Review Article
Posterior reversible encephalopathy syndrome due to targeted agents: vemurafinib among suspects!
J Oncol Pharm Practice 2015, Vol. 21(6) 443–450 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155214543212 opp.sagepub.com
Arushi Khurana1 and Constantin A Dasanu2
Abstract Posterior reversible encephalopathy syndrome features reversible cortical neurologic dysfunction and characteristic findings on brain imaging studies. This syndrome can be caused by several agents including traditional chemotherapy and immunosuppressive drugs. Targeted therapies such as agents binding vascular endothelial growth factor/VEGFR, CD20 and cytotoxic T-cell lymphocyte antigen 4 (CTLA-4) antigens are also among the culprits. Vemurafenib is a BRAF gene inhibitor that has not been previously linked with posterior reversible encephalopathy syndrome. We report herein the first such case and believe that further studies confirming this association are warranted. We further review the existing posterior reversible encephalopathy syndrome cases associated with targeted therapies in the scientific literature.
Keywords PRES, Vemurafinib, targeted therapies, Reversible posterior leukoencephalopathy syndrome (RPLS)
Introduction First described in 1996 by Hinchey et al.,1 posterior reversible encephalopathy syndrome (PRES) is an increasingly reported clinico-radiologic entity consisting of reversible cortical neurological dysfunction and characteristic findings on brain imaging studies. The clinical picture may include acute to subacute onset of headaches, nausea, vomiting, seizures, impaired visual acuity, sleepiness or coma. A complete recovery with supportive therapy is seen in almost all cases, usually within days to weeks, and is considered the ‘‘hallmark’’ of this condition.2 Magnetic resonance imaging (MRI) findings are suggestive of white matter edema on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images involving the posterior circulation areas, especially occipital and parietal lobes.1 PRES has historically been correlated with hypertensive crises, pre-eclampsia, eclampsia, connective tissue disorders, acute porphyria, Guillain-Barre´ syndrome and use of immunosuppressive agents such as calcineurin inhibitors.2 Traditional chemotherapy agents associated with this condition include platinum
agents, L-asparaginase, cyclophosphamide and gemcitabine.3,4 Erythropoietin and certain colony stimulating factors such as G-CSF have been associated with PRES as well.3 This syndrome has also been reported to be associated with newer targeted therapies such as antivascular endothelial growth factor (VEGF) agents (bevacizumab), anti-CD20 antibodies (rituximab), tyrosine kinase inhibiting (TKI) agents (sorafenib, sunitinib, pazopanib) and, most recently, with anti-cytotoxic T-cell lymphocyte antigen 4 (CTLA-4) agents (ipilimumab).5–47 Approximately 40–60% melanomas have a mutation of the BRAF (B-rapidly accelerated fibrosarcoma) gene. V600E mutation (substitution of glutamic acid for valine at position 600) constitutes >90% of the BRAF
1
Department of Internal Medicine, University of Connecticut, Farmington, CT, USA 2 Department of Hematology-Oncology, St. Francis Hospital and Medical Center, Hartford, CT, USA Corresponding author: Arushi Khurana, University of Connecticut, 263 Farmington Avenue, Farmington CT 06030, USA. Email: [email protected]
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mutations seen in melanoma. Vemurafenib is a potent selective inhibitor of BRAF V600 gene, and inhibits RAF-driven downstream signals in tumors expressing mutant BRAF V600E. This inhibition led to tumor shrinkage in 81% patients with BRAF V600E mutant melanoma in a phase 1 study.12 Hence, this oral BRAF inhibitor was approved by the FDA in 2011 for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation. We are not aware of any previous case reports of PRES associated with the use of this agent. We present a 79-year-old man with PRES suspected to be a consequence of vemurafenib use for metastatic melanoma.
