Article 1: Adult Gliomas
Howard Colman, MD, PhD, FAAN. Continuum (Minneap Minn). December 2020; 26 (6 Neuro-oncology):1452–1475.
PURPOSE OF REVIEW
This article highlights important aspects of the evaluation, diagnosis, and treatment of adult gliomas, including lower-grade astrocytomas and oligodendrogliomas, glioblastomas, and ependymomas.
The appropriate initial evaluation and accurate diagnosis of gliomas require an understanding of the spectrum of clinical and radiographic presentations. Recent advances in the understanding of distinct molecular prognostic subtypes have led to major revisions in the diagnostic classification of gliomas. Integration of these new diagnostic and molecular classifications is an important part of the modern management of gliomas and facilitates better understanding and interpretation of the efficacy of different therapies in specific glioma subtypes.
The management of adult gliomas is a multidisciplinary endeavor. However, despite recent molecular and treatment advances, the majority of diffuse gliomas remain incurable, and efforts aimed at the development and testing of new therapies in clinical trials are ongoing.
- Adult gliomas are a clinically, radiographically, histologically, and molecularly heterogeneous group of tumors.
- The clinical presentation and symptoms of gliomas are often related to anatomic location.
- The acuity of symptoms and presentation are often related to the tumor growth rate.
- MRI is more sensitive than CT for the diagnosis of potential gliomas and other brain tumors.
- Careful consideration of history, clinical factors, and imaging is needed to develop an accurate differential diagnosis in the evaluation of a newly presenting patient with imaging potentially consistent with glioma.
- The differing molecular features of diffuse gliomas are associated with distinct diagnoses and prognoses.
- The revised 2016 World Health Organization (WHO) classification of gliomas incorporates histologic and molecular features into an integrated diagnosis.
- The major molecular alterations used for diagnosis and classification of gliomas include isocitrate dehydrogenase (IDH) mutation status, chromosome 1p/19q status, and H3K27M mutation status.
- The majority of lower-grade (grade II and III) astrocytomas and oligodendrogliomas have IDH mutations.
- Loss of chromosomes 1p/19q is the molecular hallmark that distinguishes oligodendroglial from astrocytic gliomas within the IDH-mutant group.
- For the diagnosis of either astrocytoma or anaplastic astrocytoma with IDH mutation, the presence or absence of other molecular alterations including CDKN2 loss may be more important than the actual WHO grade for prognosis.
- The vast majority of primary glioblastomas in older adults are IDH-wildtype, and even lower-grade IDH-wildtype astrocytic tumors with appropriate molecular alterations (EGFR or chromosome 7 gain/chromosome 10 loss or TERT promoter) can be classified as diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV.
- H3K27M mutations are the hallmark of diffuse midline glioma, which most commonly occur in the pons and diencephalon in younger patients and are associated with poor prognosis.
- Initial treatment for most diffuse gliomas starts with maximal safe resection.
- O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation is both a prognostic marker in glioblastoma and a predictive marker of a better outcome with temozolomide.
- Standard treatment options with survival benefit in randomized studies for newly diagnosed glioblastoma include radiation, temozolomide, and tumor treating fields.
- Bevacizumab is US Food and Drug Administration (FDA)-approved for recurrent glioblastoma based on improved progression-free survival in randomized studies, but this agent has not demonstrated an overall survival benefit in glioblastoma.
- In older patients with newly diagnosed glioblastoma, a hypofractionated course of radiation is a consideration with or without temozolomide or tumor treating fields.
- The combination of radiation and chemotherapy (either procarbazine, lomustine [CCNU], and vincristine [PCV] or temozolomide) has been proven more effective for prolonging survival than radiation alone in lower-grade diffuse gliomas with IDH mutation.
- Participation in a clinical trial is an important consideration in the treatment of all histologies, grades, and molecular subtypes of glioma.
Article 2: Central Nervous System Lymphomas
Christian Grommes, MD. Continuum (Minneap Minn). December 2020; 26 (6 Neuro-oncology):1476–1494.
PURPOSE OF REVIEW
Primary central nervous system (CNS) lymphoma is a rare, aggressive extranodal non-Hodgkin lymphoma confined to the brain, eyes, CSF, or spinal cord without systemic, non-CNS involvement. This article reviews the clinical presentation, imaging characteristics, diagnostic workup, novel pathophysiologic insights, and treatment of immunocompetent patients with primary CNS lymphoma.
The prognosis of primary CNS lymphoma has significantly improved over the past few decades because of the introduction of and widespread use of high-dose methotrexate, which is now the backbone of all first-line combination chemotherapy treatments. Despite this progress, durable remission is still observed in only approximately 50% of patients. Novel insights into the pathophysiology of primary CNS lymphoma have identified the B-cell receptor pathway as well as the suppressed tumor immune microenvironment and immune evasion as key mechanisms in the pathogenesis of primary CNS lymphoma. Novel, small molecules and agents targeting these aberrant pathways have been introduced into clinical trials of recurrent/refractory primary CNS lymphomas. Agents such as the Bruton tyrosine kinase (BTK) inhibitor ibrutinib or immunomodulatory drugs such as lenalidomide and pomalidomide have shown promising response rates in the relapsed setting.
