Neurological complications of new chemotherapy agents

Abstract

This last decade has yielded more robust development of cancer treatments and first-in-class agents than ever before. Since 2006, nearly one hundred new drugs have received regulatory approval for the treatment of hematological and solid organ neoplasms. Moreover, older conventional therapies have received approval for new clinical indications and are being used in combination with these newer small-molecule targeted treatments. The nervous system is vulnerable to many of the traditional cancer therapies, manifesting both already well-described acute and chronic toxicities. However, newer agents may produce toxicities that may seem indistinguishable from the underlying cancer. Early recognition of neurotoxicities from new therapeutics is vital to avoid irreversible neurological injury. This review focuses on cancer therapies in use in the last 10 years and approved by the FDA from January 2006 through January 1, 2017.

Chemotherapy-related neurotoxicity is a well-recognized complication encountered by cancer survivors. Chemotherapy neurotoxicity tends to relate to drug mechanism of action, dose intensity, preexisting neurological injury, or underlying systemic disease. In the last decade, the FDA Center for Drug Evaluation and Research approved nearly one hundred new molecular entities or therapeutic biologics for the treatment of cancer (Tables 1, 2, and 3). In the last 10 years, there has been an expansive development of targeted therapies, and these have introduced a yet wider range of potential toxicities. Twenty classes of receptor tyrosine kinases (RTKs) have been described, each with subclasses and potential drug targets (Table 1).¹ Their small size is a convenient passage threshold for the blood–brain barrier.² Because they are generally metabolized through cytochromes P450, discretion is necessary if used in conjunction with classical inhibitors and inducers of cytochromes P450. Several of these newer agents, including some antibody therapies (Table 2), carry risks for associated neurological disease, such as progressive multifocal leukoencephalopathy (PML), increasing the risk for vaso-occlusive events, or posterior reversible leukoencephalopathy syndrome (PRES; Fig. 1). New immunotherapies incorporate various mechanisms to unleash the immune system against the tumor, though with the risk of engaging the immune system against self and potentially provoking an autoimmune neurohypophysitis (Fig. 2), myositis, or myasthenia gravis. Neurological toxicities from treatments may seem indistinguishable from the direct effects of the cancer itself or its indirect complications. Recognition and differentiation of these complications is imperative to the proper care and treatment of the patient. In this review, we summarize the neurotoxicological profiles of the newer cancer therapies approved for clinical use in the last 10 years.

Table 1.

Small-molecule kinase inhibitors approved by the FDA in the last 10 years

Drug	Trade Name	Approval Year	Cancer	Target
Afatinib	Gilotrif	2013	Metastatic NSCLC with EGFR mutation	HER2, EGFR
Alectinib	Alecensa	2015	ALK+ metastatic NSCLC	ALK
Axitinib	Inlyta	2012	RCC	PDGFR, c-Kit, VEGFR, BCR-Abl
Bosutinib	Bosulif	2012	Ph+ CML	BCR-Abl, Src family
Cabozantinib	Cometriq	2012	Metastatic medullary thyroid cancer	c-MET, VEGFR
Ceritinib	Zykadia	2014	ALK+ metastatic NSCLC	ALK
Cobimetinib	Cotellic	2015	BRAF V600E or V600K melanoma	MEK
Crizotinib	Xalkori	2011	ALK+ NSCLC	MET, ALK, ROS1
Dabrafenib	Tafinlar	2013	BRAF V600E melanoma	BRAF
Dasatinib	Sprycel	2006	CML with imatinib resistance	BCR-Abl, Src family
Ibrutinib	Imbruvica	2013	Mantle cell lymphoma, CLL	BTK
Idelalisib	Zydelig	2014	CLL, follicular NHL, and small lymphocytic lymphoma	PI3K
Lapatinib	Tykerb	2007	Breast cancer	HER2, EGFR
Lenvatinib	Lenvima	2015	Thyroid cancer	VEGFR1, VEGFR2, VEGFR3
Nilotinib	Tasigna	2007	CML	BCR-Abl
Osimertinib	Tagrisso	2015	EGFR T790M mutation NSCLC	EGFR
Palbociclib	Ibrance	2015	ER+ HER2− breast cancer	CDK4, CDK6
Panitumumab	Vectibix	2006	Colorectal cancer	EGFR
Pazopanib	Votrient	2009	Soft tissue sarcoma, RCC	c-Kit, FGFR, PDGFR, VEGFR
Ponatinib	Iclusig	2012	CML, Ph+ ALL	BCR-Abl
Regorafenib	Stivarga	2012	GIST, metastatic colorectal cancer	VEGFR2
Sunitinib	Sutent	2006	RCC, GIST, pancreatic NET	VEGFR, PDGFR, c-Kit, RET
Trametinib	Mekinist	2013	BRAF V600E or V600K melanoma	MEK
Vandetanib	Vandetanib	2011	Thyroid cancer	VEGFR, RET, EGFR
Vemurafenib	Zelboraf	2011	BRAF+ melanoma	BRAF

Abbreviations: RCC, renal cell carcinoma; NHL, non-Hodgkin lymphoma; GIST, gastrointestinal stromal tumor; NET, neuroendocrine tumor.

