoposide, and carboplatin.
Insufficient reaction to systemic chemotherapy.
Looking at the classification of intravitreal seeds [11], we found dust in 2 cases (11.1%), spheres in 7 cases (38.9%), and clouds in 9 cases (50%) as shown in Table 1. All 18 eyes were treated with intravitreal injections as shown in Table 2. In 16 cases (88.9%), melphalan was injected exclusively. In the absence of a sufficient therapy response, additional topotecan was injected in 2 eyes (11.1%). One eye could be preserved with 1 additional injection of topotecan. The other eye had to be enucleated after 3 supplementary injections of topotecan due to a tumour involvement of the anterior chamber.
The mean number of injections was 5.0 ± 3.5. Regarding the 2 groups, the patients in the first-line group needed 3.0 ± 1.5 (range 1–6) injections, whereas more injections (6.0 ± 3.6 [range 3–12]) were required in the second-line group as shown in Table 2. Regarding the different classes of intravitreal seeds, patients with dust needed 2.0 ± 1.41 (range 1–3) injections, patients with spheres 3.0 ± 2.24 (range 3–6), and patients with clouds three 6.0 ± 3.14 (range 5–12), respectively.
All solid tumours showed a good response to brachytherapy with a type-IV or type-III regression as shown in Table 2. Six months after successful brachytherapy, 1 eye presented with a tumour recurrence at the margin of the type-IV regression, successfully treated with an additional brachytherapy approach. In 4 cases, further brachytherapy was needed due to tumour manifestations elsewhere in the eye. Regarding the second-line treatment group, almost all patients showed a good response to 1–3 cycles of chemoreduction. In one case, a switch to intra-arterial melphalan was necessary to achieve the required effect of tumour volume reduction. In 50% of the cases in the second-line therapy group, vitreous seeding occurred in the course of chemoreduction. None of the surgical procedures showed severe post-operative complications.
Table 3 summarizes the documented short- and long-term complications of both groups. Retinal or vitreous haemorrhage after brachytherapy was documented in 7 eyes (38.9%). Five of these eyes (27.8%) showed a local bleeding which resolved spontaneously within several months (range 1–3 months). The other 2 eyes showed a late onset radiation retinopathy and an extensive subretinal bleeding (7–14 months after brachytherapy). There were 8 eyes (44.4%) with a serous retinal detachment during follow-up, 5 eyes showing a spontaneous regression within weeks, and 2 cases within months. All in all, the documented complications were predominantly seen in the second-line therapy group.
Table 3.
Short- and long-term complications
| Patients, n (first-/second-line treatment) | 18 (6/12) |
| Bleeding, n (%) | 7 (38.9) (2/5) |
| Local, temporary | 5 (27.8) |
| Radiation maculo-/retinopathy | 2 (11.1) |
| Serous retinal detachment, n (%) | 8 (44.4) (1/7) |
| Reversible within weeks | 5 (27.8) |
| Reversible within months | 3 (16.7) |
| Secondary enucleation, n (%) | 6 (33.3) (1/5) |
| Massive vitreous/subretinal seeding | 2 (11.1) |
| New tumour occurrence on the optic disc | 2 (11.1) |
| Radiation retinopathy and loss of control | 1 (5.6) |
| Not related to retinoblastoma | 1 (5.6) |
Regarding IVC, 9 eyes (52.9%) showed a “salt-and-pepper retinopathy” at the injection site (shown in Fig. 1d). In 88.9% of the cases (n = 16), vitreous seeding showed complete regression or calcification during the treatment course. No metastatic disease was noticed during follow-up.
The ocular survival rate was 66.7% (n = 12). Six eyes, 5 of them assigned to our second-line treatment group, could not be preserved in the long term (33.3%). Two eyes were enucleated due to recurrent subretinal and vitreous seeding, with anterior chamber involvement in one case, as mentioned above. One patient showed a persistent vitreous bleeding with loss of tumour control, and one developed a secondary uveitis with an uncontrollable secondary glaucoma and loss of tumour control. The remaining 2 eyes had a tumour recurrence at the optic nerve head. Table 3 gives an overview. One of the enucleated specimens showed an extensive choroidal invasion with an indication of adjuvant chemotherapy. The remaining enucleated specimens showed no risk factors on histopathological workup.
