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Abstract
Background/aim To evaluate the efficacy of intravitreal topotecan for refractory or recurrent vitreous seeds in retinoblastoma.
Methods Intravitreal injection of topotecan hydrochloride (30 µg/0.15 mL) was provided every 3 weeks by the safety enhanced technique.
Results The study included 17 consecutive patients with retinoblastoma with refractory or recurrent vitreous seeds. Five eyes (29%) belonged to International Classification of Retinoblastoma group C and 12 eyes (71%) belonged to group D. Primary treatment included triple drug intravenous chemotherapy for a mean of 10 cycles (median, 9 cycles; range, 6–18 cycles). Fifteen patients (88%) had undergone 56 periocular carboplatin injections with a mean of 4 injections (median, 3 injections; range, 1–8 injections), concurrent with intravenous chemotherapy. A total of 53 intravitreal topotecan injections were performed in 17 eyes of 17 consecutive patients with refractory or recurrent vitreous seeds with a mean of 3 injections (median, 3 injections; range, 2–6 injections). Complete regression of vitreous seeds was achieved in 17 of 17 eyes (100%). At a mean follow-up of 23.8 months (median, 24 months; range, 15.1–34.1 months), one eye (6%) with a recurrent retinal tumour needed enucleation, and the rest of the 16 eyes (94%) maintained complete regression. Final visual acuity could be reliably assessed in all 16 eyes (100%), of whom 12 eyes (75%) had visual acuity ≥20/200. None of the patients developed ocular or systemic complications.
Conclusion Three-weekly intravitreal topotecan appears effective and safe in controlling focal or diffuse refractory or recurrent vitreous seeds in retinoblastoma.
- eye(globe)
- retina
- neoplasia
- treatment other
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From improving patient survival to salvaging eye and vision, the management of retinoblastoma continues to evolve. The introduction of intravenous chemotherapy (IVC) in the 1990s established a standard treatment protocol leading to improved life, eye and vision salvage. IVC alone can achieve an impressive tumour control in less advanced cases, with success rates of 100%, 93% and 90% in International Classification of Retinoblastoma (ICRB) groups A, B and C, respectively.1 Complete tumour regression with IVC alone is seen in only 30% of eyes with diffuse vitreous seeds.1 A combination of IVC and external beam radiation therapy in eyes with vitreous seeds yields eye salvage rates ranging from 22% to 70%.2–4 Primary high-dose IVC with concurrent periocular carboplatin provides marginally better eye salvage (76%) in eyes with focal and diffuse vitreous seeds.4 Primary intra-arterial chemotherapy achieves better control of vitreous seeds, with eye salvage up to 90% in group D retinoblastoma.5
In eyes with refractory vitreous seeds, intravitreal delivery of chemotherapeutic agents has emerged as a promising modality of treatment. Intravitreal chemotherapy in retinoblastoma was first described in the 1960s using thiotepa.6 Currently, melphalan is the most extensively used intravitreal drug in the treatment of vitreous seeds in retinoblastoma.7–10 Intravitreal melphalan injections are given every 7–10 days, and the mean number of injections that is necessary to achieve vitreous seed regression is 5.7 9 10 Intravitreal melphalan is associated with certain ocular complications including retinal pigment epithelial alterations, retinal vasculitis, transient vitreous haemorrhage and paraxial posterior lens opacity.7–10 Uveitis, vitritis and posterior synechiae formation were also noted in six patients of retinoblastoma with refractory vitreous seeds who received intravitreal melphalan at our centre.
Topotecan is a potent drug against retinoblastoma, remains stable on reconstitution, and has a safe toxicity profile.11–16 Topotecan has been used as a systemic chemotherapy for resistant intraocular retinoblastoma and systemic metastasis.13 As a periocular injection, topotecan has been used in patients with recurrent tumour and in those not amenable to systemic chemotherapy.14 Intravitreal topotecan injection in combination with melphalan has been reported to achieve complete vitreous seed regression with no change observed on electroretinogram (ERG).16 Herein, we analysed the efficacy and safety of three-weekly intravitreal topotecan injection in the management of focal and diffuse refractory or recurrent vitreous seeds.
