Patients with brain tumor exhibit wide-ranging prognoses and functional implications of their disease and treatments. In general, the supportive care needs of patients with brain tumor, including disabling effects, have been recognized to be high. This review (1) briefly summarizes brain tumor types, treatments, and prognostic information for the rehabilitation clinician; (2) reviews evidence for rehabilitation, including acute inpatient rehabilitation and cognitive rehabilitation, and the approaches to selected common symptom and medical management issues; and (3) examines emerging data about survivorship, such as employment, community integration, and fitness.
Key points
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Brain tumors carry a high likelihood of near-term and long-term functional sequelae.
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Although primary brain malignancy comprises just 1.4% of all cancers, the incidence of brain tumor is really higher, considering that metastatic brain tumor is estimated as being at least 10 times more common than primary brain malignancy. Benign brain tumor, with incidence more than double that of malignant primary brain tumor, is also a significant group.
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Primary brain tumors occur along the full age spectrum. In fact, primary brain malignancy is the most common solid tumor in children, and data from that group inform our knowledge of long-term outcomes.
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Brain tumors encompass an extremely wide prognostic spectrum, ranging from benign brain lesions with minimal effect on life expectancy to conditions such as metastatic brain lesions and glioblastoma, which carry unfavorable prognoses.
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Many factors, such as tumor location, oncologic characteristics, and treatment effects, influence outcomes. Radiation therapy in particular has been associated with adverse long-term effects, including late (delayed onset) effects. Corticosteroid myopathy can also be a significant morbidity.
Introduction
Although malignant primary brain tumor (PBT), estimated at 24,790 new cases in the United States in 2016, comprises just 1.4% of all cancers, brain tumor is actually far more common when one considers benign brain tumor, with estimated incidence of more than double that, at 52,880 cases, and metastatic brain tumor, which is yet more common. Estimated prevalence rate of individuals living with history of PBT is nearly 700,000. Systematic statistical surveillance is lacking for incidence of brain metastasis, has been estimated at between 200,000 and 300,000 people per year, or at least 10 times more common than primary brain malignancy, with more than half of patients with metastatic disease presenting with multiple tumors, most commonly in the cerebrum. Brain is the most common site for central nervous system (CNS) malignancy; cranial nerves, spinal cord, and cauda equina account for a collective 10% of tumors, and pituitary and pineal tumors account for 16%.
PBT is seen over the entire age spectrum. Although most common in adults, with median age of 59 at diagnosis, malignant brain tumor is the most common solid tumor of childhood (more than 4600 cases estimated in 2016), and thus, has high representation in pediatric oncology. Seven percent of all primary CNS tumors occur in children ages 0 to 19, and another nearly 9% in young adults ages 20 to 34. Brain metastasis is uncommon in children.
Types of tumor vary over the age spectrum, with pilocytic astrocytomas and embryonal tumors (especially medulloblastoma) most common in childhood, pituitary tumors in late adolescence and young adulthood (ages 15–34), and meningiomas and glioblastomas through the remainder of adulthood.
Prognostically, for malignant PBT, survival varies greatly, especially by type of tumor, including in some cases by their molecular markers, and also by age, with older age being less favorable. Primary malignant brain tumor of childhood averages 74% 5-year survival, but through the full age spectrum averages just 34%, and greater than age 75 averages only 6.1%. Of note, malignant PBT outnumbers benign PBT in childhood (3.3:1.9, per 100,000, ages 0–19), whereas benign PBT is more common than malignant PBT in adults (17.9:8.9 per 100,000). Five-year survival for benign brain tumor is 92%.
Brain tumors have long been recognized as producing a high rate of disabling effects, with recognition that the creation of a “culture of hope” is an important part of management. Rehabilitation needs have historically been described in upwards of 80% of individuals with CNS malignancy, with multiple impairments often present. Long-term effects on employment and general health have consistently been described. Rehabilitation emphasizes individualized interdisciplinary care to address the functional impact of tumor and/or treatment-related impairments. Although the rehabilitation therapy itself is similar in approach to other neurologic disorders such as stroke or traumatic brain injury, the underlying context of the oncology-related factors must be incorporated into the clinician’s perspective, so that best care and guidance can be provided. Rates of receiving rehabilitation have not been systematically studied but are generally considered to be low.
This review follows the general outline of providing (1) a brief summary of relevant background information about brain tumors, (2) evidence for rehabilitation’s significant role in the supportive care of patients with brain tumor, and related management considerations, and (3) an outline of survivorship issues. These categories should be viewed as having indistinct boundaries and rather serve as a general conceptual framework to approach patient care needs over the continuum of care.
