Case Report
Reversible Posterior Leukoencephalopathy Syndrome Induced by Axitinib Antonin Levy,1 Lyes Benmoussa,1 Samy Ammari,2 Laurence Albiges,1 Bernard Escudier1 Clinical Practice Points Reversible posterior leukoencephalopathy syndrome
Because diastolic blood pressure was proposed as a
(RPLS) is a clinicoradiological syndrome that might be caused by anti-vascular endothelial growth factor (VEGF)-targeted compounds such as bevacizumab, sunitinib, and sorafenib. We report herein the first case of RPLS induced by axitinib, a multi-VEGF receptor tyrosine kinase inhibitor, with antiangiogenic activity.
predictive biomarker of axitinib efficacy, oncologists should be aware of this rare complication, because rapid stopping of the drug is key for complete recovery.
Clinical Genitourinary Cancer, Vol. 12, No. 1, e33-4 ª 2014 Elsevier Inc. All rights reserved. Keywords: Axitinib, Clear-cell renal adenocarcinoma, Reversible posterior leukoencephalopathy syndrome, Side-effect, Vascular endothelial growth factor
Introduction Reversible posterior leukoencephalopathy syndrome (RPLS) is a clinicoradiological syndrome of various causes characterized by headache, altered consciousness, visual disturbances, acute hypertension, and characteristic magnetic resonance imaging (MRI) findings.1 Anti-vascular endothelial growth factor (VEGF)-targeted compounds such as bevacizumab, sunitinib, and sorafenib have yet to be reported to be associated with RPLS.2-4 We report herein the first case, to our knowledge, of RPLS induced by axitinib, a multi-VEGF receptor (VEGFR) tyrosine kinase inhibitor, with antiangiogenic activity.
Case Report A 55-year-old woman with metastatic clear-cell renal adenocarcinoma who, since 2008, had previously received treatment with an anti-programmed cell death 1-ligand 1 (PD-L1) antibody, was rechallenged with axitinib 5 mg twice daily because of tumor progression, mainly diffuse liver metastases. She had a previous medical history of anti-VEGFeinduced Grade 2 hypertension (treated with 1
Department of Medical Oncology Department of Radiology Gustave Roussy Institute, Paris XI University, Villejuif, France 2
Submitted: Jul 2, 2013; Accepted: Aug 27, 2013; Epub: Oct 14, 2013 Address for correspondence: Bernard Escudier, MD, Department of Medical Oncology, Gustave Roussy Institute, 114 Rue Edouard Vaillant, 94800 Villejuif Cedex, France E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2013.08.008
ibesartan 150 mg daily, that was stopped after the completion of treatment) and hypothyroidism treated with levothyroxin. Two weeks after starting axitinib treatment, she developed Grade 3 hypertension for which she received ibesartan (300 mg daily). Three days later, she was admitted to the emergency unit for a generalized tonic-clonic seizure and loss of consciousness with a Glasgow coma scale score of 5 (E1, V1, M3). Physical examination indicated high blood pressure of 193/101 mm Hg and right hemiparesia. Initial brain computed tomography scan, and lumbar puncture analysis were normal, and an electroencephalogram showed left parietotemporal intermittent electrographic seizure activity. The patient was hospitalized, axitinib was discontinued, and she was treated with intravenous (I.V.) nicardipin, lysine acetylsalicylate, and antiepileptic drugs. Her blood pressure returned to normal (137/96 mm Hg) within 1 day. MRI of the brain revealed typical T2-fluid attenuated inversion recovery signal changes in the posterior cerebral white matter, consistent with the diagnosis of RPLS (Fig. 1A). There was no evidence of metastatic disease or stroke and I.V. lysine acetylsalicylate was stopped. She recovered almost completely from neurological symptoms after 1 week. A repeat MRI scan of the brain 1 week later showed complete resolution of previous changes (Fig. 1B). Interestingly, liver metastases were observed to be dramatically decreased on a control ultrasound performed 2 weeks after she stopped axitinib.
Discussion Class effects of VEGF inhibitors (inhibiting either ligand or receptors) include cardiovascular effects. Hypertension is a very well
Clinical Genitourinary Cancer February 2014
- e33
RPLS Induced by Axitinib Figure 1 T2-FLAIR Weighted MRI. (A) Confluent Hyperintense Signal Involving Subcortical White Matter of the Occipital and Parietal Lobes Consistent With a Reversible Posterior Leukoencephalopathy Syndrome. (B) Repeated MRI Scan 1 Week Later Showed Complete Resolution of Previous Radiologic Changes.
