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Visual electrophysiological evaluation in paclitaxel-treated patients. Pathophysiological mechanisms involved in retinal and optic nerve dysfunctions
International Congress Series 1278 (2005) 37 – 40
www.ics-elsevier.com
Visual electrophysiological evaluation in paclitaxel-treated patients. Pathophysiological mechanisms involved in retinal and optic nerve dysfunctions V. Scaiolia,*, A. Caracenib, C. Martinib, A. Miccoa, S. Curzia, G. Caprib, G. Lucab a
National Institute of Neurology C. Besta, Department of Clinical Neurophysiology, Via Celoria 11, 20133 Milan, Italy b National Institute of Cancer, Milan, Italy
Abstract. We studied 30 breast cancer patients to clarify the underlying pathophysiological mechanisms of visual pathway involvement during paclitaxel treatment. Pattern visual-evoked potentials (VEPs) and transient, 30 Hz flicker (FLK) and oscillatory potential (OP) white flash electroretinograms (ERG) were performed before treatment, after the third and sixth cycles, and at the end of treatment. Abnormal pretreatment VEP and OP and FLK changes were observed in respectively about 75% and just under 50% of the patients; transient ERG was normal in over 90%. Serial recordings: VEP unchanged; ERG b-wave latency increased at the end of therapy; OP and FLK mildly attenuated. Various combinations of ERG, OP, FLK and VEP changes occurred in 50%, and poorly correlated with the visual symptoms reported by 12 patients. A few patients had stable and persistent subclinical electrophysiological changes. The high incidence of pretreatment, subclinical electrophysiological abnormalities correlated with the administration of tamoxifen and/or other chemotherapeutic drugs most of the patients had been taking before starting paclitaxel. On the basis of our findings, we suggest that the more likely mechanism of visual symptoms and electrophysiological changes during paclitaxel administration is vascular dysregulation in the retina or ischemic mechanisms when the optic nerve is involved. D 2004 Elsevier B.V. All rights reserved. Keywords: Paclitaxel; Toxicity; Evoked potentials; Retina; Optic nerve
* Corresponding author. Tel.: +39 02 2394275; fax: +39 02 70600775. E-mail address: [email protected] (V. Scaioli). 0531-5131/ D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.ics.2004.11.065
38
V. Scaioli et al. / International Congress Series 1278 (2005) 37–40
1. Introduction The two taxanes (paclitaxel and docetaxel) are widely used in standard antineoplastic practice, although some toxic side effects have been reported [1]. The most prominent neurotoxicity is sensory neuropathy [2]. The mechanisms of paclitaxel neurotoxicity have not yet been clarified [3]. It has been suggested that the taxanes are intrinsically toxic and directly injure cells, manifesting as neurotoxicity of the central nervous system because of their ability to penetrate the blood/brain barrier [2] and thus explaining the rare occurrence of central nervous system complications [4]. Ocular toxicity secondary to or due to chemotherapy has been reported in association with various chemotherapeutic agents including paclitaxel [5–7]. The aim of this electrophysiological study was to clarify the underlying pathophysiological mechanisms of visual pathway involvement related to paclitaxel administration. 2. Material and methods The study involved 30 patients with breast cancer: 14 were treated with paclitaxel alone (group 1) and 16 with paclitaxel and doxorubicin (group 2). Pattern visual-evoked potentials (VEPs) and transient, 30 Hz flicker (FLK) and oscillatory potential (OP) white flash electroretinogram (ERG) were performed before treatment, after the third and sixth cycles, and at the end of the programmed regimen. 3. Results 3.1. Pretreatment Abnormal VEP, OP and FLK changes occurred in respectively about 75% and just under 50% of the patients; transient ERG was normal in over 90%. 3.2. Serial recordings Group analysis: VEP unchanged; increased ERG b-wave latency in group 1 (ANOVA Pb0.005); OP and FLK were characterised by nonsignificant mild attenuation. Various combinations of ERG, OP, FLK and VEP changes occurred in 50% of cases. The association with transitory lightning scotoma or blurred vision reported by 12 patients (Table 1) was poor with VEP, ERG and FLK, and satisfactory with OP (Table 1). A few patients showed stable and persistent subclinical electrophysiological changes. Representative recordings of a group 1 patient is shown in Figs. 1, 2 and 3, which show
Table 1 Correlation between VEP and/or ERG and visual symptoms during paclitaxel treatment EP changes
None
Yes
Total
Unchanged Changed Total
8 9 17
6 6 12
14 15 29
V. Scaioli et al. / International Congress Series 1278 (2005) 37–40
39
Fig. 1. Group 1 patient: 30 Hz flicker. From bottom to top: pretreatment, 2nd recording after the third cycle, and final recording (right side power spectrum; left side raw traces; time scale 30 ms/div). After the third cycle, there was an attenuation in flicker followed by partial recovery after the sixth cycle. There was concordance between the electrophysiology findings and visual symptoms, as the patient complained of blurred vision and lightning scotoma.