Primary Treatment
Tumor types including incidence data, standard treatments, and prognostic information are summarized in Table 1 . MRI with and without contrast is the diagnostic modality of choice for brain tumor.
| Tumor Type | % of PBT | Clinical and Structural Correlates | Treatment | Prognosis |
|---|---|---|---|---|
| Metastatic | Estimated at 10–20× incidence of all PBT; affects 8%–10% of all patients with cancer | Lung, breast, colorectal, melanoma, genitourinary 80% affect cerebral hemispheres; cerebellum 15%, brainstem 5% | Historically, WBRT; solitary brain metastasis sometimes resectable; recent trend to avoid WBRT or combine with more targeted modalities such as stereotactic radiosurgery due to acute and late effects of WBRT Chemotherapy if other modalities have failed, or for chemosensitive tumors | Life expectancy usually <6 mo but death often from other effects of the tumor Graded Prognostic Assessment categorizes patients in 4 groups with median survival ranging 2.6–11 mo Resection associated with improved survival (40 vs 15 wk) and functional outcomes (maintain independence 38 vs 8 wk) |
| Meningioma | 36 | Originate in dura | Usually surgically resectable | Usually benign, rarely anaplastic |
| Gliomas | 27 80% of all malignant PBT | Heterogeneous molecular subtypes Headaches, focal signs, such as hemiparesis, cognitive-behavioral changes, visual field or sensory changes Fluctuating symptoms common | See below, subcategories of astrocytoma (glioblastoma, anaplastic astrocytoma, diffuse-and other low-grade astrocytoma and pilocytic astrocytoma), oligodendroglioma, ependymoma; also others (mixed glioma or oligoastrocytoma, optic glioma, gliomatosis cerebri); 75% are astrocytomas | Endothelial growth factor receptor mutations associated with poor prognosis, predispose to glioblastoma Ki-67 associated with reduced survival in anaplastic glioma p53 marker seen in up to 88% of patients with low-grade astrocytomas, unclear effect on survival |
| Glioblastoma (grade IV) | 15 55% of all gliomas and 82% of malignant gliomas | Usually cerebrum Pseudoprogression (radiographic worsening) may occur after radiation therapy May be primary or evolve secondarily from other gliomas | Surgical resection for relieving mass effect and for cytoreduction Radiation therapy TMZ Carmustine biodegradable polymers implanted into tumor bed Bevacizumab monoclonal antibody targeting angiogenesis | 35% 1-y, 4.7% 5-y survival; 2-y 27% with TMZ vs 10% without Bevacizumab increases progression-free survival but not overall survival Tumors with promoter methylation of MGMT show better response to TMZ Isocitrate dehydrogenase genes 1 and 2 associated with better prognosis |
| Anaplastic astrocytoma (grade III) | 2 | Usually cerebrum Often progresses to a secondary glioblastoma | Similar to glioblastoma; surgical resection, radiation therapy; TMZ often used | Median survival 2–3 y 60% 1 y; 25.9% 5 y |
| Diffuse astrocytoma (grade II) | 2–3 | Usually cerebrum; may progress | Surgical resection; sometimes radiation therapy in adults and older children, especially if incomplete resection | 72% 1 y, 47% 5 y |
| Pilocytic astrocytoma (grade I) | 1.5 | Often but not necessarily at optic pathways, thalamus, basal ganglia | Surgical resection, sometimes radiation therapy | Best when completely resectable 91% 10 y survival |
| Oligodendroglioma | 2 6% of gliomas | Usually cerebrum Codeletion of 1p/19q chromosomes (19p to 1q translocation) associated with improved response to treatment | Surgical resection Radiation therapy Chemotherapy—procarbazine, lomustine and vincristine; TMZ under investigation | 94% 1 y 79% 5 y (if anaplastic type 81%/49%) |
| Mixed glioma | 1 | Grade I or II, vary in degree astrocytoma/oligodendroglioma | Surgical resection; sometimes chemotherapy (such as TMZ), or radiation | 88% 1-y, 60% 5-y survival |
| Ependymoma | 2 | In childhood, 90% involve brain (especially posterior fossa); in adults 60% involve spinal cord | Surgical resection, sometimes radiation or chemotherapy | 82% 5-y survival May be benign or malignant 10%–15% may spread within CNS |
| Pituitary | 14–15 | Endocrine effects, optic pathways | Surgical resection | Usually benign, very rarely malignant |
| Nerve sheath tumors | 8.3 | Cranial nerve findings—hearing loss, vertigo, facial palsy, dysphagia, facial numbness; hydrocephalus | Monitoring vs surgical resection | Usually benign, very rarely malignant |
| Craniopharyngioma | 0.9 | Embryonic malformations of the sellar area, affect hypothalamus, pituitary (vision, hormonal; growth retardation); Obesity, cognitive deficits; hydrocephalus | Resection but can be difficult, incomplete; radiation sometimes used if incomplete resection. Shunting sometimes needed | Benign >90% 5- and 10-y survival |
| Primary CNS lymphoma | 2.2 | Multifocal presentation common when in association with HIV | Better survival with chemotherapy, ± radiation, than resection | 48% 1-y, 28% 5-y survival |
| Embryonal—medulloblastoma and primitive Neuroectodermal | <2 18%–20% of childhood CNS tumors | Cognitive deficits, ataxia, facial weakness, endocrine abnormalities Late cognitive decline may occur | Surgical resection, radiation therapy, chemotherapy | 80% long-term survival in medulloblastoma, which is the most common type, and 50% in other types Overall 82% 1 y, 61% 5 y |
| Leptomeningeal | 5% of patients with cancer | Hematologic, lung, breast, melanoma, gastric | May include supportive care, intrathecal chemotherapy alone or ± systemic chemotherapy or radiation | Median survival 10–12 wk |
Surgery
Surgical resection is a mainstay for management of most PBT, and when feasible, for metastatic brain tumors, and has been associated with better outcomes and quality of life. Guiding principles include maximal tumor removal when appropriate, minimization of surgical morbidity, and obtaining accurate diagnosis. When gross total resection is not feasible, other options can include stereotactic biopsy, open biopsy/debulking followed by planned observation or adjuvant therapy, and chemotherapy implants, when indicated. Newer techniques such as functional imaging are increasingly incorporated to minimize morbidity.
