Dr Constantine D Georgakopoulos, Morfou 1 Street, 26441 Patras, GREECE. E-mail: email@example.com
Bilateral macular oedema is an uncommon side-effect of paclitaxel administration in oncological patients. We report the case of a 64-year-old man who presented with decreased visual acuity due to bilateral macular oedema after paclitaxel administration for lung cancer. Optical coherence tomography scans of both eyes revealed cystoid macular oedema. Fluorescein angiography demonstrated the unusual finding of the absence of localised retinal capillary leakage. Ketorolac eye drops and acetazolamide tablets were prescribed and one month later the cystoid macular oedema resolved with subsequent improvement in visual acuity. This case illustrates the unusual presentation of cystoid macular oedema induced by paclitaxel.
An increasing number of patients receive the oncological agents paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ, USA) and docetaxel (Taxotere; Sanofi-Aventis, Bridgewater, NJ, USA) that form the drug category of taxanes. They are mitotic inhibitors, preventing normal reorganisation of the microtubule network within cells and are used to treat lung, ovarian, breast, head and neck cancer, and advanced forms of Kaposi's sarcoma. They also have been used in the treatment of metastatic cutaneous melanoma, while a recently published phase 2 study1 examined the effectiveness of weekly administration of docosahexaenoic acid–paclitaxel in patients with metastatic uveal melanoma.
Cystoid macular oedema has been reported in patients receiving this class of drug but by no means is it a common side-effect. It tends to be bilateral and can be confirmed by its biomicroscopic appearance and optical tomography scans (OCT), but fluorescein angiography shows no compromise to the blood–retinal barrier. We report a relevant case of cystoid macular oedema in a patient with lung cancer treated with paclitaxel.
A 64-year-old Caucasian man presented with a one-month history of blurred vision in both eyes at all distances. The patient's medical history was significant for metastatic non-small-cell lung cancer, diagnosed one year earlier, and he was undergoing chemotherapy with intravenous infusion of polyethylated castor oil-based paclitaxel at a dosage of 175 mg/m2 every three weeks, concomitant with carboplatin dosed at an area under the curve of 6.0 and bevacizumab 15 mg/Kg. As per plan, the patient received the fifth and last dose of paclitaxel and two weeks later the symptom of blurred vision started. His ocular history was negative for previous eye disease, diabetic retinopathy, intraocular surgery or use of prostaglandin eye drops. The patient did not receive any additional drugs. His family history was negative for X-linked retinoschisis.
On initial examination, Snellen visual acuity was 6/15 in the right eye and 6/18.9 in the left eye. Anterior segment examination revealed no inflammation and 1+ nuclear sclerosis in both eyes. Dilated funduscopic evaluation revealed bilateral cystoid macular oedema with no other signs of pathology. OCT scans (RTVue-100; Optovue, Fremont, CA, USA) showed fluid accumulation into multiple well-defined cyst-like spaces in the outer and inner plexiform layers. The cystic formations were larger and more centrally located in the outer plexiform layer, whereas in the inner plexiform layer they were smaller and more broadly distributed. Central macular thickness, provided by thickness map function, was 557 µm in the right eye and 554 µm in the left eye (Figure 1A and 1B). Fluorescein angiography was normal without a delay in the retinal arteriovenous transit time, with an intact parafoveal capillary net and no discernible leakage in the early or late phases in either eye (Figure 2). The patient was diagnosed with bilateral cystoid macular oedema secondary to paclitaxel and ketorolac 0.5% eye drops qid in both eyes and acetazolamide 125 mg tid orally were prescribed.
Ten weeks after the last administration of paclitaxel, the patient had bilateral visual improvement (6/9.6 in the right eye and 6/7.5 in the left eye). Ophthalmic examination did not indicate any pathology and cystoid spaces were absent on OCT imaging with central macular thickness reduced to 283 µm in the right eye and 306 µm in the left eye (Figure 1C and 1D). The patient was re-evaluated at one-month intervals for three months and there was no recurrence.