Table 3.

Additional cancer therapies recently approved, their trade names, approval year, cancer, and mechanism

Drug	Trade Name	Approval Year	Cancer	Mechanism
Abiraterone	Zytiga	2011	Prostate cancer	Anti-androgen
Belinostat	Beleodaq	2014	Relapsed T-cell lymphoma	HDAC inhibitor
Cabazitaxel	Jevtana	2010	Prostate cancer	Antimicrotubule, taxane derivative
Carfilzomib	Kyprolis	2012	Multiple myeloma	Proteasome inhibitor
Degarelix	Degarelix	2008	Prostate cancer	Anti–gonadotropin-releasing hormone
Enzalutamide	Xtandi	2012	Prostate cancer	Anti-androgen
Eribulin mesylate	Halaven	2010	Metastatic breast cancer	Antimicrotubule
Everolimus	Afinitor	2009	Renal angiomyolipoma, SEGA, breast cancer, NET, RCC	mTOR kinase inhibitor
Ixabepilone	Ixempra	2007	Breast cancer	Antimicrotubule, taxane derivative
Ixazomib	Ninlaro	2015	Multiple myeloma	Proteasome inhibitor
Ms-275	Entinostat	2013	Breast cancer	HDAC inhibitor
Olaparib	Lynparza	2014	BRCA mutated advanced ovarian cancer	PARP inhibitor
Omacetaxine mepesuccinate	Synribo	2012	CML	Cephalotaxine, protein synthesis inhibitor
Pomalidomide	Pomalyst	2013	Multiple myeloma	Thalidomide analog
Pralatrexate injection	Folotyn	2009	Peripheral T-cell lymphoma	Antimetabolite
Romidepsin	Istodax	2009	CTCL	HDAC inhibitor
Rucaparib	Rubraca	2016	BRCA mutated advanced ovarian cancer	PARP inhibitor
Sipuleucel-T	Provenge	2010	Prostate cancer	CD54+ cells, autologous
Sonidegib	Odomzo	2015	Advance basal cell carcinoma	Hedgehog pathway inhibitor
Talimogene laherparepvec	Imlygic	2015	Recurrent melanoma	Oncolytic virus
Temsirolimus	Torisel	2007	RCC	mTOR kinase inhibitor
Trabectedin	Yondelis	2015	Liposarcoma or leiomyosarcoma	FUS-CHOP inhibitor
Trifluridine and tipiracil	Lonsurf	2015	Metastatic colorectal cancer	Antimetabolite
Venetoclax	Venclexta	2016	CLL with 17p deletion	Bcl-2 inhibitor
Vincristine sulfate liposomes	Marqibo	2012	ALL	Antimicrotubule, vinca alkaloid
Vismodegib	Erivedge	2012	Basal cell carcinoma	Hedgehog pathway inhibitor
Vorinostat	Zolinza	2006	CTCL	HDAC inhibitor

Additional abbreviations: CTCL, cutaneous T-cell lymphoma; SEGA, subependymal giant cell astrocytoma.

Table 2.

Antibody therapies recently approved by the FDA, their trade names, approval year, cancers for which they are approved, and their targets

Drug	Trade Name	Approval Year	Cancer	Antibody Target
Blinatumomab	Blincyto	2014	Ph− B cell ALL	CD19/CD3
Obinutuzumab	Gazyva	2013	CLL	CD20
Ofatumumab	Arzerra	2009	CLL	CD20
Brentuximab vedotin	Adcetris	2011	Hodgkin lymphoma, large cell lymphoma	CD30
Daratumumab	Darzalex	2015	Multiple myeloma	CD38
Ipilimumab	Yervoy	2011	Metastatic melanoma	CTLA-4
Necitumumab	Portrazza	2015	Metastatic squamous NSCLC	EGFR
Dinutuximab	Unituxin	2015	Pediatric neuroblastoma	GD2
Pertuzumab	Perjeta	2012	HER2+ metastatic breast cancer	HER2
Ado-trastuzumab emtansine	Kadcyla	2013	HER2+ metastatic breast cancer	HER2, antimicrotubule agent
Nivolumab	Opdivo	2015	Metastatic squamous NSCLC, metastatic melanoma	PD-1
Pembrolizumab	Keytruda	2014	Unresectable, recurrent, and metastatic melanoma	PD-1
Atezolizumab	Tecentriq	2016	NSCLC, urothelial carcinoma	PD-1 ligand
Olaratumab	Lartruvo	2016	Soft tissue sarcoma	PDGFRα
Elotuzumab	Empliciti	2015	Multiple myeloma	SLAMF7
Ziv-aflibercept	Zaltrap	2012	Metastatic colorectal cancer	VEGF
Ramucirumab	Cyramza	2014	Gastric cancer	VEGFR2

Fig. 1.

Neurotoxicities implicated with their cancer therapy targets within the neuraxis.

Fig. 2.

Neurohypophysitis with infundibulo-panhypophysitis induced by ipilimumab; arrow points to enhancing pituitary gland and stalk on a T1 post-gadolinium midline sagittal MRI.