Methods
Our retrospective, non-comparative, interventional case series included 17 eyes of 17 consecutive patients with retinoblastoma with refractory or recurrent, focal or diffuse vitreous seeds following primary IVC. Our objective was to study vitreous seed regression and eye salvage. The study setting was an integrated retinoblastoma management centre at a tertiary care eye hospital. Institutional review board approval was obtained. An informed consent was obtained from all parents/guardians.
Our treatment protocol included IVC with a combination of standard dose vincristine (0.05 mg/kg body weight on day 1), carboplatin (18.6 mg/kg body weight on day 1) and etoposide (5 mg/kg body weight on days 1 and 2) for a minimum of six cycles given every 4 weeks. High-dose chemotherapy consisted of vincristine (0.025 mg/kg body weight on day 1), carboplatin (28 mg/kg body weight on day 1) and etoposide (12 mg/kg body weight on days 1 and 2) for a minimum of six cycles given every 4 weeks, and was reserved for those with extensive diffuse vitreous seeds. Concurrent transpupillary thermotherapy or cryotherapy for focal consolidation of the residual retinal tumours and subretinal seeds was performed when necessary. Periocular carboplatin was administered specifically in eyes with residual viable vitreous seeds after the initial three cycles of IVC. Intravitreal topotecan was administered in patients who continued to have viable vitreous seeds after the completion of IVC, or had recurrent vitreous seeds during follow-up examinations.
The procedure involved a thorough clinical examination under anaesthesia and documentation of the findings with annotated fundus diagram and wide-field fundus imaging. The injection site was carefully chosen with no tumour scar, vitreous seeds or subretinal fluid within two clock hours of the site of entry. Under sterile precautions, safety-enhanced intravitreal injection of topotecan hydrochloride was administered at a dose of 30 µg in 0.15 mL using a 30-gauge needle by the transconjunctival pars plana route (figure 1A). The needle was withdrawn through the first ice ball (figure 1B), followed by completion of triple freeze–thaw cryotherapy at the injection site (figure 1C). Forceps-assisted gentle jiggling of the eye was done for 30 seconds to disperse the drug evenly within the vitreous cavity (figure 1D). The eye was patched overnight after the procedure with an antibiotic and a cycloplegic ointment.
Technique of intravitreal topotecan chemotherapy. (A) Transconjunctival pars plana intravitreal injection of topotecan at a dose of 30 µg in 0.15 mL with a 30-gauge needle. (B) Needle withdrawal through the first ice ball of cryotherapy. (C) Triple freeze–thaw cryotherapy at the injection site. (D) Forceps-assisted jiggling of the eyeball following the injection for even dispersion of topotecan.
Three-weekly intravitreal topotecan was planned until complete regression of the vitreous seeds, followed by an additional injection for consolidation of possible subclinical vitreous seeds. The ocular status was objectively monitored with wide-field fundus photography and fundus drawings. Local (anterior chamber flare and cells, cataract, retinal pigment epithelial mottling) and systemic complications (haematological toxicity) were assessed at every visit. The outcome in every case was monitored by an experienced ocular oncologist.
