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.

Chemotherapy-induced peripheral neuropathy

CIPN (also see Chapter 28 for further case-based discussion of CIPN) is among the most common long-term adverse effect of many antineoplastic agents, and decreases QOL in cancer survivors with symptoms that include pain in the hands and feet with associated inability to complete basic activities of daily living (ADLs) and risk of falling. It has been estimated that injuries are three times as common in patients with CIPN as in those without neuropathy. CIPN is likely underdiagnosed by clinicians, especially in younger age groups. CIPN may require dose modifications and treatment interruptions, thereby negatively influencing patient survival as well. The most common offending drugs include docetaxel and paclitaxel (e.g., taxanes), platinum compounds, vinca alkaloids, and the proteasome inhibitor bortezomib. For these drugs, neuropathy may be the dose-limiting toxicity. A metaanalysis of over 4,000 patients estimated CIPN prevalence to be about 68% at the end of the first month and 30% at 6 months. In a study of 121 childhood cancer survivors who received chemotherapy before age 17 with a median of 8.5 years of follow-up, over half treated with vinca alkaloids and platinum compounds continued to have lower limb sensory axonal neuropathy and deficits in manual dexterity, distal sensation, and balance consistent with CIPN. Often these symptoms (which may be greater in the presence of comorbidities such as diabetes mellitus and patients’ age) are not specifically addressed in follow-up of childhood cancer survivors, and multimodal testing with objective neurophysiologic measures and subjective patient-reported outcome measures is important.

Treatment-related peripheral neuropathies must be distinguished from those similarly appearing immune-mediated neuropathies associated with a limited number of cancers such as multiple myeloma (e.g., POEMS), thymoma (e.g., anti-CV2 sensorimotor), lymphoplasmacytic lymphoma (previously known as Waldenstrom’s), and small-cell lung cancer (e.g., paraneoplastic anti-Hu antibody dorsal root ganglionopathy) (see Chapter 20 for further discussion of paraneoplastic neurological syndromes). Sensory neurons in the dorsal root ganglia lack a blood-brain barrier (BBB) and therefore can be more vulnerable to systemically administered chemotherapy toxins than are motor neurons. Large myelinated fibers are affected by platinum drugs and small fibers are preferentially affected by taxanes and microtubule poisons such as vincristine. Toxicity is dose dependent and may continue to worsen after cessation of chemotherapy, a phenomenon called coasting. The neuropathy from oxaliplatin and bortezomib improves slowly, though up to a third of patients may have persistent discomfort with burning dysesthesias, proprioceptive problems, and/or allodynia that impair QOL.

Unfortunately, no therapy for CIPN has been approved by the Food and Drug Administration (FDA), and duloxetine is the only drug with modest demonstrated benefit in a prospective randomized clinical trial (RCT). Neurologic consultants offer helpful input by ruling out alternative explanations, including immune-mediated demyelinating neuropathies or spinal cord pathology that require investigation with imaging or spinal fluid sampling for leptomeningeal involvement. Neurologists can define the severity of neuropathy to guide decisions about whether symptoms will be worsened by additional neurotoxic regimens.

Clinical cases

The following cases illustrate the often-multifactorial dilemmas that result from successful cancer therapy.

Case 27.1

Ongoing Infectious Risks Many Years After Successful Chemotherapy

Case . A 68-year-old man presented with a 3-month history of clumsiness of the left hand, balance difficulties, and dysarthria. Forty-one years earlier he had been treated for stage 1A nodular sclerosing Hodgkin’s disease with mechlorethamine hydrochloride, vincristine, procarbazine, and prednisone (MOPP), splenectomy, and extended field radiation of 2000 cGY to the mantle field (e.g., all lymph node areas in the neck, chest, and arms). Coronary artery disease presented at age 50 years (he had stopped smoking at age 35 years), and he underwent triple coronary artery bypass grafting. MRI showed a non-enhancing lesion of the left cerebellum ( Fig. 27.1 ). The differential diagnosis was thought to be PML versus a low-grade radiation–induced glial neoplasm. He was HIV negative with a CD4+ count of 170 cells/mL (duration unknown, as it had not been regularly measured in the many decades since his original treatment). He had acellular cerebrospinal fluid (CSF) that was negative for John Cunningham virus (JCV). However, brain biopsy revealed PML, and he received pembrolizumab as part of an investigational trial. Subsequently, he was found to have a second, probably radiation-induced tumor, a mesothelioma subsequently found on PET/CT.

This MRI fluid-attenuated inversion recovery sequence shows an area of hyperintensity in the left cerebellum that does not produce significant mass effect and that did not show enhancement on gadolinium-enhanced MRI sequences (not shown). The radiographic differential diagnosis was low-grade glial neoplasm or progressive multifocal leukoencephalopathy.

Teaching Points . This case demonstrates the long-term risk of infection that extends well beyond the initial active treatment period. A high index of suspicion was needed, as commercially available testing for JCV was initially negative and a brain biopsy was required to establish the diagnosis and open up options for clinical trial therapy.

Clinical Pearls

• 1.
  

  The risk for infection continues well beyond the active treatment period.

  
  
• 2.
  

  CSF can be negative for JC virus when tested by commercially available methods.

  
  
• 3.
  

  CSF formulas in immunocompromised patients can fail to reflect inflammation in the presence of cytopenias or impaired immune response.

  
  
• 4.
  

  PML can have variable appearances with or without contrast enhancement.

  
  
• 5.
  

  Immunocompromised patients should have screening CT/MRI before lumbar puncture.

  
  
• 6.
  

  There is no established therapy for PML, but pembrolizumab is being investigated.

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