Acta Ophthalmologica 2014
He did not have the severe weight loss pathognomonic for classic WD. He was diagnosed with kidney sarcoidosis before the WD diagnosis and was pharmacologically immunosuppressed. After the patient had his first cataract surgery performed, a severe mostly posterior uveitis was diagnosed. It did not respond to neither topical nor systemic immunosuppressive treatment. Case reports have described uveitis after intraocular operations in patients unknown to have WD, only diagnosed later on by vitreous samples. It is uncertain whether it is the operation in itself or the use of post-operative topical steroids that provokes the development of uveitis in these WD patients (Drancourt et al. 2009). In parallel with the eye problems, the patient developed significant neurological symptoms indicating involvement of the brain. WD is a fascinating disease entity with a wide range of clinical manifestations and has been considered to be an extremely rare disease (Raoult et al. 2000). This makes it difficult for clinicians to identify cases, especially the non-classic cases, with more atypical symptoms and findings. New data indicate that Tropheryma whipplei is ubiquitous in the environment (Maiwald et al. 1998). Clinicians treating patients with diffuse symptoms involving the brain and the eyes should not forget about this very rare disease which can be treated effectively with antibiotics.
References Drancourt M, Fenollar F, Denis D & Raoult D (2009): Postoperative panophthalmitis caused by Whipple disease. Emerg Infect Dis 15: 825–827. Maiwald M, Schuhmacher F, Ditton HJ & von Herbay A (1998): Environmental occurrence of the Whipple’s disease bacterium (Tropheryma whippelii). Appl Environ Microbiol 64: 760–762. Raoult D, Birg ML, La Scola B et al. (2000): Cultivation of the bacillus of Whipple’s disease. N Engl J Med 342: 620–625. Schneider T, Moos V, Loddenkemper C, Marth T, Fenollar F & Raoult D (2008): Whipple’s disease: new aspects of pathogenesis and treatment. Lancet Infect Dis 8: 179–190. Touitou V, Fenollar F, Cassoux N, MerleBeral H, LeHoang P, Amoura Z, Drancourt M & Bodaghi B (2012): Ocular Whipple’s disease: therapeutic strategy and long-term follow-up. Ophthalmology 119: 1465–1469.
e694
Correspondance: Elin Holm, MD Department of Ophtalmology National Hospital of the Faroe Islands Queen Alexandrines Teaching Hospital J.C. Svabosgøta 41-49 FO-100 T orshavn, Faroe Islands Tel: +298 304500 Fax: +298 314213 Email: [email protected]
Ozurdex® reduces the retinal thickness in radiation maculopathy refractory to bevacizumab Lisa Tarmann, Gerald Langmann, Christoph Mayer, Martin Weger, Anton Haas and Werner Wackernagel Department of Ophthalmology, Medical University of Graz, Graz, Austria doi: 10.1111/aos.12424
Editor, adiation retinopathy and maculopathy are common side-effects of radiotherapy for posterior uveal melanoma, occurring in up to 84% of cases (Haas et al. 2002). Recently, the administration of dexamethasone intravitreal implant (Ozurdexâ) has been approved by the U.S. Food and Drug Administration for the treatment of retinal oedema in retinal vein occlusion and non-infectious posterior uveitis (London et al. 2011; Bezatis et al. 2013; Matonti et al. 2013). This dexamethasone ‘drug delivery system’ (DDS) has been developed for a sustained drug release and longlasting effect up to 3–6 months, for superior dose consistency, and shows a favourable safety profile (London et al. 2011). We report the effect of dexamethasone DDS on retinal thickness and visual acuity after ineffective bevacizumab therapy in patients with radiation maculopathy. Institutional review board (IRB) approval was obtained for a retrospective evaluation of clinical records. All patients developed a radiation maculopathy with cystoid macular oedema,
