Exploring Novel Therapeutic Avenues for Chemotherapy Related Cognitive Impairment.

Many cancer patients are at risk of developing cognitive symptoms that often become evident during or after cancer-directed therapy and may involve difficulties with attention, concentration, multitasking, executive function, and memory. Despite recent advances in identifying potential molecular and cellular mechanisms underlying cancer and chemotherapy-related cognitive impairment, there is generally a lack of effective treatment strategies, and the development of novel therapeutic interventions represents a major unmet medical need in clinical practice. A recent study by Kim and colleagues suggests that multi-sensory 40-Hz gamma entrainment using sensory stimuli (GENUS) with combined visual and auditory stimuli is associated with powerful neuroprotective effects in mouse models of cisplatin or methotrexate-induced 'chemobrain'. While the study has some limitations and successful interventions in animal models have often failed to translate into clinical practice, this non-invasive treatment modality has promise to protect brain structure and function and could be tested in cancer patients who are at risk for cognitive decline.

Mitigating Radiotoxicity in the Central Nervous System: Role of Proton Therapy.

OPINION STATEMENT: Central nervous system (CNS) radiotoxicity remains a challenge in neuro-oncology. Dose distribution advantages of protons over photons have prompted increased use of brain-directed proton therapy. While well-recognized among pediatric populations, the benefit of proton therapy among adults with CNS malignancies remains controversial. We herein discuss the role of protons in mitigating late CNS radiotoxicities in adult patients. Despite limited clinical trials, evidence suggests toxicity profile advantages of protons over conventional radiotherapy, including retention of neurocognitive function and brain volume. Modelling studies predict superior dose conformality of protons versus state-of-the-art photon techniques reduces late radiogenic vasculopathies, endocrinopathies, and malignancies. Conversely, potentially higher brain tissue necrosis rates following proton therapy highlight a need to resolve uncertainties surrounding the impact of variable biological effectiveness of protons on dose distribution. Clinical trials comparing best photon and particle-based therapy are underway to establish whether protons substantially improve long-term treatment-related outcomes in adults with CNS malignancies.

Cognitive issues in patients with IDH mutant gliomas: from neuroscience to clinical neuropsychology.

PURPOSE: The understanding of cognitive symptoms in patients with IDH-Mutant gliomas (IDH-Mut) is rapidly developing. In this article, we summarize the neuroscientific knowledge base regarding the influence of IDH-Mut tumors and their treatment on cognition and provide guidance regarding the management of these symptoms in patients. METHODS: We performed a review of peer reviewed publications relevant to IDH-Mut glioma and cognitive outcomes and provide an overview of the literature as well as a case example to clarify management strategies. RESULTS: At the time of presentation, patients with IDH-Mut gliomas have a favorable cognitive profile as compared with those with IDH-wild type (WT) tumors. The relatively low cognitive burden may reflect the slower growth rate of IDH-Mut tumors, which is less disruptive to both local and widespread neural networks. Human connectomic research using a variety of modalities has demonstrated relatively preserved network efficiency in patients with IDH-Mut gliomas as compared with IDH-WT tumors. Risk of cognitive decline from surgery can potentially be mitigated by careful integration of intra-operative mapping. Longer term cognitive risks of tumor treatment, including chemotherapy and radiation, are best managed by instituting neuropsychological assessment as part of the long-term care of patients with IDH-Mutant glioma. A specific timeline for such integrative care is provided. CONCLUSIONS: Given the relative recency of the IDH-mutation based classification of gliomas, as well as the long time course of this disease, a thoughtful and comprehensive strategy to studying patient outcomes and devising methods of cognitive risk reduction is required.

Cognitive function after concurrent temozolomide-based chemoradiation therapy in low-grade gliomas.