Diagnosis of primary CNS lymphoma requires a high level of suspicion because clinical signs and deficits can vary and depend on the involved CNS compartments. Rapid initiation of therapy is essential for recovery and prognosis. The optimal treatment regimen has not been defined, but methotrexate-based chemotherapy regimens are considered the standard treatment approach for induction treatment. Novel, targeted agents have recently been introduced into the therapeutic arsenal.
- The majority of primary central nervous system (CNS) lymphoma cases are diffuse large B-cell lymphomas that cause neurologic deficits within weeks. Primary CNS lymphoma is highly sensitive to high-dose methotrexate with some long-term survivors after treatment with methotrexate alone. Still, the rate of long-term disease control is lower than in lymphomas outside the brain.
- Neurologic deficits depend on the area of the CNS affected by primary CNS lymphoma. The diagnosis, therefore, requires a high level of suspicion.
- MRI is the standard imaging modality for primary CNS lymphoma. Primary CNS lymphoma lesions are characterized by homogeneous enhancement and usually affect deep brain structures.
- Diagnosis of primary CNS lymphoma should be based on tissue collected through a biopsy. Vitreous biopsy or CSF can also add diagnostic value. Corticosteroid use before diagnosis could lead to partial radiographic response and false-negative biopsy results.
- Surgery is only used to collect tissue for the histopathologic diagnosis through stereotactic biopsy. No survival benefit from surgical resection has been proven.
- The majority of primary CNS lymphomas are of the non–germinal center subtype. The B-cell receptor signaling pathway is affected by frequent recurrent mutations and seems to play an essential role in primary CNS lymphoma pathogenesis. The role of immune evasion markers (programmed cell death 1 or programmed death ligand 1) is currently less clear.
- Baseline evaluations in primary CNS lymphoma should include clinical, laboratory, and radiographic evaluations to document CSF or ocular involvement as well as systemic lymphoma. The detection of systemic lymphoma will lead to a change in management and chemotherapy choice.
- The two most important prognostic factors for primary CNS lymphoma are age and performance status.
- Newly diagnosed primary CNS lymphoma is treated in remission-induction (induction) and remission-consolidation (consolidation) phases.
- Historically, whole-brain radiation therapy has been used with high response rates but poor long-term disease control.
- Chemotherapy regimens used in systemic lymphoma (cyclophosphamide, doxorubicin, vincristine, and prednisone) are ineffective in primary CNS lymphoma, most likely due to poor brain penetration.
- Methotrexate chemotherapy is considered the standard treatment approach in primary CNS lymphoma. Methotrexate-based combination chemotherapies are more effective than methotrexate alone.
- Whole-brain radiation therapy–related neurotoxicity is a significant problem causing morbidities including cognitive impairment, incontinence, and gait disturbance. Older patients are particularly vulnerable.
- The optimal dose and schedule of high-dose methotrexate and the optimal chemotherapy combination have not yet been defined. The role of rituximab and whole-brain radiation in patients with newly diagnosed primary CNS lymphoma remains unclear.
- In patients younger than 65, intensive methotrexate-based chemotherapy followed by consolidative high-dose chemotherapy with autologous stem cell rescue has high clinical efficacy.
- Responses to first-line therapy are high in patients with primary CNS lymphoma. Still, disease relapse is common, mostly occurring in the first 2 years after methotrexate-based first-line treatment. Prognosis at relapse is poor.
- Novel targeted agents have been introduced in the treatment of refractory and relapsed primary CNS lymphoma.
- In the relapsed setting, the choice of therapeutic agent depends on age, performance status, prior treatment history, and response, as well as medical comorbidities. Treatment choices include methotrexate rechallenge, palliative whole-brain radiation therapy, as well as new agents such as pemetrexed, ibrutinib, pomalidomide, and lenalidomide. The role of immune checkpoint inhibitors is not clearly defined yet, and phase 2 data are pending.
Article 3: Nonmalignant Brain Tumors
Rimas V. Lukas, MD; Maciej M. Mrugala, MD, PhD, MPH, FAAN. Continuum (Minneap Minn). December 2020; 26 (6 Neuro-oncology):1495–1522.
PURPOSE OF REVIEW
This article describes the diagnosis and management of meningioma, pituitary adenoma, craniopharyngioma, and glioneuronal tumors.
Both meningiomas and pituitary adenomas are common brain tumors. In many cases, these lesions are found incidentally on imaging when patients are being evaluated for a variety of symptoms and signs. While nonmalignant, these tumors are occasionally associated with significant morbidity due to location and resulting secondary symptoms. Rarely, these tumors can also transform into malignant variants. Surgical techniques allow for more complete resections with minimal complications. Significant progress is being made in understanding the molecular biology of meningioma, which may result in wider availability of targeted therapies, especially for patients who are not candidates for other therapeutic modalities. Medical therapies for secretory pituitary adenomas continue to evolve. Craniopharyngiomas are nonmalignant tumors associated with significant morbidity due to their location. Molecular subtypes exist and may respond to targeted agents. Glioneuronal tumors are low-grade neoplasms potentially cured by gross total resection; however, residual and recurrent disease may require additional therapy. Recent studies have identified potentially targetable molecular alterations in more than half of cases.