Small-Molecule Kinase Inhibitors

Breakpoint Cluster Region–Abelson Murine Leukemia Kinase Inhibitors

Imatinib is the oldest of the tyrosine kinase inhibitors (TKIs), first approved in 2001, and now has 17 indications for use. Second-generation bosutinib has since emerged and been suggested to increase stroke risk, though the relative stroke risk against imatinib is uncertain. Three of the new-generation breakpoint cluster region–Abelson murine leukemia (BCR-Abl) TKIs (nilotinib, ponatinib, and dasatinib) demonstrate a moderately elevated risk of vascular occlusive events compared with imatinib.³ Nilotinib is a potent selective BCR-Abl kinase inhibitor that received FDA approval in 2007, and subsequent meta-data have indicated an increased risk of stroke, possibly via accelerating intra- and extracranial atherosclerosis or by potentiating a prothrombotic state.^4,5 Ponatinib has broad-spectrum efficacy against both mutated and nonmutated BCR-Abl1 and is the most effective known drug against specifically the BCR-Abl T315I kinase domain mutation. It was issued an FDA black box warning in 2012 for arterial and peripheral vascular complications noted in 24%–48% of patients.⁶ The mechanism for the induced vascular damage is unclear, though it may be attributed to being both pro-atherogenic as well as disabling to plaque-stabilizing endothelial cells. Lipid and blood glucose levels should be monitored while on therapy and may lead to long-term increased risk for stroke. Dasatinib is an Src/Abl TKI approved for patients with chronic myeloid leukemia (CML) refractory to imatinib. The most common side effect of dasatinib is headache, affecting at least one-third of patients, though it has also been associated with a risk for arterial occlusive events.⁷ Dasatinib has also been rarely implicated with a secondary effect of optic neuropathy causing visual field loss.⁸

Epidermal Growth Factor Receptor Inhibitors

The human epidermal growth factor receptor (HER), of the RTK superfamily, comprises epidermal growth factor receptor (EGFR; ErbB-1), HER2 (ErbB-2), HER3 (ErbB-3), and HER4 (ErbB-4). Afatinib, erlotinib, and gefitinib are the orally available EGFR inhibitors. Cetuximab and panitumumab are intravenously administered monoclonal antibodies against EGFR.⁹ Erlotinib and gefitinib are reversible EGFR TKIs used in metastatic non–small cell lung carcinoma (NSCLC) harboring EGFR mutations.¹⁰ Osimertinib is a third-generation EGFR TKI used in NSCLC. Fatigue is the most common neurological complaint of the EGFR inhibitors, affecting up to 90% of patients, and more likely when used in combination therapy.¹¹ Targeted therapies have become standard of care against metastatic breast cancer with HER2, a tyrosine kinase receptor overexpressed in 20%–30% of breast cancers. Patients with a good performance status are typically offered combination therapy of pertuzumab-trastuzumab and a taxane. Pertuzumab is a monoclonal antibody against the extracellular domain of HER2 dimerizing with other HER family members, while trastuzumab targets only HER2 homodimerization.^12,13 Trastuzumab emtansine (T-DM1) is a targeted antibody-drug conjugate of DM1, a maytansine derivative that inhibits microtubule polymerization with greater potency than the vinca alkaloids. There may be significant neurotoxicity, with 2.4% having grade ≥3 peripheral neuropathy compared with 0.2% in the lapatinib plus capecitabine group in the EMILIA trial.^14,15 While the brain is often the first site of metastasis in these patients, the blood–brain barrier is not penetrated well by pertuzumab and trastuzumab because of their large molecular weights. Lapatinib, approved in 2007, is a small-molecular inhibitor of HER2. Despite known CNS penetration, serious neurotoxicity remains uncommon, with 20%–41% reporting grade 1 headache per the Common Terminology Criteria for adverse events, as applied by the Common Terminology Criteria for Adverse Events.¹⁶

EGFR has also been an attractive target for inhibition by antibody therapy. Panitumumab is a human monoclonal antibody against EGFR, approved in 2006 for use against metastatic colorectal cancer, most effectively with Kras wild-type.¹⁷ With a side effect profile similar to other EGFR inhibitors, fatigue and malaise are the most common neurological complaints of these monoclonal antibodies. There have been at least 10 case reports of cetuximab-associated self-limiting aseptic meningitis occurring several hours after infusion.¹⁸ Necitumumab is an EGFR antibody used in combination therapy for metastatic squamous cell carcinoma. In the INSPIRE trial comparing necitumumab plus pemetrexed and cisplatin versus pemetrexed and cisplatin, there were greater arterial and venous thromboembolic events in the patients exposed to necitumumab without survival benefit.¹⁹

