MEK inhibitor-associated retinopathy (MEKAR) in metastatic melanoma: Long-term ophthalmic effects.

BACKGROUND: Mitogen-activated protein kinase kinase (MEK) inhibitors have aroused considerable interest in oncology. Activity has been demonstrated in various types of cancer, especially melanoma. MEK inhibitors induce a transient retinopathy, considered to be a class effect. At present, only sparse data are available on retinal effects with long-term MEK inhibition. PATIENTS AND METHODS: In this prospective, observational study, patients with advanced melanoma participating in different phase 1/2 or phase 3 clinical trials were treated with the MEK inhibitor binimetinib, with a v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitor, or with combination therapy. They underwent regular ophthalmological examinations including determination of visual function, biomicroscopy, dilated fundoscopy and optical coherence tomography (OCT) for a period of up to 2 years. Retinopathy was diagnosed on defined OCT criteria. RESULTS: Sixty-two patients were investigated between 1st October 2011 and 31st July 2015: 13 were treated with the MEK inhibitor binimetinib alone, 10 with a selective BRAF inhibitor, and 39 with combination therapy. In 92% of patients on monotherapy and 100% of those on combination treatment, binimetinib caused dose-related lesions with serous neuroretinal detachments and oedema, strongly dependent on the time after medication. With continued treatment, retinal volume and thickness decreased to levels below baseline, without any apparent functional deficits or changes in structural integrity. CONCLUSIONS: Binimetinib induces a specific retinopathy with daily fluctuations depending on the time interval after medication. The retinopathy partially recovers, but can still be detected many months later. Retinal thinning, possible first signs of retinal atrophy have been observed after long-term treatment, but, so far, without functional relevance.

Transient MEK inhibitor-associated retinopathy in metastatic melanoma.

BACKGROUND: Melanoma is one of the most aggressive skin cancers. Recently, selective MEK inhibitors have shown efficacy in patients with advanced BRAF- and NRAS-mutant melanoma. Soon after the initiation of clinical oncology trials with MEK inhibitors, it was observed that some participants developed an eye condition resembling central serous chorioretinopathy. The present article addresses the clinical features and management of these MEK inhibitor-associated retinal syndromes. PATIENTS AND METHODS: Thirty-two patients with advanced cutaneous melanoma were treated with the selective MEK inhibitor binimetinib (MEK162) in three different Phase 1b or 2 clinical trials. Twenty patients on binimetinib monotherapy and 12 on binimetinib plus RAF inhibitor [pan-kinase RAF inhibitor RAF265 (n = 7) or selective BRAF inhibitor encorafenib (LGX818) (n = 5)] combination therapy underwent ophthalmological examinations at regular intervals, including determination of best corrected visual acuity, perimetry, colour vision testing, dilated fundus examination, and multimodal imaging. RESULTS: Grade 1-2 bilateral retinopathies with multiple lesions were observed in 13 of 20 patients on binimetinib monotherapy, 4 of 7 patients on binimetinib plus RAF265 combination therapy, and 2 of 5 patients on binimetinib plus encorafenib combination therapy. In this study population, the rate ranged from 40% to 65%. Retinopathy events appeared during the first 4 weeks, and in some cases, during the first few days of treatment. Patients reported mild and only short-lived visual symptoms. Optical coherence tomography revealed neuroretinal elevations. Central retinal thickness and volume showed dose-dependent increases after the start of treatment, followed by a marked decrease despite continued treatment, which was associated with symptom resolution. No vascular abnormalities were found with fluorescein and indocyanine green angiography. CONCLUSIONS: Treatment with the selective MEK inhibitor binimetinib as a single agent or in combination with RAF inhibitors induced transient retinopathy with multiple bilateral lesions in some patients. Binimetinib-induced retinopathy was usually mild, self-limiting, and tolerable as visual function was not seriously impaired.

[Prevention of cystoid macular edema following cataract extraction using local indomethacin application]. / Prävention des zystoiden Makulaödems nach Kataraktextraktion durch lokale Indomethacin Applikation.