transient 30 Hz flicker and VEP changes and persisting ERG b-wave and OP abnormalities. 4. Discussion The results of our study showed that, before starting paclitaxel, most of the patients showed electrophysiological changes involving both the retina and the retroretinal visual pathways. The same patients had been treated with drugs with documented ocular neurotoxicity, i.e. tamoxifen and doxorubicin [8–10]. In the majority of the patients, they ran a subclinical course; only a few had ophthalmologic and subjective changes. The electrophysiological hallmark of retinal toxicity was flicker attenuation; b-wave changes occurred less frequently and the criteria for abnormal oscillatory potentials, which were frequently detected in our series, are more difficult to define. The high incidence of OP changes suggests a possible ischemic mechanism or interference with the mechanisms involved in retinal microvascular regulation, possibly related to previous doxorubicin and/ or cisplatin administration, whereas the flicker changes were in line with the mechanisms of neurotoxicity associated with tamoxifen, which is known to penetrate a number of retinal structures including the pigmentary epithelium, the anatomical site of flicker origin. The VEP abnormalities suggest that retroretinal visual disturbances occurred probably independently of the retinal disturbances. The abnormal findings involved latency and amplitude, and showed a higher incidence at small than large or medium check sizes. Tamoxifen was probably the drug involved. The VEP and the OP changes in the retina suggest an ischemic mechanism, which is supported by the consolidated literature concerning OPs and vascular mechanisms of the retina in normal subjects and dysregulation under pathological conditions.
Fig. 2. Group 1 patient. ERG b-wave (left side) and OP (right side) changes after the third cycle, but persisting after the sixth cycle with a slight improvement.
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V. Scaioli et al. / International Congress Series 1278 (2005) 37–40
Fig. 3. Group 1 patient. VEP P100 amplitude attenuation and slightly increased latency after the third cycle. P100 peak downward deflection (arrows) (time scale 30 ms/div).
The degree of correlation between visual symptoms and electrophysiologic changes was weak for VEP and ERG, and satisfactory for OP. The most likely mechanism of visual symptoms and electrophysiological changes during paclitaxel administration is vascular dysregulation in the retina or ischemic mechanisms when the optic nerve is involved. References [1] L. Gianni, et al., Cardiac function following combination therapy with paclitaxel and doxorubicin: an analysis of 657 women with advanced breast cancer, Ann. Oncol. 12 (8) (2001) 1067 – 1073. [2] E.K. Rowinsky, et al., Neurotoxicity of taxol, J. Natl. Cancer Inst. Monographs (15) (1993) 107 – 115. [3] H. Hagiwara, Y. Sunada, Mechanism of taxane neurotoxicity, Breast Cancer 11 (1) (2004) 82 – 85. [4] C.G. Ziske, et al., Acute transient encephalopathy after paclitaxel infusion: report of three cases, Ann. Oncol. 13 (4) (2002) 629 – 631. [5] V. Scaioli, et al., Visual evoked potentials findings in course of paclitaxel doxorubicin combination chemotherapy. Report of a case, J. Neurooncol. 25 (3) (1995) 221 – 225. [6] D.W. Johnson, et al., Optic disc and retinal microvasculopathy after high-dose chemotherapy and autologous hematopoietic progenitor cell support, Bone Marrow Transplant. 24 (7) (1999) 785 – 792. [7] W.W. Tan, T. Walsh, Ocular toxicity secondary to paclitaxel in two lung cancer patients, Med. Pediatr. Oncol. 31 (3) (1998) 177. [8] R.H. Costa, et al., Tamoxifen retinopathy. A case report, Bull. Soc. Belge Ophtalmol. 238 (1990) 161 – 168. [9] S.M. Colley, J.S. Elston, Tamoxifen optic neuropathy, Clin. Exp. Rheumatol. 32 (1) (2004) 105 – 106. [10] S. Ostrow, et al., Ophthalmologic toxicity after cis-dichlorodiammineplatinum(II) therapy, Cancer Treat. Rep. 62 (10) (1978) 1591 – 1594.