Multiple Receptor Tyrosine Kinases

Many of the vascular endothelial growth factor (VEGF) targeting agents have a similar side effect profile of fatigue, hypertension, thrombotic events, and risk for PRES. Sunitinib, FDA approved in 2006, is a multiple receptor TKI including targets VEGF receptor (VEGFR), RET (“rearranged during transfection”), and platelet-derived growth factor receptor (PDGFR). It is used in the treatment of gastrointestinal stromal tumor after progression on imatinib, renal cell carcinoma, and pancreatic neuroendocrine tumors. As targeted PDGFR antibody therapies have fairly low direct neurotoxicity, the effects may be more attributable to sunitinib’s VEGFR activity. There have been case reports of Guillain-Barré syndrome associated with sunitinib.^20,21 Neurological autoimmunity is thought to be a result of VEGFR inhibition leading to increased levels of both cerebrospinal fluid (CSF) and circulating VEGF, and this may destabilize the microvasculature at the choroid plexus. There, the excess VEGF enhances angiogenesis and increases local vascular permeability, and these increased VEGF levels are comparable to those seen in Guillain-Barré and chronic inflammatory demyelinating polyneuropathy.²⁰ The precise role of sunitinib in the primary immune response, however, has been debated and is not well understood. PRES has indeed been described in patients receiving sunitinib.²² The first TKI approved for metastatic medullary thyroid cancer, vandetanib, inhibits EGFR, VEGFR, and RET tyrosine kinase. Vandetanib has also been implicated in PRES in the context of clinical trials for primary brain tumors.^23,24 Axitinib, approved in 2012, is a potent second-generation VEGF inhibitor used in renal cell cancer, also carrying risk for PRES.^25–27 Lenvatinib is a multiple receptor kinase inhibitor against receptors, including VEGFR, fibroblast growth factor receptor (FGFR), PDGFR, RET, and c-Kit, and is used in progressive thyroid cancers or in combination with everolimus for renal cell carcinoma. It may also carry a similar side effect profile and appears to carry lower direct neurotoxicity than sunitinib.²⁸ Pazopanib is a multitargeted receptor TKI against c-Kit, FGFR, PDGFR, and VEGFR used in the treatment of renal cell carcinoma and soft tissue sarcoma. There is a reported rare toxicity of hallucinations associated with its use as well as PRES.^29,30 Regorafenib is an oral multikinase agent against VEGFR1/3, PDGFR, FGFR, tunica interna endothelial cell kinase 2, c-Kit, RET, Raf1, and B-Raf. It was first FDA approved in 2012 for colorectal cancer, also with low direct neurotoxicity, though with potential for VEGF target side effects.

Chronic lymphocytic leukemia (CLL) is typically treated with a combination of fludarabine, cyclophosphamide, and rituximab. Older and frail individuals with CLL or recurrent disease may not be good candidates for myelosuppressive therapy; therefore, newer agents have become attractive options for targeting the B-cell receptor pathway. Ibrutinib is a first-in-class oral irreversible inhibitor of Bruton tyrosine kinase (BTK), thereby downregulating nuclear factor-kappaB as well as several other kinases, including EGFR and Tec, as well as extracellular signal-regulated kinase (ERK).³¹ The side effects of BTK are typically mild; however, given its multiple targets, several side effects have been evident. In phase I/II studies for mantle cell lymphoma, 2% of patients had intracranial hemorrhage despite platelets being normal or slightly reduced.³² BTK is present on platelets, and bleeding is thought to be related to ibrutinib’s inhibition of collagen-dependent platelet aggregation.³³ Ibrutinib can cross the blood–brain barrier, with up to 7% of systemic dose found in CSF.³⁴ The most common CNS side effects are fatigue, dizziness, and headaches.³⁵ There has also been a report of PML after ibrutinib therapy for CLL.³⁶ Idelalisib is a first-in-class inhibitor of phosphatidylinositol 3-kinase (PI3K) delta that blocks BCR signaling as well as interrupting the homing of CLL cells from the lymph node. The PI3K inhibitors as a class are tolerated well neurologically and do not cross a healthy blood–brain barrier when studied in animals.³⁷ They do convey a high toxicity profile systemically with a black box warning for diarrhea/colitis, hepatotoxicity, pneumonitis, and intestinal perforation.

Anaplastic lymphoma kinase (ALK) inhibitors

Crizotinib has offered improved progression-free survival in patients with ALK-rearranged NSCLC, though with 40% experiencing metastatic progression to the CNS. CNS drug side effects are largely limited to fatigue and headache. There have been rare case reports of optic neuropathy associated with crizotinib.³⁸ Myalgias were present in almost a fifth of patients treated with alectinib, a more potent ALK inhibitor in ALK-rearranged NSCLC, with good CNS penetration and a CNS objective response rate of 57% in patients with baseline measurable CNS metastases.³⁹ Ceritinib is an alternative for patients with progression while on crizotinib.^40,41 Fatigue and neuropathy have been reported with its use, with neuropathy affecting 17% of patients.^42,43 Cabozantinib is a small-molecule inhibitor targeted against both c-MET and VEGFR2 for the treatment of medullary thyroid cancer and renal cell carcinoma. Cabozantinib may overcome crizotinib resistance in ROS1 fusion acquired mutations in NSCLC; blood pressure monitoring is recommended because of risk for hypertensive crisis and PRES.^44,45

BRAF Kinase Inhibitors

For the subset of patients with melanoma containing the BRAF V600 mutations, vemurafenib and dabrafenib are orally administered inhibitors of activated BRAF kinase. BRAF inhibitor therapies are radiation sensitizers, and consensus guidelines recommend avoiding its use several days prior to and after radiation in order to limit skin toxicity within the field in conventional fractionated radiotherapy.^46,47 Stereotactic radiotherapy with concurrent BRAF inhibitors for melanoma may pose a risk of cerebral edema and hemorrhage; overall, severe cerebral edema was seen in 15% of patients.⁴⁸ There have been several reported cases of bilateral facial nerve palsy associated with vemurafenib use.^49,50 The presumed mechanism is unclear but presumed to be immune mediated, as steroids appear to resolve symptoms.

