Optic atrophy after cabazitaxel treatment in a patient with castration-resistant prostate cancer: a case report

Introduction

Taxanes are a group of anti-cancer agents that inhibit mitosis with disruption of microtubule function. They include docetaxel and paclitaxel along with the new generation drugs such as cabazitaxel and nab-paclitaxel. Taxanes are widely used for the treatment of various solid tumours. Cabazitaxel is approved for the treatment of castration-resistant prostate cancer and shows lesser drug resistance compared with the older taxanes. ¹ While docetaxel and paclitaxel have visual adverse effects, such as dry eyes, keratitis, glaucoma, macular oedema and optic neuropathy (ON; damage to the optic nerve),^2,3 information about cabazitaxel’s tendency to cause similar side effects is very sparse. Herein, we report a 63-year-old male patient with a diagnosis of metastatic prostate cancer who developed unilateral visual loss and optic atrophy during cabazitaxel treatment. To our knowledge, our case is the first report of optic atrophy which may be due to cabazitaxel use.

Case report

A 63-year-old male patient was diagnosed in 2010 as having prostate adenocarcinoma with lumbosacral vertebral metastases. His treatment started with leuprolide acetate 22.5 mg subcutaneous every three months plus pamidronate monthly. He had metastatic stage disease, so androgen-deprivation treatment was applied until disease progression. In January 2015, abiraterone acetate was started, as the prostate-specific antigen (PSA) level had increased from 5 to 11.85 ng/mL and he also complained of lower back pain. PSA levels remained steady until August 2015. After seven months, PSA increased to 24.4 ng/mL, and there was progression in bone metastases, so abiraterone acetate was stopped. The patient was started on docetaxel. PSA serum levels were checked before each treatment cycle and these decreased steadily. Nine cycles of docetaxel were applied until April 2016. PSA level started to increase in May 2016. He complained about back pain again and, in August 2016, lumbar spinal magnetic resonance imaging (MRI) showed some metastatic bone lesions. He received palliative radiotherapy for these. He also complained of occasional headaches. A brain MRI was carried out and showed some extradural mass lesions at the left temporal brain region. Palliative radiotherapy was undertaken in September 2016. After that, cabazitaxel treatment was started in October 2016. PSA levels were checked before starting cabazitaxel and a reading of 118.42 ng/mL was recorded. This was repeated before each treatment cycle and decreased to 8.53 ng/mL after six cycles of cabazitaxel. There was no toxicity noted with cabazitaxel treatment other than grade 1 peripheral neuropathy. The plan was to continue the drug until disease progression or unacceptable toxicity. Serum PSA level remained stable and the drug was continued until September 2017. Shortly after the 12th cycle, the patient complained of subacute visual loss in his right eye, that had progressed in the previous month. Ophthalmologic examination revealed total loss of vision on the right eye with optic atrophy, but normal findings in the left eye. Contrast-enhanced brain MRI showed nonspecific, sparse, subcortical ischemic gliotic lesions with no sign of sinus venous thrombosis, demyelinating plaque, brain metastasis or leptomeningeal carcinomatosis. Contrast-enhanced orbital MRI was normal with no sign of optic nerve inflammation. Subacute onset, progressing symptoms over weeks was not compatible with ischaemic ON which one would expect to occur acutely. The brain and orbital MRI seemed to rule out infectious, inflammatory or compressive aetiologies. In view of the emergence of symptoms during chemotherapy, we believed cabazitaxel to be the likely causative agent for the optic atrophy.

Discussion

Taxanes make up a group of chemotherapy agents that includes docetaxel and paclitaxel, along with the new generation molecules such as cabazitaxel and nab-paclitaxel. They lead to polymerisation of tubulin, thereby stabilising the microtubules and inhibit their normal reorganisation. In this way, they interfere with normal cell division and cause cell death.^4,5

Taxanes have been used in the treatment of various solid tumours, including head and neck, breast, lung, ovary, cervical, uterine, stomach, pancreas, oesophagus and prostate cancers. The most important side effects are hypersensitivity reactions, bone marrow suppression, alopecia, nausea, vomiting and peripheral neuropathy which can be dose-limiting, painful and often irreversible.^6–9