Case report A 79-year-old man presented with complaints of nausea, vomiting, generalized weakness, and more than 9 kg weight loss over the previous 4 months. The patient’s complaints were gradual in onset, but became severe two days prior to admission. Past medical history was significant for controlled hypertension, hyperlipidemia, diabetes mellitus, cerebrovascular disease and seizure disorder. He also had history of earlystage prostate cancer 6 years prior that was treated with external beam radiotherapy, with no evidence of recurrence. Family history was negative for any cancers. Physical examination showed stable vital signs, along with normal head and neck, cardiovascular and respiratory system examination. Abdominal exam showed no hepatosplenomegaly; he had no lymphadenopathy or suspicious skin lesions. He was worked up extensively in the hospital for possible systemic infections, inflammatory disorders and malignancies. A computed tomography (CT) scan was significant for small bilateral lung lesions, multiple low-density liver lesions, along with studding of omentum and peritoneal lining in the right upper quadrant and moderate ascites. Head CT was within normal limits. Liver biopsy showed malignant cells strongly positive for vimentin, S100 protein, Melan A and HMB-45 but negative for keratins that was consistent with metastatic malignant melanoma. BRAF V600E gene mutation was detected on special testing. As a result, the patient was started on oral vemurafenib, which he initially tolerated well. However, after 8 weeks of therapy, he developed swelling of the upper extremities and confusion. He also claimed impaired visual acuity and had a partial seizure involving right upper extremity, followed by unresponsiveness. In the emergency room, the patient was non-verbal, and only responsive to deep pain stimuli and sternal rub. His examination was unremarkable, except for high blood pressure readings at 180/90 mm Hg. Glasgow coma
scale (GCS) was 10; he had normal deep tendon reflexes and spontaneous movement of all four extremities. Laboratory tests were within normal limits for all electrolytes, thyroid-stimulating hormone (TSH), rapid plasma reagin (RPR), vitamin B12/folate levels, erythrocyte sedimentation rate (ESR), liver function tests (LFT) and ammonia levels. Urinalysis was remarkable for the presence of proteinuria at 100 mg/ d (normal: no detectable protein). CT scan of head was negative for any acute infarct, mass or midline shift. Brain MRI could not be performed as the patient had a pacemaker implanted in the past. He was investigated for any potential stroke, infection, vasculitis and other causes with an echocardiogram with bubble study, CT angiogram of head and neck, vasculitis panel, electroencephalogram (EEG), all of which were negative/ normal. He had frequent neurological exams and was treated with antihypertensive medications. Vemurafenib was discontinued and the patient’s condition improved gradually, with resolution of altered mental status within seven days. A surveillance CT scan showed significant improvement in his disease burden, with the resolution of lung nodules, ascites and a considerable shrinkage of liver lesions. As a result, vemurafenib was restarted. Three weeks later, the patient had a similar presentation with altered mental status. He was again managed in a similar fashion, and his symptoms resolved within four days after stopping vemurafenib. The patient’s disease ultimately relapsed 2 months later as the disease likely developed resistance to vemurafenib. He was too debilitated and weak to withstand any further therapy and was managed with only comfort measures until his demise.
Methods We carried out a MEDLINE search of published work in English to identify patients with PRES linked with some form of targeted therapy for malignancy. Key words used were ‘‘posterior reversible encephalopathy syndrome,’’ ‘‘hypertensive encephalopathy,’’ ‘‘reversible posterior leukoencephalopathy syndrome,’’ reversible posterior cerebral edema syndrome,’’ ‘‘cancer,’’ ‘‘malignancy,’’ ‘‘targeted therapy,’’ ‘‘anti-VEGF,’’ ‘‘tyrosine kinase inhibitor,’’ ‘‘anti-CD20’’ and ‘‘melanoma.’’ This also included the names of individual drugs as key words ‘‘bevacizumab,’’ sunitinib,’’ ‘‘sorafenib,’’ ‘‘rituximab,’’ ‘‘pazopanib,’’ ipilimumab,’’ ‘‘alemtuzumab’’ and ‘‘vemurafinib.’’ Papers from 1 January 1996 to 30 December 2013 were included. Articles that fulfilled the criteria for adequate information including patient characteristics, presence of a malignant disease, use of specific targeted therapy agents, typical imaging findings and characteristic clinical outcomes were reviewed.
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55/F
33/F
68/F
49/M
6/M
63/F
45/F
68/F
63/F
46/F
72/F
Burki et al.20
Peter et al.21
Koopman et al.22
Levy et al.23
Lau et al.24
Chang et al.25
Seet et al.26
Seet et al.26
Lou et al.27
Sclafani et al.28
52/M
Allen et al.17
El Maalouf et al.19
59/F
Glusker et al.16
62/F
52/F
Ozcan et al.6
Pinedo et al.18
Age/sex
Reference
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Bevacizumab (2 cycles)
Bevacizumab (3 cycles)
Bevacizumab (3 cycles) Bevacizumab
Bevacizumab (3 cycles) Bevacizumab (6 cycles) Bevacizumab (3 cycles) Bevacizumab (7 cycles) Bevacizumb (10 cycles) Bevacizumab (13 infusions)
Bevacizumab (14 infusions)
Bevacizumab
Bevacizumab
Bevacizumab (1 dose) Bevacizumab (7 cycles)
Drug
Metastatic breast cancer
Metastatic non-small cell lung carcinoma Advanced pancreatic carcinoma Glioblastoma multiform
Rectosigmoid carcinoma Cholangiocarcinoma
Metastatic colon cancer Metastatic colorectal cancer Hepatoblastoma
Breast cancer
Rectal carcinoma with neuroendocrine differentiation Rectal adenocarcinoma Metastatic colon cancer
Rectal adenocarcinoma Renal cell carcinoma
Underlying disease
Seizures, expressive aphasia, right-sided paresthesias, nausea, vomiting Nausea, vomiting, blurred vision
Seizures, altered mental status, coma Headaches, hypertension, tonic-clonic seizures Headache, visual disturbance, drowsiness Unresponsiveness, headaches, tonic-clonic seizures Headache, confusion, nausea, vomiting Seizures, cortical blindness
Headache, nausea, vomiting, dysarthria, tonic-clonic seizures, unresponsiveness Headache, nausea, vomiting, coma Cortical blindness
Tonic-clonic seizures
Bilateral vision loss, headache, confusion Tonic-clonic seizure, bilateral vision loss, extensor plantar reflexes Cortical blindness, headache, seizures, aphasia, delirium
Symptoms/Signs
Table 1. Published reports of PRES syndrome associated with targeted therapies and their characteristics.