R
between 15 months and 4 years after radiotherapy for uveal melanoma (Table 1). All 4 patients had previously been treated with intravitreal bevacizumab (Avastinâ), and one patient had received adjunct panretinal laser coagulation followed by an intravitreal triamcinolone. For the measurement of retinal thickness optical coherent tomography (OCT, Cirrus Operator; Zeiss, Oberkochen) five-line raster, evaluating the thickest horizontal retinal cross-sectional image directly in the perifoveolar area was used. Macular oedema: 2–4 weeks after treatment with dexamethasone, all patients showed a reduction in macular oedema; 14–17 weeks after injection retinal thickness increased to almost pretreatment values (Table 1). Visual acuity: Two patients showed a vision improvement of two or more Snellen lines within the first month of observation after treatment. Persistent improvement of vision was found in only one patient (14–17 weeks after treatment). Side-effects: An elevation of intraocular pressure was measured in one patient 2 months postoperatively (27 mmHg), which was treated by topical antiglaucomatous therapy. No infections or haemorrhages were seen after injection. Local tumour recurrence was not recorded during follow-up. Currently used off-label therapies for radiation maculopathy are as follows: periocular and intravitreal triamcinolone, intravitreal antivascular endothelial growth factor agents (anti-VEGF), photodynamic therapy and panretinal and central laser photocoagulation. Recently, intravitreal injection of antiVEGF has been published to reduce macular oedema, stabilize retinal vessels and reduce leakage after radiotherapy (Wen & McCannel 2009). Anatomical and functional results were promising; however, drug effect was not long lasting and frequent injections were necessary for continued response. In our study, we used the intravitreal Ozurdexâ as salvage treatment for radiation induced macular oedema, unresponsive to bevacizumab. Among the corticosteroids, dexamethasone is known to be one of the most potent substances, and due to its polymer structure of dexamethasone DDS, the drug effect lasts longer with consistent levels of drug release (London et al. 2011).
Acta Ophthalmologica 2014
Table 1. Patient, treatment and tumour data.
Case
Age (years) Sex
Treatment
Case 1
45 female
Ru-106
Case 2
58 female
Ru-106
Case 3
58 male
Ru-106
Case 4
66 female
GK-RS
Tumour data T-LBD (mm) T-height (mm) T-DtD (mm) T-DtF (mm) RD () 8.4 4.2 6.6 9.0 RD 10.5 5.5 5.5 3.5 RD+ 14.2 6.9 4.5 2.25 RD+ 8.2 2.1 1.5 1.5 RD
BCVA At injection 2–4 weeks p.o. 10 weeks p.o. 14–17 weeks p.o.
RT At injection 2–4 weeks p.o. 10 weeks p.o. 14–17 weeks p.o. (lm)
TNM Location
Time to MP Pretreatment of MP
T1 nasal superior
4.5 years 2 itv. bevacizumab
20/30 20/25 20/25 20/25
432 307 329 418
T2 midline temporal
17 months 1 VE 6 itv. bevacizumab
20/120 20/40 20/30 20/40
546 364 338 488
T3 superior temporal
4 years 6 itv. bevacizumab
20/60 20/60 20/80 20/125
615 363 475 624
T1 temporal inferior
15 months 9 itv. bevacizumab, Panret. LC, itv. triamcinolone
20/400 20/125 20/480 20/660
871 564 432 744
20/100 20/50 20/80 20/100
616 399 393 568
Mean
Ru-106, ruthenium-106 brachytherapy; GK-RS, gamma knife radiosurgery; T, tumour; LBD, longest basal diameter; DtD, distance to disc; DtF, distance to foveola; RD, preexisting retinal detachment (at time of diagnosis); TNM, tumour/nodes/metastases; MP, maculopathy; CW, cotton wool; ME, macular oedema; MA, microaneurysms; FH, foveal haemorrhages; NV, neovascularizations; itv., intravitreal; VE, vitrectomy; VA, visual acuity; lm, micrometre; p.o., postoperative.
