Targ Oncol (2011) 6:253–258 DOI 10.1007/s11523-011-0201-x
DAY-TO-DAY PRACTICE
Posterior reversible encephalopathy syndrome induced by anti-VEGF agents Camille Tlemsani & Olivier Mir & Pascaline Boudou-Rouquette & Olivier Huillard & Karin Maley & Stanislas Ropert & Romain Coriat & François Goldwasser
Received: 21 September 2011 / Accepted: 1 November 2011 / Published online: 17 November 2011 # Springer-Verlag 2011
Abstract Posterior reversible encephalopathy syndrome (PRES) is a clinico-radiological entity that may occur in patients receiving anti-vascular endothelial growth factor (VEGF) agents such as bevacizumab and tyrosine kinase inhibitors. Little is known about the characteristics of patients at risk for PRES under anti-VEGF agents. We carried out a comprehensive review of reports documenting the occurrence of PRES in patients receiving anti-VEGF agents. Twenty-six patients are described with a majority of females (73.1%). Almost a third of patients had a past history of hypertension. The most common symptoms included headache, visual disturbance and seizure. A vast majority of patients had hypertension at the diagnosis of PRES, and proteinuria was detectable each time it was investigated. Neurological outcome was favorable in all cases with a symptomatic treatment including blood pressure control. The risk of PRES is increased when blood pressure is poorly controlled and when proteinuria is detectable. The clinical course appears favorable with a symptomatic treatment. PRES is a potentially severe but manageable toxicity of anti-VEGF agents. Keywords Reversible posterior leukoencephalopathy syndrome . Angiogenesis inhibitors . VEGF-A . Cancer . Outcomes
C. Tlemsani : O. Mir (*) : P. Boudou-Rouquette : O. Huillard : K. Maley : S. Ropert : R. Coriat : F. Goldwasser CERIA (Centre for Research on Angiogenesis Inhibitors), Department of Medical Oncology, Cochin Teaching Hospital, AP-HP, Université Paris Descartes, Sorbonne Paris Cité, 27 rue du Faubourg Saint Jacques, 75014 Paris, France e-mail:
[email protected]
Introduction Posterior reversible encephalopathy syndrome (PRES) is a clinico-radiological entity that includes clinical symptoms such as headache, nausea and emesis, visual loss and seizures. Brain magnetic resonance imaging (MRI) typically shows white-matter abnormalities predominantly in the posterior regions of the brain. Although most symptoms are reversible, secondary cerebral ischemia or bleeding may occur, leading to permanent neurological disability [1–3]. PRES is usually seen in hypertensive encephalopathy, pre-eclampsia, but also in patients receiving immunosuppressive and cytotoxic drugs [1]. More recently, PRES has been reported in patients receiving bevacizumab (a monoclonal antibody to vascular endothelial growth factor [VEGF]), VEGF-trap (aflibercept), and tyrosine kinase inhibitors targeting the VEGF pathway (sunitinib and sorafenib) [4–7]. PRES therefore emerges as a rare but potentially severe class-effect of anti-VEGF agents. Anti-VEGF agents induce a number of vascular toxicities, the more frequent being hypertension [8]. Hypertension induced by anti-VEGF agents is usually well controlled by anti-hypertensive drugs [9], and is therefore rarely dose-limiting in routine practice. However, severe cardiac and neuro-vascular toxicities possibly related to hypertension have been reported in a sizeable population of patients receiving anti-VEGF agents [10]. The occurrence of such life-threatening toxicities may lead to treatment discontinuation, and subsequently impact prognosis. Although a meta-analysis pinpointed that patients at risk for arterial thrombo-embolic events (stroke or myocardial infarction) under bevacizumab were aged >65 years and had previous cardio-vascular risk factors [10], little is known on the population at risk for PRES. Indeed, PRES
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is a rare event and clinicians obviously lack information on its diagnosis and management. We aimed to better describe the population of patients who experienced PRES while under anti-VEGF agents and their management, and therefore carried out a review of the literature on PRES in patients receiving anti-VEGF agents.
Materials and methods Data for this review were identified by search of Pubmed, Web of Knowledge, ASCO Annual Meetings Abstracts, and references from relevant articles using the search terms “drug name AND reversible encephalopathy”, the drug names being “bevacizumab”, “sunitinib”, “sorafenib”, “aflibercept”, “pazopanib” and “axitinib”. Only papers published in English from 2000 to 07 September 2011 were included.