150/100
201/117
190/94
221/84
194/112
Not stated
160/120
180/100
140/70
170/80
190/120
190/88
150 systolic
178/98
172/100
Max BP readings (mm Hg)
BP control
BP control
BP control
BP control
BP control
Not stated
BP control
BP control
Not stated
BP control
BP control
BP control
BP control
BP control
BP control
BP control
(continued)
Full recovery (1 week)
Full recovery (1 day) Full recovery (4 days) Full recovery (2 days)
Full recovery (2 days)
Full recovery
Full recovery
Full recovery
Full recovery
Full recovery
Full recovery
Full recovery
Full recovery
Full recovery
Full recovery
Outcome
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Age/sex
72/M
41/F
62/M
39/F
25/F
66/F
61/F
49/F
58/M
81/F
70/F
54/F
39/F
48/F
Reference
Lazarus et al.29
Dersch et al.30
Haefner et al.31
Hosoi et al.32
Zito et al.33
Siddiqi34
Mizutani et al.35
Govindarajan et al.8
Dogan et al.36 (2010)
Medioni et al.37
Martin et al.7
Kapiteijn et al.38
Cumurciuc et al.39
Chen et al.40
Table 1. Continued.
Sunitinib (22 weeks) Sunitinib (2 weeks) Sunitinib (34 weeks) Sunitinib (1 week) Sunitinib (1 week)
Sorafenib (4 months) Sorafenib (1 week)
Rituximab (1st dose) Rituximab
Rituximab (2 cycles) Rituximab (17th day, 2nd cycle) Rituximab
Bevacizumab (7 cycles)
Bevacizumab (8 cycles)
Drug
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Renal cell carcinoma
Gastrointestinal stromal tumor Renal cell carcinoma
Renal cell carcinoma
Renal cell carcinoma
Metastatic cholangiocarcinoma Hepatocellular carcinoma
Pure red cell dysplasia and hepatitis C Diffuse large B-cell lymphoma Diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma Diffuse large B-cell lymphoma
Lung adenocarcinoma
Metastatic pulmonary adenocarcinoma
Underlying disease
Tonic-clonic seizures, headache, papilledema Seizures, altered mental status, transient cortical blindness Headache, vision loss, seizures, loss of consciousness Hypertension, epistaxis, headaches, visual disturbances Altered mental status, confusion, dizziness Headaches, tonic-clonic seizures, vision changes Tonic-clonic seizures, vision changes Nausea, vomiting, headache, seizures, confusion Headaches, ataxia, seizures, upper extremity weakness, hyper-reflexia
Bilateral vision loss, headache
Tonic-clonic seizures, headaches
Nausea, vomiting, headaches, tonic-clonic seizures, confusion, ataxia Tonic-clonic seizures, coma
Nausea, vomiting, aphasia, agitation, status epilepticus
Symptoms/Signs
190/130
160/102
210/110
170/100
155/85
165/100
197/131
Not stated
197/114
138/87
170/110
Not stated
245/140
164/75
Max BP readings (mm Hg)
BP control
BP control
BP control
BP control
Not stated
BP control
BP control
BP control and supportive BP control
Supportive
BP control
BP control
BP control
Not stated
BP control
(continued)
Full recovery (few days) Full recovery (6 days) Full recovery (duration not stated) Full recovery (3 days)
Full recovery
Full recovery (2 days) Full recovery (5 days)
Full recovery (1 week) Full recovery (2 weeks) Full recovery (40 hours)
Full recovery (7 days) Full recovery (1 day)
Full recovery (7 days), later death after 2nd episode of PRES Full recovery
Outcome
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76/M
62/F
58/F
79/M
Asaithambi et al.45
Foerster et al.46
Maur et al.47
Our case (2014)
Vemurafenib (8 weeks)
Ipilimumab (1 dose)
Pazopanib (3 weeks) Pazopanib (4 weeks) Pazopanib (8 weeks)
Sunitinib (9 weeks)
Sunitinib (15 weeks)
Sunitinib (8 days)
Drug
Metastatic melanoma
Metastatic vaginal melanoma
Renal cell carcinoma
Renal cell carcinoma
Renal cell carcinoma
Renal cell carcinoma
Renal cell carcinoma
Renal cell carcinoma
Underlying disease
Impaired visual acuity, unresponsiveness, confusion, tonic-clonic seizures
Nausea, vomiting, headache, vision changes, seizures, cerebellar signs Headache, seizures, vision loss Headache, vomiting, vision loss, disorientation Nausea, vomiting, seizures, vision loss, ataxia, left arm paresis Sudden bilateral blindness, headache, tonic-clonic seizures
Headache, dizziness, upper extremity weakness, vision loss, seizures, hyperreflexia Seizures
Symptoms/Signs
BP: blood pressure; F: female; M: male; Max: maximum; PRES: posterior reversible encephalopathy syndrome.
40/F
Chelis et al.44
61/M
Hadj et al.42
48/F
65/M
Padhy et al.41
Khan et al.43
Age/sex
Reference
Table 1. Continued.