Russo et al. (2012) published a case, previously treated with bevacizumab responding well to dexamethasone. Recently, another case series was published describing effects of Ozurdexâ for the treatment of radiation macular oedema with promising results (Baillif et al. 2013). In contrast to the report by Russo et al., all patients in their series were treated ‘first line’ with dexamethasone intravitreal implant and did not receive any previous therapy. Our patients all received dexamethasone DDS as salvage treatment after ineffective therapy with bevacizumab, and, in one patient, after additional panretinal laser treatment and good response to intravitreal triamcinolone. This was also evident in one patient after vitrectomy when intravitreal bevacizumab has been shown to be less effective (Kakinoki et al. 2012). A limitation of our report is the retrospective character, particularly the absence of fluorescence angiography examinations. In our case series, the use of dexamethasone DDS resulted in transient
reduction in foveal thickness and might be a beneficial adjunct treatment after irradiation. Long-term effectiveness and results of repeated treatment of Ozurdexâ are to be evaluated.
References Baillif S, Maschi C, Gastaud P & Caujolle JP (2013): Intravitreal dexamethasone 0.7-mg implant for radiation macular edema after protone beam therapy for choroidal melanoma. Retina 33: 1784– 1790. Bezatis A, Spital G, H€ ohn F et al. (2013): Functional and anatomical results after a single intravitreal Ozurdex injection in retinal vein occlusion: a 6-month follow-up – the SOLO study. Acta Ophthalmol 91: e340–e347. Haas A, Pinter O, Papaefthymiou G et al. (2002): Incidence of radiation retinopathy after high-dosage single-fraction gamma knife radiosurgery for choroidal melanoma. Ophthalmology 109: 909–913. Kakinoki M, Sawada O, Sawada T, Saishin Y, Kawamura H & Ohji M (2012): Effect of vitrectomy on aqueous VEGF concentration
and pharmacokinetics of bevacizumab in macaque monkeys. Invest Ophthalmol Vis Sci 53: 5877–5880. London NJ, Chiang A & Haller JA (2011): The dexamethasone drug delivery system: indications and evidence. Adv Ther 28: 351– 366. Matonti F, Meyer F, Guigou S et al. (2013): Ozurdex in the management of the macular edema following retinal vein occlusion in clinical practice. Acta Ophthalmol 91: e584– e586. Russo A, Avitabile T, Uva M et al. (2012): Radiation macular edema after Ru-106 plaque brachytherapy for choroidal melanoma resolved by an intravitreal dexamethasone 0.7-mg implant. Case Rep Ophthalmol 3: 71–76. Wen JC & McCannel TA (2009): Treatment of radiation retinopathy following plaque brachytherapy for choroidal melanoma. Curr Opin Ophthalmol 20: 200–204.