PURPOSE: We sought to evaluate the effects of concurrent temozolomide-based chemoradiation therapy on neurocognitive function in patients with low-grade glioma (LGG). MATERIALS/METHODS: We included adult patients with LGG who were treated postoperatively with radiotherapy (RT) with concurrent and adjuvant temozolomide (TMZ). Patients were evaluated with comprehensive psychometric tests at baseline (prior to RT + TMZ) and at various time intervals following RT + TMZ. Baseline cognitive performance was analyzed by sex, age, education history, history of seizures, IDH mutation status, and 1p/19q codeletion status. Changes in neurocognitive performance were evaluated over time. RESULTS: Thirty-seven LGG patients (mean age 43.6, 59.5% male) had baseline neurocognitive evaluation. Patients with an age > 40 years old at diagnosis and those with an education > 16 years demonstrated superior baseline verbal memory as assessed by HVLT. No other cognitive domains showed differences when stratified by the variables mentioned above. A total of 22 LGG patients had baseline and post RT + TMZ neurocognitive evaluation. Overall, patients showed no statistical difference between group mean test scores prior to and following RT + TMZ on all psychometric measures (with the exception of HVLT Discrimination). CONCLUSION: Cognitive function remained stable following RT + TMZ in LGG patients evaluated prospectively up to 2 years. The anticipated analysis of RTOG 0424 will provide valuable neurocognitive outcomes specifically for high risk LGG patients treated with RT + TMZ.

Factors associated with psychological distress in caregivers of patients with malignant gliomas.

PURPOSE: Caregivers of patients with malignant gliomas are at risk for psychological distress. However, factors associated with distress in this population have not been well described. We conducted a prospective study evaluating psychological distress in patients with malignant gliomas and their caregivers and exploring factors associated with caregiver distress. METHODS: We enrolled patients with newly diagnosed malignant gliomas (N = 77) and their caregivers (N = 61). At baseline and 3, 6, and 9 months after diagnosis, we administered the Hospital Anxiety and Depression Scale to assess psychological distress and the Caregiver Reaction Assessment to evaluate caregiver burden. We performed multivariable regression analyses to investigate caregiver-related, patient-related, and tumor-related factors associated with caregivers' distress. RESULTS: At baseline, 48.3% (29/60) and 26.2% (16/61) of caregivers reported clinically significant anxiety and depression symptoms, respectively. Anxiety and depression symptoms persisted over time. Greater caregiver depression was associated with male gender (B = 1.48, 95% CI 0.16-2.81, p = 0.03), higher caregiver burden (B = 0.08, 95% CI 0.01-0.15, p = 0.02), caregiver anxiety (B = 0.53, 95% CI 0.38-0.68, p < 0.0001), patient depression (B = 0.34, 95% CI 0.13-0.55, p = 0.002), and caring for a younger patient (B = -0.07, 95% CI -0.15 to 0.00, p = 0.049). Factors associated with greater caregiver anxiety symptoms were caregiver depression (B = 0.91, 95% CI 0.71-1.12, p < 0.0001) and younger patient age (B = -0.15, 95% CI -0.24 to -0.05, p = 0.003). CONCLUSION: Male gender, higher caregiver burden, greater patient depression symptoms, and younger patient age are associated with increased distress among caregivers of patients with malignant gliomas, underscoring the need for tailored supportive care interventions targeting caregivers at highest risk for psychological distress.

Quality of life following concurrent temozolomide-based chemoradiation therapy or observation in low-grade glioma.

PURPOSE: Low-grade glioma (LGG) exhibits longer median survival than high-grade brain tumors, and thus impact of our therapies on patient quality of life remains a crucial consideration. This study evaluated the effects of concurrent temozolomide-based chemoradiation (RT + TMZ) or observation on quality of life (QOL) in patients with low-grade glioma. METHODS: We completed a retrospective cross-sectional study of adults with LGG who underwent surgery with known molecular classification from 1980 to 2018. Postoperatively, patients were either observed or received adjuvant concurrent temozolomide-based chemoradiation. EQ-5D and PHQ-9 depression screen were completed before outpatient visits every 2-3 months. Baseline score was defined as ± 30 days within initial operation. RESULTS: Of the 63 patients (mean age 44 ± 17 years, 51% female) with baseline EQ-5D or PHQ-9 depression screen data and at least one follow-up measure, 30 (48%) were observed and 33 (52%) received RT + TMZ. No significant decline was seen in EQ-5D or PHQ-9 scores at 3, 6, 9, 12, and 24 months compared to baseline scores for all patients. At each time point, there was no significant difference between those who were observed or received adjuvant therapy. The linear mixed model estimating PHQ-9 value or EQ-5D index demonstrated that there was no significant difference in PHQ-9 or EQ-5D index between treatment groups (p = 0.42 and p = 0.54, respectively) or time points (p = 0.24 and p = 0.99, respectively). CONCLUSION: Our study found no significant decline in patient QOL or depression scores as assessed by patient- reported outcome measures for patients with low-grade glioma up to 2 years following surgery. We found no difference between RT + TMZ compared to observation during this time frame. Additional follow-up can help identify the longer-term impact of treatment strategy on patient experience.