Radiation therapy
Radiation approach and dosing vary with the type of tumor. External beam radiation is most commonly used, localized to the tumor via 3-dimensional mapping. For metastatic tumor, whole brain radiation may be used. More specialized radiation therapy techniques have been developed with the goal of improved outcomes and decreased morbidity, including stereotactic radiation with gamma knife, brachytherapy (implanted radiation sources), and proton beam therapy.
Radiation can have significant long-term consequences, either episodic or static, and may factor highly in the differential diagnosis of a decline or lability in a patient’s status. Because of correlation between radiation dose to the hippocampus and poor cognitive outcomes, hippocampal-sparing techniques are being explored in pediatric medulloblastoma.
Acute radiation encephalopathy has onset days to weeks after initiation of therapy, corresponding to a time frame in which the patient may be receiving acute rehabilitation. Symptoms include headaches, lethargy, and worsening of existing focal symptoms, and respond to increase in corticosteroid dosing.
Decline in status occurring at 1 to 6 months is known as early delayed encephalopathy, producing a somnolence syndrome, which is related to demyelination from radiation injury to oligodendrocytes, and may respond to corticosteroids.
Patients with recent radiation therapy receiving temozolomide therapy may develop a syndrome of “pseudoprogression” on imaging (with or without transient clinical worsening), in which the tumor appears larger or brighter on imaging, seen in about 25% of glioblastoma patients.
Beyond 6 months to a year, late delayed encephalopathy may occur, especially after high doses exceeding 55 to 60 Gy, and typically presenting as a focal necrosis that can be life threatening. Physiologically, vascular endothelial injury occurs, and damage is thought to be related to dynamic interactions between multiple cell types in the brain, including astrocytes, microglia, and neurons, with proinflammatory changes, and eventual neuronal damage related to oxidative stress.
On a more chronic basis, long-term cognitive changes may be seen after radiation. Cognitive sequelae have been well described in survivors of pediatric brain tumor (see Survivorship section) and have also been reported in up to 50% to 90% of adult patients with brain tumor who survive greater than 6 months after radiation.
Areas of investigation into therapeutics with potential to prevent or ameliorate radiation-induced cognitive changes include anti-inflammatory agents, angiotensin-converting enzyme inhibitors, angiotensin type-1 receptor blockers, and stem cell therapies. There have been reports of improvement with other agents, including pentoxyfylline, warfarin, bevacizumab, or vitamin E. Symptomatically, agents such as methylphenidate, modafinil, memantine, and donepezil have been proposed.
Chemotherapy
Temozolamide, the first-line agent for glioblastoma, is generally well tolerated but may produce fatigue, reported to occur in more than 50% of patients, as well as constipation and headache. Other protocols include combination therapy with procarbazine, lomustine and vincristine, bevacizumab (a monoclonal antibody to vascular endothelial growth factor), carmustine (bis-chloroethylnitrosourea), including implanted biodegradable polywafer form, and methotrexate (for CNS lymphoma).
Novel therapies
Treatments on the horizon include NovoTTF-100A, an electrical field therapy applied via disposable transducers to the scalp, for inhibiting cell growth, and US Food and Drug Administration approved for recurrent glioblastoma. Immunotherapeutic techniques are also under investigation, including various vaccine-based approaches and oncolytic virotherapy.