Meningiomas and pituitary adenomas are frequently encountered in neurologic practice, and familiarity with their presentation and management is essential for a practicing neurologist. Craniopharyngiomas, meningiomas, and glioneuronal tumors are characterized by a high frequency of potentially actionable genetic alterations, and targeted therapies may eventually supplement surgical therapy of these nonmalignant tumors.
- Meningiomas are the most common primary brain tumor.
- Most meningiomas grow slowly and may be followed radiographically as the initial management approach as long as they are asymptomatic.
- Surgery is the primary treatment for meningioma in most cases, and recurrence rates are associated with the extent of resection and the grade of the tumor.
- Radiation therapy is usually reserved for unresectable meningiomas, incompletely resected meningiomas, recurrent meningiomas, and higher-grade meningiomas.
- Cytotoxic and hormonal medical therapies are largely ineffective in meningioma.
- Novel medical therapies for meningioma including tyrosine kinase inhibitors are under study.
- Pituitary adenomas are the second most common primary brain tumor and are frequently discovered on imaging incidentally.
- Pituitary adenomas smaller than 10 mm in diameter are termed microadenomas whereas pituitary adenomas 10 mm in diameter or larger are termed macroadenomas.
- Common categories of pituitary adenomas include functioning/secreting tumors and nonfunctioning/nonsecreting tumors.
- Medical therapies are commonly used for functioning/secreting pituitary adenomas as the primary treatment.
- Large pituitary adenomas may cause compression of adjacent critical structures including the optic pathways and often require prompt surgical intervention.
- Radiation therapy is used for patients with unresectable pituitary adenomas, recurrent pituitary adenomas, or those not responding to medical therapy.
- Craniopharyngiomas are low-grade, slow-growing tumors arising from the suprasellar region.
- Craniopharyngiomas can be divided into two subtypes, BRAF mutated (papillary) and CTNNB1 mutated (adamantinomatous), based on their molecular alterations.
- Current management of craniopharyngiomas consists of resection by either a transcranial or an endoscopic approach.
- Surgery for craniopharyngioma may be followed by radiation, with either protons or photons, for recurrent or residual disease.
- Targeted therapies for craniopharyngioma remain investigational but hold substantial promise.
- Glioneuronal tumors are most often World Health Organization grade I; however, rare high-grade variants with poor prognosis occur.
- Dysembryoplastic neuroepithelial tumors (DNETs) and other glioneuronal tumors are associated with a high incidence of seizures.
- Resection is the primary treatment modality for glioneuronal tumors, and complete resection can often be curative.
- Molecular alterations including BRAF mutations and NTRK fusions occur in the majority of glioneuronal tumors and should be screened for; targeted agents against these alterations may be effective.
Article 4: Familial Nervous System Tumor Syndromes
Roy E. Strowd III, MD, MEd MS; Scott R. Plotkin, MD, PhD. Continuum (Minneap Minn). December 2020; 26 (6 Neuro-oncology):1523–1552.
PURPOSE OF REVIEW
Although sporadic primary neoplasms account for the majority of nervous system tumors, familial nervous system tumor syndromes are important and clinically relevant conditions for the neurologist to understand. This article reviews common inherited nervous system tumor syndromes including neurofibromatosis type 1, neurofibromatosis type 2, schwannomatosis, tuberous sclerosis complex, and von Hippel-Lindau syndrome. The epidemiology, genetics, approach to diagnosis, neurologic and nonneurologic manifestations, and management options are reviewed.
Awareness of the more common and clinically relevant familial nervous system tumor syndromes is important. These conditions teach us about the underlying biology that drives tumor development in the central and peripheral nervous systems including peripheral nerve sheath tumors (eg, neurofibroma, schwannoma), meningioma, vestibular schwannoma, subependymal giant cell astrocytoma, and hemangioblastoma. Knowledge of the clinical manifestations ensures that the neurologist will be able to diagnose these conditions, recommend appropriate surveillance, refer to specialists, and support optimal management. Important discoveries in the role of the underlying genetics have contributed to the launch of several novel drug trials for these tumors, which are changing therapeutic options for patients.
Familial nervous system tumor syndromes are uncommon conditions that require specialized surveillance and management strategies. Coordination across a multidisciplinary team that includes neurologists, neuro-oncologists, radiologists, neurosurgeons, radiation oncologists, otolaryngologists, pathologists, neuropsychologists, physical medicine and rehabilitation specialists, and geneticists is necessary for the optimal treatment of these patients.
- The Knudson two-hit hypothesis refers to an inactivating germline mutation that results in a first “hit,” which increases susceptibility to subsequent somatic loss of heterozygosity (ie, a second hit) and resultant tumor formation.
- Neurofibromatosis type 1 (NF1) is the most common neurogenetic disorder with clinical manifestations that include café au lait macules, axillary and inguinal freckling, cutaneous and plexiform neurofibromas, optic pathway gliomas, and characteristic bony abnormalities.
- Severity of NF1 disease cannot be predicted based on the underlying NF1 genotype except in cases of microdeletion (eg, when a large portion of the gene, more than 1.4 megabase pairs, is involved), which are associated with a more severe phenotype.
- Café au lait macules are frequently the first manifestation of NF1 and typically are present in early infancy and within the first 2 years of life.
