Ophthalmic Surgery, Lasers and Imaging Retina

Case Report 

Exudative Retinal Detachment Following Intravitreal Chemotherapeutic Treatment for Retinoblastoma

Boleslav Kotlyar, MD; Michael Shapiro, MD; Michael Blair, MD

Abstract

A 35-month-old boy was diagnosed with retinoblastoma and underwent combination intra-arterial (IAC) and intravitreal chemotherapy. His course was complicated by anaphylactic reaction to IAC, yet he continued to improve with sustained intravitreal therapy. Eight months into treatment, the affected eye developed exudative retinal detachment, which resolved with sub-Tenon's steroid administration. As the management of retinoblastoma evolves, treaters need to be aware of potential complications of therapy.

[Ophthalmic Surg Lasers Imaging Retina. 2019;50:248–252.]

Abstract

A 35-month-old boy was diagnosed with retinoblastoma and underwent combination intra-arterial (IAC) and intravitreal chemotherapy. His course was complicated by anaphylactic reaction to IAC, yet he continued to improve with sustained intravitreal therapy. Eight months into treatment, the affected eye developed exudative retinal detachment, which resolved with sub-Tenon's steroid administration. As the management of retinoblastoma evolves, treaters need to be aware of potential complications of therapy.

[Ophthalmic Surg Lasers Imaging Retina. 2019;50:248–252.]

Introduction

Retinoblastoma is the most common primary intraocular malignancy during childhood. Survival rate for this diagnosis has increased from 5% in the late 19th century to 99% in the developed world, with more than 90% of patients retaining normal vision in at least one eye.1 It has become the pediatric cancer with the highest rates of survival in the 21st century and has allowed physicians to advance care beyond just enucleation and survival. Eye-salvaging treatments include external beam radiation, cryotherapy, laser photocoagulation, thermotherapy, brachytherapy, systemic intravenous chemotherapy, and more recently, with lower incidence of systemic complications, intra-arterial (ophthalmic artery) and intravitreal administration of chemotherapeutic agents. As treatment strategies evolve, treaters must remain mindful of risks, side-effects, and complications.

Herein, we present a case of exudative retinal detachment following intravitreal injection of melphalan and topotecan for unilateral somatic retinoblastoma in a patient who had previously undergone intra-arterial chemotherapy (IAC).

Case Report

A 35-month-old boy was referred for suspected retinoblastoma. Initial exam demonstrated normal anterior segment bilaterally and normal right posterior segment. The left eye had a large, predominantly endophytic tumor with large and fine vitreous seeds. The optic nerve and macula were not visible. Ultrasound demonstrated a hyperechoic 10-mm mass (Figure 1). The patient was diagnosed with Group D retinoblastoma. MRI of the brain did not demonstrate other tumors or extraocular extension, and genetic testing did not find mutations or variants within the RB1 gene. Treatment with IAC with melphalan 5 mg and topotecan 0.4 mg was initiated. Two weeks later, exam showed worsening vitreous seeds (Figure 2), and 20 μg intravitreal melphalan was administered. Cryotherapy was applied to the injection site.

(A) Large, predominantly endophytic tumor in the left eye. (B) Ultrasound demonstrated homogenous hyperechoic mass and few calcifications.

Figure 1.

(A) Large, predominantly endophytic tumor in the left eye. (B) Ultrasound demonstrated homogenous hyperechoic mass and few calcifications.

Regressing endophytic tumor with significant vitreous seeds 2 weeks after intra-arterial chemotherapy.

Figure 2.

Regressing endophytic tumor with significant vitreous seeds 2 weeks after intra-arterial chemotherapy.

After the third IAC, an anaphylactic reaction occurred and further IAC was deferred. The patient had an adverse reaction to the fluoroscopy agent prior to intravenous administration of chemotherapy. Therapy was continued with 20 μg intravitreal injections each of melphalan and topotecan, with cryotherapy to the injection site. In order to increase vascular permeability and effectiveness of intravitreal chemotherapy, 532 nm focal indirect laser therapy was used. Through 7 months, the patient had received three applications of IAC and nine intravitreal injections with continued regression (Figure 3).

Improvement in size of tumor documented by color photography (5 months into therapy).

Figure 3.

Improvement in size of tumor documented by color photography (5 months into therapy).

The 8 month exam showed retinal detachment (RD) without breaks. As RD may be a sign of tumor resurgence, intravitreal melphalan and topotecan were administered with additional laser to the tumor. Three weeks later, the tumor continued to regress, but subretinal fluid (SRF) increased (Figure 4). Fluorescein angiography showed patchy hyperfluorescence and disc staining. Forty milligrams of triamcinolone acetate was injected into the sub-Tenon's space to treat suspected exudative detachment. An exam 3 weeks later showed significant improvement in retinal detachment (Figure 5). The detachment has subsequently resolved with sustained regression of tumor without further chemotherapy. Recent visual acuity was 20/30 OS with macula attached (Figure 6).