Corticosteroids
Corticosteroids are often needed to manage edema, especially dexamethasone, because of its relatively low mineralocorticoid (salt-retaining) activity, with starting does of 16 mg/d or more in the setting of severe symptoms, and 4 to 8 mg/d for milder symptoms. Effects are typically seen within 24 to 48 hours, and taper should proceed as soon as possible, but over at least a 2-week period to avoid rebound symptoms. A recent review notes that despite wide use of corticosteroids in oncology, relatively little research has been performed on optimal dosing. Of note, fluorinated glucocorticoids such as dexamethasone have been implicated as more likely to cause myopathy than nonfluorinated glucocorticoids like prednisone or hydrocortisone; therefore, corticosteroids should be kept to the lowest dose that is needed and with consideration of switching from dexamethasone when feasible. Symptomatic corticosteroid myopathy occurs in about 10% of patients with brain tumor receiving dexamethasone for more than 2 weeks, is most pronounced in proximal muscles of the lower limbs, and is most common in the elderly and when prolonged use of high doses is required. Treatment consists of physical exercise.
Supportive Care
This category contains an extremely wide range of interventions including rehabilitation interventions, management of medical complications, symptom control, psychosocial interventions (including caregiver needs), nutrition, and end-of-life comfort measures. Although thorough coverage of this topic is beyond the scope of this review, a few subtopics will be highlighted.
Acute inpatient rehabilitation
Studies of acute rehabilitation for patients with brain tumor comprise a relatively well developed area of the literature ( Table 2 ) and have shown mostly consistent findings, including comparable functional improvement (usually measured by the Functional Independence Measure, or FIM) and discharge to community rates as brain injury or stroke peers, with shorter or similar lengths of stay, and higher rates of discharge back to acute care. Recently, improved functional performance was also demonstrated among a small cohort of patients with paraneoplastic cerebellar degeneration. Whether the brain tumor is benign, primary malignant, or metastatic has not been demonstrated to significantly affect acute rehabilitation outcomes, and reports have been conflicting as to whether concurrent radiation therapy is favorable or detrimental to acute rehabilitation outcomes.
| Authors | Design | Core Results | Other Findings |
|---|---|---|---|
| Philip et al, 1994 | Retrospective study of 30 children ages 3–20 (mean 10) with history of PBT; follow-up data in 20 patients | Increased total WeeFIM score between rehabilitation admission and discharge ( P = .001) and discharge to follow-up ( P = .0001); similar pattern in subgroups of self-care, mobility, and locomotion | Significant gains in sphincter control not seen until following discharge ( P = .006); gains in communication ( P = .01) and social cognition ( P = .004) became significant after discharge |
| O’Dell et al, 1998 | Retrospective, case-matched series of 40 patients with brain tumor matched with 40 TBI patients by age, gender, and admission functional status | No significant difference in FIM efficiency between TBI and BT groups (1.9 vs 1.5) or LOS (22.1 vs 17.8 d); greater total FIM increase in TBI patients (34.6 vs 25.4) | Favorable recovery patterns in meningioma, left-sided lesions, and no concurrent radiation therapy |
| Huang et al, 1998 | Retrospective case controlled comparison of 63 BT patients matched with 63 stroke patients by age, gender, and location of lesion | No difference in total FIM gains (23.6 in BT group vs 29.1 in stroke group), FIM efficiency (8.4/wk in BT group vs 7.2/wk in stroke group), or discharge to community rate (86% in BT group vs 94% for stroke group); BT with shorter LOS (25 vs 34 d, P <.01) | Higher admission MOB-FIM in BT group (13.6 vs 11.1, P = .04); lower gains in ADL-FIM score in BT group (8.3 vs 10.8, P = .03) |
| Huang et al, 2001 | Prospective study of 10 consecutively admitted PBT patients, reporting longitudinal data (admission, discharge, 3 mo of FIM, DRS, KPS, and FACT-BR scores, and 1-mo scores of DRS, KPS, and FACT-BR) | At 3- mo postdischarge, FIM increased 46.84 ( P <.05), KPS 10.11 ( P <.05), and DRS also improved significantly (F = 19.25, P <.05). FACT-BR improvement did not reach significance until 1 and 3 mo; 90% discharged to home; LOS = 19.4 d | The functional measures correlated with each other; QOL did not correlate significantly with functional outcomes KPS less sensitive for measuring disability than DRS or FIM |