- Neurofibromas are the hallmark of NF1 and represent benign neoplasms of nonmyelinating Schwann cells in the peripheral nerve.
- Rapid growth (eg, doubling or tripling in several weeks), new unexplained pain, or new neurologic deficits may herald malignant degeneration of a plexiform neurofibroma into a malignant peripheral nerve sheath tumor.
- Focal areas of signal intensity are common and nearly pathognomonic for NF1; they represent areas of benign hamartomatous brain development, are asymptomatic, do not enhance with contrast, and do not require surveillance monitoring or treatment.
- Selumetinib, an oral selective MEK inhibitor, was approved by the US Food and Drug Administration in April 2020 for the treatment of children age 2 years and older with progressive, symptomatic, inoperable plexiform neurofibromas.
- Neurofibromatosis type 2 (NF2) is characterized by a predisposition to developing vestibular schwannomas, meningiomas, spinal cord ependymomas, peripheral nerve schwannomas, and juvenile posterior subcapsular cataracts.
- Bilateral vestibular schwannomas are pathognomonic for NF2 and typically present with hearing loss, tinnitus, balance difficulty, and, rarely, vertigo.
- Patients with NF2 should initially be monitored with neuroimaging of suspicious lesions and audiometry at 6-month intervals to establish a trajectory of tumor growth and functional impact.
- Removal of every tumor in NF2 is frequently not feasible or clinically necessary. Treatment should focus on the preservation of function and maximizing quality of life.
- Schwannomatosis is a rare neurogenetic syndrome typically presenting with multiple peripheral nerve schwannomas and chronic pain.
- Genetically, schwannomatosis is characterized by germline pathogenic variants in SMARCB1 or LZTR1 genes; additional unidentified genes also likely exist.
- Tumor formation in schwannomatosis is caused by concomitant mutational inactivation of two genes including the NF2 gene as well as either SMARCB1 or LZTR1.
- The most common symptom reported by patients with schwannomatosis is chronic pain, which is reported in more than 65% of patients.
- Tuberous sclerosis complex typically manifests with early-onset epilepsy, characteristic skin lesions, cortical tubers, subependymal nodules, subependymal giant cell astrocytomas (SEGAs), angiomyolipomas in the kidney, and lymphangioleiomyomatosis of the lung.
- Epilepsy is the most common and clinically challenging manifestation of tuberous sclerosis complex. Seizures occur in up to 85% of patients and often develop in infancy.
- The development of contrast enhancement in a subependymal nodule should raise suspicion for transformation to a subependymal giant cell astrocytoma.
- Angiomyolipomas are present in up to 80% of patients with tuberous sclerosis complex; they are frequently asymptomatic and not evident until surveillance imaging is performed.
- Lymphangioleiomyomatosis is uncommon in children with tuberous sclerosis complex and typically develops in the third to fourth decade with symptoms of worsening dyspnea or recurrent pneumothoraces.
- Response rates of greater than 50% are observed when treating SEGAs, renal angiomyolipomas, and pulmonary lymphangioleiomyomatosis with mammalian target of rapamycin (mTOR) inhibitors. Treatment of SEGA also reduces seizure frequency in patients with tuberous sclerosis complex.
- The most common nervous system manifestations of von Hippel-Lindau disease include hemangioblastomas of the cerebellum, spinal cord, and retina.
Article 5: Pediatric Brain Tumors
Sonia Partap, MD; Michelle Monje, MD, PhD. Continuum (Minneap Minn). December 2020; 26 (6 Neuro-oncology):1553–1583.
PURPOSE OF REVIEW
This article focuses on primary brain tumors in the pediatric population with an emphasis on molecular classifications and treatment strategies.
Pediatric brain tumors are a heterogeneous group of tumors that differ from adult brain cancers despite similar nomenclature. With the added complexity of the developing brain, treatment regimens are tailored to protect neurocognitive outcomes without sacrificing long-term survival. The 2016 World Health Organization’s classification incorporated molecular characteristics to aid in defining the diagnosis and prognosis of these tumors. These changes have enabled providers to stratify patients, thus intensifying therapies in those with high-risk diseases and modifying treatments to reduce morbidity for children and to provide better outcomes. Recent published findings from clinical trials have been especially helpful for gliomas, embryonal tumors, and ependymomas. By using this new information, molecular factors that correlate with survival have been identified in patients. In addition, genetic findings in tumor tissue have also led to revelations in predisposing germline mutations.
New findings from clinical trials and molecular stratification will shape the next generation of therapies in hopes of improving overall outcome, identifying pathways in tumorigenesis, and aiding in genetic counseling for children and their families.
- Increasingly, pediatric brain tumors are defined and classified molecularly.
- Despite the histologic appearance of diffuse gliomas, the presence of an H3K27M mutation classifies these tumors as World Health Organization grade IV.
- Minimization of steroid use is strongly advised in children with diffuse midline gliomas because these patients tend to receive more steroids than is useful and steroid-related toxicities contribute to morbidity and impaired quality of life.
- Unlike adult high-grade glioma, pediatric high-grade glioma is generally not responsive to temozolomide.