Correspondence: Lisa Tarmann, MD Department of Clinical Ophthalmology Medical University of Graz
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Acta Ophthalmologica 2014
Auenbruggerplatz 4 8036 Graz Tel: +43 316 385 -12394 Fax: +43 316 385 -13261 Email: [email protected]
Response of patients with metastatic uveal melanoma to combined treatment with fotemustine and sorafenib Anna Niederkorn,1 Werner Wackernagel,2 Monika Artl,3 Gerold Schwantzer,4 Birgit Aigner1 and Erika Richtig1 1
Department of Dermatology, Medical University of Graz, Graz, Austria; 2 Department of Ophthalmology, Medical University of Graz, Graz, Austria; 3 Institute of Humane Genetics, Medical University of Graz, Graz, Austria; 4 Institute of Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria Conflicts of interest: None declared. doi: 10.1111/aos.12432
Editor, veal melanoma is the 2nd most common type of melanoma after cutaneous melanoma. Survival time for unselected stage IV uveal melanoma patients with liver involvement is poor with mean 4–5 months, and there are currently no approved systemic treatments (Augsburger et al. 2009). Fotemustine is a nitrosourea alkylating agent with a high hepatic extraction rate. A phase III study, which was performed on uveal melanoma patients
U
with hepatic metastases, showed an overall survival of 14.6 months for intrahepatic and 13.7 for intravenous fotemustine (Leyvraz et al. 2012). The multikinase inhibitor sorafenib targets both tumour-cell proliferation and angiogenesis. In preclinical studies, sorafenib inhibited growth in conjunctival melanoma cell lines efficiently and was also able to enhance the antitumour activity of chemotherapeutic agents (Heim et al. 2003; Carter et al. 2007). We evaluated retrospectively the benefit of a combination therapy with fotemustine and sorafenib in eight patients with stage IV uveal melanoma referred to our department for systemic therapy in the years 2010–2012. Fotemustine 100 mg/m² was injected intravenously every 3 weeks after an induction cycle with administration on days 1 and 8. It was combined with sorafenib 400 mg orally twice daily. Array-CGH for genetic aberrations was performed on tumour samples. Survival data were calculated using Kaplan–Meier estimates. The patients were unselected, and six of eight had progressed under previous therapies such as systemic dacarbazine-based chemotherapy, hepatic intra-arterial therapies and histopathologically incomplete removal of liver metastases. The median interval between diagnosis of the primary tumour and the detection of metastases was 30.7 months (range 17.3–183.2); ECOG performance status was 0–1. A total of 25 cycles of fotemustine were administered to our patients. Reasons for discontinuation were disease progression in seven patients and grade III pancytopenia and neutropenic fever in one patient. Haematologic side-effects grade 1–3 made delay of chemotherapy necessary
in all our patients, as well as dose reductions in fotemustine to 75% or 50% in two patients. Dose reductions in sorafenib to 400 mg once daily were performed in three patients due to neutropenia and/or thrombocytopenia. Hand–foot syndrome and/or a maculopapular rash were observed in half of our patients leading to sorafenib dose reduction in one patient. One patient’s sorafenib dosage had to be reduced due to an exudative multiforme-like exanthema. Median survival from first detection of metastases was 22.3 months (range 7.1–30.3 months). The 1-year survival rate was 75%. Two patients were still alive at data analysis (Table 1). Median survival time from start of therapy was 15.9 months (range 5.6– 29.6 months). Three of our eight patients showed partial response or stable disease, equalling a disease control rate of 37.5%. The patient who suffered only from lung metastases showed a partial remission. Two patients with liver metastases depicted stable disease up to 13 months. Similar results were observed by Kaempgen et al., who could show a disease control rate of 42.8% for patients with metastatic uveal melanoma treated with the fotemustine i.v. and sorafenib p.o. after they had progressed under treatment with i.a. or i.v. fotemustine (Kaempgen et al. 2012). Tumour tissue of six of our eight patients was analysed and showed a monosomy of chromosome 3 and a gain on chromosome 8q24, associating the tumours with aggressive biological behaviour and poor response to metastatic treatment compared to those with only a partial change in chromosome 3 or chromosome 3 disomy (Abdel-Rahman et al. 2012).
Table 1. Results of patients with metastatic uveal melanoma treated with fotemustine and sorafenib.
Age (yrs)
Sex
Metastatic sites
Baseline LDH (U/l)
Cycles of fotemustine
Sorafenib reduction
Response
Survival from therapy start (mo)
55 61 76 64 52 62 70 62
M M M F F F F M
Liver Liver Lung Liver Liver, s.c., lymph nodes Liver, s.c. Liver Liver
199 267 163 156 199 415 233 840
2 6 5 4 2 1 1 4
No Yes Yes Yes Yes No Yes Yes
PD SD PR SD PD PD PD PD
20.3 15.9 +29.6 7.9 19.1 14.2 +12.8 5.6
Yrs, years; mo, months; s.c., subcutaneous; PD, progressive disease; SD, stable disease; PR, partial remission; (+), patient still alive at data analysis.