Feasibility and Acceptance of Direct-to-Home Tele-neuropsychology Services during the COVID-19 Pandemic.

OBJECTIVE: Neuropsychological assessment via video conferencing has been proposed during the COVID-19 pandemic. Existing literature has demonstrated feasibility and acceptance of neuropsychological measures administered by videoconference, although few studies have examined feasibility and patient acceptance of TNP visits directly to patients' homes (DTH-TNP). METHODS: We modified a previously published patient satisfaction survey for DTH-TNP and developed a clinician feasibility survey to examine experiences during DTH-TNP. RESULTS: Seventy-two patients (age range: preschool-geriatric) evaluated by DTH-TNP for cognitive problems at an academic medical center responded to voluntary surveys between April 20, 2020, and August 19, 2020, and 100% indicated satisfaction. Fifty-nine percent of patients reported limitations (e.g., technological concern) during the appointment. 134 clinician surveys were collected and indicated that clinicians achieved the goal of their appointment in 90% of encounters. CONCLUSIONS: These qualitative data suggest that patients and clinicians found DTH-TNP to be satisfactory during the COVID-19 pandemic, while also recognizing limitations of the practice. These results are limited in that voluntary surveys are subject to bias. They support the growing body of literature suggesting that DTH-TNP provides a valuable service, though additional research to establish reliability and validity is needed.

Preservation of neurocognitive function in the treatment of brain metastases.

Neurocognitive function (NCF) deficits are common in patients with brain metastases, occurring in up to 90% of cases. NCF deficits may be caused by tumor-related factors and/or treatment for the metastasis, including surgery, radiation therapy, chemotherapy, and immunotherapy. In recent years, strategies to prevent negative impact of treatments and ameliorate cognitive deficits for patients with brain tumors have gained momentum. In this review, we report on research that has established the efficacy of preventative and rehabilitative therapies for NCF deficits in patients with brain metastases. Surgical strategies include the use of laser interstitial thermal therapy and intraoperative mapping. Radiotherapy approaches include focal treatments such as stereotactic radiosurgery and tailored approaches such as hippocampal avoidant whole-brain radiotherapy (WBRT). Pharmacologic options include use of the neuroprotectant memantine to reduce cognitive decline induced by WBRT and incorporation of medications traditionally used for attention and memory problems. Integration of neuropsychology into the care of patients with brain metastases helps characterize cognitive patterns, educate patients and families regarding their management, and guide rehabilitative therapies. These and other strategies will become even more important for long-term survivors of brain metastases as treatment options improve.

Reliability and validity of a novel cognitive self-assessment tool for patients with cancer.

BACKGROUND: Subjective cognitive function is an important outcome measure in oncology. The Functional Assessment of Cancer Therapy-Brain (FACT-Br) is a quality of life (QoL) measure that includes indices of physical, emotional, social, and neurologic aspects of disease but does not measure cognitive function. This study seeks to validate a novel index of cognition derived from the FACT-Br. METHODS: Patients with heterogeneous cancer diagnoses (N = 214) completed neuropsychological evaluation and self-report measures. Nine FACT-Br items regarding cognition were combined to form the FACT-Br-cognitive index (CI). Reliability was evaluated by exploratory factor analysis and internal consistency. Concurrent validity was assessed by correlating FACT-Br-CI with the Patient-Reported Outcomes Measurement Information System (PROMIS) Cognitive-8 scales. Discriminant validity was assessed by correlating FACT-Br-CI with other FACT-Br indices and the Beck Depression and Anxiety Inventories (BDI, BAI). Exploratory analyses evaluated the impact of cognitive performance and disease variables on FACT-Br-CI. RESULTS: The FACT-Br-CI consisted of a single factor that demonstrated high internal consistency (α = 0.867) and strong concurrent validity, correlating strongly with PROMIS Cognitive-8 scales (r = 0.675-0.782). The relationship between the FACT-Br-CI and other FACT subscales ranged from moderate to strong (r = 0.372-0.601), as did correlations with measures of depression (BDI, r = -0.621) and anxiety (BAI, r = -0.450). Modest correlations were observed with neuropsychological measures (rs = 0.249-0.300). CONCLUSIONS: The FACT-Br-CI is a reliable and valid measure of self-reported cognition. Studies that included the FACT-Br could be retrospectively analyzed to assess subjective cognitive outcomes, enriching the information from prior research. Integration of the FACT-Br-CI in routine clinical care may be an efficient method of monitoring cognition.