MEK Inhibitors

Trametinib and cobimetinib are oral mitogen-activated protein kinase kinase (MEK) inhibitors used in melanoma with BRAF V600 mutations. They are used in combination therapy alongside BRAF inhibition.⁵¹ Patients receiving combination therapy may experience pyrexia, alleviated by low-dose corticosteroids. Elevated creatine phosphokinase is not uncommon. Rhabdomyolysis and retinal detachment with a serous retinopathy are class effects of MEK inhibitors, affecting about 1% of patients.⁵²

Cyclin-Dependent Kinase Inhibitor

Palbociclib is a small-molecule inhibitor of cyclin-dependent kinases 4 and 6 used in advanced hormone receptor– positive patients. Mild neurotoxicities have been reported in its use, such as myalgia, fatigue, and dysgeusia.⁵³

Other Novel Inhibitors

Hedgehog Pathway Inhibitors

Sonidegib and vismodegib are Smoothened antagonists targeting the hedgehog pathway for the treatment of basal cell carcinomas. Both sonidegib and vismodegib have class-specific neurotoxicities of dysgeusia, myalgia, and muscle spasms.⁵⁴ The hedgehog pathway is known to have activity in the taste papillae, and dysgeusia rates are as high as 57% in studies using vismodegib.⁵⁵ Zinc gluconate supplementation may help in dysgeusia management.

Histone Deacetylase Inhibitors

While histone deacetylase (HDAC) compounds have several different classifications of chemical structures, they possess a similar toxicity profile. Vorinostat, belinostat, and panobinostat are all hydroxamic acids, while romidepsin is a depsipeptide, and entinostat is a benzamide. All have activity against class 1 HDAC enzymes but different activities against other HDAC isoenzymes. Fatigue is a common constitutional symptom seen in all HDAC inhibitors, with dose-limiting toxicity in a quarter of patients in phase II trials.⁵⁶

Mechanistic TOR Kinase Inhibitors

The first generation of mechanistic target of rapamycin (mTOR) inhibitors are the rapalogs, including rapamycin, everolimus, and temsirolimus, with forthcoming second- and third-generation agents. The rapalogs share a common class effect, and while these may be very severe to other organ systems, the rate of direct neurological side effects is rare. Rapamycin treatment has been attributed to the development of PRES in organ transplant patients.⁵⁷ Rapalogs induce hyperglycemia and an mTOR-induced diabetes, and there is an mTOR-induced dyslipidemia which may elevate risk for stroke.⁵⁸ Phosphate levels may be reduced, which may manifest as fatigue and muscle weakness.

PARP Inhibitors

Olaparib and rucaparib are oral poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer in patients with breast cancer (BRCA) mutation and prior chemotherapy. Neurotoxicity is minimal, with the most common toxicity being fatigue.⁵⁹ Nearly half of patients on rucaparib had mild dysgeusia.⁶⁰

Protein Synthesis Inhibitors

Omacetaxine mepesuccinate, formally homoharringtonine, is a subcutaneously delivered protein synthesis inhibitor intended for patients with CML with intolerance to 2 or more TKIs. It received accelerated FDA approval in 2012, and safety data revealed significant hematological toxicity, with high-grade thrombocytopenia occurring in 76% of patients and reported deaths from intracerebral hemorrhage.⁶¹

Proteasome Inhibitors

Second-generation proteasome inhibitors are now approved for treatment of multiple myeloma. Carfilzomib and ixazomib have demonstrated less painful sensory neuropathy than bortezomib, which tends to carry a high rate of neuropathy.^62,63 The CIPN is typically reversible with drug discontinuation or dose reduction, though this may take months to years. Ixazomib is a once weekly fixed dose oral therapy and is considered to carry the lowest incidence of CIPN.⁶⁴ As it is used now, the sensory neuropathy reported is typically grade 1 or 2 and this is likely related to prior exposure to bortezomib.⁶⁵

B-cell Lymphoma 2 Inhibitor

Venetoclax is a first-in-class B-cell lymphoma (Bcl-2) inhibitor newly approved for use in hematological malignancies. Despite significant hematological toxicity, neurotoxicity is limited to low-grade fatigue (40%) and headache (24%).⁶⁶