| Marciniak et al, 2001 | Retrospective study of 132 patients, divided into 4 categories: 44 (33%) meningioma, 33 (26%) astrocytoma, 21 (16%) metastatic disease, and 33 (25%) miscellaneous PBT diagnoses | No difference in motor or cognitive FIM efficiencies by tumor type; shorter LOS in metastatic disease patients (18 d vs 21–28 d for the other categories, P = .03) | Better motor FIM efficiency in patients receiving radiation (1 vs 0.78, P <.05) Those with recurrent tumors had smaller FIM motor efficiency than those with initial presentation (0.55 vs 0.98, P = .018) |
| Greenberg et al, 2006 | Retrospective comparison of patients with PBT/craniotomy due to meningioma (n = 128) or glioma (n = 40), and acute stroke (n = 1660) | Comparable functional gains per FIM points (17.9 for meningioma, 17.2 for glioma, 21.8 for stroke) | Shorter length of stay for BT patients vs stroke patients Similar discharge to home rates, all >80% |
| Geler-Kulcu et al, 2009 | 21 brain tumor (mix of benign and malignant) and 21 stroke patients, matched by side of lesion Compared FIM, Berg Balance Score, Postural Assessment Scale for Stroke, Motor Assessment Scale | No significant difference between brain tumor and stroke patients nor brain tumor subgroups in any of the outcome measures | |
| Alam et al, 2008 | Retrospective; 188 cancer (and benign neurologic tumor) patients compared with 2801 noncancer patients; includes 72 patients with brain tumor | Patients with brain tumor more likely (25%) than brain rehabilitation controls (12%) to be transferred back to acute care ( P = .004); no difference in transfer rate between benign PBT, malignant PBT, or metastatic BT; lower FIM score associated with higher risk of transfer | Infection is most common reason for transfer, compared with cardiopulmonary concerns as most common reason in controls Only 1 of 14 patients with lung cancer (7%) with brain metastasis requires transfer |
| Tang et al, 2008 | Analysis of 63 patients with brain tumor, nearly all with malignant BT diagnoses, compared by demographic, clinical, and functional variables GBM 18 Metastatic 25 Other 20 | Estimated median survival: metastatic group, 141 d; GBM, 214 d; other, 439 d GBM: better survival with higher FIM gain ( P = .01) or low admission dexamethasone dose ( P = .027); metastatic disease: better survival with higher FIM gain ( P = .018), low admission dexamethasone dose ( P = .012) and absence of organ metastasis ( P = .003) | Metastatic disease patients had higher admit FIM score (94) vs 84 for GBM and 71 for Other patients Metastatic disease patients had shorter LOS ( P = .023) at 20 d compared with 28 d for GBM and 37 d for Other patients No difference in discharge site |
| Fu et al, 2010 | Retrospective study of 21 high-grade and 21 low-grade astrocytoma patients, matched by tumor location, age, gender, and time period | Greater length of stay (13 vs 9 d, P = .04) and FIM gains (21.7 vs 13 points, P = .02) in the high-grade group; FIM efficiency and home discharge (90%), no difference | |
| Bartolo et al, 2012 | 75 brain tumor (meningioma or glioblastoma) and 75 stroke patients, matched for age, gender, side of lesion | All outcomes (FIM, gait scores including Hauser Index, MGHFAC) improved in both groups | Meningioma patients improved more in activities of daily living ( P = .02) and mobility ( P = .04) than others |
| Roberts et al, 2014 | Retrospective study of newly diagnosed GBM patients, 100 who received inpatient rehabilitation (KPS 70) and 312 who did not (KPS 80); examined functional status of the rehabilitation patients and survival time of all patients | 89 (93.7%) of patients improved Rehabilitation patients survived median 14.3 mo; nonrehabilitation group 17.9 mo ( P = .03) No significant difference in survival ( P = .12) when adjusted for age, extent of resection, and KPS | Among the rehabilitation group, age ( P = .0006), low degree of resection ( P = .02), and lack of Stupp regimen ( P = .05) were associated with higher mortality |
| Asher et al, 2014 | Retrospective study of predictive factors for transfers back to acute care among 184 patients with cancer diagnoses, 90 with PBT and 110 coded as having “brain dysfunction” | 17.4% transfer rate; neurosurgical complications were most common reason (31%) |
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Examination of other levels of inpatient rehabilitation care, such as rehabilitation concurrent with acute oncology or neurosurgical care, or rehabilitation at a skilled nursing facility level present a relative gap in the literature. The relative lack of data for other inpatient settings is a significant concern because in order to receive acute rehabilitation, patients need to meet strict regulatory standards, and some patients may be either too mildly affected or too severely affected to receive care at the acute rehabilitation setting. One study of home-based care for 121 malignant patients with brain tumor showed that function as measured by Barthel index improved in 39%, was maintained in 20%, and worsened in 44%; 72% of patients improved in at least one quality-of-life domain. Studies of rehabilitation in the outpatient setting, other than cognitive rehabilitation, have been limited and are summarized in Table 3 .