- In approximately 75% of pediatric low-grade astrocytomas, a KIAA1549-BRAF truncation/fusion alteration is present and confers a better prognosis than that associated with a BRAF V600E mutation. MEK inhibitors hold significant promise in the treatment of these KIAA1549-BRAF truncation/fusion pediatric low-grade astrocytomas.
- BRAF inhibitors should be avoided in patients with pediatric low-grade astrocytoma with the KIAA1549-BRAF truncation/fusion alteration because of paradoxical stimulation of tumor growth.
- Unlike adult low-grade glioma, pediatric low-grade glioma rarely transforms to higher-grade glioma.
- Although posterior fossa tumors can occur at all childhood ages, specific types prevail in various age groups.
- Ependymoma is now subclassified by molecular alterations, which often correlate to location and age at diagnosis.
- Embryonal tumors are highly compact and cellular tumors and, consequently, can demonstrate diffusion restriction on MRI.
- Nonglial tumors and ependymal tumors warrant evaluation for metastasis with contrast-enhanced MRI of the entire spine and lumbar puncture for CSF cytology.
- Embryonal tumors are all small round blue cell tumors that are now distinguished by their molecular alterations and/or location. Primitive neuroectodermal tumor is no longer used as a descriptor.
- The most common cerebellar masses in children are pilocytic astrocytomas, medulloblastomas, and ependymomas.
- Risk stratification for medulloblastoma is dependent on extent of surgical resection, evidence of metastasis, patient age, histology, and molecular subgroup.
- Obtaining tumor serum markers for β-human chorionic gonadotropin (βHCG) and α-fetoprotein is an appropriate first step when the differential diagnosis includes a CNS germ cell tumor.
- The differential diagnosis for a suprasellar/pituitary lesion with diabetes insipidus includes lymphocytic hypophysitis, Langerhans cell histiocytosis, and CNS germ cell tumor.
- Craniopharyngiomas, although low grade (WHO grade I), have high morbidity because of their suprasellar location and impact on vision and hypothalamic-pituitary function.
Article 6: Metastasis to the Central Nervous System
Adrienne Boire, MD, PhD. Continuum (Minneap Minn). December 2020; 26 (6 Neuro-oncology):1584–1601.
PURPOSE OF REVIEW
Management of metastasis to the central nervous system (CNS) has evolved, and molecular characterization of metastatic disease is now routinely done. Targeted therapies, once few in number with limited penetration into the CNS, have multiplied in number and increased in CNS coverage. This article addresses recent advances in the evaluation and clinical management of patients with CNS metastasis.
Metastasis of cancer to the CNS can be diagnosed and characterized with novel techniques, including molecular analyses of the spinal fluid, so-called liquid biopsies. Resected parenchymal CNS metastases are now routinely subjected to genomic sequencing. For patients with CNS metastases displaying targetable mutations, a wide variety of treatment options are available, including deferral of radiation therapy in favor of a trial of an orally bioavailable targeted therapy or immunotherapy. For patients without a molecularly targetable lesion, local treatment in the form of radiation therapy, now most often stereotactic radiosurgery, is supplanting untargeted whole-brain radiation therapy.
Technologic advances in diagnosis and management have resulted in new diagnostic and therapeutic approaches to patients with metastasis to the CNS, with resulting improvements in progression-free and overall survival.
- Central nervous system metastases are common in patients with cancer and may occur in the brain, spinal cord, leptomeninges, epidural space, or dura.
- Patients may harbor metastases in the brain parenchyma, spinal cord, leptomeninges, and epidural and dural spaces either singly or, more commonly, in combination. If a single discovered metastasis cannot adequately explain a patient’s symptoms or signs, imaging of additional sites is warranted.
- Treatment of symptomatic lesions is the initial primary focus of care in patients with metastases to the central nervous system.
- Parenchymal brain metastases grow within the confines of the blood-brain barrier, and systemic therapies must penetrate this space to be effective.
- Leptomeningeal metastasis growth is bound by the blood-CSF barrier; treatments for malignancy within this space include intrathecal therapy and CSF-penetrant systemic therapies.
- Central nervous system metastases are the result of selective genetic pressures and may therefore harbor mutations unlike those of the primary cancer.
- When feasible, surgical resection of the symptomatic lesion(s) is preferred as it enables molecular and genetic characterization of the lesion.
- When not surgically accessible, symptomatic central nervous system metastases may be treated with radiation therapy.
- After surgical resection of central nervous system metastases, radiation is generally applied to the surgical bed to reduce the likelihood of recurrence.
- The indications for the use of whole-brain radiation therapy are more restricted now than in the past.
- Dural and epidural metastases reside outside the blood-brain and blood-CSF barriers and thus can be treated with standard chemotherapies, immunotherapies, and targeted therapies.
- Intrathecal therapy is inappropriate for patients with elevated intracranial pressure or bulky leptomeningeal deposits.
- Delivery of intrathecal therapy through an intraventricular catheter, such as an Ommaya reservoir, is preferable to delivery of the drug into the lumbar cistern.
- Many new central nervous system–penetrating targeted therapies and immunotherapies have emerged that may be used in select cases to treat central nervous system metastases in lieu of radiation therapy.
- Immunotherapy shows promise for parenchymal brain metastases from melanoma and non–small cell lung cancer in certain patient subpopulations.