(A) At month 9, retinal detachment was present. (B) Patchy leakage is seen on fluorescein angiography with hyperfluorescence of the optic nerve. (C) Ultrasound documents the height of the subretinal fluid.

Figure 4.

(A) At month 9, retinal detachment was present. (B) Patchy leakage is seen on fluorescein angiography with hyperfluorescence of the optic nerve. (C) Ultrasound documents the height of the subretinal fluid.

Optical coherence tomography demonstrates significant improvement in height of retinal detachment (A) 3 weeks after steroid injection and (B) complete resolution 9 weeks post-injection.

Figure 5.

Optical coherence tomography demonstrates significant improvement in height of retinal detachment (A) 3 weeks after steroid injection and (B) complete resolution 9 weeks post-injection.

Discussion

As treatment for retinoblastoma evolves, there has been greater use of intravitreal chemotherapy, primarily to treat vitreous seeding.2–4 IAC in the present patient was stopped due to development of anaphylactic response to the fluoroscopy agent, but intravitreal chemotherapeutic treatment was continued. The patient's tumor and vitreous seeding continued to regress. The disease has remained in remission despite a lack of systemic or intravascular chemotherapy since his third IAC.

For many years, intravitreal injection of chemotherapy was avoided as method of treatment of retinoblastoma with vitreous seeding due to concern for extraocular tumor dissemination.2,3 However with improved safety techniques, intravitreal melphalan is now generally accepted as treatment for control of vitreous seeding and has been shown to significantly reduce the number of eyes requiring enucleation secondary to the presence of vitreous seeds.4–6 Although intravitreal melphalan may effectively save eyes that could previously be managed only with enucleation, it is not without its own toxicities.7 In addition to the more expected injection-associated adverse effects, such as conjunctival, or vitreous hemorrhages, dose-dependent effect on retinal pigment epithelium (RPE) cells can be measured by electroretinogram.8,9 Munier et al. proposed a grading system for ocular changes seen following intravitreal melphalan injections, ranging from localized changes that have no visual consequences to diffuse toxicity with irreversible vision loss.10,11 Rare cases of anterior ocular toxicity have also been described.12 Generally, significant ocular complications seem to be uncommon, and systemic toxicity has not been detected.6,7,9 There have also been no reports of extraocular spread,5,6 although extrascleral spread with subconjunctival tumor development was noted in one retrospective chart review from 2015.13 Clinical use of combined intravitreal melphalan and topotecan has been demonstrated to be effective in combatting resistant or recurrent vitreous seeds from retinoblastoma.14

Our patient developed exudative retinal detachment following intravitreal therapy with melphalan and topotecan. The cause of the SRF is not entirely clear, but we believe it may be related to ciliary body dysfunction following repeated cryotherapy applications in combination with ciliary body and RPE toxicity due to intravitreal chemotherapeutic agents. Cryotherapy was applied to the pars plana region to reduce the chance of the spreading of tumor cells5,14 but likely treated pars plicata, as well. It is conceivable that SRF accumulation was related to the tumor itself, whether through death of tumor cells or reactivation. Reactivation in our patient seems unlikely, as there was no regrowth of the main tumor. Tumor cell death remains a possible etiology, but it would be expected during the rapid shrinkage during initial treatment with IAC rather than months later when treatment consisted solely of intravitreal chemotherapy and non-ablative laser. Rhegmatogenous etiology is unlikely, given that no break was found during multiple examinations under anesthesia. Nonetheless, occult break in the far periphery related to injection and / or cryotherapy or at the edge of the solid tumor related to laser is possible. However, given that patient had a rapid improvement in detachment after sub-Tenon's steroid administration we believe this to have been an exudative detachment. It is also possible that improvement would have happened spontaneously without steroid administration.

This case demonstrates tumor control with intravitreal therapy alone, after initial IAC. Providers taking care of patients with retinoblastoma should be aware of the possible complication of exudative retinal detachment, likely related to the treatment regimen. We suggest steroids as effective treatment.

References

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Authors

From Retina Consultants Limited, Chicago (BK, MS, MB); and the Department of Ophthalmology, Stroger Cook County Hospital, Chicago (BK).

The authors report no relevant financial disclosures.

Address correspondence to Michael Blair, MD, 2454 E. Dempster St, Suite 400, Des Plaines, IL 60016; email: michaelblairmd@gmail.com.

Received: June 11, 2018
Accepted: January 03, 2019

10.3928/23258160-20190401-09

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