The development and implementation of teleneuropsychology in an academic lifespan neuropsychology center: Lessons learned from the COVID-19 pandemic.

INTRODUCTION: Teleneuropsychology (TNP) became a critical means for providing care during the COVID-19 pandemic and may continue as an option for delivery of neuropsychological services. To understand how patient characteristics impact clinician decisions and service models, this study examines practice patterns within a lifespan outpatient neuropsychology center before, during and post-pandemic. METHODS: Patient volume, demographics, and characteristics were compared across four, 3-month time intervals in 2019-2020. Two baseline intervals when the center was physically open (PO) were compared to one interval when the center was physically closed (PC) (all evaluations were conducted via direct-to-home TNP) and a fourth interval when the center was physically reopened (RO) and evaluations were conducted in one of the three modalities: in-person, virtual only or hybrid (both virtual/in-person). RESULTS: A total of 1,459 total neuropsychological evaluations were conducted with a 64.6% reduction during PC. At RO, the number of evaluations returned to pre-COVID baseline during which in-person (72.4%) evaluations were conducted at a higher rate than hybrid (7.1%) or virtual only (20.4%). Across the lifespan, mean number of appointments to complete evaluations was significantly greater during PC (p< .001) than at other time intervals, and during RO, hybrid evaluations required significantly more appointments (p < .001) than in-person and virtual. The majority of evaluations were conducted with adult patients (71.4%). For adult patients, neurodegenerative/memory disorders received TNP evaluations at a higher rate during PC and RO. Pediatric patients were significantly older during PC (p < .001); neurodevelopmental referrals received more hybrid and virtual evaluations. CONCLUSIONS: Results indicate that patient characteristics, especially age and referral categories, impact the feasibility of TNP. Data from the RO period suggest that in-person evaluations not surprisingly remain the mainstay; however, for adult patients, and especially older adults with neurodegenerative/memory disorders, TNP may provide an important option for delivery of neuropsychological evaluations.

Cancer, cognition, and COVID: delivering direct-to-home teleneuropsychology services to neuro-oncology patients.

BACKGROUND: The COVID-19 pandemic induced rapid adoption of telemedicine services for neuro-oncology patients at an increased risk of infection. Neuropsychological assessment is important to neuro-oncology care yet challenging to complete outside of a structured testing environment. Teleneuropsychology (TNP) has been explored in limited populations and proven feasible and reliable. Conducting TNP visits directly to patients' home (DTH) had minimal prior study. METHODS: We used two voluntary surveys to examine acceptance (patients) and feasibility (providers) of DTH-TNP at two regionally diverse medical institutions providing neuropsychological services to neuro-oncology patients from April to September 2020. RESULTS: A total of 119 patients were scheduled during the study period, 79 of whom completed neuropsychological testing via DTH-TNP. Neuropsychology providers completed surveys on 68 of these encounters (86%). In 98% of cases, neuropsychologists were able to achieve or partially achieve the individually defined goals of their assessment. Common problems reported included patient dysregulation (16%) and slow/unreliable internet (15%). Of the 52 patients who responded, 98% were satisfied with the DTH-TNP experience, and 92% would recommend the virtual visit to others. All respondents felt understood by the examiner (100%) and the majority denied technical difficulties (90%), communication challenges (94%), or privacy concerns (98%). Patients reported reduced risk of infection and saved travel time as favorable aspects of DTH-TNP. CONCLUSIONS: These preliminary results suggest neuro-oncology patients find DTH-TNP acceptable and neuropsychologists find it a feasible practice, while also recognizing its limitations. Results suggest that further study of DTH-TNP (eg, reliability, validity) for neuro-oncology patients is warranted.