Article 7: Paraneoplastic Disorders of the Nervous System
Eoin P. Flanagan, MBBCh. Continuum (Minneap Minn). December 2020; 26 (6 Neuro-oncology):1602–1628.
PURPOSE OF REVIEW
This article reviews paraneoplastic neurologic disorders and includes an overview of the diagnostic approach, the role of autoantibody testing, the pathophysiology of these disorders, and treatment approaches. This article also provides an overview of the emerging clinical scenarios in which paraneoplastic and autoimmune neurologic disorders may occur.
The number of autoantibodies associated with paraneoplastic neurologic disorders has rapidly expanded over the past 2 decades. These discoveries have improved our ability to diagnose patients with these disorders and have provided insight into their pathogenesis. It is now recognized that these antibodies can be broadly divided into two major categories based on the location of the target antigen: intracellular and cell surface/synaptic. Antibodies to intracellular antigens are almost always accompanied by cancer, respond less well to immunotherapy, and have an unfavorable outcome. In contrast, antibodies to cell surface or synaptic targets are less often accompanied by cancer, generally respond well to immunotherapy, and have a good prognosis. Paraneoplastic and autoimmune neurologic disorders are now being recognized in novel settings, including their occurrence as an immune-related adverse effect of immune checkpoint inhibitor treatment for cancer.
This article discusses when to suspect a paraneoplastic neurologic syndrome, the diagnostic utility and pitfalls of neural autoantibody testing, how to best detect the underlying tumor, and the treatment approach that involves combinations of antineoplastic treatments, immunosuppressants, and supportive/symptomatic treatments.
- Paraneoplastic neurologic syndromes frequently manifest before a cancer diagnosis, and their recognition can lead to the detection of an occult malignancy.
- Major advances have occurred in the field of paraneoplastic neurologic disorders with the discovery of a multitude of autoantibody biomarkers of paraneoplastic disease that can confirm the diagnosis and provide insight into the type and location of the underlying cancer.
- Limbic encephalitis is a characteristic paraneoplastic neurologic syndrome that manifests with subacute memory loss, encephalopathy, and seizures accompanied by mesial temporal MRI T2 hyperintensities; it can be associated with a wide array of antibodies.
- Anti–N-methyl-d-aspartate (NMDA) receptor encephalitis is a characteristic paraneoplastic encephalitis that has a predilection for young women and manifests clinically with a combination of psychosis, seizures, encephalitis, orofacial dyskinesia, autonomic dysfunction, and hypoventilation in the setting of an underlying ovarian teratoma.
- Paraneoplastic cerebellar degeneration begins with subacute progressive ataxia and is associated with a wide variety of paraneoplastic antibodies.
- A hallmark subacute sensory neuronopathy is described in association with antineuronal nuclear antibody type 1 (ANNA-1)/anti-Hu antibodies and small cell lung cancer.
- Paraneoplastic Lambert-Eaton myasthenic syndrome typically presents with proximal muscle weakness with depressed reflexes that improve with exercise and is seen in the setting of an underlying small cell lung cancer.
- Myasthenia gravis is most often associated with antibodies targeting the muscle acetylcholine receptor, and 10% of cases are paraneoplastic and associated with an underlying thymoma.
- Paraneoplastic neural antibody testing helps confirm the diagnosis of a paraneoplastic neurologic disorder as the cause of the neurologic syndrome. The antibody detected can also give a clue to the type and location of the underlying cancer and may help guide treatment and predict outcome.
- The techniques for testing neural autoantibodies have evolved over time, and improvements in antibody-detection methods have resulted in improvements in sensitivity and specificity.
- Although a positive antibody can confirm a paraneoplastic neurologic disorder, some antibodies detected with earlier-generation techniques occur at a sufficiently high frequency in the general population, so their detection must be put into clinical context to avoid misdiagnosis.
- The cancers most commonly associated with paraneoplastic neurologic disorders include neuroendocrine tumors, thymomas, gynecologic cancers, testicular germ cell tumors, breast cancers, and hematologic malignancies.
- In patients with a paraneoplastic disorder, a general screening approach should be considered, with CT of the chest, abdomen, and pelvis or body positron emission tomography (PET)-CT obtained while antibody test results are awaited.
- Fludeoxyglucose positron emission tomography (FDG-PET) combined with CT has higher sensitivity for cancer detection and is particularly useful when an antibody with high positive predictive value for cancer is present.
- Antibodies that bind intracellular antigens are almost always associated with cancer, and the immune-mediated damage appears to be driven by a cytotoxic T-cell–mediated process resulting in cell damage or death, which may explain the poor prognosis and the lack of response to immunotherapy.
- When compared with antibodies to intracellular antigens, antibodies that bind cell surface antigens are less commonly associated with cancer, have the potential to be directly pathogenic, and tend to respond better to immunotherapy, particularly treatments that deplete antibodies or B cells.
- The first step in the treatment of a paraneoplastic neurologic disorder is to detect and treat the underlying cancer, and earlier treatment is associated with better outcomes.
- Concurrent or adjuvant immunosuppressive treatment after oncologic treatment should be considered in paraneoplastic neurologic disorders, unless they resolve with cancer treatment alone, which is rare.
- Neurologic immune-related adverse effects can occur in patients with cancer treated with immune checkpoint inhibitors.