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He did not have the severe weight loss pathognomonic for classic WD. He was diagnosed with kidney sarcoidosis before the WD diagnosis and was pharmacologically immunosuppressed. After the patient had his first cataract surgery performed, a severe mostly posterior uveitis was diagnosed. It did not respond to neither topical nor systemic immunosuppressive treatment. Case reports have described uveitis after intraocular operations in patients unknown to have WD, only diagnosed later on by vitreous samples. It is uncertain whether it is the operation in itself or the use of post-operative topical steroids that provokes the development of uveitis in these WD patients (Drancourt et al. 2009). In parallel with the eye problems, the patient developed significant neurological symptoms indicating involvement of the brain. WD is a fascinating disease entity with a wide range of clinical manifestations and has been considered to be an extremely rare disease (Raoult et al. 2000). This makes it difficult for clinicians to identify cases, especially the non-classic cases, with more atypical symptoms and findings. New data indicate that Tropheryma whipplei is ubiquitous in the environment (Maiwald et al. 1998). Clinicians treating patients with diffuse symptoms involving the brain and the eyes should not forget about this very rare disease which can be treated effectively with antibiotics.
References Drancourt M, Fenollar F, Denis D & Raoult D (2009): Postoperative panophthalmitis caused by Whipple disease. Emerg Infect Dis 15: 825–827. Maiwald M, Schuhmacher F, Ditton HJ & von Herbay A (1998): Environmental occurrence of the Whipple’s disease bacterium (Tropheryma whippelii). Appl Environ Microbiol 64: 760–762. Raoult D, Birg ML, La Scola B et al. (2000): Cultivation of the bacillus of Whipple’s disease. N Engl J Med 342: 620–625. Schneider T, Moos V, Loddenkemper C, Marth T, Fenollar F & Raoult D (2008): Whipple’s disease: new aspects of pathogenesis and treatment. Lancet Infect Dis 8: 179–190. Touitou V, Fenollar F, Cassoux N, MerleBeral H, LeHoang P, Amoura Z, Drancourt M & Bodaghi B (2012): Ocular Whipple’s disease: therapeutic strategy and long-term follow-up. Ophthalmology 119: 1465–1469.
e694
Correspondance: Elin Holm, MD Department of Ophtalmology National Hospital of the Faroe Islands Queen Alexandrines Teaching Hospital J.C. Svabosgøta 41-49 FO-100 T orshavn, Faroe Islands Tel: +298 304500 Fax: +298 314213 Email: [email protected]
Ozurdex® reduces the retinal thickness in radiation maculopathy refractory to bevacizumab Lisa Tarmann, Gerald Langmann, Christoph Mayer, Martin Weger, Anton Haas and Werner Wackernagel Department of Ophthalmology, Medical University of Graz, Graz, Austria doi: 10.1111/aos.12424
Editor, adiation retinopathy and maculopathy are common side-effects of radiotherapy for posterior uveal melanoma, occurring in up to 84% of cases (Haas et al. 2002). Recently, the administration of dexamethasone intravitreal implant (Ozurdexâ) has been approved by the U.S. Food and Drug Administration for the treatment of retinal oedema in retinal vein occlusion and non-infectious posterior uveitis (London et al. 2011; Bezatis et al. 2013; Matonti et al. 2013). This dexamethasone ‘drug delivery system’ (DDS) has been developed for a sustained drug release and longlasting effect up to 3–6 months, for superior dose consistency, and shows a favourable safety profile (London et al. 2011). We report the effect of dexamethasone DDS on retinal thickness and visual acuity after ineffective bevacizumab therapy in patients with radiation maculopathy. Institutional review board (IRB) approval was obtained for a retrospective evaluation of clinical records. All patients developed a radiation maculopathy with cystoid macular oedema,