| Authors | Design | Interventions | Outcome Measures | Results |
|---|---|---|---|---|
| Sherer et al, 1997 | Retrospective case series of 13 adult PBT patients after resection, chemotherapy, and radiation therapy; assessed level of independence, vocational outcomes | Individualized outpatient speech and occupational therapy, psychology, and vocational assistance; typical quantity 5 h/d, averaging 2.6-mo duration | Independence Rating Scale, Productivity Status Rating Scale |
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| Khan et al, 2014 | Prospective trial of 106 glioma survivors, 53 in treatment group and 53 waitlist controls, allocated based on “clinical need” | Comprehensive individualized multidisciplinary rehabilitation for up to 6–8 wk, including social, psychology, occupational therapy, and physiotherapy | Outcome measure of FIM, secondary outcomes of Depression, Anxiety Distress Scale, Perceived Impact Problem Profile, and Cancer Rehabilitation Evaluation System | Treatment group with improved outcomes at 3 mo in subscales of self-care, sphincter, locomotion, mobility, and communication (all P <.01), and psychosocial ( P <.05) No differences in the secondary outcome measures at 6 mo, between-group differences maintained for sphincter, communication, and cognitive subscales (all P <.01) |
Cognition
Cognitive function is gaining increasing attention in oncologic disease in general. In the setting of brain neoplasm, tumor involvement itself directly affects cognition. In Brinkman’s study of cognitive impairment among 224 childhood brain tumor survivors, severe cognitive impairment was seen up to 15 times more frequently than in the general population. Cognitive deficits associated with brain neoplasms tend to be most pronounced in attention, memory, and executive functioning.
After chemotherapy, cognitive changes may relate to effects including elevated levels of cytokines, DNA damage, neurotoxicity-related brain white matter damage, as secondary effects of fatigue or depression, and psychosomatic effects. See the Radiation Therapy section for discussion of radiation effects on brain tissue, which can include both white matter and neuronal damage.
As an aside, no single brief screening tool has been recognized as effective for cancer-associated cognitive dysfunction. This concern is perhaps less pertinent to the specific clinical setting of brain tumor, where cognitive deficits may be severe, than for cancer rehabilitation in general, but is nonetheless applicable here because some patients will be high functioning and virtually all will be at risk. The Mini-Mental Status Exam (MMSE) is considered insufficiently sensitive, and full neuropsychological testing, while sometimes indicated, is too laborious for many clinical situations. The Montreal Cognitive Assessment has been widely used for mild cognitive dysfunction in other clinical settings. Use of computer-based cognitive screening, as sometimes used in mild brain injury and dementia care, has not been reported in cancer populations, including brain tumor. Function-based assessments, such as the Executive Function Performance Test and Complex Task Performance Assessment, hold promise. Patient-reporting tools, such as FACT-Cog or FACT-Brain, which have a few cognitive items, may be useful from a cognitive symptom perspective. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire brain subscale, and the MD Anderson Symptom Inventory Brain Tumor Module, also are of potential utility in identifying or monitoring cognitive symptoms.
Table 4 and Table 5 describe details of studies to date on cognitive therapy and medications for patients with brain tumor. In general, trials of cognitive therapy have shown favorable although not always consistent results. In addition to the cognitive case series noted in the tables, there have been other case reports of effective use of cognitive strategies in this population. Based on results of 2 class II studies by Butler and colleagues, Langenbahn and colleagues in a recent evidence-based review have recommended cognitive rehabilitation as a practice guideline for children and adolescents treated for brain neoplasm. Virtual reality data are also emerging, with positive effects found for visual and auditory continuous concentration, short-term memory, and visual motor coordination.
| Authors | Design | Intervention | Outcome Measures | Core Results |
|---|---|---|---|---|
| Locke et al, 2008 | 19 dyads of adult patients with brain tumor and their caregivers (13 dyads completing study) | Six 50-min cognitive therapy sessions over 2 wk incorporating calendar training Six additional 50-min sessions over 2 wk for problem-solving training | Compensation Techniques Questionnaire, Post Study Feedback Questionnaire (intervention group). FACT-brain and Mayo-Portland Adaptability Inventory-4; additional measures of cognitive functioning, quality of life, caregiver burden, mood, and fatigue | Good tolerance; 88% reported using strategies including use of a calendar and specific problem-solving skills; Quality of Life Scores per Functional Assessment of Cancer Therapy-Brain did not differ between subjects and controls, nor did functional status (MPAI scores) |
| Gehring et al, 2009 | 140 adult patients with low-grade and anaplastic gliomas, randomized to cognitive therapy or control group | Six weekly sessions, 2 h each, incorporating cognitive training (computer-based), and compensatory strategies | Battery of numerous neuropsychological tests and self-report questionnaires pretreatment and posttreatment and 6 mo later | Therapy group performed better on some neuropsychological measures of attention and verbal memory and reported less mental fatigue at 6 mo but not right after treatment |