Antibody Therapies

Anti-CD20 Antibodies

Postmarketing data of rituximab found that 22 patients developed PML in 2006; in 2007, the FDA issued a black box warning for all anti-CD20 antibodies. Ofatumumab is a human type I CD20 monoclonal antibody FDA approved in 2014 for second-line treatment of CLL. Obinutuzumab is a type II monoclonal antibody against CD20 approved in 2013 and is used against CLL and follicular lymphoma. Obinutuzumab provokes more direct cell-mediated cytotoxicity than the type I antibodies, which tend to be stronger activators of complement-mediated cytotoxicity. Obinutuzumab has been implicated in an increased risk for PML.⁶⁷ Patients receiving monoclonal antibody treatment may present with different clinical features from those presenting with classic PML, such as sensory changes and seizures.⁶⁸ Definitive diagnosis, according to 2013 guidelines, is made by confirming the presence of John Cunningham (JC) virus in CSF by PCR, or brain biopsy if JC virus is undetectable in CSF and alternative explanations are unrevealing.⁶⁹

Vascular Endothelial Growth Factor Antibodies

Bevacizumab is a monoclonal immunoglobulin (Ig)G1 antibody against human VEGF with multiple clinical applications and a shared side effect profile with other anti-angiogenic agents against VEGF and its receptor. As a class, inhibitors against VEGF include hypertension, proteinuria, and delayed wound healing. The anti-VEGF-mediated hypertension may be a product of nitric oxide pathway inhibition and oxidative stress.⁷⁰ Thromboembolic events have been reported, and in 2006, bevacizumab label was updated to indicate increased risk of PRES.^71,72 Ziv-aflibercept is a fusion protein of IgG1 fused to binding portions of VEGFR used in metastatic colorectal cancer. Both arterial and venous thromboembolism have been seen with its use, likely due to its effects on VEGF. In a phase III study, thromboembolic events were seen in 9.7% of the treatment arm compared with 6.8% in the control arm.⁷³ Ramucirumab is a monoclonal antibody against the extracellular domain of VEGFR2 and is used as salvage therapy in gastric and colorectal cancer. It carries similar toxicities as the aforementioned anti-angiogenic agents.⁷⁴

Platelet-Derived Growth Factor Receptor Antibodies

Olaratumab, targeted against PDGFR alpha, was approved in late 2016 for use in soft tissue sarcoma in combination with doxorubicin. Fatigue affects 69% of patients in both the olaratumab and doxorubicin cohorts.⁷⁵

Anti-Glycolipid Antibodies

Dinutuximab, also referred to as ch14.18, is an anti-glycolipid disialoganglioside (GD2) monoclonal antibody used in combination with cytokines, isotretinoin, and granulocyte-macrophage colony-stimulating factor for the maintenance treatment of high-risk pediatric neuroblastoma. Gangliosides are glycosylated lipid molecules, and low levels of GD2 are found on the surface of normal neurons and peripheral nerve fibers. There are fairly high GD2 levels on the cell surface of neuroblastoma, and dinutuximab triggers an antibody-dependent cell-mediated cytotoxity when it binds to GD2.⁷⁶ Severe neuropathic pain, more so abdominal than in the extremities, has been seen in the first cycle, then typically dissipates in subsequent cycles, and is typically opioid resistant. Because of the pain experienced, the package insert warns against neuropathy, and the FDA has issued a boxed warning for neuropathic pain with recommendations to palliate pain, including pretreatment with acetaminophen and opiates.

Other Monoclonal Antibodies

Daratumumab is a first-in-class anti-CD38 monoclonal antibody used in multiple myeloma with no significant neurotoxicity aside from mild fatigue.⁷⁷ Elotuzumab, also used against multiple myeloma, targets signaling lymphocytic activation molecule F7 (SLAMF7), which is minimally present on normal healthy tissues. The most common neurotoxicity is fatigue, affecting half of patients receiving it, and muscle spasms affecting 30%.⁷⁸ Blinatumomab is a monoclonal antibody that engages CD3-CD19 in hematological malignancies. Due to its robust immune activation, it carries a black box warning for cytokine release syndrome and neurotoxicity.⁷⁹ These toxicities are dose dependent, and 13%–22% of patients on blinatumomab have grade 3 or greater neurological adverse events.^80,81 Blinatumomab releases pro-inflammatory cytokines which peak 2–48 hours after the first dose.⁸² Neurological symptoms are likely due to pro-inflammatory cytokines at the neuroendothelium.⁸³ Patients may present with seizures, encephalopathy, coma, aphasia, or imbalance occurring about a week after therapy. Neurotoxicity prophylaxis involves premedication with dexamethasone. In a phase II BiTE trial, a fifth of patients had grade 3 neurotoxicity, most commonly encephalopathy, somnolence, and disorientation. Symptoms were treated with dexamethasone 8 mg i.v. every 8 hours for 3 days followed by a taper with complete resolution in all but one patient in each cohort.⁸⁴