R
between 15 months and 4 years after radiotherapy for uveal melanoma (Table 1). All 4 patients had previously been treated with intravitreal bevacizumab (Avastinâ), and one patient had received adjunct panretinal laser coagulation followed by an intravitreal triamcinolone. For the measurement of retinal thickness optical coherent tomography (OCT, Cirrus Operator; Zeiss, Oberkochen) five-line raster, evaluating the thickest horizontal retinal cross-sectional image directly in the perifoveolar area was used. Macular oedema: 2–4 weeks after treatment with dexamethasone, all patients showed a reduction in macular oedema; 14–17 weeks after injection retinal thickness increased to almost pretreatment values (Table 1). Visual acuity: Two patients showed a vision improvement of two or more Snellen lines within the first month of observation after treatment. Persistent improvement of vision was found in only one patient (14–17 weeks after treatment). Side-effects: An elevation of intraocular pressure was measured in one patient 2 months postoperatively (27 mmHg), which was treated by topical antiglaucomatous therapy. No infections or haemorrhages were seen after injection. Local tumour recurrence was not recorded during follow-up. Currently used off-label therapies for radiation maculopathy are as follows: periocular and intravitreal triamcinolone, intravitreal antivascular endothelial growth factor agents (anti-VEGF), photodynamic therapy and panretinal and central laser photocoagulation. Recently, intravitreal injection of antiVEGF has been published to reduce macular oedema, stabilize retinal vessels and reduce leakage after radiotherapy (Wen & McCannel 2009). Anatomical and functional results were promising; however, drug effect was not long lasting and frequent injections were necessary for continued response. In our study, we used the intravitreal Ozurdexâ as salvage treatment for radiation induced macular oedema, unresponsive to bevacizumab. Among the corticosteroids, dexamethasone is known to be one of the most potent substances, and due to its polymer structure of dexamethasone DDS, the drug effect lasts longer with consistent levels of drug release (London et al. 2011).
Acta Ophthalmologica 2014
Table 1. Patient, treatment and tumour data.
Case
Age (years) Sex
Treatment
Case 1
45 female
Ru-106
Case 2
58 female
Ru-106
Case 3
58 male
Ru-106
Case 4
66 female
GK-RS
Tumour data T-LBD (mm) T-height (mm) T-DtD (mm) T-DtF (mm) RD () 8.4 4.2 6.6 9.0 RD 10.5 5.5 5.5 3.5 RD+ 14.2 6.9 4.5 2.25 RD+ 8.2 2.1 1.5 1.5 RD
BCVA At injection 2–4 weeks p.o. 10 weeks p.o. 14–17 weeks p.o.
RT At injection 2–4 weeks p.o. 10 weeks p.o. 14–17 weeks p.o. (lm)
TNM Location
Time to MP Pretreatment of MP
T1 nasal superior
4.5 years 2 itv. bevacizumab
20/30 20/25 20/25 20/25
432 307 329 418
T2 midline temporal
17 months 1 VE 6 itv. bevacizumab
20/120 20/40 20/30 20/40
546 364 338 488
T3 superior temporal
4 years 6 itv. bevacizumab
20/60 20/60 20/80 20/125
615 363 475 624
T1 temporal inferior
15 months 9 itv. bevacizumab, Panret. LC, itv. triamcinolone
20/400 20/125 20/480 20/660
871 564 432 744
20/100 20/50 20/80 20/100
616 399 393 568
Mean
Ru-106, ruthenium-106 brachytherapy; GK-RS, gamma knife radiosurgery; T, tumour; LBD, longest basal diameter; DtD, distance to disc; DtF, distance to foveola; RD, preexisting retinal detachment (at time of diagnosis); TNM, tumour/nodes/metastases; MP, maculopathy; CW, cotton wool; ME, macular oedema; MA, microaneurysms; FH, foveal haemorrhages; NV, neovascularizations; itv., intravitreal; VE, vitrectomy; VA, visual acuity; lm, micrometre; p.o., postoperative.
