High-dose topotecan (90 and 180 μG) for recurrent subretinal and vitreous seeding in retinoblastoma

Abstract

Purpose

To report on the use of intravitreal high-dose topotecan (90 and 180 μG) for recurrent subretinal and vitreous retinoblastoma, the toxicity of these injections, and the use of a 180-μG injection of intravitreal topotecan in humans.

Observations

High-dose (90 and 180 μG) intravitreal topotecan was effective in treating recurrent subretinal and vitreous retinoblastoma without anterior segment or retinal toxicity or altered electroretinogram function in two cases.

Conclusion and importance

Recurrent subretinal and vitreous retinoblastoma after intraarterial chemotherapy are difficult to treat. High-dose intravitreal topotecan (90 and 180 μG) was used to salvage two such eyes without measurable toxicity.

Highlights

• •Recurrent subretinal or vitreous seeding in retinoblastoma is difficult to treat.
• •High-dose topotecan (90/180 μG) successfully treated two patients with recurrent retinoblastoma.
• •Intravitreal high-dose topotecan (90/180 μG) for recurrent retinoblastoma was effective without toxicity.

1. Introduction

Intravitreal chemotherapy for vitreous seeds has become routine in the management of retinoblastoma, with a high success rate1, 2, 3, 4 and, as a result of enhanced safety measures, minimal risk of extraocular extension.⁵

Many chemotherapy drugs have been tried for intravitreal injections, but most centers have been using melphalan at doses of 8–50 μG6, 7, 8 (usually 20–30 μG^9,10). High success rates in treating vitreous seeds (as high as 100 %) have been reported without systemic side effects. With experience, however, disturbing toxicity was found in both the anterior (e.g., cataracts, iris synechiae) and posterior segments (e.g., pigment retinopathy, diminished electroretinogram [ERG] function) noted within a month of receiving the injection, and this toxicity was found to be greater in heavily pigmented eyes.^2,11,12

Because of the toxicity of intravitreal melphalan, clinicians sought an alternative for intravitreal injection, and topotecan has been the chemotherapeutic agent most often used. Experimental work demonstrated its safety and predicted efficacy based on careful pharmacokinetics.^13,14 Numerous studies have confirmed its safety when delivered intravitreally and efficacy in humans at doses of 8–90 μG,15, 16, 17, 18 and intravitreal melphalan and topotecan (at doses of 30–60 μG) have been tried in select cases of retinal and subretinal tumor recurrences.19, 20, 21

Following our initial report on the use of high-dose topotecan (90 μG) for retinal tumors,²² other groups have had similar, encouraging results.²³ After conducting a literature review on May 1, 2025 utilizing PubMed and Google Scholar with the keywords “topotecan” and “180 μG”, we did not find any prior reports of intravitreal topotecan at doses of 180 μG for retinoblastoma in humans.

2. Case 1

A 3.5-month-old boy was seen with bilateral retinoblastoma, with no family history of the disease. The right eye had a large retinal tumor, partial retinal detachment, and vitreous seeds (Reese Ellsworth Vb, International Classification of Retinoblastoma “D”). The 30-Hz ERG was 51 μV. The left eye had two small midperipheral retinal tumors (Reese Ellsworth IIIa, International Classification of Retinoblastoma “A”). The ERG was 94 μV. The left eye was treated successfully with one session of indirect 810-nm diode laser. The right eye received intraarterial chemotherapy with melphalan (2.5 mg) and topotecan (0.3 mg) through the ophthalmic artery three times (monthly). We noted marked shrinkage of the main tumor, which completely calcified, and resolution of the partial retinal detachment. ERG function improved to 140 μV.

Three months later, the main tumor in the right eye remained inactive but multiple subretinal tumors were evident (Fig. 1A) and documented as subretinal on optical coherence tomography (OCT) (Fig. 1B). That eye received one injection of topotecan 90 μG and diode laser. Eight months later the ERG of the right eye was unchanged, the main tumor remained inactive, and all subretinal tumors were scars (Fig. 1C), confirmed with OCT (Fig. 1D). There were no anterior segment toxicities nor retinal toxicities noted with follow-up of 12 months. Subsequent genetic testing revealed a germline Rb1 defect.

Fig. 1.

Fundus photo and optical coherence tomography (OCT) of the right eye in a 3.5-month-old boy with bilateral retinoblastoma involving the fovea demonstrating recurrent subretinal seeding before (A, B) and after (C, D) 90 μG of intravitreal topotecan (once). The tumors are scars, and OCT demonstrates the disappearance of tumors. Black horizontal lines in (A) and (C) indicate where OCT slice was taken.