Immunotherapies

The immune system plays a pivotal role in recognizing and preventing the growth of cells with tumorigenic potential, and tumors may hold immune resistance through altered immune checkpoint pathways. Checkpoint molecules include the newly targeted programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4). The treatment for metastatic melanoma, in particular, has made substantial progress in recent years with the use of checkpoint inhibitors.⁸⁵ Common side effects include mild fatigue and headache, with grade 3 cases affecting less than 3% of patients. Autoimmune toxicities from checkpoint inhibitors are typically distinct from cytokine therapy toxicities, with a majority of the events involving the skin, gastrointestinal tract, and the endocrine system, including hypophysitis and thyroid disorders.⁸⁶ Typically, an autoimmune adverse event occurs within the first 3 months of therapy. The use of steroids to mitigate autoimmune toxicity has not been shown to affect the overall efficacy of the therapy.⁸⁷ Both the CNS and peripheral nervous system have been vulnerable to autoimmunity. CNS demyelination has been reported in conjunction with checkpoint inhibitors for several cases. One case report reveals a patient on ipilimumab, a CTLA-4 inhibitor, with both acute optic neuritis and focal CNS neurological deficits complementary to the demyelination seen on MRI and later confirmed by biopsy.⁸⁸ Another patient had a severe multiple sclerosis relapse after being treated with ipilimumab for melanoma.⁸⁹ A metastatic melanoma patient being treated with nivolumab, an IgG4 anti–PD-1 monoclonal antibody, had a demyelinated tumefactive lesion with extensive CNS demyelination on autopsy in the absence of CNS metastases.⁹⁰ Pembrolizumab also targets PD-1 and is used in treating metastatic melanoma. There are rare cases of peripheral inflammatory neuropathy, Guillain-Barré syndrome, and myasthenia gravis with the application of these agents.⁹¹ Both sensory and motor immune-mediated polyneuropathies occur in less than 1% of patients.⁹² Typically the neuropathic symptoms are mild and steroid responsive and do not require discontinuation of therapy. There are rare cases of more severe and refractory steroid-responsive polyradiculitis and meningoradiculitis while on checkpoint inhibitors.⁹³ Meningoradiculitis was diagnosed in a patient on anti–PD-1 therapy with proximal arm pain with weakness which was responsive to oral steroids but recurrent when steroids were discontinued.⁹⁰ Another patient from the same series presented with leg weakness and paresthesia, with an MRI revealing contrast enhancement of the caudal nerve fibers. The patient’s immune-mediated polyradiculitis was diagnosed and treated with steroids and his checkpoint inhibitor was discontinued, but he subsequently developed progressive disease. A demyelinating polyradiculopathy has also been implicated with anti–PD-1 therapy.⁹⁴ There have been a dozen case reports of newly diagnosed seropositive and seronegative myasthenia gravis while on checkpoint inhibitors.⁹⁵ These cases widely vary in their patient outcomes to treatment regimens of steroids, plasmapheresis, intravenous immunoglobulin, or a combination. Inflammatory myopathy, dermatomyositis, and myositis have also been described. Dermatomyositis was described in a patient receiving ipilimumab, presenting with a cutaneous eruption followed by acute proximal muscle weakness and a significantly elevated creatine kinase and aldolase.⁹⁶ Ipilimumab was discontinued and the dermatomyositis was responsive to high-dose steroids. Early recognition of neurotoxicities may mitigate their severity, with corticosteroids being the primary therapy for immune-oncology drug-related reactions. Low-grade toxicities may be treated with oral steroid dosing strategies, while more severe toxicities may be addressed with intravenous steroids, with more severe cases even considering i.v. Ig.⁹¹

Hypophysitis is a known toxicity of both anti–CTLA-4 and PD-1 inhibition and may occur in up to 5% of patients.⁹⁷ It may present as a variety of neurological symptoms, including fatigue and headache. Hypophysitis is diagnosed by measuring low pituitary hormone levels, and a brain MRI may show enhancement or enlargement of pituitary or its infundibulum (Fig. 2). Treatment typically consists of high-dose steroids and hormone supplementation. Atezolizumab is a PD-1 ligand inhibitor approved in 2016 for urothelial carcinoma and NSCLC. No serious neurological immune-related adverse events have yet been described in its phase II trials (BIRCH, POPLAR, FIR).⁹⁸

Classical Therapies

Antimicrotubule Agents

Chemotherapy-induced peripheral neuropathy (CIPN) is a familiar side effect of many conventional vinca alkaloids, cisplatin, taxanes, and thalidomide agents. In 2012, vincristine emerged in a sphingomyelin/cholesterol encapsulated form (VSLI) for the treatment of relapsed Philadelphia chromosome negative acute lymphoblastic leukemia (ALL).⁹⁹ This formula was designed for improved drug exposure to the tumor while reducing systemic toxicity. Peripheral neuropathy remains the most common dose-related nonhematological toxicity, with 10% requiring discontinuation of the therapy.¹⁰⁰ In one study of ALL patients receiving VSLI at 2.25 mg/m², patients could tolerate higher dosing with no reported grade 3 peripheral motor neuropathy and lower rates of neuropathy and paresthesia than what is reported for patients receiving standard vincristine at 1.4 mg/m².¹⁰¹ CIPN can also be a dose-limiting toxicity with several newer microtubule-binding agents—eribulin mesylate, cabazitaxel, and ixabepilone. Within this class, paclitaxel and ixabepilone have highest risk for high-grade neuropathy, while eribulin conveys a lower risk despite higher dorsal root ganglion penetration.¹⁰² Optic neuropathy has also been reported in both older taxanes as well as cabazitaxel, approved since 2010 for hormone-refractory prostate cancer.¹⁰³ Overall, there is a lower frequency and grade of both neuropathy and dysgeusia in prostate cancer patients receiving cabazitaxel compared with docetaxel.¹⁰⁴

