Approach to the patient with a delayed posttreatment CNS neurotoxicity

Introduction

With significant advances in cancer treatment, both the number of long-term cancer survivors and the complications to which these patients are vulnerable have grown. These complications can involve the peripheral and/or central nervous systems, significantly impairing quality of life (QOL) and not infrequently affecting overall survival. This chapter complements other chapters’ discussion of treatment-related complications, concentrating on those that occur after the acute phase of chemotherapy or combined modality regimens. The chapter begins with a brief discussion of some of the peripheral nervous system complications that can occur following chemotherapy and targeted treatments for cancer—and some of these are discussed in further detail in subsequent chapters (see Chapter 28 for discussion of chemotherapy induced peripheral neuropathy). This is followed by a case-based review of central nervous system complications of systemic therapies. Complications unique to immunotherapies and chimeric antigen receptor (CAR) T-cell interventions are covered in Chapter 29, Chapter 30 , respectively.

Overview of chemotherapy

Table 27.1 summarizes the common complications of cytotoxic and targeted therapies based on the syndrome, etiology, and acuity of the neurological problem. Table 27.2 emphasizes the special adverse effects and drug interactions of corticosteroids, one of the most ubiquitous agents used in oncology. Corticosteroid complications are both dose and duration dependent.

Both nervous and extra-nervous complications may occur following systemic treatments for cancer. Within the neuroaxis, both central nervous system (CNS) and peripheral nervous system (PNS) complications can occur. In the PNS, chemotherapy-induced peripheral neuropathy (CIPN) is the most common late complication of chemotherapy, whereas in the CNS, neurocognitive dysfunction is the most common. Systemically, a number of late effects predispose patients to infectious, toxic, metabolic, and immune-mediated complications of cancer treatment including long-term hematologic toxicities, endocrinopathies, and infections.

Hematologic toxicities

High-grade cytopenias are less common in standard adult brain tumor therapy than in regimens for other malignancies. Nitrosoureas are more likely than temozolomide to produce significant cytopenias, but chronic high-grade lymphopenia with the latter can predispose to Pneumocystis jirovecii (PJP) and other infections. It is recommended that PJP prophylaxis be given to patients being treated with chemoradiation on the Stupp regimen (see Chapter 4 for background on evidence-based chemotherapies for brain tumors). PJP has been reported in other brain tumor patients treated with chemotherapy and radiation such as primary CNS lymphoma (PCNSL). It is appropriate to follow serial lymphocyte counts and consider prophylaxis when lymphocyte counts are <500 cells/mL, but no clear guidelines have been prospectively validated.

The American Society of Clinical Oncology (ASCO) recommends a threshold of 10,000 platelets for prophylactic transfusion in solid tumors, but clinicians may consider a threshold of 20,000 for patients with necrotic tumors at increased risk of intracranial hemorrhage: there is an absence of firm data. For neurosurgery, platelet counts of >100,000 are preferable and should be at least >75,000 cells/mL.

Endocrine and fertility issues

Alkylating agents are among the most gonadotoxic chemotherapy drugs, resulting in follicular depletion, destruction of oocytes, and premature ovarian failure. In some men, drugs such as temozolomide may have deleterious effects on sperm counts, sperm motility, and sperm density that appear to be transient in most but may be permanent.

Treatment-induced infectious complications

Immune-suppressive agents such as cyclophosphamide, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, mitoxantrone, and methotrexate predispose patients to a wide range of bacterial, fungal, and viral pathogens, whereas immunomodulatory drugs confer a generally lower risk of infection, as they target only one or a few immune system components. Table 27.1 summarizes reported CNS infections associated with commonly used antineoplastic agents. Common among these infections is reactivation of herpesviruses with disseminated varicella zoster (VZV) or cytomegalovirus (CMV). Rituximab-related infections include progressive multifocal leukoencephalopathy (PML), CMV, enterovirus meningoencephalitis, increased severity of West Nile, Babesiosis, and PJP. Reactivation of hepatitis B can occur and re-vaccination may be necessary.

Clinicians should consider the patient’s underlying cancer diagnosis and treatment regimen when evaluating infectious complications. For patients on active treatment, timing of prophylactic and vaccination strategies should be considered to avoid blood count nadir. Clinicians should be aware of transfusion safety, travel and zoonotic exposures, community and nosocomial epidemiologic trends, and remember that presentation and course of any pathogen in a cancer patient may be different from those of patients without immune-compromising conditions. Radiation and chemotherapy complications may mimic infection with novel syndromes.