The medical records of 17 patients who underwent intravitreal topotecan injections were retrospectively reviewed. Demographic data included age at presentation (in months), gender (male or female), race (Asian Indians or others) and heredity (hereditary or sporadic). Ocular features included the laterality of retinoblastoma (unilateral or bilateral) and tumour grouping at initial presentation (ICRB groups A–E). Details of the prior treatment including IVC cycles received by the patient (number of cycles, standard or high dose), use of periocular carboplatin (yes, no) and the number of injections were noted. The nature of the vitreous seeds (refractory or recurrent), their extent (focal or diffuse) and type (dust, sphere, cloud) on completion of IVC were documented. Vitreous seeds were defined as refractory if they were present during and persisted beyond primary IVC cycles and concurrent periocular carboplatin. Recurrent vitreous seeds were those that appeared after the completion of primary IVC. Focal vitreous seeds were those located 3 mm or less from the tumour, and diffuse vitreous seeds were those located more than 3 mm from the tumour. Use of focal treatment for the control of retinal tumour or subretinal seeds (yes, no) was documented. The number of intravitreal topotecan injections that was required to achieve vitreous seed regression, duration of follow-up and the visual acuity in the final follow-up were also noted. Presence of any ocular and systemic complication (anterior chamber flare and cells, iritis, cataract formation, retinal pigment epithelial mottling, haematotoxicity and others) was documented. The clinical data were tabulated and analysed with regard to the main outcome measures: vitreous seed regression and eye salvage.
Results
There were 17 eyes of 17 consecutive patients treated with intravitreal topotecan injections over a period of 2 years. The demographics of the patients are listed in table 1.
Intravitreal topotecan for refractory and recurrent vitreous seeds in retinoblastoma: patient demographics
The mean patient age at the time of presentation with refractory or recurrent vitreous seeds was 35 months (median, 31 months; range, 12–60 months). Eleven eyes of 11 patients with bilateral retinoblastoma (65%) and 6 eyes of 6 patients with unilateral retinoblastoma (35%) were included in the study.
At the time of diagnosis, 5 eyes (29%) belonged to ICRB group C and 12 (71%) belonged to group D. The clinical characteristics of the patients are listed in table 2.
Intravitreal topotecan for refractory and recurrent vitreous seeds in retinoblastoma: clinical features
Visual acuity before initiation of intravitreal topotecan was 20/20 in two eyes (12%), 20/30 in two eyes (12%), 20/60 in one eye (6%), 20/80 in one eye (6%), counting finger in one eye (6%) and light perception in one eye (6%), while others (n=9, 53%) were preverbal. Each patient received IVC for a mean of 10 cycles (median, 9 cycles; range, 6–18 cycles). Of these, four patients (24%) of ICRB group D with extensive vitreous seeds received high-dose IVC. A total of 56 periocular carboplatin injections were administered concurrently with systemic chemotherapy in 15 eyes (88%) with a mean of 4 injections (median, 3 injections; range, 1–8 injections).
After the completion of systemic chemotherapy and periocular carboplatin injections, vitreous seeds were persistent in 3 eyes (18%) and recurrent in 14 eyes (82%). The distribution of vitreous seeds was diffuse in 13 eyes (76%) and focal in 4 eyes (24%). A total of 53 intravitreal topotecan injections and a mean of 3 injections (median, 3 injections; range, 2–6 injections) per eye were performed. Complete regression of vitreous seeds was achieved in all 17 eyes (100%) (table 3).
Intravitreal topotecan for refractory and recurrent vitreous seeds in retinoblastoma: outcomes
The number of injections that was required to achieve complete regression of vitreous seeds was two in seven eyes (41%), three in four eyes (23%), four in four eyes (23%), five in one eye (6%) and six in one eye (6%). At a mean follow-up of 23.8 months (median, 24 months; range, 15.1–34.1 months), 16 eyes (94%) maintained regression (figure 2A–F). In one eye (6%), enucleation was necessary at 5 months of follow-up for a large recurrent retinal tumour. Histopathological examination of the enucleated eye showed no viable tumour cells in the sclera at the site of prior intravitreal injections. At the final follow-up, the visual acuity was 20/20 in four eyes (25%), 20/30 in one eye (6%), 20/40 in one eye (6%), 20/60 in three eyes (19%), 20/80 in two eyes (13%), 20/200 in one eye (6%), counting finger in one eye (6%) and light perception in three eyes (19%). No patient showed ocular or systemic complications.