Abbreviations: FLAIR ¼ fluid attenuated inversion recovery; MRI ¼ magnetic resonance imaging.
known adverse effect of axitinib, which targets VEGFR-1, -2, -3, and platelet derived growth factor receptor. Preclinical evidence suggests that elevated blood pressure during axitinib treatment is related to its inhibitory effects on VEGFR-2, because axitinib rapidly inhibits downstream signaling via the endothelial nitric oxide synthase/protein kinase B pathway implicated in normal vascular homeostasis.5 This was confirmed in clinical studies, such as the pivotal AXIS randomized phase 3 trial, in which axitinib was associated with higher rates of severe (Grade 3/4) hypertension compared with sorafenib (16% vs. 11%).6 In contrast, diastolic blood pressure was proposed as a predictive biomarker of axitinib efficacy.5
Conclusion
This is the first case, to our knowledge, of RPLS induced by axitinib. Interestingly, this patient had already received axitinib without any neurological symptoms. Whether previous exposure to the drug might have favored such an adverse event remains unknown. Either way, oncologists should be aware of this rare
e34
-
Clinical Genitourinary Cancer February 2014
complication, because rapid stopping of the drug is key for complete recovery.
Disclosure B.E. has received honoraria from AVEO, Bayer, GlaxoSmithKline, Novartis, and Pfizer.
References 1. Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996; 334:494-500. 2. Ozcan C, Wong S, Hari P. Reversible posterior leukoencephalopathy syndrome and bevacizumab. N Engl J Med 2006; 354:980-2, discussion 980-2. 3. Govindarajan R, Adusumilli J, Baxter DL, et al. Reversible posterior leukoencephalopathy syndrome induced by RAF kinase inhibitor BAY 43-9006. J Clin Oncol 2006; 24:e48. 4. Martín G, Bellido L, Cruz JJ, et al. Reversible posterior leukoencephalopathy syndrome induced by sunitinib. J Clin Oncol 2007; 25:3559. 5. Rini BI, Schiller JH, Fruehauf JP, et al. Diastolic blood pressure as a biomarker of axitinib efficacy in solid tumors. Clin Cancer Res 2011; 17:3841-9. 6. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011; 378:1931-9.
Reversible Posterior Leukoencephalopathy Syndrome Induced by Axitinib Antonin Levy,1 Lyes Benmoussa,1 Samy Ammari,2 Laurence Albiges,1 Bernard Escudier1 Clinical Practice Points Reversible posterior leukoencephalopathy syndrome
Because diastolic blood pressure was proposed as a
(RPLS) is a clinicoradiological syndrome that might be caused by anti-vascular endothelial growth factor (VEGF)-targeted compounds such as bevacizumab, sunitinib, and sorafenib. We report herein the first case of RPLS induced by axitinib, a multi-VEGF receptor tyrosine kinase inhibitor, with antiangiogenic activity.
predictive biomarker of axitinib efficacy, oncologists should be aware of this rare complication, because rapid stopping of the drug is key for complete recovery.
Clinical Genitourinary Cancer, Vol. 12, No. 1, e33-4 ª 2014 Elsevier Inc. All rights reserved. Keywords: Axitinib, Clear-cell renal adenocarcinoma, Reversible posterior leukoencephalopathy syndrome, Side-effect, Vascular endothelial growth factor
Introduction Reversible posterior leukoencephalopathy syndrome (RPLS) is a clinicoradiological syndrome of various causes characterized by headache, altered consciousness, visual disturbances, acute hypertension, and characteristic magnetic resonance imaging (MRI) findings.1 Anti-vascular endothelial growth factor (VEGF)-targeted compounds such as bevacizumab, sunitinib, and sorafenib have yet to be reported to be associated with RPLS.2-4 We report herein the first case, to our knowledge, of RPLS induced by axitinib, a multi-VEGF receptor (VEGFR) tyrosine kinase inhibitor, with antiangiogenic activity.