Brentuximab vedotin is an anti-CD30 antibody-drug conjugate approved for the treatment of relapsed Hodgkin lymphoma.¹⁰⁵ Its vinca-like action on axonal transport is likely the mechanism of the peripheral neuropathy associated with it, though the neuropathy appears to be dose dependent and usually resolves after discontinuation of the drug.¹⁰⁶ Additionally, its action against CD30 has implicated it in the reactivation of the JC virus leading to PML.

Antimetabolites

Since 2009 a potent intravenous folate analog pralatrexate has come to market with a milder toxicity profile than methotrexate and is currently in use for refractory T-cell lymphomas. Pretreatment with folic acid and vitamin B12 injections mitigate toxicity, and its potential efficacy is being explored in clinical trials for other lymphoid malignancies.¹⁰⁷ Trifluridine/tipiracil is an oral antimetabolite consisting of a thymidine-based nucleoside analog with a thymidine phosphorylase inhibitor. It was FDA approved in 2015 for the treatment of metastatic colorectal cancer and carries low direct neurotoxicity. In the RECOURSE trial, while hematological adverse events were significant, less than 40% of patients reported fatigue and <5% had greater than grade 2 nonhematological toxicities.¹⁰⁸

DNA-Damaging Agents

Trabectedin is approved for use in liposarcoma and leiomyosarcoma previously treated with anthracyclines. It is a tetrahydroisoquinoline with multiple mechanisms of action, including direct binding to DNA leading to strand breaks and inhibiting tumor angiogenesis in the microenvironment.¹⁰⁹ While there is significant hematological and hepatic toxicity, no direct neurotoxicity has been reported in clinical trials.¹¹⁰

Immunomodulatory Imide Drugs

There has been further development of thalidomide analogs for myeloma and lymphoma, namely lenalidomide for mantle cell lymphoma and pomalidomide for multiple myeloma and myelofibrosis. Historically developed as a sedative, the most common neurological side effect of thalidomide and its analogs is somnolence. However, the analogs are reported to have less central and peripheral neurotoxicity than thalidomide.¹¹¹ While a axonal sensory neuropathy is clinically present in up to 50% of patients, neuropathy can also be mild or subclinical, only detectable by electromyography.^112,113

Anti-Androgen Therapy

Abiraterone is an anti-androgen therapy used in the treatment of prostate cancer. Fatigue is the most common severe neurotoxicity, occurring in 9% in its landmark trial.¹¹⁴ Enzalutamide is a second-generation androgen receptor antagonist. The AFFIRM trial reported a high risk for fatigue, and rare incidences of seizure were also reported.¹¹⁵ The subsequent PREVAIL trial excluded patients with history of seizure disorder. Degarelix is a gonadotropin-releasing hormone antagonist with mild neurological symptoms of fatigue not requiring discontinuation of treatment.¹¹⁶

Future Directions

Manipulating the immune system has been an appealing mechanism against malignancy, with recent improved survival and disease control in metastatic melanoma using ipilimumab. There are over 500 open immunotherapy clinical trials in the USA at the time of this review. Sipuleucel-T is an autologous cellular immunotherapy for the treatment of metastatic prostate cancer. It was FDA approved in 2010, and in clinical trial may present a slightly elevated risk for cerebrovascular events.¹¹⁷ Talimogene laherparepvec is the first oncolytic viral therapy approved in the USA, and it is injected directly into melanoma lesions with the intention to create a local antitumor response.¹¹⁸ In the future we may look forward to chimeric antigen receptor (CAR)–modified T-cell therapies, which are retargeted T cells used in adoptive immunotherapy.¹¹⁹ Their chimeric receptors are composed of a specific antigen binding domain and an intracellular T-cell activation domain. This allows an immunocompetent T cell to be redirected against a new antigen such as a tumor protein, DNA, or other biological material.¹²⁰ Ideally, these will have a high specificity for the target and low long-term immunity against off-target host tissue. In clinical trials of patients receiving CAR T-cell infusions, there have been several case reports of what appears to be a cytokine release syndrome with neurological toxicity, similar to that of blinatumomab.¹²¹ Patients are described as having delirium, EEG confirmed seizures, and altered mentation requiring airway support with mechanical ventilation. CAR T cells have been found in the CSF of some of these patients by quantitative PCR.¹²² Reversible neurological toxicity uses CD19-CAR T cells found in CSF, with one reversible splenial lesion syndrome.¹²³ Tocilizumab, an antibody that blocks interleukin-6 receptor, has been used to mitigate cytokine storm.¹²⁴

Funding

No funding sources.

Conflict of interest statement. No conflicts of interest.