Vitreous seed control with intravitreal topotecan injections. (A) Refractory diffuse vitreous seeds in the only eye of a patient with bilateral retinoblastoma after nine cycles of chemotherapy. (B) Ten months after two doses of intravitreal topotecan injections showing complete control of vitreous seeds. (C) Refractory diffuse vitreous seeds in the only eye of a patient after six cycles of chemotherapy and three periocular carboplatin injections. (D) Eighteen months after two doses of intravitreal topotecan injections with complete regression of vitreous seeds. (E) Refractory focal vitreous seeds in unilateral retinoblastoma after six cycles of chemotherapy and three periocular carboplatin injections. (F) At 12 months follow-up after two doses of intravitreal topotecan showing complete and stable regression.
Discussion
Vitreous seeds pose a major challenge in the management of retinoblastoma. Focal and diffuse vitreous seeds result from proliferation of retinoblastoma cells in the avascular vitreous and tend to be relatively chemoresistant.17 Intravitreal chemotherapy in retinoblastoma was first introduced by Ericson and Rosengren6 in 1961 to achieve a tumouricidal concentration of the chemotherapeutic drug intraocularly and reduce systemic side effects. They treated six eyes with weekly intraocular thiotepa injections (1.0–1.5 mg), while X-ray irradiation was given simultaneously in three eyes, and concluded that intraocular thiotepa could achieve regression of vitreous seeds.6 The idea of intravitreal injections was revisited when Seregard et al 18 performed injections of 2 mg thiotepa intravitreally through a pars plana approach. Intravitreal methotrexate has also been tried for vitreous seeds, and complete regression was achieved in two of the six eyes (33%).19
Inomata and Kaneko20 investigated the sensitivity of retinoblastoma to 12 anticancer drugs and found that the tumour cells were most sensitive to melphalan in vitro. Currently, melphalan is the most extensively used drug to control the vitreous seeds in retinoblastoma.7–10 In a study by Munier et al 7 8 reporting the use of intravitreal melphalan in 23 eyes of 23 patients, regression of persistent or recurrent vitreous seeds in 21 eyes (91%) and eye salvage in 20 (87%) was noted, and the authors also discussed a potentially safe technique to perform intravitreal injections. Ghassemi and Shields21 evaluated the efficacy and complications of intravitreal melphalan at two different doses of 8–10 µg/0.05 mL (eight eyes) and 50 µg/0.05 mL (four eyes). Although vitreous seed control was achieved in 60% of the eyes, two eyes that received a dose of 50 µg had to be enucleated due to vitreous haemorrhage and phthisis.21 They suggested that an intermediate dose of 20–30 µg/0.1 mL was ideal with minimal complications.21 Shields et al 10 achieved complete vitreous seed regression (100%) and eye salvage (100%) with intravitreal melphalan injections at a dose of 20–30 µg in 11 consecutive eyes with persistent or recurrent vitreous seeds. More recently, in a study that included a total of 87 eyes that received weekly intravitreal injections of melphalan, the authors reported excellent 2-year Kaplan-Meier estimate for vitreous seed regression (90.4%) and eye salvage (98.5%).9 Our initial experience with intravitreal melphalan showed complications including anterior chamber flare and cells, vitritis, synechiae formation and cataract. The severity of inflammation could be related to the darkly pigmented iris of Asian Indians.
Topotecan is a semisynthetic derivative of the pentacyclic alkaloid camptothecin that is isolated from the Chinese yew tree, Camptotheca acuminata. Its use has been described in different types of cancers, including cervical cancers and small cell lung carcinoma. It is active against various solid paediatric tumours such as neuroblastoma and rhabdomyosarcoma.22 Camptothecins exert their cytotoxic effect predominantly in S-phase because of their selective topoisomerase I inhibiting effect. The second recently discovered mechanism of action of topotecan is inhibition of the hypoxia-inducible factor. The dose-limiting adverse effect of systemic administration is neutropaenia and thrombocytopaenia occurring between day 8 and day 15, which is reversible and requires no intervention.
