Intravitreal dexamethasone implant use as first-line therapy for cancer-associated retinopathy

Abstract

We present a 65-year-old female smoker who presented with acute bilateral blurred vision. Investigations led to an endobronchial ultrasound-guided fine-needle aspiration resulting in an early diagnosis of limited stage small cell lung cancer. Positive recoverin antibodies supported the diagnosis of cancer-associated retinopathy (CAR). CAR was the first manifestation of systemic malignancy in our patient and early diagnosis enabled curative intent systemic treatment with chemotherapy and radiotherapy. Ocular-specific treatment is required in CAR, although no standardised treatment exists. Current treatment options include steroids and immunosuppressive agents. Our patient was administered bilateral intravitreal dexamethasone implants, resulting in significant visual field and electroretinogram improvement at 8 weeks post-intervention. To our knowledge, this represents the first reported successful use of intravitreal dexamethasone implants as first-line therapy, in conjunction with chemoradiotherapy. Intravitreal dexamethasone implants therefore may provide an effective and safe treatment for CAR by reducing intraocular inflammation without systemic effects.

Background

Cancer-associated retinopathy (CAR) is a rare remote cancer-driven process whereby autoantibodies directed at retinal antigens cause photoreceptor degeneration, leading to vision loss. Despite its discovery in 1976 there remains no standard treatment.¹ Current first-line treatment of CAR includes systemic steroids and immunosuppressive therapy such as cyclosporine, azathioprine and rituximab, with limited and variable efficacy and potential interactions and toxicity when combined with chemotherapy; however, no standard treatment algorithm exists.² Systemic treatment, particularly steroids, can cause significant side effects and therefore a local treatment that limits these systemic effects would be preferred to minimise interactions and additive toxicity when combined with myelosuppressive chemotherapy.³ Intravitreal dexamethasone implants for CAR have been reported once previously as second line therapy.³ We present the first successful use as first-line therapy, in conjunction with chemoradiotherapy.

Case presentation

A 65-year-old female smoker (10-pack-year history) without significant medical or ophthalmic history presented with acute visual blurring and bilateral central scotomas. Best corrected visual acuity (BCVA) was 6/18 aided in the right eye (OD) and 6/24 in the left eye (OS). Slit lamp ophthalmoscopy revealed normal anterior segments in both eyes (OU). Fundus examination OU demonstrated plus one vitreous cells with periphlebitis and macular drusen OU (figure 1A). Fundus autofluorescence revealed hyperautofluorescence concentrated at the macula, with peripheral hyperautofluorescent spots (OU) (figure 1C). Optical coherence tomography (OCT) showed disruption and irregularity of outer nuclear layer, loss of ellipsoid zone and photoreceptor segments, with soft drusen OU (figure 1B). Fluorescein angiography illustrated mild optic disc leakage, non-occlusive periphlebitis and scattered peripheral telangiectasia OU (figure 1D). Bilateral visual fields were grossly constricted (figure 2A). Electroretinogram (ERG) performed according to International Society for Clinical Electrophysiology of Vision (ISCEV) standards 6 weeks from presentation was electronegative, b/a ratio 0.467 (0.467–0.554) OD, 0.599 (0.599–0.679) OS, with severely reduced rod/cone activity OU.

Figure 1.

Baseline multimodal imaging of patient at baseline. (A) Fundus widefield imaging of the posterior pole with macular drusen OU. (B) Heidelberg Spectralis optical coherence tomography showing disruption and irregularity of outer nuclear layer, loss of ellipsoid zone and photoreceptor segments with soft drusen in OU. (C) Widefield fundus autofluorescence showing hyperautofluorescent spots bilaterally throughout the posterior pole. (D) Widefield fundus fluorescein angiography illustrated optic disc leakage OU and vasculitis OS.

Figure 2.

24–2 Visual fields of our patient (OD top OS bottom). (A) at presentation showing grossly constricted visual fields OU. (B) One month post presentation prior to intravitreal dexamethasone implantation showing stable visual fields. (C) Two weeks after left and 3 weeks after right intravitreal dexamethasone implant showing improvement in right eye superior nasal and left eye inferior nasal visual fields. (D) Six weeks after left and 7 weeks after right implant showing further improvement in right eye superior nasal and left eye inferior nasal visual fields.

