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Keywords:

  • letrozole;
  • macular oedema;
  • multifocal electroretinogram;
  • ranibizumab

Abstract

  1. Top of page
  2. Abstract
  3. Case Report
  4. Discussion
  5. References

A 72-year-old woman presented with unexplained, progressive, painless visual loss in the right eye during the past six months. At presentation visual acuity (VA) was 3/60 in the right eye and 6/6 in the left eye. Anterior segment examination and intraocular pressures were normal. Dilated fundoscopy revealed significant macular oedema in the right eye and a normal fundus appearance in the left eye. Her medical history was noteworthy for breast ductal carcinoma in situ, for which she had undergone right mastectomy three years earlier. She had not received chemotherapy or radiotherapy but she had been under treatment with letrozole 2.5 mg/day over the past three years. She did not receive any other medication.

Optical coherence tomography showed intraretinal fluid and a significant increase in retinal thickness in the foveal and parafoveal areas, while fluorescein angiography detected foveal hyperfluorescence and leakage of the dye in the late phase. Multifocal electroretinogram showed a decreased response in both eyes. In suspicion of letrozole-related retinopathy, the patient was advised to stop the medication. The patient agreed to receive an intravitreal injection of 0.05 ml/0.5 mg ranibizumab. One month later, VA in the right eye was 6/9 and macular oedema had apparently improved. This is the first reported case of letrozole-associated macular oedema treated with intravitreal ranibizumab.

Letrozole (Femara®, Novartis) is an oral non-steroidal aromatase inhibitor, more effective than tamoxifen and is used as a first-line adjuvant therapy for post-surgical treatment of hormonally responsive breast cancer.[1] Ophthalmic side effects, such as retinopathy, macular oedema or keratopathy, are well documented for tamoxifen.[2-5] There are several studies or case reports presenting ocular side effects of other aromatase inhibitors, that is, anastrozole or examestane.[6-10] Specifically, patients undergoing anastrozole or examestane treatment may develop retinal haemorrhage,[6] macular hole,[7] retinal detachment,[7] hemi-central retinal artery occlusion[8] and vitreo-retinal traction,[9] while corneal intraepithelial cysts have been reported in a female patient, using examestane.[10] Interestingly, there is no evidence of ocular adverse effects in patients receiving letrozole.

Macular oedema consists of an accumulation of fluid in the retinal layers around the fovea. It contributes to loss of vision by changing the relationship between functional cells in the retina and promoting an inflammatory reparative response. In most cases, it is associated with disruption of the blood–retinal barrier (BRB). A wide variety of ocular conditions, including uveitis, trauma, intraocular surgery, vascular retinopathies, vitreoretinal adhesions, hereditary dystrophies, diabetes and age-related macular degeneration may lead to macular oedema.[11]

We present a case of macular oedema, diagnosed in a female patient using letrozole. We believe this is the first reported case of letrozole-associated retinopathy.

Case Report

  1. Top of page
  2. Abstract
  3. Case Report
  4. Discussion
  5. References

A 72-year-old woman presented with unexplained, progressive, painless visual loss in the right eye during the past six months. A complete ophthalmological examination was performed, including visual acuity (VA) measurement by Snellen charts, slitlamp examination, intraocular pressure measurement and fundoscopy. At presentation, VA was 3/60 in the right eye and 6/6 in the left eye. The anterior segment and intraocular pressures (14 mmHg and 15 mmHg in the right and left eyes, respectively) were normal in both eyes. Dilated fundus examination with stereoscopic slitlamp viewing revealed substantial macular oedema in the right eye, while the fundus in the left eye was normal.

The patient had no diabetes mellitus, hypertension or any systemic vascular disease. She had undergone bilateral uneventful phacoemulsification cataract surgery with posterior chamber intraocular lens implantation four years earlier. Her medical history was noteworthy for breast ductal carcinoma in situ, for which she had undergone right mastectomy three years earlier. She had not received chemotherapy or radiotherapy but had taken letrozole 2.5 mg/day over the past three years. Of note, she did not receive any other medication.

Optical coherence tomography (OCT) and fluorescein angiography (FA) confirmed the presence of macular oedema in the right eye. The OCT scan showed intraretinal fluid and a significant increase (p < 0.001) in retinal thickness in the foveal (252 μm) and parafoveal (369 μm) areas compared to the other eye (Figure 1A, B and Table 1), while fluorescein angiography detected foveal hyperfluorescence and leakage of the dye in the late phase (Figure 2).

figure

Figure 1. Optical coherence tomography scan of the right macula showed intraretinal fluid and a significant increase (p < 0.001) in retinal thickness (A) compared to the other eye (B) at presentation. One month after ceasing letrozole, macular oedema was improved (C), as retinal thickness was decreased from 252 μm to 160 μm.

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figure

Figure 2. Fundus photography of the right eye at presentation, where macular oedema is depicted by the black arrow (A). Early (B) and late (C) phase fluorescein angiography of the right eye at presentation, revealing hyperfluorescence and leakage. Fundus photography of the left eye at presentation (D) and fluorescein angiography of the left eye at presentation (E, F).