Case Report A 55-year-old woman with metastatic clear-cell renal adenocarcinoma who, since 2008, had previously received treatment with an anti-programmed cell death 1-ligand 1 (PD-L1) antibody, was rechallenged with axitinib 5 mg twice daily because of tumor progression, mainly diffuse liver metastases. She had a previous medical history of anti-VEGFeinduced Grade 2 hypertension (treated with 1
Department of Medical Oncology Department of Radiology Gustave Roussy Institute, Paris XI University, Villejuif, France 2
Submitted: Jul 2, 2013; Accepted: Aug 27, 2013; Epub: Oct 14, 2013 Address for correspondence: Bernard Escudier, MD, Department of Medical Oncology, Gustave Roussy Institute, 114 Rue Edouard Vaillant, 94800 Villejuif Cedex, France E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2013.08.008
ibesartan 150 mg daily, that was stopped after the completion of treatment) and hypothyroidism treated with levothyroxin. Two weeks after starting axitinib treatment, she developed Grade 3 hypertension for which she received ibesartan (300 mg daily). Three days later, she was admitted to the emergency unit for a generalized tonic-clonic seizure and loss of consciousness with a Glasgow coma scale score of 5 (E1, V1, M3). Physical examination indicated high blood pressure of 193/101 mm Hg and right hemiparesia. Initial brain computed tomography scan, and lumbar puncture analysis were normal, and an electroencephalogram showed left parietotemporal intermittent electrographic seizure activity. The patient was hospitalized, axitinib was discontinued, and she was treated with intravenous (I.V.) nicardipin, lysine acetylsalicylate, and antiepileptic drugs. Her blood pressure returned to normal (137/96 mm Hg) within 1 day. MRI of the brain revealed typical T2-fluid attenuated inversion recovery signal changes in the posterior cerebral white matter, consistent with the diagnosis of RPLS (Fig. 1A). There was no evidence of metastatic disease or stroke and I.V. lysine acetylsalicylate was stopped. She recovered almost completely from neurological symptoms after 1 week. A repeat MRI scan of the brain 1 week later showed complete resolution of previous changes (Fig. 1B). Interestingly, liver metastases were observed to be dramatically decreased on a control ultrasound performed 2 weeks after she stopped axitinib.
Discussion Class effects of VEGF inhibitors (inhibiting either ligand or receptors) include cardiovascular effects. Hypertension is a very well
Clinical Genitourinary Cancer February 2014
- e33
RPLS Induced by Axitinib Figure 1 T2-FLAIR Weighted MRI. (A) Confluent Hyperintense Signal Involving Subcortical White Matter of the Occipital and Parietal Lobes Consistent With a Reversible Posterior Leukoencephalopathy Syndrome. (B) Repeated MRI Scan 1 Week Later Showed Complete Resolution of Previous Radiologic Changes.
Abbreviations: FLAIR ¼ fluid attenuated inversion recovery; MRI ¼ magnetic resonance imaging.
known adverse effect of axitinib, which targets VEGFR-1, -2, -3, and platelet derived growth factor receptor. Preclinical evidence suggests that elevated blood pressure during axitinib treatment is related to its inhibitory effects on VEGFR-2, because axitinib rapidly inhibits downstream signaling via the endothelial nitric oxide synthase/protein kinase B pathway implicated in normal vascular homeostasis.5 This was confirmed in clinical studies, such as the pivotal AXIS randomized phase 3 trial, in which axitinib was associated with higher rates of severe (Grade 3/4) hypertension compared with sorafenib (16% vs. 11%).6 In contrast, diastolic blood pressure was proposed as a predictive biomarker of axitinib efficacy.5
Conclusion
This is the first case, to our knowledge, of RPLS induced by axitinib. Interestingly, this patient had already received axitinib without any neurological symptoms. Whether previous exposure to the drug might have favored such an adverse event remains unknown. Either way, oncologists should be aware of this rare
e34
-
Clinical Genitourinary Cancer February 2014
complication, because rapid stopping of the drug is key for complete recovery.
Disclosure B.E. has received honoraria from AVEO, Bayer, GlaxoSmithKline, Novartis, and Pfizer.
References 1. Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996; 334:494-500. 2. Ozcan C, Wong S, Hari P. Reversible posterior leukoencephalopathy syndrome and bevacizumab. N Engl J Med 2006; 354:980-2, discussion 980-2. 3. Govindarajan R, Adusumilli J, Baxter DL, et al. Reversible posterior leukoencephalopathy syndrome induced by RAF kinase inhibitor BAY 43-9006. J Clin Oncol 2006; 24:e48. 4. Martín G, Bellido L, Cruz JJ, et al. Reversible posterior leukoencephalopathy syndrome induced by sunitinib. J Clin Oncol 2007; 25:3559. 5. Rini BI, Schiller JH, Fruehauf JP, et al. Diastolic blood pressure as a biomarker of axitinib efficacy in solid tumors. Clin Cancer Res 2011; 17:3841-9. 6. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011; 378:1931-9.