Investigations

Blood work up including full blood count, urea electrolytes and creatinine, liver function tests, erythrocyte sedimentation rate, C reactive protein, ACE, syphilis serology and QuantiFERON-TB Gold were unremarkable. Plain-film chest radiograph revealed right upper lobe lesions, confirmed with chest CT and whole-body positron emission tomography as two right upper lobe pulmonary nodules with mediastinal, hilar and supraclavicular lymphadenopathy (figure 3A). The patient underwent endobronchial ultrasound-guided fine-needle aspiration as well as MRI of the brain, confirming an early diagnosis of limited stage small cell lung cancer without respiratory symptoms. Immunological testing was positive for recoverin antibodies, in addition to positive results for enolase and TULP1, and positive western blotting for antiretinal autoantibodies resulting in a diagnosis of CAR.

Figure 3.

Coronal section of positron emission tomography (left) and CT (right) demonstrating one of two right upper lobe nodules with fluorodeoxyglucose-avidity, with hilar, mediastinal and supraclavicular nodal involvement.

Treatment

One-week post presentation and prior to the carcinoma diagnosis, the bilateral retinopathy and vitritis worsened, without associated vasculitis. A trial of topical prednisolone acetate/phenylephrine 0.12/1% six times per day OU was prescribed with a 1 month tapering regimen, without subjective or clinical effect (figure 2A, B). Following her diagnosis of CAR, she was given chemotherapy (carboplatin/etoposide) 5 weeks after initial presentation combined with curative intent radiotherapy to lungs, mediastinum and supraclavicular lymph nodes, 7 weeks after diagnosis. The patient’s ocular disease was then treated with bilateral intravitreal dexamethasone implants (700 µg; Ozurdex, Allergan), inserted in OD 6 weeks, and OS 7 weeks after presentation.

Outcome and follow-up

Ocular treatment resulted in significant visual field improvement (figure 2C, D). BCVA improved to 6/7.5 OU. Follow-up ERG at 8 weeks demonstrated improved response amplitudes and b/a ratio normalisation 1.62 (1.52–1.66) OD, 1.53 (1.43–1.58) OS. Imaging at the completion of chemoradiotherapy showed significant response to treatment without disease progression or metastatic disease with management now by active surveillance.

Discussion

Most case reports describe first-line treatment of CAR with systemic steroids including intravenous methyl-prednisolone (IVMP) and oral prednisolone before transitioning to steroid-sparing immunosuppressive therapy such as cyclosporine, azathioprine and rituximab, as well as intravenous immunoglobulin with limited and variable efficacy.² Visual field improvement in CAR can take 4 months and treatment can be prolonged.² Systemic treatment, particularly steroids, can cause significant side effects including metabolic syndrome, gastrointestinal disorders and further immunosuppression in an already immunocompromised cohort.³ Local treatment limits the systemic effects and may be particularly useful with the increasing role of immunotherapy in oncology where high dose steroid is generally avoided.

We uniquely report CAR treatment with intravitreal steroids without prior systemic immunosuppression. Kim et al reported using two intravitreal dexamethasone implants and eleven triamcinolone acetonide injections at 2–4 month intervals, 1 year post using oral prednisolone and mycophenolate to treat CAR.³ They described preservation of the central island on perimetry, and foveal photoreceptors on OCT, sustained following transition to local therapy.³ Huynh et al successfully used five bilateral intravitreal triamcinolone injections (IVTA) to treat CAR following a poor outcome of visual acuity with IVMP, oral steroids, mycophenolate mofetil and intravenous immunoglobulin IVIg infusions.⁴ VA improved most dramatically following resolution of cystoid macular oedema (CMO) with bilateral IVTA, but subjectively and objectively improved further with IVTA after CMO resolution.⁴

Treatment of underlying malignancy can decrease circulating autoantibodies; however, it is unclear whether this alters the course of CAR, necessitating specific ocular treatment.¹ Our patient’s visual fields showed significant improvement with bilateral intravitreal dexamethasone implants without systemic immunosuppression. Huynh et al used serial OCT to show ellipsoid zone restoration and disappearance of photoreceptor zone hyper-reflective lesions following intravitreal triamcinolone, postulating that intravitreal steroids improved vision by reducing photoreceptor inflammation.⁴ We suggest that intravitreal dexamethasone implants provide an effective and safer treatment for CAR by reducing intraocular inflammation without systemic effects; however, further research is required.

Learning points.

• Cancer-associated retinopathy (CAR) can be the first manifestation of systemic malignancy and early identification can result in diagnosis prior to incurable extensive stage or metastatic disease enabling early intervention and curative intent therapy.

• Treatment of cancer-associated retinopathy requires ocular specific treatment.

• Current treatments including steroids, steroid-sparing immunosuppressive therapy such as cyclosporine and intravenous immunoglobulin have been reported as treatment with limited and variable efficacy although no standardised treatment exists.

• Intravitreal dexamethasone implants may provide an effective and safer treatment for CAR by reducing intraocular inflammation without systemic effects.

Ethics statements

Patient consent for publication

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