Results We identified 26 reports describing 28 cases of PRES in patients receiving anti-VEGF agents (bevacizumab n=15, sunitinib n=7, sorafenib n=2, sunitinib and bevacizumab n= 3, aflibercept n=1). One paper did not provide detailed information on clinical and biological outcomes and was therefore excluded from the analysis [7]. Another paper did not provide MRI evidence of PRES and was excluded as well [11, 12]. The final analysis included 24 reports [4–6, 11, 13– 30] describing 26 patients. The median age at diagnosis was 56.5 years (range: 6–81). A majority of patients were females (73.1%). Almost a third of patients (34.6%) had a past history of hypertension before the initiation of anti-VEGF therapy. Patients received bevacizumab (57.7%), sunitinib (26.9%), both (7.7%) or sorafenib (7.7%). Chemotherapy with various regimens was given concomitantly to bevacizumab in 86.7% of patients (Table 1). Primary malignancies were mainly renal (34.8%) or digestive (26.1%). Of note, one patient (3.8%) received intravitreal bevacizumab for age-related maculopathy. Patients’ baseline characteristics are summarized in Table 1. PRES occurred after a median duration of anti-VEGF therapy of 9.5 weeks (range: 0,1–34). A vast majority of patients (92.3%) had hypertension at diagnosis of PRES, and 82.6% had diastolic blood pressure ≥100 mm Hg. Most common symptoms at presentation included headaches (53.8%), visual disturbance (46.1%) and seizures (46.1%). Of note, proteinuria was detectable in the 7 patients in whom it was investigated. Patients’ characteristics at the time of PRES are reported in Table 2. The described treatment was mainly symptomatic, including anti-hypertensive drugs (AHD) in 76.9% of
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patients, with a median of 1.3 (0–3) AHD per patient. Diuretics and calcium channels blockers were the most commonly used classes of AHD (Table 3). Other symptomatic treatments were anticonvulsants (23%) and corticosteroids (7.7%). Three patients (11.5%) needed oral intubation (Table 2). Neurological outcome was favourable in all cases (Table 2), with a median delay to neurological recovery of 8.9 days (range: 2–28). Anti-VEGF agents were discontinued in all but 3 patients. Bevacizumab (n=2) and sunitinib (n=1) were re-introduced in patients with previous history of PRES [20, 29, 31]. No further complication was reported in these three patients.
Discussion PRES is an increasingly recognized complication of cancer treatment, including conventional cytotoxic agents but also anti-VEGF agents. In the present review, we were able to identify several clinical characteristics shared by the patients who experienced PRES under anti-VEGF therapy. First, a majority of patients were females, and PRES occurred at any age, as previously described with conventional chemotherapy. PRES occurred after a median time on treatment of 9.5 weeks. Of note, one third of cases occurred during the first 2 weeks of treatment. Second, one third of patients had a past history of hypertension, and all patients but two had high blood pressure at the onset of PRES. This finding is consistent with the retrospective data collected at the MD Anderson Cancer Center in patients experiencing PRES while under conventional chemotherapy [32]. Similarly, the original description of PRES mentioned abrupt increases in blood pressure in a majority of patients with eclampsia or severe renal diseases [2]. Whether uncontrolled hypertension after initiation of anti-VEGF agents could favour the occurrence of PRES is plausible, although few reports described blood pressure control before the occurrence of acute neurological events. Most importantly, proteinuria was positive each time it was assessed, suggesting that ongoing toxicities induced by anti-VEGF agents could precede the occurrence of PRES. Paraclinical investigations showed constantly MRI abnormalities consistent with the diagnosis of PRES, whereas lumbar puncture was normal in 10 of 10 cases. One could therefore assume that this last procedure would be dispensable in patients harbouring typical PRES symptomatology. Therapeutic management mostly consisted in blood pressure control, using various classes of agents. The management remained otherwise symptomatic, with 3 patients requiring oral intubation, stressing the potential severity of this condition. The use of anticonvulsants should be advised in case of confirmed comitiality.