Article 8: Neurologic Complications in Patients With Cancer
Eudocia Q. Lee, MD, MPH. Continuum (Minneap Minn). December 2020; 26 (6 Neuro-oncology):1629–1645.
PURPOSE OF REVIEW
Neurologic complications in patients with cancer can significantly impact morbidity and mortality. Although these complications can be seen in patients without cancer as well, the purpose of this review is to highlight how the presentation, etiology, and management of delirium, seizures, cerebrovascular disease, and central nervous system infections may be different in patients with cancer.
Some of the newer anticancer therapies are associated with neurologic complications. Delirium and seizures have been described in patients receiving chimeric antigen receptor (CAR) T-cell therapy and other immune effector cell therapies. Angiogenesis inhibitors can increase the risk of bleeding and clotting, including intracranial hemorrhage and stroke. The risk of opportunistic fungal infections, including aspergillosis, is elevated with the Bruton tyrosine kinase inhibitor ibrutinib.
Providers should familiarize themselves with neurologic complications in patients with cancer because early diagnosis and intervention can improve outcomes. The differential diagnosis should be broad, including conventional causes as seen in patients who do not have cancer, with special consideration of etiologies specific to patients with cancer.
- Delirium is particularly common in advanced-stage cancer, at the end of life, in advanced age, and in patients with preexisting dementia.
- Precipitants of delirium in patients with cancer include central nervous system (CNS) metastases, infections, nutritional and vitamin deficiencies, metabolic abnormalities (eg, hypercalcemia, hyponatremia), endocrinopathies, organ dysfunction, seizures, paraneoplastic disorders, psychoactive medications (eg, opioids, benzodiazepines, antidepressants, antihistamines, and anticholinergics), chemotherapy, corticosteroids, alcohol, dehydration, surgery, and uncontrolled pain.
- Approximately half of delirium episodes can be reversed, especially those precipitated by medications, infections, and electrolyte abnormalities.
- The risk of brain tumor–related seizures varies depending on the tumor location (higher risk for tumors involving the frontal, temporal, or insular cortical gray matter) and underlying pathology (highest risk for glioneuronal tumors).
- In brain tumor–related seizures, seizure control from tumor resection depends on whether the seizure focus is or is not located in the tumor.
- The 2000 American Academy of Neurology (AAN) practice guideline recommends against prophylactic use of antiepileptic drugs in patients with brain tumors and no history of seizures.
- In patients with cancer, the risk of hemorrhagic and ischemic stroke is highest in the first 6 months after a cancer diagnosis, decreasing after the first 6 months but remaining elevated even more than 10 years after diagnosis.
- Radiation-induced vasculopathy resulting in stroke is a delayed complication of radiation, often occurring years after completion of radiation.
- Acquired immunodeficiency related to hematologic malignancy, chemotherapy, hematopoietic stem cell transplantation, or immunosuppressants increases the risk of opportunistic infections including CNS infections.
- Aspergillosis is an invasive fungal infection observed in immunocompromised patients and can involve the CNS, most notably in the form of brain abscesses.
- Progressive multifocal leukoencephalopathy is an aggressive and often fatal disease caused by JC virus resulting in demyelinating lesions involving subcortical U fibers.
- Unlike its counterpart in immunocompetent hosts, primary CNS lymphoma in immunocompromised patients is driven by Epstein-Barr virus and is more often multifocal and ring-enhancing on brain MRI.
Article 9: Neurotoxicity of Cancer Therapies
Jorg Dietrich, MD, PhD, FAAN. Continuum (Minneap Minn). December 2020; 26 (6 Neuro-oncology):1646–1672.
PURPOSE OF REVIEW
This article reviews neurologic complications associated with chemotherapy, radiation therapy, antiangiogenic therapy, and immunotherapy.
Cancer therapies can cause a wide range of neurologic adverse effects and may result in significant patient morbidity and mortality. Although some treatment-associated neurologic complications manifest acutely and are often reversible and transient, others occur with delayed onset, can be progressive, and are uniquely challenging to patient management. With an increase in multimodality and combination therapies, including targeted therapies and immunotherapies, and prolonged patient survival, novel and unique patterns of neurologic complications have emerged.
Both conventional and novel cancer therapies can adversely affect the nervous system, thereby producing a wide range of neurologic complications. Increased awareness among neurologists and early recognition of cancer therapy–induced neurotoxic syndromes is critically important to minimize patient morbidity, prevent permanent injury, and improve patient outcomes.
- Cancer-directed therapy can be harmful to the central and peripheral nervous systems, and patients may develop a wide range of acute and delayed neurologic complications.
- Neurotoxicity from cancer therapy is a major cause of impaired quality of life in patients with cancer, especially in long-term survivors.
- Chemotherapy-induced peripheral neuropathy is the most common form of neurotoxicity in patients with cancer, and its manifestation is usually dose dependent.
- The most common form of chemotherapy-induced peripheral neuropathy is characterized by a predominantly sensory, length-dependent, symmetric, and painful polyneuropathy.
- A unique phenomenon referred to as coasting is observed after treatment with platinum agents and is characterized by peripheral neuropathy that worsens several months after chemotherapy discontinuation.