Ophthalmic adverse events related to taxanes are reported as transient blurred vision and photopsia during infusion, dry eyes, keratitis, epiphora, scotomata, ON, bilateral hemianopsia, painless glaucoma and cystoid macular oedema (a disruption of the normal blood–retinal barrier with intraretinal accumulation of intracellular fluid).^2,3

Paclitaxel has been associated with transient scintillating scotomas during infusion, which was suggested to be caused by retinal vascular dysregulation or optic nerve ischaemia. ¹⁰

Toxic ON related to docataxel has been previously reported.^11,12 In those cases, symptoms related to ON, such as constriction of visual fields, loss of visual acuity and loss of colour vision started within the first few cycles, gradually worsening over weeks in a subacute fashion. Detailed evaluations including brain and orbital MRIs excluded other aetiologies. Generally, both eyes were affected; however, initially symptoms started in one eye, later involving the other, and there was usually an asymmetry in the severity of the visual loss. Continuation of the agent led to worsening of the symptoms. Visual recovery was achieved after discontinuation of docetaxel and treatment with corticosteroids.

Cabazitaxel is a new taxane with a favourable pharmacokinetic and safety profile. Unlike other taxanes, it has poor affinity for the P-glycoprotein drug efflux pump, which decreases intracellular concentrations of paclitaxel/docetaxel and causes drug resistance. ¹ While neutropenia and fatigue are known to be the most common side effects of cabazitaxel, information about ophthalmologic side effects is limited. Only one case of a ‘possible’ ON related to cabazitaxel use has previously been reported. Noguchi et al., ¹³ written in Japanese only with abstract in English, reported a 78-year-old man diagnosed with prostate cancer who complained of a decline in vision during the second and third administration cycles of cabazitaxel. However, although administration was continued through six cycles in that patient, the symptoms were unchanged and ‘no drastic exacerbation’ was seen, in contrast to what we expect from toxic neuropathy.

Our case developed subacute ON, following 12 cycles of cabazitaxel, that had progressed to optic atrophy – which implies permanent axonal loss of optic nerve. He had not complained of any visual disturbance during the previous cycles, and he was not checked by an ophthalmologist before administration of cabazitaxel. His last ophthalmologist visit was in April 2016, when he was noted to have conjuctivitis and myopia.

There are many aetiologies for optic nerve injury which can progress to optic atrophy. Ischaemic ON is more commonly seen over 50 years of age. For non-arteritic ischaemic ON, our patient had no risk factors for atherosclerosis, such as hypertension, smoking history or diabetes. Brain MRI did not show evidence of small artery disease or large artery atherosclerosis. For arteritic ischaemic ON, clinical features such as headache, scalp tenderness or jaw claudication, raised ESR or C-reactive protein were absent. The onset of symptoms was more insidious (with progression) than the acute onset of ischaemia. Brain and orbital MRI was normal with no sign of meningeal or optic nerve inflammation, demyelination or any compressive lesion. Hence, inflammatory, infectious or compressive ONs seemed to be excluded. When compared to ON occurring with other taxanes, our case developed later, after 12 cycles of cabazitaxel. Cumulative dosage for cabazitaxel to cause ON may be higher than older taxanes. Unilateral ON in our case is not typical for toxic ONs; however, reported cases with other taxanes also showed a unilateral onset and asymmetrical involvement, although both sides were eventually involved. Although the exact cause of our patient’s ON could not be accurately ascertained, toxicity of cabazitaxel could still be inferred as the primary cause.

To our knowledge, optic atrophy as a consequence of cabazitaxel use has not been reported previously.

Conclusion

Treatment options for cancer patients have expanded rapidly. Neurological side effects may be seen with specific agents. Although further research is needed to clearly identify its mechanism, the probability of a cabazitaxel-induced ON should be kept in mind when visual problems occur in cancer patients under this chemotherapy agent. The natural progress of cabazitaxel-related toxic ON is unknown at present. However, we recommend considering a visual assessment before and if patients experience visual symptoms during cabazitaxel treatment to detect early evidence of toxic ON.