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Table 1 Patients’ baseline characteristics (n=26)
a HCC, breast, hepatoblastoma, neuroendocrine carcinoma, glioblastoma, nons-mall cell lung cancer, pancreatic carcinoma: 1 each; no tumor (n=1) b
Dosing of anti-VEGF agents
Bevacizumab: 5 mg/kg/cycle (n=6), 10 mg/kg/cycle (n=4), 7.5 mg/kg/cycle (n=1), 15 mg/ kg/cycle (n=1), intravitreal (n= 1), not reported (n=4) Sunitinib: 50 mg daily (4 weeks on/2 weeks off) Sorafenib: 400 mg bid Sunitinib: 50 mg daily+bevacizumab 10 mg/kg TKI tyrosine kinase inhibitors; mRCC metastatic renal cell carcinoma; GIST gastro-intestinal stromal tumor; FOLFOX 5fluorouracil, leucovorin and oxaliplatin; GEMOX gemcitabine and oxaliplatin; XELOX capecitabine and oxaliplatin; FOLFIRI 5-fluorouracil, leucovorin and irinotecan; LV5FU2 5fluorouracil and leucovorin
n (%)
Bevacizumab (n=15)
Gender: n, (male/female)
7/19 (26.9/73.1)
4/11 (26.7/73.3)
Age - years: median (range) Hypertension history: Yes No Not reported Primary tumor: mRCC Colorectal GIST Cholangiocarcinoma Othera Anti-VEGF agent: Bevacizumab Sunitinib Sorafenib Sunitinib+bevacizumab Concomitant chemotherapy: FOLFOX
55.4 (6–81)
52.5 (6–68)
9 (34.6) 12 (46.2) 5 (19.2) 8 (30.8) 6 (23) 2 (7.7) 2 (7.7) 8 (30.8)
3/6 (33.3/66.6)
Bevacizumab+ sunitinib (n=2) 0/2 (0/100)
57.4 (39–81)
66.5 (57–76)
4 (26.7) 7 (46.6) 4 (26.7)
3 (33.3) 5 (55.5) 1 (11.2)
2 (100) 0 (0) 0 (0)
1 6 0 1 7
5 0 2 1 1
2 0 0 0 0
(6.7) (40) (0) (6.7) (46.6)
(55.5) (0) (22.1) (11.2) (11.2)
(100) (0) (0) (0) (0)
15 (57.7) 7 (26.9) 2 (7.7) 2 (7.7) 3 (11.4)
GEMOX XELOX FOLFIRI Doxorubicine LV5FU2 Temozolomide Carboplatin-paclitaxel None Cumulative doseb: Median (range) Bevacizumab (mg/kg) Sunitinib (mg) Sorafenib (mg)
TKIs (n=9)
3 2 1 1 1 1 1 13
(11.4) (7.7) (3.8) (3.8) (3.8) (3.8) (3.8) (50)
3 (20)
0 (0)
0 (0)
3 2 1 1 1 1 1 2
0 0 0 0 0 0 0 9
0 0 0 0 0 0 0 2
(20) (13.3) (6.7) (6.7) (6.7) (6.7) (6.7) (13.3)
(0) (0) (0) (0) (0) (0) (0) (100)
(0) (0) (0) (0) (0) (0) (0) (100)
45 (5–100) 2,844 (350–8,400) 50,400 (11,200–89,600)
Interestingly, one patient receiving sunitinib who developed PRES with concomitant hypertension experienced clinical improvement 3 days after the introduction of antihypertensive drugs, whereas sunitinib was stopped only on day 4 [18]. This case suggests that blood pressure control is critical for the management of PRES, whereas the discontinuation of the anti-VEGF per se might not be sufficient to improve the neurological status. Indeed, bevacizumab (n= 2) and sunitinib (n=1) were re-introduced in patients with previous history of PRES while under anti-VEGF, without any iterative neuro-vascular complication [20, 29, 31]. In view of these data, we would advocate the temporary discontinuation of the anti-VEGF agents at the time of PRES. However, in selected patients in whom therapeutic alternatives are limited (i.e., when anti-VEGF therapy
represents a cornerstone of the treatment of the underlying malignancy, typically in patients with metastatic renal cell carcinoma [mRCC]), the re-introduction of an anti-VEGF agent appeared feasible pending close blood pressure monitoring and aggressive management of hypertension. Although the pathophysiology of PRES remains unclear, it is admitted that the mechanism of PRES depends on failure of the blood–brain barrier to maintain the compartmentalization of intravascular fluid [1]. This alteration of the blood–brain barrier depends not only on the systemic blood pressure, but also on the integrity of the vascular endothelium, under the influence of various medical conditions and medications [1]. Of note, VEGF is a critical factor for vascular permeability [33], and the disruption of VEGF signalling pathway results in a decrease in NO
