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Severe loss of vision during adjuvant interferon alfa-2b treatment for malignant melanoma
Severe loss of vision during adjuvant interferon alfa-2b treatment for malignant melanoma Chris P Lohmann, Gisela Kroher, Thomas Bogenrieder, Det l ev Spiegel, Jürgen Preuner
The incidence rate of melanoma continues to rise faster than that of any other human cancer and at least 20% of individuals diagnosed with melanoma will die within 5 years of diagnosis. Kirkwood and colleagues1 showed that adjuvant therapy with high-dose interferon (alfa) can improve the relapse-free and overall survival of patients with melanoma after curative surgery.1 However, the therapeutic effectiveness of interferon alfa is often comprised by various systemic side-effects, including constitutional and neurological symptoms, hepatotoxicity, and laboratory findings of myelosuppression.2 Ocular sideeffects of interferon alfa are very uncommon and, so far, two phenomena have been observed. In ten patients ischaemic retinopathy with “cotton wool” spots (nervefibre-layer infarcts), retinal haemorrhages, and retinal capillary non-perfusion have been noted,3 whereas in two patients anterior ischaemic optic neuropathy was diagnosed. 4 In all these cases visual loss was mild and nonprogressive. These effects have occurred weeks to months after initiation of therapy and resolved after cessation. We report on a 60-year-old man with cutaneous melanoma (Breslow’s Micro Index 4·2 mm; Clark’s level V; pT 4, N0, M0), which was excised and subsequently treated with interferon alfa-2b (Intron-A, Essex-ScheringPlough) 20⫻106 U intravenously five times per week for 2 months followed by 3⫻106 U subcutaneously three times per week for 15 weeks. He was otherwise in good health and was receiving no other medication. In relation to the pathogenesis of vascular diseases it should be mentioned that he was smoking 20 cigarettes a day. Results of his ocular examination were normal 6 weeks before the initiation of interferon alfa therapy. 23 weeks after therapy was started, the patient reported a rapid and progressive loss of peripheral visual field in the left eye. On examination, his left eye showed optic disc oedema and a left relative afferent pupillary defect. At this time the optic disc of the right eye appeared healthy. However, in both eyes the retinal arteries were notably constricted (figure). Visual acuity was 20/20 in both eyes. Goldmann perimetry showed a full field in the right eye, whereas the left eye showed a significant circular constriction with only the central 30° left. Results of an examination for other systemic causes for anterior ischaemic optic neuropathy were unremarkable; these examinations included measurement of blood pressure, complete blood-cell count, erythrocyte sedimentation rate, chemistry panel, serum protein electrophoresis, antinuclear antibody determination, and serology of HIV, herpes simplex viruses, lyme and lues. Scans by both computed tomography and magnetic resonance imaging of the head and orbits before and after contrast infusion and a lumbar puncture, including cytological examination, were all normal. Treatment with acetylsalicylic acid (100 mg per day), high-dose dexamethasone (100 mg per day), and high-dose heparin (25 000 units per day intravenously) was initiated. On advice he reduced smoking to four cigarettes per day. Within 7 days loss of visual function continued in the left eye to a final visual acuity of 20/400 and a residual visual field of the central 5° to 10°. At this time he
1326
Circumferential oedema of the optic disc and constricted arteries (arrowed) in a patient with cutaneous melanoma treated with interferon alfa
also noted loss of peripheral visual field in his right eye, and the optic disc of the right eye showed segmental oedema inferiorly. Treatment with interferon alfa was stopped immediately and dexamethasone was increased to 1000 mg per day. However, loss of visual acuity and visual field in the right eye continued. 3 days later, visual acuity dropped down to 20/120 and only a central part of the visual field was left. At this time cyclosporin therapy was started (4 mg per kg body weight per day) and under this therapy visual acuity and visual fields remained stable in both eyes over a period of 3 weeks. By contrast with other reports on retinal and optic nerve complications of interferon alfa therapy3,4 our patient will suffer from permanent and irreversible loss of visual function. Although the pathophysiology of interferon-alfa associated anterior ischaemic optic neuropathy is unclear, it is most likely to be linked to an immunological phenomenon. It has been postulated that interferon alfa i s able to produce autoantibodies and subsequently causes deposition of immune complexes in the small retinal or optic nerve arteries.3,4 Interferon is also a welldefined immunomodulator and is able to stimulate o t h e r cytokines, such as various interleukins, and up-regulate histocompatibility complex class II proteins. 5 These interleukins can cause an inflammatory reaction of the blood vessels and subsequently lead to ischaemia. 1
Kirkwood JM, Strawderman MH, Ernsthoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996; 14: 7–17. 2 Borden EC, Parkinson D. A perspective on the clinical effectiveness and tolerance of interferon-␣. Semin Oncol 1998; 2 5 (suppl): 3–8. 3 Guyer DR, Tiedeman J, Yannuzzi LA, et al. Interferon-associated retinopathy. Arch Ophthalmol 1993; 111: 350–56. 4 Purvin VA. Anterior ischemic optic neuropathy secondary to interferon alfa. Arch Ophthalmol 1995; 113: 1041–44. 5 Taylor JL, Grossberg SE. The effects of interferon-␣ on the production and action of other cytokines. Semin Oncol 1998; 2 5 (suppl): 23–29. Departments of Ophthalmology, Dermatology, and Cardiovascular Surgery, University of Regensburg, and University Eye Clinic Regensburg ( C P Lohmann), D-93042 Regensburg, Germany