Discussion
Since EBRT of retinoblastomas has been largely replaced due to the high rate of subsequent second primary malignancies in hereditary retinoblastoma, and as systemic chemotherapy shows serious systemic complications [3, 12], the search for further therapy options focuses on local procedures. These local procedures include laser- and cryocoagulation, IAC, brachytherapy, and IVC, all with specific advantages and limitations.
Brachytherapy of retinoblastoma has been pioneered by Moore et al. [13] when treating the first patient with intrascleral radon seeds in 1929. It was further defined by Stallard [14] (cobalt-60 plaques), Sealy et al. [15] (low energy γ-plaques using iodine-125), and Lommatzsch and Vollmar [16] (β-particle-emitting ruthenium-106 plaques).
Currently, iodine and ruthenium plaques are the most frequently used plaques. In comparison, ruthenium plaques have a steeper dose fall-off, resulting in a better protection of radiosensitive intraocular structures and a smaller target volume [17]. However, this means that they are no longer recommended if the maximum tumour height exceeds 6 mm [6]. Another advantage is their low height (thickness of 1 mm), making positioning on children's eyes easier and more precise.
Although the eye preservation rate with ruthenium-106 brachytherapy as first- or second-line treatment is hugely satisfying, vitreous seeding and fish flesh regression are the main risk factors for tumour recurrence and therapy failure. Schueler et al. [7] published a series of 175 tumours in 140 eyes of 134 patients with a mean tumour height of 3.7 ± 1.4 mm and the largest tumour diameter of 5.0 ± 2.8 disc diameters treated with a mean prescribed dose of 419 Gy at the sclera and 138 Gy at the tumour apex. In this study, 16 eyes had to be enucleated mainly due to local tumour recurrence and active vitreous seeding, loss of tumour control from persistent vitreous haemorrhage, and functional blindness. A similar study was published by Murakami et al. [6]. They could maintain 58.7% of all treated eyes with a significantly lower dose of 162.3 Gy to the sclera and 47.4 Gy to the tumour apex. The 2-year local tumour control rate was 33.7%, suggesting that a low radiation dose at the tumour apex could be responsible for the poorer results. Again, advanced tumour stages with vitreous and subretinal seeding, tumour size greater than 5 disc diameters, maximum tumour height of more than 5 mm, dose rate at reference depth lower than 0.7 Gy/h, and dose reference depth lower than 35 Gy were associated with an unfavourable outcome. Nevertheless, 20% of the advanced eyes were preserved with brachytherapy alone.
Just recently, Echegaray et al. [1] published their results on brachytherapy, using mainly iodine plaques, of 11 tumours as a first-line or second-line treatment. Again, the group D eyes with diffuse subretinal or intravitreal seeding could not be preserved during treatment course.
Considering the studies cited above, it seems to be obvious that vitreous or subretinal seeding is one of the most significant risk factors for failure of brachytherapy in retinoblastoma. IVC, which is now available for this aggravating complication of the disease, could thus significantly improve treatment failure.
IVC as pioneered by Kaneko and Suzuki [18] in 1994 and further developed by Munier et al. [8, 19] has significantly improved the chance of globe preservation in retinoblastoma eyes harbouring vitreous seeds. The adverse effects of this relatively new therapy method are limited and well-studied. A common adverse event of IVC is a circumscribed salt-and-pepper retinopathy at the injection site, which we could observe in the majority of our cohort without visible damage to the fovea [20]. Functional studies however demonstrated a 5.3-μV reduction of ERG amplitudes with each injection [21]. Since, as already mentioned, vitreous seeding plays a decisive role in the therapeutic failure of brachytherapy, a combination with intravitreal therapy seems to be a reasonable approach. Our study is the first to address this therapeutic approach.
We treated a retinoblastoma population with ruthenium-106 brachytherapy in combination with IVC, resulting in a high ocular survival rate (66.7%). In total, 16 of the included 18 eyes (88.9%) were classified as group C or worse. With regard to the combined approach, we could even treat eyes which would otherwise have had to be enucleated or treated with EBRT.