Russo et al. (2012) published a case, previously treated with bevacizumab responding well to dexamethasone. Recently, another case series was published describing effects of Ozurdexâ for the treatment of radiation macular oedema with promising results (Baillif et al. 2013). In contrast to the report by Russo et al., all patients in their series were treated ‘first line’ with dexamethasone intravitreal implant and did not receive any previous therapy. Our patients all received dexamethasone DDS as salvage treatment after ineffective therapy with bevacizumab, and, in one patient, after additional panretinal laser treatment and good response to intravitreal triamcinolone. This was also evident in one patient after vitrectomy when intravitreal bevacizumab has been shown to be less effective (Kakinoki et al. 2012). A limitation of our report is the retrospective character, particularly the absence of fluorescence angiography examinations. In our case series, the use of dexamethasone DDS resulted in transient
reduction in foveal thickness and might be a beneficial adjunct treatment after irradiation. Long-term effectiveness and results of repeated treatment of Ozurdexâ are to be evaluated.
References Baillif S, Maschi C, Gastaud P & Caujolle JP (2013): Intravitreal dexamethasone 0.7-mg implant for radiation macular edema after protone beam therapy for choroidal melanoma. Retina 33: 1784– 1790. Bezatis A, Spital G, H€ ohn F et al. (2013): Functional and anatomical results after a single intravitreal Ozurdex injection in retinal vein occlusion: a 6-month follow-up – the SOLO study. Acta Ophthalmol 91: e340–e347. Haas A, Pinter O, Papaefthymiou G et al. (2002): Incidence of radiation retinopathy after high-dosage single-fraction gamma knife radiosurgery for choroidal melanoma. Ophthalmology 109: 909–913. Kakinoki M, Sawada O, Sawada T, Saishin Y, Kawamura H & Ohji M (2012): Effect of vitrectomy on aqueous VEGF concentration
and pharmacokinetics of bevacizumab in macaque monkeys. Invest Ophthalmol Vis Sci 53: 5877–5880. London NJ, Chiang A & Haller JA (2011): The dexamethasone drug delivery system: indications and evidence. Adv Ther 28: 351– 366. Matonti F, Meyer F, Guigou S et al. (2013): Ozurdex in the management of the macular edema following retinal vein occlusion in clinical practice. Acta Ophthalmol 91: e584– e586. Russo A, Avitabile T, Uva M et al. (2012): Radiation macular edema after Ru-106 plaque brachytherapy for choroidal melanoma resolved by an intravitreal dexamethasone 0.7-mg implant. Case Rep Ophthalmol 3: 71–76. Wen JC & McCannel TA (2009): Treatment of radiation retinopathy following plaque brachytherapy for choroidal melanoma. Curr Opin Ophthalmol 20: 200–204.
Correspondence: Lisa Tarmann, MD Department of Clinical Ophthalmology Medical University of Graz
e695
Acta Ophthalmologica 2014
Auenbruggerplatz 4 8036 Graz Tel: +43 316 385 -12394 Fax: +43 316 385 -13261 Email: [email protected]
Response of patients with metastatic uveal melanoma to combined treatment with fotemustine and sorafenib Anna Niederkorn,1 Werner Wackernagel,2 Monika Artl,3 Gerold Schwantzer,4 Birgit Aigner1 and Erika Richtig1 1
Department of Dermatology, Medical University of Graz, Graz, Austria; 2 Department of Ophthalmology, Medical University of Graz, Graz, Austria; 3 Institute of Humane Genetics, Medical University of Graz, Graz, Austria; 4 Institute of Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria Conflicts of interest: None declared. doi: 10.1111/aos.12432
Editor, veal melanoma is the 2nd most common type of melanoma after cutaneous melanoma. Survival time for unselected stage IV uveal melanoma patients with liver involvement is poor with mean 4–5 months, and there are currently no approved systemic treatments (Augsburger et al. 2009). Fotemustine is a nitrosourea alkylating agent with a high hepatic extraction rate. A phase III study, which was performed on uveal melanoma patients
U