THE LANCET • Vol 353 • April 17, 1999
The incidence rate of melanoma continues to rise faster than that of any other human cancer and at least 20% of individuals diagnosed with melanoma will die within 5 years of diagnosis. Kirkwood and colleagues1 showed that adjuvant therapy with high-dose interferon (alfa) can improve the relapse-free and overall survival of patients with melanoma after curative surgery.1 However, the therapeutic effectiveness of interferon alfa is often comprised by various systemic side-effects, including constitutional and neurological symptoms, hepatotoxicity, and laboratory findings of myelosuppression.2 Ocular sideeffects of interferon alfa are very uncommon and, so far, two phenomena have been observed. In ten patients ischaemic retinopathy with “cotton wool” spots (nervefibre-layer infarcts), retinal haemorrhages, and retinal capillary non-perfusion have been noted,3 whereas in two patients anterior ischaemic optic neuropathy was diagnosed. 4 In all these cases visual loss was mild and nonprogressive. These effects have occurred weeks to months after initiation of therapy and resolved after cessation. We report on a 60-year-old man with cutaneous melanoma (Breslow’s Micro Index 4·2 mm; Clark’s level V; pT 4, N0, M0), which was excised and subsequently treated with interferon alfa-2b (Intron-A, Essex-ScheringPlough) 20⫻106 U intravenously five times per week for 2 months followed by 3⫻106 U subcutaneously three times per week for 15 weeks. He was otherwise in good health and was receiving no other medication. In relation to the pathogenesis of vascular diseases it should be mentioned that he was smoking 20 cigarettes a day. Results of his ocular examination were normal 6 weeks before the initiation of interferon alfa therapy. 23 weeks after therapy was started, the patient reported a rapid and progressive loss of peripheral visual field in the left eye. On examination, his left eye showed optic disc oedema and a left relative afferent pupillary defect. At this time the optic disc of the right eye appeared healthy. However, in both eyes the retinal arteries were notably constricted (figure). Visual acuity was 20/20 in both eyes. Goldmann perimetry showed a full field in the right eye, whereas the left eye showed a significant circular constriction with only the central 30° left. Results of an examination for other systemic causes for anterior ischaemic optic neuropathy were unremarkable; these examinations included measurement of blood pressure, complete blood-cell count, erythrocyte sedimentation rate, chemistry panel, serum protein electrophoresis, antinuclear antibody determination, and serology of HIV, herpes simplex viruses, lyme and lues. Scans by both computed tomography and magnetic resonance imaging of the head and orbits before and after contrast infusion and a lumbar puncture, including cytological examination, were all normal. Treatment with acetylsalicylic acid (100 mg per day), high-dose dexamethasone (100 mg per day), and high-dose heparin (25 000 units per day intravenously) was initiated. On advice he reduced smoking to four cigarettes per day. Within 7 days loss of visual function continued in the left eye to a final visual acuity of 20/400 and a residual visual field of the central 5° to 10°. At this time he
1326
Circumferential oedema of the optic disc and constricted arteries (arrowed) in a patient with cutaneous melanoma treated with interferon alfa
also noted loss of peripheral visual field in his right eye, and the optic disc of the right eye showed segmental oedema inferiorly. Treatment with interferon alfa was stopped immediately and dexamethasone was increased to 1000 mg per day. However, loss of visual acuity and visual field in the right eye continued. 3 days later, visual acuity dropped down to 20/120 and only a central part of the visual field was left. At this time cyclosporin therapy was started (4 mg per kg body weight per day) and under this therapy visual acuity and visual fields remained stable in both eyes over a period of 3 weeks. By contrast with other reports on retinal and optic nerve complications of interferon alfa therapy3,4 our patient will suffer from permanent and irreversible loss of visual function. Although the pathophysiology of interferon-alfa associated anterior ischaemic optic neuropathy is unclear, it is most likely to be linked to an immunological phenomenon. It has been postulated that interferon alfa i s able to produce autoantibodies and subsequently causes deposition of immune complexes in the small retinal or optic nerve arteries.3,4 Interferon is also a welldefined immunomodulator and is able to stimulate o t h e r cytokines, such as various interleukins, and up-regulate histocompatibility complex class II proteins. 5 These interleukins can cause an inflammatory reaction of the blood vessels and subsequently lead to ischaemia. 1
Kirkwood JM, Strawderman MH, Ernsthoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996; 14: 7–17. 2 Borden EC, Parkinson D. A perspective on the clinical effectiveness and tolerance of interferon-␣. Semin Oncol 1998; 2 5 (suppl): 3–8. 3 Guyer DR, Tiedeman J, Yannuzzi LA, et al. Interferon-associated retinopathy. Arch Ophthalmol 1993; 111: 350–56. 4 Purvin VA. Anterior ischemic optic neuropathy secondary to interferon alfa. Arch Ophthalmol 1995; 113: 1041–44. 5 Taylor JL, Grossberg SE. The effects of interferon-␣ on the production and action of other cytokines. Semin Oncol 1998; 2 5 (suppl): 23–29. Departments of Ophthalmology, Dermatology, and Cardiovascular Surgery, University of Regensburg, and University Eye Clinic Regensburg ( C P Lohmann), D-93042 Regensburg, Germany
THE LANCET • Vol 353 • April 17, 1999