Besides the frequently reported systemic side-effects of paclitaxel, with the most serious being bone marrow toxicity, there are few reports of ophthalmic sequellae arising in patients using either docetaxel or paclitaxel. The reported ophthalmic adverse events include transient blurred vision and photopsiae due to ocular toxicity during paclitaxel infusion, dry eyes, keratitis, epiphora, scotomata, optic neuropathy, bilateral hemianopsia, reduced visual evoked potential and development of open-angle glaucoma.2,3 Furthermore, bilateral cystoid macular oedema has been described as a highly unusual adverse event after administration of taxanes. A review of English literature yielded two cases of cystoid macular oedema secondary to docetaxel use4,5 and five due to paclitaxel,6–9 either polyethylated castor oil-based or albumin bound. The time of cystoid macular oedema occurrence in the above cases varies from two months to 2.5 years of therapy.
In the present case, bilateral cystoid macular oedema occurred approximately four months after initiation of paclitaxel treatment and two weeks after the last dose. Funduscopic view was confirmed with a characteristic OCT image, which demonstrated fluid accumulation into multiple cyst-like spaces in the outer and inner plexiform layers. The distribution of the cysts could be attributed to the extent of fluid, resulting in the coalescence of multiple cysts, rather than chronicity of the oedema. Similar findings have been described by Smith, Benz and Brown7 and Joshi and Garretson.8 Nevertheless, fluorescein angiography noted no choroidal leakage in the early phases or capillary bed compromise in the late phase images. A similar angiographic picture has been described in niacin-induced cystoid macular oedema.10
The pathophysiology of paclitaxel-induced cystoid macular oedema remains unclear because no histopathological studies have been conducted. It is possible that the simultaneous use of intravenous bevacizumab in this patient was responsible for the cystoid macular oedema; however, this is extremely unlikely because improvement of visual acuity and resolution of the cystoid macular oedema occurred while the patient was still on bevacizumab treatment. Furthermore, the fact that the cystoid macular oedema occurred while the patient was on intravenous administration of bevacizumab implies that vascular endothelial growth factor is not involved in the pathogenetic mechanism of the paclitaxel-induced cystoid macular oedema.9 As a possible pathogenetic mechanism, Joshi and Garretson8 suggested a toxic effect of paclitaxel on Müller cells, which are responsible for maintaining osmotic gradients within the neurosensory retina, resulting in intracellular fluid accumulation. Another, less favoured, theory suggests that subclinical leakage of the extracellular fluid is the causative mechanism, a hypothesis comparable to that proposed for niacin-induced maculopathy.11 In that case, bevacizumab would prevent the accumulation of extracellular fluid, resulting in angiographically silent cystoid macular oedema. On the contrary, of the seven published cases of angiographically silent taxane-induced cystoid macular oedema, only one patient9 was on concomitant bevacizumab therapy.
There is no specific treatment plan proposed in the literature for paclitaxel-induced cystoid macular oedema. Any decision should be in consultation with the oncologist. Discontinuation of the causative factor and possible change of the chemotherapeutic regimen is the common decision. In some cases, this was accompanied with administration of topical steroids and non-steroidal anti-inflammatory drugs6 or oral acetazolamide.5 In the present case, there was no need to cease the paclitaxel therapy, because the patient had already completed his chemotherapeutic treatment. Administration of topical ketorolac and oral acetazolamide was the treatment of choice with a favourable outcome within a month. For those cases, where withdrawal of the causative factor is not recommended, Teitelbaum and Tresley4 suggest the consideration of topical, intravitreal or periocular steroids. Additionally, because there is no specific relationship between the duration of paclitaxel administration and the occurrence of cystoid macular oedema, a possible follow-up scheme could be the one that was used in the phase II trial of albumin-bound paclitaxel in women with metastatic breast cancer (for example, every two treatment cycles).12
Despite prompt treatment and complete resolution of the cystoid macular oedema, the visual acuity of the patient in the present case never returned to normal. This can be attributed to the pre-existing cataract and possibly to photoreceptor toxicity. The duration of the cystoid macular oedema could be a prognostic factor for the final visual outcome. Furthermore, complications like macular hole formation or serous retinal detachment have not been described.
This patient highlights the potential for bilateral retinal involvement in oncological patients receiving paclitaxel treatment. Even though ophthalmic adverse events rarely occur in patients receiving taxane therapy, ophthalmic practitioners should be alert to the possibility of visual side-effects and ophthalmologic evaluation could be considered at baseline and at regular intervals during the therapy. As cessation of the precipitating factor is often the therapeutic choice in taxane-induced cystoid macular oedema, early recognition with dilated fundus examination, enhanced by fluorescein angiography and optical coherence tomography imaging, and co-operation between oncologists and ophthalmologists is needed, including Amsler grid self-assessment by patients on taxane therapy.