- Underlying genetic neuropathies (eg, Charcot-Marie-Tooth disease and other hereditary neuropathies) may confer an elevated risk of developing chemotherapy-induced peripheral neuropathy.
- Most forms of chemotherapy-induced peripheral neuropathy are reversible after discontinuation of the offending drug and with supportive management.
- Acute encephalopathy has been associated with a wide range of chemotherapeutic agents.
- Posterior reversible encephalopathy syndrome (PRES) has been associated with a large number of anticancer agents and can present in the absence of hypertension.
- Diffuse white matter injury, a frequent complication of radiation therapy, may also occur after chemotherapy and can be irreversible.
- Cognitive impairment is one of the most frequent complications of cancer therapy and can negatively impact quality of life in cancer patients.
- Radiation-induced neurotoxicity can be categorized into acute, early-delayed, and late-delayed complications.
- Delayed neurologic complications from radiation therapy are often irreversible.
- Neuroprotective strategies have been increasingly used to prevent or limit radiation-induced neurologic complications. These strategies include radiation therapy, hippocampal avoidance, and the use of pharmacologic interventions during and after radiation therapy. There is a need for prospective, randomized clinical trials to validate the benefit of these strategies.
- Cerebral radiation necrosis is a delayed and severe complication of brain radiation therapy and can mimic tumor recurrence.
- Cerebrovascular complications and secondary tumors are serious delayed complications from radiation therapy, and children and long-term survivors are at the highest risk.
- Immunotherapies such as chimeric antigen receptor T cells and checkpoint inhibitors are associated with unique and serious patterns of neurotoxicity.
Article 10: Palliative and Supportive Care in Neuro-oncology
Deborah A. Forst, MD. Continuum (Minneap Minn). December 2020; 26 (6 Neuro-oncology):1673–1685.
PURPOSE OF REVIEW
This article reviews the supportive care needs of patients with primary brain tumors and their caregivers, outlines the management of selected common symptoms of patients with brain tumors, and describes challenges and opportunities in providing palliative care for this population.
Patients with primary malignant brain tumors generally have a poor prognosis and experience progressive neurologic decline and significant physical and psychological symptoms. Management of these symptoms, including fatigue, mood disorders, and the manifestations of cerebral edema, can be challenging. Caregivers for these patients have high rates of psychological distress and report significant caregiving burden. Although the benefit of early palliative care for patients with other advanced solid tumors is well established, our understanding of the role of palliative care in neuro-oncology is incomplete, and thus palliative care and hospice services remain underutilized.
Patients with brain tumors and their caregivers have significant supportive care needs, which often differ from the needs of patients with cancers outside of the nervous system. Clinicians face challenges associated with managing patients’ symptoms and adequately facilitating prognostic understanding and decision making. Palliative care and hospice services may offer important benefits for this population.
- Neurologic palliative care is a relatively new field, and the palliative care needs of patients with serious neurologic illnesses, and neuro-oncologic diseases, in particular, remain understudied.
- As neuro-oncology practitioners treat patients with unique symptoms and needs, the palliative care models that have proven beneficial for other patient populations may not be applicable and may need to be amended to adequately address this specific population.
- Compared with patients with other cancers, patients with primary brain tumors more frequently report drowsiness, irritability, difficulty speaking, cognitive impairment, and confusion, whereas they have lower rates of pain, nausea, vomiting, dyspnea, constipation, and anorexia.
- Corticosteroids, which effectively reduce cerebral edema and lead to associated symptom improvement, have long been the mainstay of treatment for patients with symptomatic cerebral edema related to brain tumors.
- It is often difficult to discontinue steroids in patients with primary brain tumors because of associated symptom worsening as well as symptomatic adrenal insufficiency.
- Patients requiring prolonged steroids for the management of symptomatic cerebral edema should be treated at the lowest dose possible and for the shortest period of time.
- The use of bevacizumab in patients with symptomatic cerebral edema may decrease steroid requirements, reduce neurologic symptoms, and improve quality of life, and it improves progression-free survival in patients with glioblastoma.
- Fatigue is a prevalent symptom in patients with cancer and is particularly problematic for patients with primary brain tumors, occurring in 20% to 95% of these patients.
- No pharmacologic or nonpharmacologic interventions have proven consistently effective for the treatment of brain tumor–associated fatigue.
- Despite negative randomized controlled trials, stimulants such as methylphenidate or dextroamphetamine/amphetamine and wakefulness-promoting agents such as modafinil or armodafinil can be useful for the management of fatigue in selected patients with persistent fatigue despite nonpharmacologic interventions.
- Depression occurs in approximately 15% to 20% of patients with gliomas, and anxiety has been reported in up to 30%.
- The diagnosis of mood disorders in patients with brain tumors may be difficult, as many of the symptoms associated with depression and anxiety can also be observed as a consequence of the cancer or cancer treatment.
- Decision-making capacity may be impaired in patients with primary brain tumors at the time of diagnosis or early in the disease course.
- Advance care planning can help ensure that end-of-life care matches the patient’s wishes and can result in less psychological distress for bereaved caregivers after the patient’s death.
- In addition to the financial, psychosocial, and emotional burden of caring for a loved one with advanced cancer, caregivers of patients with brain tumors are subject to additional stressors associated with their loved ones’ loss of cognitive and neurologic functions.