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Table 2 Characteristics of PRES syndrome at presentation (n=26)
a
Time on treatment (weeks): median range Clinical featuresa: BP>140/90 mm Hg Headaches Visual disturbance Seizures Convulsions Biological features: Proteinuria MAHAb Not investigated 1 not reported
b
1 patient had both proteinuria and MAHA features
c mannitol (2), ceftriaxone (1), fresh frozen plasma (1), none (1) d
3 not reported
TKI tyrosine kinase inhibitors; BP blood pressure; MAHA microangiopathy with hemolytic anemia; AHD anti-hypertensive drugs
Treatment: Anticonvulsants Corticosteroids AHD Oral intubation Otherc Not reported Time to favorable neurologic outcome (days)d
bioavailability [34], suggesting that not only hypertension but also other pharmacodynamic effects of anti-VEGF agents could trigger the occurrence of PRES. In line with this hypothesis, PRES is also seen in patients with pre-eclampsia, an obstetrical condition characterized by high levels of soluble VEGF receptors (sFlt1) [35] that shares common clinical features with toxicities induced by anti-VEGF agents [36]. Due to these similarities, an aggressive management of proteinuria and hypertension in patients receiving anti-VEGF agents should be advised, based on recommendations made in patients with preeclampsia [37]. In this review of the literature, the population at risk for PRES among patients receiving anti-VEGF agents included
n (%)
Bevacizumab (n=15)
9.5 (0.1–34)
10.5 (0.1–31)
24 14 12 12 3
(92.3) (53.8) (46.1) (46.1) (11.4)
18.5 (8.5–20)
8 (88.8) 6 (66.7) 6 (66.7) 3 (33.3) 2 (22.1)
2 0 0 1 0
7 (26.9) 3 (11.4) 18 (69.2)
6 (40) 0 (0) 10 (66.7)
1 (11.2) 1 (11.2) 8 (88.8)
0 (0) 2 (100) 0 (0)
6 2 20 3 5 3 8.9
3 2 12 3 5 0 7.2
(23) (7.7) (76.9) (11.4) (19.2) (11.4) (2–28)
(20) (13.3) (80) (20) (33.3) (0) (2–28)
3 0 7 0 0 2 10.3
(33.3) (0) (77.8) (0) (0) (22.1) (3–28)
(100) (0) (0) (50) (0)
0 0 1 (50) 0 0 1 (50) ? (?–21)
women, patients with a past history of hypertension and those who develop proteinuria and/or hypertension while under treatment. Further reports of PRES occurring in patients under anti-VEGF therapy should not only include the description of the acute neurological symptoms, but also report on the specific toxicities observed in the weeks preceding the occurrence of PRES, in particular hypertension and proteinuria. In conclusion, PRES is a potentially severe but manageable toxicity of anti-VEGF agents. Including recommendations derived from the obstetrical experience with preeclampsia could improve the early detection of patients at risk, as well as their therapeutic management. Close monitoring of blood pressure and proteinuria during anti-
Number of agents/patient: median (range) AHD Class: n (%) Calcium channel blockers ACE inhibitors TKI tyrosine kinase inhibitors; AHD anti-hypertensive drugs; ACE angiotensin-converting enzyme
9.7 (1–34)
Bevacizumab+ sunitinib (n=2)
14 (93.3) 8 (53.3) 6 (40) 8 (53.3) 1 (6.7)
Table 3 Anti-hypertensive therapy for PRES associated with anti-VEGF agents
Diuretics Beta-blockers Nitrates Not specified
TKIs (n=9)
All patients (n=26)
Bevacizumab (n=15)
TKI (n=9)
Bevacizumab+ sunitinib (n=2)
1.3 (0–3)
1 (0–2)
1.6 (0–3)
not detailed
5 (19.2) 1 (3.8)
2 (13.3) 0 (0)
3 (33.3) 1 (11.2)
0 1 (50)
5 5 1 9
1 2 1 5
3 (33.3) 2 (22.1) 0 3 (33.3)
0 1 (50) 0 0
(19.2) (19.2) (3.8) (34.6)
(6.7) (13.3) (6.7) (33.3)
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VEGF therapy is mandatory in order to prevent the occurrence of neuro-vascular adverse events.
Conflicts of interest statement Dr. Mir has acted as paid consultant for Roche. Prof. Goldwasser has acted as paid consultant for Pfizer and Bayer. The other authors have no conflict of interest to declare.
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