with hepatic metastases, showed an overall survival of 14.6 months for intrahepatic and 13.7 for intravenous fotemustine (Leyvraz et al. 2012). The multikinase inhibitor sorafenib targets both tumour-cell proliferation and angiogenesis. In preclinical studies, sorafenib inhibited growth in conjunctival melanoma cell lines efficiently and was also able to enhance the antitumour activity of chemotherapeutic agents (Heim et al. 2003; Carter et al. 2007). We evaluated retrospectively the benefit of a combination therapy with fotemustine and sorafenib in eight patients with stage IV uveal melanoma referred to our department for systemic therapy in the years 2010–2012. Fotemustine 100 mg/m² was injected intravenously every 3 weeks after an induction cycle with administration on days 1 and 8. It was combined with sorafenib 400 mg orally twice daily. Array-CGH for genetic aberrations was performed on tumour samples. Survival data were calculated using Kaplan–Meier estimates. The patients were unselected, and six of eight had progressed under previous therapies such as systemic dacarbazine-based chemotherapy, hepatic intra-arterial therapies and histopathologically incomplete removal of liver metastases. The median interval between diagnosis of the primary tumour and the detection of metastases was 30.7 months (range 17.3–183.2); ECOG performance status was 0–1. A total of 25 cycles of fotemustine were administered to our patients. Reasons for discontinuation were disease progression in seven patients and grade III pancytopenia and neutropenic fever in one patient. Haematologic side-effects grade 1–3 made delay of chemotherapy necessary
in all our patients, as well as dose reductions in fotemustine to 75% or 50% in two patients. Dose reductions in sorafenib to 400 mg once daily were performed in three patients due to neutropenia and/or thrombocytopenia. Hand–foot syndrome and/or a maculopapular rash were observed in half of our patients leading to sorafenib dose reduction in one patient. One patient’s sorafenib dosage had to be reduced due to an exudative multiforme-like exanthema. Median survival from first detection of metastases was 22.3 months (range 7.1–30.3 months). The 1-year survival rate was 75%. Two patients were still alive at data analysis (Table 1). Median survival time from start of therapy was 15.9 months (range 5.6– 29.6 months). Three of our eight patients showed partial response or stable disease, equalling a disease control rate of 37.5%. The patient who suffered only from lung metastases showed a partial remission. Two patients with liver metastases depicted stable disease up to 13 months. Similar results were observed by Kaempgen et al., who could show a disease control rate of 42.8% for patients with metastatic uveal melanoma treated with the fotemustine i.v. and sorafenib p.o. after they had progressed under treatment with i.a. or i.v. fotemustine (Kaempgen et al. 2012). Tumour tissue of six of our eight patients was analysed and showed a monosomy of chromosome 3 and a gain on chromosome 8q24, associating the tumours with aggressive biological behaviour and poor response to metastatic treatment compared to those with only a partial change in chromosome 3 or chromosome 3 disomy (Abdel-Rahman et al. 2012).
Table 1. Results of patients with metastatic uveal melanoma treated with fotemustine and sorafenib.
Age (yrs)
Sex
Metastatic sites
Baseline LDH (U/l)
Cycles of fotemustine
Sorafenib reduction
Response
Survival from therapy start (mo)
55 61 76 64 52 62 70 62
M M M F F F F M
Liver Liver Lung Liver Liver, s.c., lymph nodes Liver, s.c. Liver Liver
199 267 163 156 199 415 233 840
2 6 5 4 2 1 1 4
No Yes Yes Yes Yes No Yes Yes
PD SD PR SD PD PD PD PD
20.3 15.9 +29.6 7.9 19.1 14.2 +12.8 5.6
Yrs, years; mo, months; s.c., subcutaneous; PD, progressive disease; SD, stable disease; PR, partial remission; (+), patient still alive at data analysis.
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