The rationale for the use of topotecan in retinoblastoma stems from various clinical and animal studies.11–16 Topotecan is active against a variety of paediatric tumours, including retinoblastoma.11–14 Carboplatin and topotecan proved to be the most effective systemic drug combination in a study that compared different single drugs and chemotherapy combinations in an animal model and in cell lines.11 Chantada et al 13 used intravenous topotecan in nine patients and demonstrated that topotecan was effective in extraocular and refractory intraocular retinoblastoma without any major systemic toxicity. Despite the antineoplastic activity demonstrated by topotecan, the main drawback is its haematotoxicity associated with systemic delivery.23
Regarding intravitreal injections, it has been shown in animal studies that topotecan attains very high vitreous levels.24 25 The vitreous-to-plasma concentration achieved by topotecan is five times higher as compared with melphalan.24 In addition, reconstituted topotecan has better stability, which offers a distinct advantage over melphalan.24 In clinical practice, melphalan is used within 1–2 hours of reconstitution at room temperature (25°C). On the other hand, topotecan diluted with sterile saline is chemically stable for up to 4 days at 25°C room temperature.
The ocular and systemic side effects of topotecan are very few.16 24 25 Following subconjunctival injections of 10 µg in mice, there was no toxicity on fundus examination or histopathology.24 Topotecan as a periocular injection for retinoblastoma has also been well-tolerated, with only minimal conjunctival congestion and eyelid chemosis, and negligible systemic complications.14 Rabbit eyes injected with four-weekly doses of up to 5 µg/0.1 mL of intravitreal topotecan showed no significant retinal or systemic toxicity.25 Ghassemi et al 16 used intravitreal topotecan at a dose of 8–20 µg/0.04 mL in combination with melphalan for vitreous seeds, and observed no changes on ERG.
While intravitreal topotecan injections are given every 3 weeks, intravitreal melphalan injections are performed every 7–10 days.7 9 10 Furthermore, the mean number of intravitreal topotecan injections that was required to achieve a total resolution of vitreous seeds was 3 (range, 2–6 injections); seven eyes (41%) showed total vitreous seed regression with only two injections of intravitreal topotecan. In contrast, the mean number of intravitreal melphalan injections that was necessary for control of vitreous seeds was 5.7 9 10 We observed no ocular or systemic toxicity and we achieved visual acuity of ≥20/200 in 75% of the eyes (n=12).
There are a few limitations to the study that should be discussed. This was a small, retrospective case series consisting of 17 patients. Further, our 17 consecutive patients did not include any group E patients. Nevertheless, the present study implies that intravitreal topotecan is effective in focal or diffuse, refractory or recurrent vitreous seeds in eyes treated for retinoblastoma.
In summary, complete vitreous seeds regression was achieved in all 17 eyes (100%). These results are comparable to studies by Shields et al and Francis et al, in which the vitreous seed regression rates with melphalan were 100% and 98.5%, respectively.9 10 In the only eye that underwent enucleation in our series, the indication was a recurrent retinal tumour, while the vitreous seeds remained regressed. Excellent control of vitreous seeds (100%) with fewer (mean, 3) and spaced-out injections and the absence of major local or systemic complications justify the conclusion that three-weekly intravitreal topotecan injection is effective and safe in the management of retinoblastoma with refractory or recurrent focal or diffuse vitreous seeds.
References
Footnotes
Contributors All four authors made contributions to conception or design of the work, drafting of the work, revising it critically, approving the final version to be published, and are accountable for all aspects of the work, and ensure the accuracy or integrity of the work. SGH had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Competing interests None declared.
Ethics approval The Ethics Committee of Centre for Sight, Hyderabad, New Delhi.
Provenance and peer review Not commissioned; externally peer reviewed.