180/90
170/90
>300 systolic to 220/120
219/55
165/105
178/117
202/101
160/100
Max BP readings (mm Hg)
BP control
BP control
BP control
BP control
BP control
BP control
BP control
BP control
BP control
Recovery from this event, with eventual death in 1 year due to disease progression Recovery from this event and a similar 2nd episode at restarting the drug, but eventual death in 2 months due to disease progression
Full recovery (5 days) Full recovery (1–2 days) Full recovery (6 days)
Partial recovery (2 weeks) but ultimate death due to disease burden Full recovery (duration not stated)
Full recovery (10 days)
Outcome
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Results A total of 36 case reports of PRES associated with targeted therapy were identified. Of these, 17 were associated with bevacizumab,6,16–30 13 with TKIs (8 for sunitinib,7,37–43 2 with sorafenib,8,36 3 with pazopanib44–46), 5 with the anti-CD20 agent rituximab,31–35 1 with the anti-CTLA-4 agent ipilimumab.47 Table 1 describes the patient characteristics of the selected case reports.
Discussion In 1996, Hinchey et al.1 described a case series of 15 patients with PRES, most of whom were found to have severe hypertension associated with either pregnancy complications or renal dysfunction. An increased incidence of this condition in the last decade is not only because of better imaging modalities but also due to more information on its pathogenesis and potential causative agents. MRI remains the diagnostic modality of choice in patients with a characteristic reversible neurological dysfunction.2,13 Occipital and parietal lobes are the most commonly affected areas of the brain, leading to symptoms of cortical blindness, seizures, lethargy and headaches.1,2,5 Loss of cerebral auto-regulation and endothelial dysfunction are postulated to be the two main mechanisms in the PRES pathophysiology. Posterior cerebral circulation is found to be more prone to abrupt changes in blood pressure as the blood vessels have less adrenergic innervation compared to the anterior cerebral circulation.1,3,14 Sudden changes in the blood pressure in the setting of dysfunctional endothelium lead to dilatation of cerebral blood vessels by surpassing the protective auto-regulatory mechanisms. Targeted cancer therapies may damage the endothelium directly, leading to release of endothelin-1, thromboxane A2 and prostacyclin. This further translates into leakage of fluid in the white matter appearing as hyperdensities on the T2weighted and FLAIR MRI images.1–3,10 Anti-VEGF agent bevacizumab6,9,16–30 is now being recognized as one of the most common targeted therapies associated with PRES. It is also associated with thrombotic events and hypertension, suggesting the presence of vascular endothelial damage/toxicity. Sorafenib, pazopanib and sunitinib are oral multikinase inhibitors that target VEGF pathway as well.7–9,36–46 Their use is also associated with increased blood pressure, peripheral edema and, more rarely, with clotting events. As PRES is also associated with hypertension and thrombotic events, these risk factors should certainly be kept in mind before institution of anti-VEGF(R) therapy. Rituximab has also been linked with cases of PRES31–35 (Table 1). It is thought that its action on
CD20 receptor of B-cells can cause blood–brain barrier damage, leading to its increased permeability to inflammatory mediators. This can eventually lead to vasogenic edema and loss of cerebral auto-regulation. Ipilimumab47 acts by overcoming CTLA 4 mediated T-cell suppression and, hence, leads to enhanced immune response against tumor cells. This could also cause true autoimmunity, resulting in endothelial cell damage via an inflammatory cytokine response and increased vessel permeability leading to brain edema. In most cases, PRES is fully reversible upon removal of the causative agent. However, failure to quickly recognize this syndrome and discontinue the offending agent may result in profound and permanent CNS damage or even death.4 Blood pressure lowering in these patients appears to help resolve the symptoms of PRES, and represents one of the important therapeutic measures. Our patient displayed classic clinical symptomatology of PRES that occurred repeatedly, given lack of information and no previously reported cases of PRES due to vemurafinib. Interestingly, the patient had increased blood pressure that is known to be associated with PRES. Although this case lacks the evidentiary support of an MRI study, a negative CT head for any stroke, bleed, mass or trauma makes the diagnosis of PRES more likely. This diagnosis is further supported by the presence of upper extremity edema, a relatively common side effect of vemurafenib. In addition, the calculated Naranjo nomogram score48 of 6 is suggestive of a probable association between vemurafenib and PRES. Increased awareness of PRES among oncologists and other providers may improve the outcome in cancer patients treated with targeted agents.4 A special consideration should be given to the situations where other agents associated with PRES such as cisplatin, oxaliplatin, carboplatin or gemcitabine are employed along with TKIs in the antineoplastic therapy. Further insights into this complication of contemporary cancer therapy through continued basic science and clinical research are needed. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest We certify that we do not have any affiliation with or financial involvement in any organization or entity with a direct financial interest in the subject matter or materials discussed in the manuscript (e.g., employment, consultancies, stock ownership, honoraria, and expert testimony). We do not have any commercial or proprietary interest in any drug, device, or equipment mentioned in the article below. No previously
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published figures or tables were used in this paper. We certify sufficient participation of each author in the conception, design, analysis, interpretation, writing, revising, and approval of the manuscript.