| Butler et al, 2008 | 108 childhood cancer survivors and 53 randomized waitlist controls, at least 1 y after treatment of CNS cancer; ages 6–17 | Intervention: Cognitive therapy, up to 20 two-hour sessions | Pretesting and posttesting of academic achievement, attention, memory, learning strategies, parent/teacher attention ratings, and a self-esteem inventory | Improved academic performance in language and mathematics ( P = .003); improved parent report of attention in daily activities ( P = .001); improved learning strategies ( P <.001); little effect on neurocognitive testing |
| Zucchella et al, 2013 | 58 adult patients with recent neurosurgery for PBT; randomization stratified by side and grade of lesion | 16 one-hour cognitive therapy sessions over 4 wk, including computer exercises and metacognitive training | Neuropsychological testing within 3 d of admission to rehabilitation and at 4 wk (both groups received other usual rehabilitation) | Improvement in treatment group in all domains; compared with controls, study group performed better in some tests of attention (TMT-A), memory (RAVLT), and executive function (TMT-B) |
| Yang et al, 2014 | 38 adult brain tumor (mixed benign and malignant PBT, and metastatic) patients randomized to VR training or control group | Four week VR training 30-min sessions 3 times a wk, plus computer-based cognitive therapy 30 min 5 d a wk; control group had only the computer-based cognitive training | Computerized neuropsychological tests, Korean Mini-Mental Status Examination (K-MMSE), and Korean version of the Modified Barthel Index (K-MBI) | Both groups showed improved in K-MMSE and K-MBI, in auditory continuous performance, forward digit span, forward visual span, verbal learning, and TMT-A; VR group performed better than controls in visual and auditory continuous performance tests, backward digit span, backward visual span, and TMT-A |
| Authors | Design | Intervention | Outcome Measures | Core Results |
|---|---|---|---|---|
| Meyers et al, 1998 | 30 mostly adult (ages 15–70, mean 40) patients, 29 with malignant glioma | Methylphenidate, dosing levels of 10, 20, and 30 mg twice daily; patients tested at baseline and at each dosing level | Attention (digit span), HVLT, processing speed (digit symbol; TMT-A), COWA, TMT-B, motor speed and dexterity (grooved pegboard); FIM; Beck Depression Inventory; State-Trait Anxiety Inventory | Improved memory, reasoning, verbal fluency, processing speed, executive function, dexterity; lowest dosing sufficient |
| Thompson et al, 2001 | Randomized study of 32 pediatric cancer survivors, ages 6–17, 25 with history of brain tumor | Methylphenidate 0.6 mg/kg (20 mg maximum) vs placebo; testing at baseline and repeated 90 min after ingesting medication or placebo | Connors’ Continuous Performance Test (CPT), California Verbal Learning Test, Visual-Auditory Learning Test | Improved sustained attention ( P = .015) per CPT, improved overall index ( P = .008); no difference in impulsiveness, reaction times, verbal learning, or visual auditory learning |
| Mulhern et al, 2004 (extension of Thompson et al) | Double-blind crossover of 83 pediatric malignancy survivors—brain tumor (43) or leukemia (40), ages 6–18 | Methylphenidate, in low (0.3 mg/kg, up to 20 mg/d) and moderate dosing (0.6 mg/kg, up to 40 mg/d), 3 wk each; randomized sequence of low dose, higher dose, and placebo | Weekly teacher and parent reports using the Child Behavior Checklist, and parent reports of side effects Side Effect Rating Scales | Improved parent ( P = .004) and teacher ( P = .004) ratings of attention; improved teacher ratings of social skills ( P = .001), problem behaviors ( P = .045), and academic competence ( P = .001) No consistent advantage of low vs moderate dosing |
| Brown et al, 2013 | Randomized trial of 508 adult patients with brain metastases | Memantine to 20 mg per day, vs placebo, for 24 wk, initiated within 3 d of starting whole brain radiation therapy Assessments at baseline, 8, 16, 24, and 52 wk | HVLT-R, TMT-A, (TMT-B), (COWA), and MMSE | Memantine arm with longer time to cognitive decline ( P = .01); 8 wk ( P = .008) and 16 wk ( P = .0041) favorable execution function status; 24 wk favorable processing speed ( P = .0137) and delayed recognition ( P = .0149); trend ( P = .059) for less decline in delayed recall |
| Rapp et al, 2015 | Randomized trial of 198 adult brain tumor survivors 6 mo after partial- or whole-brain irradiation; 66% PBT, 27% metastatic, 8% prophylactic | Donepezil (5 mg for 6 wk, 10 mg for 18 wk) vs placebo; testing at baseline, 12 and 24 wk | HVLT-R, visuomotor skills (modified Rey-Osterrieth complex figure), TMT-A, TMT-B, COWA. Digit Span Test), grooved pegboard; composite score also generated | No difference in composite scores; among subdomains, donepezil group performed better in recognition memory ( P = .027), discrimination, ( P = .007), both derived from HVLT-R, and motor speed and dexterity ( P = .016); improvements greatest in setting of greater baseline cognitive deficits |
Behavioral changes have received less attention than cognitive deficits in the brain tumor literature. Simpson and colleagues, investigating patient, caregiver, and clinical reports of behavioral changes in adult patients with benign or malignant PBT, using the Frontal Systems Behavioral Rating Scale, Emotional and Social Dysfunction Questionnaire, and Overt Behavior Scale, found highest reported rates of behavioral changes in individuals with seizure disorder, and lack of correlation with tumor grade, treatment modality, or depressed mood. Although “moderate agreement” was reported between patients and caregivers, caregiver reporting was generally higher (worse) and in good agreement with clinician ratings. Among patients, executive impairments were most frequently reported (51%) followed by apathy (40.5%), and anger and verbal aggression (both 27%). Among caregivers, highest reports were for apathy (59.5%), indifference (36.1%), and executive impairments (35.1%). Poggi and colleagues, comparing childhood brain tumor and brain injury survivors ages 8 to 15 years, reported that in general traumatic brain injury patients were more likely to externalize problems, whereas social adjustment problems in brain tumor survivors appeared associated with internalizing problems.