In a randomized, controlled study drops of 1% aqueous solution of indomethacin were compared to Placebo to assess efficacy in the prevention of cystoid macular edema. The study involved 124 patients who had undergone intracapsular cataract extraction and 40 patients with implanted lenses. The study parameters--visual acuity, biomicroscopy observations of the macula and fluorescein angiography--were assessed for three months postoperatively. The long-term course was reviewed by regular outpatient follow-up visits or by questionnaires completed by the patients' personal ophthalmologists. Fluorescein angiography could only be carried out in 13 of the 40 patients who had intraocular lenses. The relatively high incidence of secondary cataract or pupillary synechiae made technically perfect exposures difficult. In 73 patients with intracapsular extraction, fluorescein angiography showed a distinct diminution in the incidence of edema in the indomethacin group at all three observation periods (3, 6 and 12 weeks postoperatively). The difference compared with placebo was significant at weeks 6 and 12. Ophthalmoscopically visible macular changes were rare. No evidence of edema was noted in any of the 51 patients who could not have fluorescein angiography for one reason or another. The visual acuity of patients who received indomethacin was not significantly different from that of those who received placebo. Furthermore, and this is important for the patients, in the group with proven edema no conclusion could be made about the effect of therapy on the severity and persistence of visual impairment.(ABSTRACT TRUNCATED AT 250 WORDS)

[Long-term therapy with timolol for three years (author's transl)]. / Langzeitbehandlung mit Timolol über drei Jahre.

From an original group of 36 Patients (15 with relatively advanced chronic open-angle glaucoma and 21 with ocular hypertension) 21 (seven glucoma and 14 ocular hypertension) were well controlled with Timolol alone or in combination with other pressure-lowering drugs after a three years' observation period. Dropouts occurred mainly in the first half of the treatment period. In most of these cases a glaucoma operation was necessary; more rarely, Timolol was discontinued due to intolerance. The overall success rate of 40% with Timolol alone (14 out of 36 patients) is lower than the 60% to 70% found in other long-term studies. If one considers only the results in the ocular hypertension group, the figure of 68% is more in line with the aforementioned results. In the light of similar studies it appears essential to take into account not only the total number of patients treated but also the degree of severity of the glaucoma. In severe glaucoma Timolol alone is seldom effective enough.

[Clinical trials of various glaucoma drugs acting on the adrenergic system (author's transl)]. / Klinische Prüfung verschiedener am adrenergen System angreifender Glaukom-Medikamente.

The authors summarize findings in a clinical trial of the betablockers Timolol and Metoprolol, as well as the effectiveness of various concentration of the combination preparation Guanethidine-Adrenaline. In the trial Timolol proved to be the almost ideal drug for glaucoma therapy. However, as a pressure-lowering agent the guanethidine-epinephrine combination is more effective. Metroprolol, which is a pure beta 1-blocker, is probably preferable to Timolol in asthmatic patients.

Treatment of chronic simple glaucoma with an adrenaline/guanethidine combination at three different dosages (comparative double-blind study).

Undesirable side effects have limited the use of adrenaline/guanethidine combinations in the usual concentrations in the treatment of chronic simple glaucoma. Better tolerance to lower concentrations has already been demonstrated in other studies. In the double-blind study described here, three different combinations (adrenaline 1%, 0.5% and 0.2% combined respectively with guanethidine 5%, 3% and 1%) were compared in respect of their depressive action on intraocular pressure and the tolerance shown to them. All three combinations were found to be effective. The combination with the lowest concentration was significantly less hypotensive in its effect than the other two but the number of patients treated was too small to allow a clear distinction to be made between the effects of the other two combinations. Nevertheless, there was a tendency for the effectiveness to fall with decreasing concentration. As far as tolerance was concerned, there was little difference between the middle and lowest concentrations, the latter being that best tolerated. The excellent effect of the strongest concentration was impaired by the poor tolerance shown to it. The comparison between the three combinations was followed by a study of the diurnal pressure changes in patients during the course of the treatment. The slow rise up to midday and the abrupt afternoon fall remain unexplained. The low concentration of the preparation had a better hypotensive action than pilocarpine, while the middle concentration proved even a little better than the beta-blocker Timolol