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Table 1. Quantitative data of central retinal thickness at the fovea and multifocal electroretinogram (mfERG) findings in area 1 for both eyes
 NormalRight eyeLeft eye
PresentationOne monthPresentationOne month
  1. p-values were derived from comparison with normal; p* values were derived from comparison with the right eye; p** values were derived from comparison between presentation and one-month results

Central retinal thickness (μm)158 ± 24.75252160177169
(p < 0.001)(p = 0.918)(p = 0.754, p* < 0.001)(p = 0.803, p* = 0.906)
p** < 0.001p** = 0.652
mfERG mean response density (nV/deg2)294 ± 42.32161107127123
(p < 0.0001)(p < 0.0001)(p < 0.0001, p* = 0.048)(p < 0.0001, p* = 0.063)
p** = 0.021p** = 0.875
N1 latency (ms)18.7 ± 1.831.732.815.816.9
(p < 0.001)(p < 0.001)(p = 0.367, p* < 0.001)(p = 0.659, p* < 0.001)
p** = 0.804p** = 0.786
P1 latency (ms)41.2 ± 2.943.746.435.235.7
(p = 0.481)(p = 0.072)(p = 0.051, p* < 0.01)(p = 0.058, p* < 0.01)
p** = 0.892p** = 0.912

In addition to this, multifocal electroretinogram (mfERG) was performed to assess macular function. The mfERG was significantly reduced from normal in both eyes. The mean retinal response density of the foveal area (ring 1) was 161 nV/deg2 in the right eye (Figure 3A and 4A) and 127 nV/deg2 in the left eye (Figures 3B and 4 and Table 1). Additionally, N1 latency was 31.7 ms in the right eye, which differed significantly in comparison with normal values and 15.8 ms in the left eye, while P1 latency was 43.7 ms in the right eye and 35.2 ms in the left eye. Noticeably, N1 latency in the right eye was much longer than that of the left, consistent with the macular oedema in the right eye.

figure

Figure 3. Three-dimensional appearance of multifocal electroretinogram recording in the right and left eyes, respectively at presentation (A, B) and one month after ceasing letrozole (C, D)

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figure

Figure 4. Multifocal electroretinogram traces in the right and left eyes, respectively at presentation (A, B) and one month after ceasing letrozole (C, D)

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Expecting a diagnosis of letrozole-related retinopathy, the patient was advised by the multidisciplinary team (oncologist and ophthalmologist) to cease taking the medication. Treatment options were discussed with the patient and intravitreal injection of 0.05 ml/0.5 mg ranibizumab was given to treat the macular oedema in the right eye. One month later, VA in the right eye was 6/9. The macular oedema appeared to have improved and retinal thickness decreased from 252 μm to 160 μm in the foveal area (Figure 1C). No further treatment was given for the macular oedema. Nevertheless, the mfERG response remained decreased in both eyes (107 nV/deg2 in the right eye and 123 nV/deg2 in the left eye) (Figures 3 and 4). Furthermore, N1 latency in the right eye was 32.8 ms and in the left eye 16.9 ms, whereas P1 latency was 46.4 ms in the right eye and 35.7 ms in the left eye.

Discussion

  1. Top of page
  2. Abstract
  3. Case Report
  4. Discussion
  5. References

The effects of oestrogen are mediated through alpha and beta oestrogen receptors. Both oestrogen receptor subtypes are expressed and are functionally active in the human retinal pigment epithelium, the neurosensory retina and the choroid, providing neuroprotection to the retinal cells.[12] Letrozole is a non-steroidal selective aromatase inhibitor, in contrast to examestane, which is a steroidal aromatase inhibitor, interfering with the inhibition of biosynthesis of oestrogens;[1] as a result, letrozole may deprive the retina and the choroid of the beneficial, protective effects mediated by oestrogens. The restriction of oestrogen-mediated neuroprotection in the retina may be responsible for the breakdown of the BRB in our case.

Multifocal ERG showed decreased retinal response density in both eyes and especially a greater decrease in the left eye, although macular oedema developed only in the right eye. This may reflect a potential retinal toxicity due to letrozole, as it was used orally and could affect systemically both eyes. One month after ceasing letrozole and treatment with intravitreal injection of ranibizumab, the macular oedema was improved but it should be noted that mfERG measurements remained decreased in both eyes. Indeed, the mean response density of the foveal area had further decreased in the right eye over the following month. This observation might reflect the already described effects of intravitreal treatment with anti-vascular endothelial growth factor (VEGF).[13] Nevertheless, as mfERG abnormalities were present in both eyes, letrozole may interfere with retinal function. Further studies are needed on this undiscovered field.

Ranibizumab is a monoclonal antibody fragment, which has been affinity-matured to provide strong binding with VEGF-A. It is an anti-angiogenic agent, which is widely used for the treatment of the wet type of age-related macular degeneration and may prevent visual deterioration. Anti-VEGF therapy can result in some early functional and anatomical recovery in macular oedema.[14] Bourla and colleagues[15] used intravitreal anti-VEGF to treat tamoxifen-induced macular oedema, providing improvement in visual acuity and decreased retinal thickness. The case reported by Bourla and colleagues[15] as well as our experience treating diffuse diabetic macular oedema or macular oedema associated with age-related macular degeneration with intravitreal ranibizumab, led us to try this therapeutic modality in our case. Of note, one month after ranibizumab injection, macular oedema had improved with an associated improvement in VA.

There are two potential limitations of our presentation. First, the second mfERG measurement remained decreased one month after ceasing letrozole and treatment with intravitreal ranibizumab. As a result, a potential overlap between the action of letrozole and that of ranibizumab should be taken into account for the interpretation of this case. Nevertheless, the symmetry between the two eyes after one-month suggested that retinal toxicity due to letrozole is the most probable cause of the remaining decrease in mfERG findings. Second, the use of ranibizumab in this case constitutes off-label use of the agent.

We believe this to be the first reported case of macular oedema secondary to the use of letrozole. This patient responded to the use of intravitreal ranibizumab. The side effect of macular oedema should be considered in patients treated with letrozole. Ophthalmological surveillance of patients receiving letrozole seems necessary. Future studies should aim to estimate the prevalence of ocular side effects, as well as targeting optimal management.

References

  1. Top of page
  2. Abstract
  3. Case Report
  4. Discussion
  5. References
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