Bevacizumab is a recombinant, humanized monoclonal antibody against VEGF-A, and is approved by the United States Food and Drug Administration (U.S. FDA) for use in the treatment of metastatic colorectal cancer, advanced nonsquamous non-small cell lung cancer, platinum-resistant ovarian cancer, advanced cervical cancer, metastatic renal cell carcinoma, and recurrent glioblastoma [7]. Although bevacizumab is generally well tolerated, there are a few rare but serious neurologic complications. Use of bevacizumab is associated with an increased rate of intracranial hemorrhage, with incidence ranging from 0.3 to 0.7% in patients with systemic tumors [8, 9]. In patients with brain metastases or primary brain tumors, the incidence is increased and ranges from 0.8 to 3.3%; this is slightly increased from the baseline rate of spontaneous intracranial hemorrhage in patients with these tumors not treated with anti-angiogenic agents (Fig. 16.1) [8, 10, 11]. Patients receiving bevacizumab are thought to have an increased risk of arterial thromboembolic events, including ischemic stroke (Fig. 16.2). In a meta-analysis of 1745 patients with metastatic cancer, treatment with bevacizumab plus chemotherapy in comparison with chemotherapy alone resulted in an increased risk of an arterial thromboembolic event with a hazard ratio of 2.0 and an absolute rate of 5.5 events per 100 person-years. Of 37 patients with thromboembolic events noted in this study, there were 16 cerebrovascular events (stroke or TIA); rates were higher in patients over 65 years old or with a prior arterial thrombotic event. [12]. A retrospective study of recurrent high-grade glioma patients treated with bevacizumab in clinical trials found the incidence of ischemic stroke to be 1.9%, or 0.38 cases per 100 patient-months [13]. Bevacizumab administration also has been associated with the development of the rare clinical-radiologic Posterior Reversible Encephalopathy Syndrome (PRES), also known as the Reversible Posterior Leukoencephalopathy Syndrome (RPLS). This syndrome has been described in association with a variety of medications, including angiogenesis inhibitors, and is characterized by neurological symptoms including headache, visual disturbance, confusion, and seizures, in conjunction with subcortical/white matter abnormalities, including prominent vasogenic edema, especially in the parietal and occipital lobes, on MRI [14, 15]. These symptoms usually resolve with supportive care. Rarely, optic neuropathy has been described in association with bevacizumab, with an incidence of 1.2% in one study [16]. Of note, all of the patients in that study had also received radiation to the brain for glioblastoma, but at doses felt to be safe to the optic nerves; in comparison, the incidence of severe optic neuropathy in patients receiving radiation but not bevacizumab was 0.2% [16]. Another case series reported three patients with glioblastoma previously treated with radiation therapy who developed optic neuropathy following bevacizumab use [17].

Ziv-aflibercept is a recombinant fusion protein comprised of VEGF-binding portions from VEGFR-1 and -2 fused to the Fc portion of the human immunoglobulin IgG1. In August 2012, it received FDA approval for use in combination with 5-fluorouracil, leucovorin and irinotecan (the FOLFIRI regimen) in patients with progressive metastatic colorectal cancer after oxaliplatin therapy. Headache is a common side effect; rare but potentially serious neurologic complications include arterial thrombotic events and RPLS [19].

Lenvatinib is an oral inhibitor of VEGFR 1, 2, and 3, as well as an inhibitor of fibroblast growth factor receptors (FGFR) 1, 2, 3, and 4, REarranged during Transfection (RET), KIT, and platelet-derived growth factor receptor alpha (PDGFRα). It was approved by the U.S. FDA in February 2015 for the treatment of locally recurrent or metastatic radioactive iodine-refractory differentiated thyroid cancer. In the Phase III clinical trial, headache was common, experienced in 27.6% of treated patients versus 6.1% of patients receiving placebo. About 3.6% of patients experienced a serious neurologic complication, including cerebrovascular ischemic event, TIA, intracranial hemorrhage, seizures or RPLS [20].

Sorafenib is a multikinase inhibitor active against numerous targets, including VEGFR-2 and -3, PDGFR, Raf kinase, KIT and FMS-like tyrosine kinase 3 (FLT-3), and is used in the treatment of renal cell carcinoma, hepatocellular carcinoma, and radioactive iodine-refractory thyroid cancer. The most concerning potential neurologic complication associated with sorafenib use is stroke; a meta-analysis of clinical trials using sorafenib and sunitinib found a threefold increased risk of arterial thrombotic events, including ischemic stroke [21].