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Posterior reversible encephalopathy syndrome due to targeted agents: vemurafinib among suspects!
J Oncol Pharm Practice 2015, Vol. 21(6) 443–450 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155214543212 opp.sagepub.com
Arushi Khurana1 and Constantin A Dasanu2
Abstract Posterior reversible encephalopathy syndrome features reversible cortical neurologic dysfunction and characteristic findings on brain imaging studies. This syndrome can be caused by several agents including traditional chemotherapy and immunosuppressive drugs. Targeted therapies such as agents binding vascular endothelial growth factor/VEGFR, CD20 and cytotoxic T-cell lymphocyte antigen 4 (CTLA-4) antigens are also among the culprits. Vemurafenib is a BRAF gene inhibitor that has not been previously linked with posterior reversible encephalopathy syndrome. We report herein the first such case and believe that further studies confirming this association are warranted. We further review the existing posterior reversible encephalopathy syndrome cases associated with targeted therapies in the scientific literature.
Keywords PRES, Vemurafinib, targeted therapies, Reversible posterior leukoencephalopathy syndrome (RPLS)
Introduction First described in 1996 by Hinchey et al.,1 posterior reversible encephalopathy syndrome (PRES) is an increasingly reported clinico-radiologic entity consisting of reversible cortical neurological dysfunction and characteristic findings on brain imaging studies. The clinical picture may include acute to subacute onset of headaches, nausea, vomiting, seizures, impaired visual acuity, sleepiness or coma. A complete recovery with supportive therapy is seen in almost all cases, usually within days to weeks, and is considered the ‘‘hallmark’’ of this condition.2 Magnetic resonance imaging (MRI) findings are suggestive of white matter edema on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images involving the posterior circulation areas, especially occipital and parietal lobes.1 PRES has historically been correlated with hypertensive crises, pre-eclampsia, eclampsia, connective tissue disorders, acute porphyria, Guillain-Barre´ syndrome and use of immunosuppressive agents such as calcineurin inhibitors.2 Traditional chemotherapy agents associated with this condition include platinum
agents, L-asparaginase, cyclophosphamide and gemcitabine.3,4 Erythropoietin and certain colony stimulating factors such as G-CSF have been associated with PRES as well.3 This syndrome has also been reported to be associated with newer targeted therapies such as antivascular endothelial growth factor (VEGF) agents (bevacizumab), anti-CD20 antibodies (rituximab), tyrosine kinase inhibiting (TKI) agents (sorafenib, sunitinib, pazopanib) and, most recently, with anti-cytotoxic T-cell lymphocyte antigen 4 (CTLA-4) agents (ipilimumab).5–47 Approximately 40–60% melanomas have a mutation of the BRAF (B-rapidly accelerated fibrosarcoma) gene. V600E mutation (substitution of glutamic acid for valine at position 600) constitutes >90% of the BRAF
1
Department of Internal Medicine, University of Connecticut, Farmington, CT, USA 2 Department of Hematology-Oncology, St. Francis Hospital and Medical Center, Hartford, CT, USA Corresponding author: Arushi Khurana, University of Connecticut, 263 Farmington Avenue, Farmington CT 06030, USA. Email: [email protected]
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mutations seen in melanoma. Vemurafenib is a potent selective inhibitor of BRAF V600 gene, and inhibits RAF-driven downstream signals in tumors expressing mutant BRAF V600E. This inhibition led to tumor shrinkage in 81% patients with BRAF V600E mutant melanoma in a phase 1 study.12 Hence, this oral BRAF inhibitor was approved by the FDA in 2011 for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation. We are not aware of any previous case reports of PRES associated with the use of this agent. We present a 79-year-old man with PRES suspected to be a consequence of vemurafenib use for metastatic melanoma.