www.ics-elsevier.com
Visual electrophysiological evaluation in paclitaxel-treated patients. Pathophysiological mechanisms involved in retinal and optic nerve dysfunctions V. Scaiolia,*, A. Caracenib, C. Martinib, A. Miccoa, S. Curzia, G. Caprib, G. Lucab a
National Institute of Neurology C. Besta, Department of Clinical Neurophysiology, Via Celoria 11, 20133 Milan, Italy b National Institute of Cancer, Milan, Italy
Abstract. We studied 30 breast cancer patients to clarify the underlying pathophysiological mechanisms of visual pathway involvement during paclitaxel treatment. Pattern visual-evoked potentials (VEPs) and transient, 30 Hz flicker (FLK) and oscillatory potential (OP) white flash electroretinograms (ERG) were performed before treatment, after the third and sixth cycles, and at the end of treatment. Abnormal pretreatment VEP and OP and FLK changes were observed in respectively about 75% and just under 50% of the patients; transient ERG was normal in over 90%. Serial recordings: VEP unchanged; ERG b-wave latency increased at the end of therapy; OP and FLK mildly attenuated. Various combinations of ERG, OP, FLK and VEP changes occurred in 50%, and poorly correlated with the visual symptoms reported by 12 patients. A few patients had stable and persistent subclinical electrophysiological changes. The high incidence of pretreatment, subclinical electrophysiological abnormalities correlated with the administration of tamoxifen and/or other chemotherapeutic drugs most of the patients had been taking before starting paclitaxel. On the basis of our findings, we suggest that the more likely mechanism of visual symptoms and electrophysiological changes during paclitaxel administration is vascular dysregulation in the retina or ischemic mechanisms when the optic nerve is involved. D 2004 Elsevier B.V. All rights reserved. Keywords: Paclitaxel; Toxicity; Evoked potentials; Retina; Optic nerve
* Corresponding author. Tel.: +39 02 2394275; fax: +39 02 70600775. E-mail address: [email protected] (V. Scaioli). 0531-5131/ D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.ics.2004.11.065
38
V. Scaioli et al. / International Congress Series 1278 (2005) 37–40
1. Introduction The two taxanes (paclitaxel and docetaxel) are widely used in standard antineoplastic practice, although some toxic side effects have been reported [1]. The most prominent neurotoxicity is sensory neuropathy [2]. The mechanisms of paclitaxel neurotoxicity have not yet been clarified [3]. It has been suggested that the taxanes are intrinsically toxic and directly injure cells, manifesting as neurotoxicity of the central nervous system because of their ability to penetrate the blood/brain barrier [2] and thus explaining the rare occurrence of central nervous system complications [4]. Ocular toxicity secondary to or due to chemotherapy has been reported in association with various chemotherapeutic agents including paclitaxel [5–7]. The aim of this electrophysiological study was to clarify the underlying pathophysiological mechanisms of visual pathway involvement related to paclitaxel administration. 2. Material and methods The study involved 30 patients with breast cancer: 14 were treated with paclitaxel alone (group 1) and 16 with paclitaxel and doxorubicin (group 2). Pattern visual-evoked potentials (VEPs) and transient, 30 Hz flicker (FLK) and oscillatory potential (OP) white flash electroretinogram (ERG) were performed before treatment, after the third and sixth cycles, and at the end of the programmed regimen. 3. Results 3.1. Pretreatment Abnormal VEP, OP and FLK changes occurred in respectively about 75% and just under 50% of the patients; transient ERG was normal in over 90%. 3.2. Serial recordings Group analysis: VEP unchanged; increased ERG b-wave latency in group 1 (ANOVA Pb0.005); OP and FLK were characterised by nonsignificant mild attenuation. Various combinations of ERG, OP, FLK and VEP changes occurred in 50% of cases. The association with transitory lightning scotoma or blurred vision reported by 12 patients (Table 1) was poor with VEP, ERG and FLK, and satisfactory with OP (Table 1). A few patients showed stable and persistent subclinical electrophysiological changes. Representative recordings of a group 1 patient is shown in Figs. 1, 2 and 3, which show
Table 1 Correlation between VEP and/or ERG and visual symptoms during paclitaxel treatment EP changes
None
Yes
Total
Unchanged Changed Total
8 9 17
6 6 12
14 15 29
V. Scaioli et al. / International Congress Series 1278 (2005) 37–40
39
Fig. 1. Group 1 patient: 30 Hz flicker. From bottom to top: pretreatment, 2nd recording after the third cycle, and final recording (right side power spectrum; left side raw traces; time scale 30 ms/div). After the third cycle, there was an attenuation in flicker followed by partial recovery after the sixth cycle. There was concordance between the electrophysiology findings and visual symptoms, as the patient complained of blurred vision and lightning scotoma.