3. Case 2

A 3-year-old boy was referred for unilateral retinoblastoma in the right eye, with no family history of retinoblastoma. The left eye was normal. The right eye had extensive vitreous seeds filling most of the vitreous—no normal retina or optic nerve could be seen through the cloud of seeds. The ERG was 82 μV. He was treated with monthly triple-agent intraarterial chemotherapy through the ophthalmic artery four times (three sessions of melphalan 5 mg, topotecan 0.5 mg, and carboplatin 40 mg; one session of melphalan 7.5 mg, topotecan 1 mg, and carboplatin 50 mg). Because of the extensive vitreous seeding, three injections of intravitreal topotecan (90 μG) were given monthly after completion of the four intraarterial treatments; once the vitreous cleared, one session of indirect 810-nm diode laser was given to the underlying retinal tumor. Eight months after initial treatment, an increase in vitreous seeding developed (Fig. 2A). That eye then received two injections of topotecan 90 μG (in 0.18 cc) 5 minutes apart (total 180 μG) and 3 mm from the limbus using enhanced safety measures. During the intravitreal injections, the intraocular pressure (IOP) was monitored (Schiotz tonometry), and after lowering the IOP to 8.5 with digital pressure, 0.18 cc of topotecan (90 μG) was injected. The mean arterial blood pressure was monitored and remained steady at 57 mmHg. At one minute the IOP was 50; at 2 minutes, 43; and at 3 minutes when it was 32, a second identical injection was given. One minute after the second injection, the IOP was 50; 2 minutes after the second injection, 40; 3 minutes after the injection, 43; 4 minutes after injection, 29; and 5 minutes after injection, 20. Within a month, the recurrent seeds were gone (Fig. 2B). The ERG before the injection of 180 μG topotecan was 40 μV and a month after the injection was 82 μV. There were no anterior segment or retinal toxicities seen with 6 months follow-up.

Fig. 2.

Fundus photo of the right eye of a 3-year-old boy before (A) and after (B) one intravitreal topotecan injection totaling 180 μG, showing complete disappearance of the seeding that had recurred despite prior treatment with four monthly triple-agent intraarterial chemotherapy, three monthly injections of intravitreal topotecan (90 μG), and one session of indirect 810-nm diode laser to the underlying retinal tumor.

4. Discussion

Both intravitreal melphalan and topotecan have been used in the past 13 years to treat vitreous seeds with great success.^1,7,8 Only recently have intravitreal injections been used to treat retinal and subretinal tumors.^20,23

We reported on the use of intravitreal chemotherapy for retinal/subretinal disease in 2018. Using melphalan (often with concurrent laser), we had a high success rate treating recurrent subretinal seeding and local retinal recurrences.²⁰

In 2023, we reported on the use of intravitreal topotecan 90 μg for retinal disease in 3 patients with efficacy and no toxicity.²² Recently, Shields and colleagues reported on their success using intravitreal topotecan 90 and 100 μG for recurrent retinal tumors.²³ Of the 13 cases they reported, 8 also received intraarterial chemotherapy, and 1 intravenous chemotherapy. Of the three eyes that received intravitreal topotecan alone, local control was attained in all three initially but one subsequently recurred. No eye was lost.

As in the cases reported previously by us and by Shields and colleagues, one of these eyes received concurrent treatment with the diode laser. We have previously shown that diode laser and intravitreal melphalan are effective for subretinal seeding. Laser alone rarely is successful—while some eyes treated with melphalan alone have responded well, it is not known what the response of high-dose topotecan alone will be. Future studies may allow us to appreciate the contribution of laser with the intravitreal injections, but clinical experience is that it is difficult to control recurrent subretinal seeding with laser alone.

With longer follow-up and experience in more eyes with recurrent retinal and subretinal retinoblastoma, the utility, safety, and efficacy of high-dose intravitreal topotecan will become known; however, recurrent vitreous seeds and recurrent retinal and subretinal retinoblastoma are difficult to manage, and the prompt and complete response in case 2 to a total dose of topotecan 180 μG (without toxicity) opens a new path in the use of intravitreal chemotherapy for recurrent retinoblastoma.

CRediT authorship contribution statement

David H. Abramson: Writing – review & editing, Writing – original draft, Supervision, Investigation, Formal analysis, Data curation, Conceptualization. Jasmine H. Francis: Writing – review & editing, Validation, Resources, Formal analysis.

Patient consent

Written consent to publish this case has not been obtained. This report does not contain any personal identifying information.

Authorship

All authors attest that they meet the current ICMJE criteria for authorship.

Funding

Supported by the NIH P30 CA009748 and the Fund for Ophthalmic Knowledge Inc.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.