Case report A 79-year-old man presented with complaints of nausea, vomiting, generalized weakness, and more than 9 kg weight loss over the previous 4 months. The patient’s complaints were gradual in onset, but became severe two days prior to admission. Past medical history was significant for controlled hypertension, hyperlipidemia, diabetes mellitus, cerebrovascular disease and seizure disorder. He also had history of earlystage prostate cancer 6 years prior that was treated with external beam radiotherapy, with no evidence of recurrence. Family history was negative for any cancers. Physical examination showed stable vital signs, along with normal head and neck, cardiovascular and respiratory system examination. Abdominal exam showed no hepatosplenomegaly; he had no lymphadenopathy or suspicious skin lesions. He was worked up extensively in the hospital for possible systemic infections, inflammatory disorders and malignancies. A computed tomography (CT) scan was significant for small bilateral lung lesions, multiple low-density liver lesions, along with studding of omentum and peritoneal lining in the right upper quadrant and moderate ascites. Head CT was within normal limits. Liver biopsy showed malignant cells strongly positive for vimentin, S100 protein, Melan A and HMB-45 but negative for keratins that was consistent with metastatic malignant melanoma. BRAF V600E gene mutation was detected on special testing. As a result, the patient was started on oral vemurafenib, which he initially tolerated well. However, after 8 weeks of therapy, he developed swelling of the upper extremities and confusion. He also claimed impaired visual acuity and had a partial seizure involving right upper extremity, followed by unresponsiveness. In the emergency room, the patient was non-verbal, and only responsive to deep pain stimuli and sternal rub. His examination was unremarkable, except for high blood pressure readings at 180/90 mm Hg. Glasgow coma
scale (GCS) was 10; he had normal deep tendon reflexes and spontaneous movement of all four extremities. Laboratory tests were within normal limits for all electrolytes, thyroid-stimulating hormone (TSH), rapid plasma reagin (RPR), vitamin B12/folate levels, erythrocyte sedimentation rate (ESR), liver function tests (LFT) and ammonia levels. Urinalysis was remarkable for the presence of proteinuria at 100 mg/ d (normal: no detectable protein). CT scan of head was negative for any acute infarct, mass or midline shift. Brain MRI could not be performed as the patient had a pacemaker implanted in the past. He was investigated for any potential stroke, infection, vasculitis and other causes with an echocardiogram with bubble study, CT angiogram of head and neck, vasculitis panel, electroencephalogram (EEG), all of which were negative/ normal. He had frequent neurological exams and was treated with antihypertensive medications. Vemurafenib was discontinued and the patient’s condition improved gradually, with resolution of altered mental status within seven days. A surveillance CT scan showed significant improvement in his disease burden, with the resolution of lung nodules, ascites and a considerable shrinkage of liver lesions. As a result, vemurafenib was restarted. Three weeks later, the patient had a similar presentation with altered mental status. He was again managed in a similar fashion, and his symptoms resolved within four days after stopping vemurafenib. The patient’s disease ultimately relapsed 2 months later as the disease likely developed resistance to vemurafenib. He was too debilitated and weak to withstand any further therapy and was managed with only comfort measures until his demise.
Methods We carried out a MEDLINE search of published work in English to identify patients with PRES linked with some form of targeted therapy for malignancy. Key words used were ‘‘posterior reversible encephalopathy syndrome,’’ ‘‘hypertensive encephalopathy,’’ ‘‘reversible posterior leukoencephalopathy syndrome,’’ reversible posterior cerebral edema syndrome,’’ ‘‘cancer,’’ ‘‘malignancy,’’ ‘‘targeted therapy,’’ ‘‘anti-VEGF,’’ ‘‘tyrosine kinase inhibitor,’’ ‘‘anti-CD20’’ and ‘‘melanoma.’’ This also included the names of individual drugs as key words ‘‘bevacizumab,’’ sunitinib,’’ ‘‘sorafenib,’’ ‘‘rituximab,’’ ‘‘pazopanib,’’ ipilimumab,’’ ‘‘alemtuzumab’’ and ‘‘vemurafinib.’’ Papers from 1 January 1996 to 30 December 2013 were included. Articles that fulfilled the criteria for adequate information including patient characteristics, presence of a malignant disease, use of specific targeted therapy agents, typical imaging findings and characteristic clinical outcomes were reviewed.
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55/F
33/F
68/F
49/M
6/M
63/F
45/F
68/F
63/F
46/F
72/F
Burki et al.20
Peter et al.21
Koopman et al.22
Levy et al.23
Lau et al.24
Chang et al.25
Seet et al.26
Seet et al.26
Lou et al.27
Sclafani et al.28
52/M
Allen et al.17
El Maalouf et al.19
59/F
Glusker et al.16
62/F
52/F
Ozcan et al.6
Pinedo et al.18
Age/sex
Reference
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Bevacizumab (2 cycles)
Bevacizumab (3 cycles)
Bevacizumab (3 cycles) Bevacizumab
Bevacizumab (3 cycles) Bevacizumab (6 cycles) Bevacizumab (3 cycles) Bevacizumab (7 cycles) Bevacizumb (10 cycles) Bevacizumab (13 infusions)
Bevacizumab (14 infusions)
Bevacizumab
Bevacizumab
Bevacizumab (1 dose) Bevacizumab (7 cycles)
Drug
Metastatic breast cancer
Metastatic non-small cell lung carcinoma Advanced pancreatic carcinoma Glioblastoma multiform
Rectosigmoid carcinoma Cholangiocarcinoma
Metastatic colon cancer Metastatic colorectal cancer Hepatoblastoma
Breast cancer
Rectal carcinoma with neuroendocrine differentiation Rectal adenocarcinoma Metastatic colon cancer
Rectal adenocarcinoma Renal cell carcinoma
Underlying disease
Seizures, expressive aphasia, right-sided paresthesias, nausea, vomiting Nausea, vomiting, blurred vision
Seizures, altered mental status, coma Headaches, hypertension, tonic-clonic seizures Headache, visual disturbance, drowsiness Unresponsiveness, headaches, tonic-clonic seizures Headache, confusion, nausea, vomiting Seizures, cortical blindness
Headache, nausea, vomiting, dysarthria, tonic-clonic seizures, unresponsiveness Headache, nausea, vomiting, coma Cortical blindness
Tonic-clonic seizures
Bilateral vision loss, headache, confusion Tonic-clonic seizure, bilateral vision loss, extensor plantar reflexes Cortical blindness, headache, seizures, aphasia, delirium
Symptoms/Signs
Table 1. Published reports of PRES syndrome associated with targeted therapies and their characteristics.