transient 30 Hz flicker and VEP changes and persisting ERG b-wave and OP abnormalities. 4. Discussion The results of our study showed that, before starting paclitaxel, most of the patients showed electrophysiological changes involving both the retina and the retroretinal visual pathways. The same patients had been treated with drugs with documented ocular neurotoxicity, i.e. tamoxifen and doxorubicin [8–10]. In the majority of the patients, they ran a subclinical course; only a few had ophthalmologic and subjective changes. The electrophysiological hallmark of retinal toxicity was flicker attenuation; b-wave changes occurred less frequently and the criteria for abnormal oscillatory potentials, which were frequently detected in our series, are more difficult to define. The high incidence of OP changes suggests a possible ischemic mechanism or interference with the mechanisms involved in retinal microvascular regulation, possibly related to previous doxorubicin and/ or cisplatin administration, whereas the flicker changes were in line with the mechanisms of neurotoxicity associated with tamoxifen, which is known to penetrate a number of retinal structures including the pigmentary epithelium, the anatomical site of flicker origin. The VEP abnormalities suggest that retroretinal visual disturbances occurred probably independently of the retinal disturbances. The abnormal findings involved latency and amplitude, and showed a higher incidence at small than large or medium check sizes. Tamoxifen was probably the drug involved. The VEP and the OP changes in the retina suggest an ischemic mechanism, which is supported by the consolidated literature concerning OPs and vascular mechanisms of the retina in normal subjects and dysregulation under pathological conditions.
Fig. 2. Group 1 patient. ERG b-wave (left side) and OP (right side) changes after the third cycle, but persisting after the sixth cycle with a slight improvement.
40
V. Scaioli et al. / International Congress Series 1278 (2005) 37–40
Fig. 3. Group 1 patient. VEP P100 amplitude attenuation and slightly increased latency after the third cycle. P100 peak downward deflection (arrows) (time scale 30 ms/div).
The degree of correlation between visual symptoms and electrophysiologic changes was weak for VEP and ERG, and satisfactory for OP. The most likely mechanism of visual symptoms and electrophysiological changes during paclitaxel administration is vascular dysregulation in the retina or ischemic mechanisms when the optic nerve is involved. References [1] L. Gianni, et al., Cardiac function following combination therapy with paclitaxel and doxorubicin: an analysis of 657 women with advanced breast cancer, Ann. Oncol. 12 (8) (2001) 1067 – 1073. [2] E.K. Rowinsky, et al., Neurotoxicity of taxol, J. Natl. Cancer Inst. Monographs (15) (1993) 107 – 115. [3] H. Hagiwara, Y. Sunada, Mechanism of taxane neurotoxicity, Breast Cancer 11 (1) (2004) 82 – 85. [4] C.G. Ziske, et al., Acute transient encephalopathy after paclitaxel infusion: report of three cases, Ann. Oncol. 13 (4) (2002) 629 – 631. [5] V. Scaioli, et al., Visual evoked potentials findings in course of paclitaxel doxorubicin combination chemotherapy. Report of a case, J. Neurooncol. 25 (3) (1995) 221 – 225. [6] D.W. Johnson, et al., Optic disc and retinal microvasculopathy after high-dose chemotherapy and autologous hematopoietic progenitor cell support, Bone Marrow Transplant. 24 (7) (1999) 785 – 792. [7] W.W. Tan, T. Walsh, Ocular toxicity secondary to paclitaxel in two lung cancer patients, Med. Pediatr. Oncol. 31 (3) (1998) 177. [8] R.H. Costa, et al., Tamoxifen retinopathy. A case report, Bull. Soc. Belge Ophtalmol. 238 (1990) 161 – 168. [9] S.M. Colley, J.S. Elston, Tamoxifen optic neuropathy, Clin. Exp. Rheumatol. 32 (1) (2004) 105 – 106. [10] S. Ostrow, et al., Ophthalmologic toxicity after cis-dichlorodiammineplatinum(II) therapy, Cancer Treat. Rep. 62 (10) (1978) 1591 – 1594.