Sunitinib is a multikinase inhibitor with targets including VEGFR, PDGFR, and KIT, and is approved for use in metastatic renal cell carcinoma, progressive pancreatic neuroendocrine tumors, and imatinib-resistant gastrointestinal stromal tumor. Sunitinib has been associated with increased risk of ischemic stroke, with threefold increased risk of arterial thrombotic events, including ischemic stroke , in a meta-analysis of clinical trials using sorafenib and sunitinib [21]. A reversible syndrome of cognitive dysfunction has been described, with symptoms including confusion, language problems, extrapyramidal symptoms, and gait abnormalities [22]. RPLS also has been reported in association with sunitinib therapy [23].

Pazopanib is a multi-tyrosine kinase inhibitor of VEGFR, PDGFR, KIT, fibroblast growth factor receptor (FGFR), interleukin-2 receptor inducible T-cell kinase (Itk), and colony-stimulating factor 1 receptor (c-Fms) that is FDA approved for the treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma. Headache has been in reported in 10–23% of patients; serious adverse events are rare, including arterial thrombotic events [stroke and transient ischemic attack (TIA)] and central nervous system (CNS) hemorrhage (subarachnoid hemorrhage, intracranial hemorrhage) [24–26]. Cases of RPLS also have been described [27–29].

Ponatinib is an oral multi-target tyrosine kinase inhibitor designed as a pan-BCR-ABL inhibitor but also targeting VEGFR, PDGFR, FGFR, ephrin receptor, Src family kinases, c-Kit, RET, tunica interna endothelial cell kinase 2 (TIE2), and FLT-3 [30]. It received accelerated FDA approval in 2012 for the treatment of patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia, whose disease was resistant or intolerant to prior tyrosine kinase inhibitor therapy [30]. Headache was common in clinical trial participants, and arterial thrombotic events were noted, with cerebrovascular events considered to be at least possibly attributable to the drug in 0.7% of patients in the initial study [31]. Additional data gathered after initial FDA approval showed a high incidence of venous and arterial thrombotic events, some of which were fatal or life-threatening, noted in approximately 24% of patients in the phase II trial and 48% of patients in the phase I trial. This led to temporary suspension of ponatinib marketing and sales by the FDA, a black box warning on the drug, and cancelation of a planned randomized trial of imatinib versus ponatinib [31, 32]. Peripheral neuropathy has been reported in 13% of ponatinib-treated patients (2% grade 3–4) [33].

Axitinib is a potent, selective, second-generation inhibitor of VEGFR-1, -2, and -3 [37]. It is FDA approved for the treatment of advanced renal cell carcinoma. Neurologic side effects are rare, but as with other agents of this class, serious adverse effects including arterial thrombotic events and RPLS have been described [38].

Thalidomide was the first immunomodulatory drug approved for use in multiple myeloma, and has potent immune mediating and antiangiogenic properties [39]. Frequent but mild (grade 1–2) neurologic side effects in the phase II multiple myeloma trial included (at the 200 mg/day dose) somnolence in 34%, tingling or numbness in 12%, incoordination in 16%, tremors in 10%, and headache in 12% [40]. The most prominent neurologic complication associated with thalidomide use is peripheral neuropathy, which has been reported in 23–70% of patients, and appears to be dose-dependent (worse with doses in excess of 200 mg per day) and cumulative with longer duration of treatment. Length-dependent sensory neuropathy is most commonly reported, and autonomic neuropathy is thought to mediate some thalidomide-related side effects including constipation, orthostatic hypotension, bradycardia and sexual dysfunction; motor symptoms are rare [41]. Other than somnolence, CNS toxicity is uncommon. There is a reported case of thalidomide-induced altered mental status progressing to coma, promptly reversed with drug discontinuation [42]. Thalidomide has also been associated with worsening of preexisting Parkinson’s disease [43].

Lenalidomide is a second-generation immunomodulatory agent derived from thalidomide, initially approved for use in transfusion-dependent anemia in patients with myelodysplastic syndrome, and subsequently approved for use in multiple myeloma and mantle cell lymphoma. In addition to its immunomodulatory effects, it has direct cytotoxic and antiangiogenic properties [39]. In contrast to thalidomide, lenalidomide is much less neurotoxic; although mild to moderate neuropathy during treatment has been reported, the phase III trial of lenalidomide plus dexamethasone in comparison with lenalidomide alone in relapsed multiple myeloma showed no significant increase in the incidence of peripheral neuropathy in lenalidomide-treated patients [41]. Lenalidomide use rarely has been associated with CNS toxicity, with case reports of reversible cognitive decline, memory problems and expressive language difficulties [42].

Pomalidomide is a second-generation thalidomide analog approved for the treatment of progressive multiple myeloma. From the neurologic standpoint, it is generally well tolerated, with 9% of patients experiencing grades 1–2 peripheral neuropathy and no reported cases of grades 3–4 neuropathy in clinical trials [44, 45]. CNS toxicity is uncommon, with one case report of reversible expressive language difficulties associated with pomalidomide use [42].