150/100
201/117
190/94
221/84
194/112
Not stated
160/120
180/100
140/70
170/80
190/120
190/88
150 systolic
178/98
172/100
Max BP readings (mm Hg)
BP control
BP control
BP control
BP control
BP control
Not stated
BP control
BP control
Not stated
BP control
BP control
BP control
BP control
BP control
BP control
BP control
(continued)
Full recovery (1 week)
Full recovery (1 day) Full recovery (4 days) Full recovery (2 days)
Full recovery (2 days)
Full recovery
Full recovery
Full recovery
Full recovery
Full recovery
Full recovery
Full recovery
Full recovery
Full recovery
Full recovery
Outcome
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Age/sex
72/M
41/F
62/M
39/F
25/F
66/F
61/F
49/F
58/M
81/F
70/F
54/F
39/F
48/F
Reference
Lazarus et al.29
Dersch et al.30
Haefner et al.31
Hosoi et al.32
Zito et al.33
Siddiqi34
Mizutani et al.35
Govindarajan et al.8
Dogan et al.36 (2010)
Medioni et al.37
Martin et al.7
Kapiteijn et al.38
Cumurciuc et al.39
Chen et al.40
Table 1. Continued.
Sunitinib (22 weeks) Sunitinib (2 weeks) Sunitinib (34 weeks) Sunitinib (1 week) Sunitinib (1 week)
Sorafenib (4 months) Sorafenib (1 week)
Rituximab (1st dose) Rituximab
Rituximab (2 cycles) Rituximab (17th day, 2nd cycle) Rituximab
Bevacizumab (7 cycles)
Bevacizumab (8 cycles)
Drug
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Renal cell carcinoma
Gastrointestinal stromal tumor Renal cell carcinoma
Renal cell carcinoma
Renal cell carcinoma
Metastatic cholangiocarcinoma Hepatocellular carcinoma
Pure red cell dysplasia and hepatitis C Diffuse large B-cell lymphoma Diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma Diffuse large B-cell lymphoma
Lung adenocarcinoma
Metastatic pulmonary adenocarcinoma
Underlying disease
Tonic-clonic seizures, headache, papilledema Seizures, altered mental status, transient cortical blindness Headache, vision loss, seizures, loss of consciousness Hypertension, epistaxis, headaches, visual disturbances Altered mental status, confusion, dizziness Headaches, tonic-clonic seizures, vision changes Tonic-clonic seizures, vision changes Nausea, vomiting, headache, seizures, confusion Headaches, ataxia, seizures, upper extremity weakness, hyper-reflexia
Bilateral vision loss, headache
Tonic-clonic seizures, headaches
Nausea, vomiting, headaches, tonic-clonic seizures, confusion, ataxia Tonic-clonic seizures, coma
Nausea, vomiting, aphasia, agitation, status epilepticus
Symptoms/Signs
190/130
160/102
210/110
170/100
155/85
165/100
197/131
Not stated
197/114
138/87
170/110
Not stated
245/140
164/75
Max BP readings (mm Hg)
BP control
BP control
BP control
BP control
Not stated
BP control
BP control
BP control and supportive BP control
Supportive
BP control
BP control
BP control
Not stated
BP control
(continued)
Full recovery (few days) Full recovery (6 days) Full recovery (duration not stated) Full recovery (3 days)
Full recovery
Full recovery (2 days) Full recovery (5 days)
Full recovery (1 week) Full recovery (2 weeks) Full recovery (40 hours)
Full recovery (7 days) Full recovery (1 day)
Full recovery (7 days), later death after 2nd episode of PRES Full recovery
Outcome
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76/M
62/F
58/F
79/M
Asaithambi et al.45
Foerster et al.46
Maur et al.47
Our case (2014)
Vemurafenib (8 weeks)
Ipilimumab (1 dose)
Pazopanib (3 weeks) Pazopanib (4 weeks) Pazopanib (8 weeks)
Sunitinib (9 weeks)
Sunitinib (15 weeks)
Sunitinib (8 days)
Drug
Metastatic melanoma
Metastatic vaginal melanoma
Renal cell carcinoma
Renal cell carcinoma
Renal cell carcinoma
Renal cell carcinoma
Renal cell carcinoma
Renal cell carcinoma
Underlying disease
Impaired visual acuity, unresponsiveness, confusion, tonic-clonic seizures
Nausea, vomiting, headache, vision changes, seizures, cerebellar signs Headache, seizures, vision loss Headache, vomiting, vision loss, disorientation Nausea, vomiting, seizures, vision loss, ataxia, left arm paresis Sudden bilateral blindness, headache, tonic-clonic seizures
Headache, dizziness, upper extremity weakness, vision loss, seizures, hyperreflexia Seizures
Symptoms/Signs
BP: blood pressure; F: female; M: male; Max: maximum; PRES: posterior reversible encephalopathy syndrome.
40/F
Chelis et al.44
61/M
Hadj et al.42
48/F
65/M
Padhy et al.41
Khan et al.43
Age/sex
Reference
Table 1. Continued.