Patient and caregiver psychological and supportive care needs
The supportive care needs of patients with brain tumor, especially those with high-grade malignancy, are well documented. Areas that have received attention include communication and informational strategies, management of psychological stress, anxiety, and depression, caregiver needs and well-being, end-of-life supports, complementary therapies (homeopathy, vitamin or herbal supplements, meditation, and massage), sexuality, and models of care for providing a “helping system” for patients and caregivers. Langbecker and Yates found the highest degree of self-reported unmet supportive care needs in recently diagnosed (mean 3 months) PBT patients in the areas of physical (47.9%) and psychological (45.8%) needs, followed by health system/information needs (37.9%) and sexuality needs (34.8%).
Introduction
Although malignant primary brain tumor (PBT), estimated at 24,790 new cases in the United States in 2016, comprises just 1.4% of all cancers, brain tumor is actually far more common when one considers benign brain tumor, with estimated incidence of more than double that, at 52,880 cases, and metastatic brain tumor, which is yet more common. Estimated prevalence rate of individuals living with history of PBT is nearly 700,000. Systematic statistical surveillance is lacking for incidence of brain metastasis, has been estimated at between 200,000 and 300,000 people per year, or at least 10 times more common than primary brain malignancy, with more than half of patients with metastatic disease presenting with multiple tumors, most commonly in the cerebrum. Brain is the most common site for central nervous system (CNS) malignancy; cranial nerves, spinal cord, and cauda equina account for a collective 10% of tumors, and pituitary and pineal tumors account for 16%.
PBT is seen over the entire age spectrum. Although most common in adults, with median age of 59 at diagnosis, malignant brain tumor is the most common solid tumor of childhood (more than 4600 cases estimated in 2016), and thus, has high representation in pediatric oncology. Seven percent of all primary CNS tumors occur in children ages 0 to 19, and another nearly 9% in young adults ages 20 to 34. Brain metastasis is uncommon in children.
Types of tumor vary over the age spectrum, with pilocytic astrocytomas and embryonal tumors (especially medulloblastoma) most common in childhood, pituitary tumors in late adolescence and young adulthood (ages 15–34), and meningiomas and glioblastomas through the remainder of adulthood.
Prognostically, for malignant PBT, survival varies greatly, especially by type of tumor, including in some cases by their molecular markers, and also by age, with older age being less favorable. Primary malignant brain tumor of childhood averages 74% 5-year survival, but through the full age spectrum averages just 34%, and greater than age 75 averages only 6.1%. Of note, malignant PBT outnumbers benign PBT in childhood (3.3:1.9, per 100,000, ages 0–19), whereas benign PBT is more common than malignant PBT in adults (17.9:8.9 per 100,000). Five-year survival for benign brain tumor is 92%.
Brain tumors have long been recognized as producing a high rate of disabling effects, with recognition that the creation of a “culture of hope” is an important part of management. Rehabilitation needs have historically been described in upwards of 80% of individuals with CNS malignancy, with multiple impairments often present. Long-term effects on employment and general health have consistently been described. Rehabilitation emphasizes individualized interdisciplinary care to address the functional impact of tumor and/or treatment-related impairments. Although the rehabilitation therapy itself is similar in approach to other neurologic disorders such as stroke or traumatic brain injury, the underlying context of the oncology-related factors must be incorporated into the clinician’s perspective, so that best care and guidance can be provided. Rates of receiving rehabilitation have not been systematically studied but are generally considered to be low.
This review follows the general outline of providing (1) a brief summary of relevant background information about brain tumors, (2) evidence for rehabilitation’s significant role in the supportive care of patients with brain tumor, and related management considerations, and (3) an outline of survivorship issues. These categories should be viewed as having indistinct boundaries and rather serve as a general conceptual framework to approach patient care needs over the continuum of care.
Primary Treatment
Tumor types including incidence data, standard treatments, and prognostic information are summarized in Table 1 . MRI with and without contrast is the diagnostic modality of choice for brain tumor.
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