In our first-line group the median tumour height was 6.0 ± 2.5 mm and in the second-line group, following local or systemic chemoreduction, with 5.0 ± 0.8 mm slightly lower. When focussing on the first-line treatment group, 3 patients underwent primary brachytherapy with a tumour height exceeding the recommended tumour height of 6 mm. Two cases presented with a tumour height of 7.0 mm, and the third had a maximum height of 8.0 mm, respectively. To avoid systemic side effects of a chemoreduction, the higher risk of radiogenic complications was accepted resulting in a mild, reversible local bleeding as a sign of radiogenic complications in 2 cases. These manageable and reversible short-term radiogenic complications with simultaneously good therapeutic response could encourage using brachytherapy even in retinoblastomas exceeding the usually proposed 6 mm in height.
All patients in the second-line therapy group presented with tumours exceeding 7.0 mm in height, with a maximum of 11.0 mm in 1 eye. In all cases, the various types of chemoreduction resulted in tumour shrinkage, which subsequently allowed for local brachytherapy. Findings in our study suggest that the combined therapeutic approach in the second-line treatment group might be associated with an increased cumulative toxicity and therefore associated with a worse outcome. The patients in our second-line treatment group showed a higher incidence of intraocular haemorrhage and serous retinal detachment, and 5 of the 6 enucleations were performed in this group. Therefore, as mentioned earlier, brachytherapy alone might be superior, even in retinoblastomas exceeding 6 mm in height.
In addition to the corresponding toxic aspects of IVC, there are the known radiogenic complications after brachytherapy, as already mentioned above. Schueler et al. [7] published the largest series on ruthenium-106 brachytherapy in retinoblastoma. Regarding radiogenic complications, with a mean prescribed dose of 419 Gy at the sclera and 138 Gy at the tumour apex, radiation retinopathy was observed in 22%, radiation optic neuropathy in 21%, and cataract formation in 17% of treated eyes after a mean follow-up of 5 years. Radiation-related complications were more severe in non-treatment-naive patients. With 38.9% radiogenic complications (without cataract progression), the results of our study and the study just referenced are quite similar despite the lower apex dose of 88 Gy chosen in our study. Nevertheless, the lower apex dose in our study showed good results in terms of tumour control and recurrences, which emphasizes that there is so far no sufficient answer to the optimal dosage of brachytherapy in retinoblastomas.
However, the above discussed radiation-induced complications also occur after other radiation modalities including EBRT and iodine-125 brachytherapy. Shields et al. [22] treated 84 retinoblastomas with iodine-125 plaques as a salvage treatment after chemoreduction. They documented persistent radiogenic complications such as proliferative retinopathy in 19%, ischaemic maculopathy in 24%, optic neuropathy in 16%, cataract in 43%, and glaucoma in 4% of the treated eyes after 5 years of follow-up. These results were mostly stable during the extended follow-up period and correspond to the side-effect profile of ruthenium-106, except for the increased risk of radiogenic cataract.
We did not observe an increased incidence of cataract formation in our patient population which may be due to the shorter follow-up time in our series. Concerning eye preservation rate, we were able to permanently preserve 12 of the included 18 eyes, resulting in an eye preservation rate of 66.7%. Six eyes, all of them advanced group D eyes, had to be enucleated after a period of several months. Looking more closely at the reasons for enucleation, only 3 eyes had to be removed due to treatment failure. Regarding this, the globe salvage rate could be adapted to 83.3%.
Overall, the results of the combined approach of brachytherapy and IVC in retinoblastoma eyes are encouraging. In tumours with a height of more than 6 mm, a minimal number of no more than 2 courses of systemic chemotherapy were usually sufficient to achieve the required tumour reduction. The radiogenic complications after brachytherapy are well investigated and manageable so that we do not expect a significant increase during further follow-up. The combined effect of brachytherapy and IVC cannot yet be conclusively assessed, but there is no doubt that, in general, a local procedure with a comparable therapeutic success and reduced collateral damage is always preferable to a systemic procedure.
Statement of Ethics
The paper is exempt from Ethical Committee approval because of a retrospective and anonymous data collective.
Conflict of Interest Statement
M.S. obtained research funding to the institution from AstraZeneca and honoraria (advisory board function) from AstraZeneca, Bristol-Myers Squibb, Sanofi-Aventis, and Janssen-Cilag. The other authors have no conflict of interest to disclose.
Funding Sources
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Author Contributions
S.S., E.B., N.B., and N.E.B. contributed to conceptualization; E.V., T.K., S.G., D.F., M.S., and P.K. contributed to investigation; S.S. and E.B. contributed to methodology; S.S. and E.B. contributed to writing of the original draft.
Data Availabilty Statement
All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.
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