180/90
170/90
>300 systolic to 220/120
219/55
165/105
178/117
202/101
160/100
Max BP readings (mm Hg)
BP control
BP control
BP control
BP control
BP control
BP control
BP control
BP control
BP control
Recovery from this event, with eventual death in 1 year due to disease progression Recovery from this event and a similar 2nd episode at restarting the drug, but eventual death in 2 months due to disease progression
Full recovery (5 days) Full recovery (1–2 days) Full recovery (6 days)
Partial recovery (2 weeks) but ultimate death due to disease burden Full recovery (duration not stated)
Full recovery (10 days)
Outcome
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Results A total of 36 case reports of PRES associated with targeted therapy were identified. Of these, 17 were associated with bevacizumab,6,16–30 13 with TKIs (8 for sunitinib,7,37–43 2 with sorafenib,8,36 3 with pazopanib44–46), 5 with the anti-CD20 agent rituximab,31–35 1 with the anti-CTLA-4 agent ipilimumab.47 Table 1 describes the patient characteristics of the selected case reports.
Discussion In 1996, Hinchey et al.1 described a case series of 15 patients with PRES, most of whom were found to have severe hypertension associated with either pregnancy complications or renal dysfunction. An increased incidence of this condition in the last decade is not only because of better imaging modalities but also due to more information on its pathogenesis and potential causative agents. MRI remains the diagnostic modality of choice in patients with a characteristic reversible neurological dysfunction.2,13 Occipital and parietal lobes are the most commonly affected areas of the brain, leading to symptoms of cortical blindness, seizures, lethargy and headaches.1,2,5 Loss of cerebral auto-regulation and endothelial dysfunction are postulated to be the two main mechanisms in the PRES pathophysiology. Posterior cerebral circulation is found to be more prone to abrupt changes in blood pressure as the blood vessels have less adrenergic innervation compared to the anterior cerebral circulation.1,3,14 Sudden changes in the blood pressure in the setting of dysfunctional endothelium lead to dilatation of cerebral blood vessels by surpassing the protective auto-regulatory mechanisms. Targeted cancer therapies may damage the endothelium directly, leading to release of endothelin-1, thromboxane A2 and prostacyclin. This further translates into leakage of fluid in the white matter appearing as hyperdensities on the T2weighted and FLAIR MRI images.1–3,10 Anti-VEGF agent bevacizumab6,9,16–30 is now being recognized as one of the most common targeted therapies associated with PRES. It is also associated with thrombotic events and hypertension, suggesting the presence of vascular endothelial damage/toxicity. Sorafenib, pazopanib and sunitinib are oral multikinase inhibitors that target VEGF pathway as well.7–9,36–46 Their use is also associated with increased blood pressure, peripheral edema and, more rarely, with clotting events. As PRES is also associated with hypertension and thrombotic events, these risk factors should certainly be kept in mind before institution of anti-VEGF(R) therapy. Rituximab has also been linked with cases of PRES31–35 (Table 1). It is thought that its action on
CD20 receptor of B-cells can cause blood–brain barrier damage, leading to its increased permeability to inflammatory mediators. This can eventually lead to vasogenic edema and loss of cerebral auto-regulation. Ipilimumab47 acts by overcoming CTLA 4 mediated T-cell suppression and, hence, leads to enhanced immune response against tumor cells. This could also cause true autoimmunity, resulting in endothelial cell damage via an inflammatory cytokine response and increased vessel permeability leading to brain edema. In most cases, PRES is fully reversible upon removal of the causative agent. However, failure to quickly recognize this syndrome and discontinue the offending agent may result in profound and permanent CNS damage or even death.4 Blood pressure lowering in these patients appears to help resolve the symptoms of PRES, and represents one of the important therapeutic measures. Our patient displayed classic clinical symptomatology of PRES that occurred repeatedly, given lack of information and no previously reported cases of PRES due to vemurafinib. Interestingly, the patient had increased blood pressure that is known to be associated with PRES. Although this case lacks the evidentiary support of an MRI study, a negative CT head for any stroke, bleed, mass or trauma makes the diagnosis of PRES more likely. This diagnosis is further supported by the presence of upper extremity edema, a relatively common side effect of vemurafenib. In addition, the calculated Naranjo nomogram score48 of 6 is suggestive of a probable association between vemurafenib and PRES. Increased awareness of PRES among oncologists and other providers may improve the outcome in cancer patients treated with targeted agents.4 A special consideration should be given to the situations where other agents associated with PRES such as cisplatin, oxaliplatin, carboplatin or gemcitabine are employed along with TKIs in the antineoplastic therapy. Further insights into this complication of contemporary cancer therapy through continued basic science and clinical research are needed. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest We certify that we do not have any affiliation with or financial involvement in any organization or entity with a direct financial interest in the subject matter or materials discussed in the manuscript (e.g., employment, consultancies, stock ownership, honoraria, and expert testimony). We do not have any commercial or proprietary interest in any drug, device, or equipment mentioned in the article below. No previously
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published figures or tables were used in this paper. We certify sufficient participation of each author in the conception, design, analysis, interpretation, writing, revising, and approval of the manuscript.
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