Assessment and Management of Cognitive Symptoms in Patients With Brain Tumors.

Cognitive symptoms occur in almost all patients with brain tumors at varying points in the disease course. Deficits in neurocognitive function may be caused by the tumor itself, treatment (surgery, radiation, or chemotherapy), or other complicating factors (e.g., seizures, fatigue, mood disturbance) and can have a profound effect on functional independence and quality of life. Assessment of neurocognitive function is an important part of comprehensive care of patients with brain tumors. In the neuro-oncology clinic, assessment may include cognitive screening tools and inquiry into subjective cognitive function. Neuropsychological assessment is an important adjunct to identify cognitive symptoms and can be used as an opportunity to intervene through transformative feedback and treatment planning. Preventative measures can be taken to reduce cognitive side effects of treatment, such as awake craniotomies with intraoperative mapping during neurosurgery or prophylactic measures during radiation therapy (e.g., hippocampal avoidance, neuroprotectant treatment with memantine). Rehabilitative therapies, including cognitive rehabilitation and computerized cognitive exercise, are options for managing cognitive problems in an individualized manner. Pharmacotherapy, including use of stimulant medications and acetylcholinesterase inhibitors, has shown benefits for patients with brain tumors when tailored to an individual's cognitive profile. Identification and management of co-occurring issues, such as sleep disturbance, fatigue, and depression, can also improve neurocognitive function. There are promising therapies under development that may provide new options for treatment in the future. Integrating careful assessment and treatment of cognition throughout the disease course for patients with brain tumors can improve functional outcomes and quality of life.

Perceptions of prognosis and goal of treatment in patients with malignant gliomas and their caregivers.

BACKGROUND: Patients with malignant gliomas have a poor prognosis. However, little is known about patients' and caregivers' understanding of the prognosis and the primary treatment goal. METHODS: We conducted a prospective study in patients with newly diagnosed malignant gliomas (N = 72) and their caregivers (N = 55). At 12 weeks after diagnosis, we administered the Prognosis and Treatment Perceptions Questionnaire to assess understanding of prognosis and the Hospital Anxiety and Depression Scale to evaluate mood. We used multivariable regression analyses to explore associations between prognostic understanding and mood and McNemar tests to compare prognostic perceptions among patient-caregiver dyads (N = 48). RESULTS: A total of 87.1% (61/70) of patients and 79.6% (43/54) of caregivers reported that it was "very" or "extremely" important to know about the patient's prognosis. The majority of patients (72.7%, [48/66]) reported that their cancer was curable. Patients who reported that their illness was incurable had greater depressive symptoms (B = 3.01, 95% CI, 0.89-5.14, P = .01). There was no association between caregivers' prognostic understanding and mood. Among patient-caregiver dyads, patients were more likely than caregivers to report that their primary treatment goal was cure (43.8% [21/48] vs 25.0% [12/48], P = .04) and that the oncologist's primary goal was cure (29.2% [14/48] vs 8.3% [4/48], P = .02). CONCLUSIONS: Patients with malignant gliomas frequently hold inaccurate perceptions of the prognosis and treatment goal. Although caregivers more often report an accurate assessment of these metrics, many still report an overly optimistic perception of prognosis. Interventions are needed to enhance prognostic communication and to help patients cope with the associated distress.

Monitoring of Neurocognitive Function in the Care of Patients with Brain Tumors.

PURPOSE OF REVIEW: A detailed characterization of the nature of neurocognitive impairment in patients with brain tumors is provided, as well as considerations for clinical practice regarding neuropsychological assessment throughout the disease course. RECENT FINDINGS: Neurocognitive impairment is common in patients with brain tumors and may result from the tumor itself, as a consequence of treatment, including surgery, chemotherapy, and radiation, or in association with supportive care medications (e.g., anticonvulsant and pain medications). Serial surveillance of neurocognitive functioning in this population can facilitate medical decision-making and inform recommendations to improve patient daily functioning and quality of life. Neuropsychological assessment is increasingly recognized as a critical component of the multidisciplinary care of patients with brain tumors and has already had practice-changing effects. Further understanding of genetic risk factors for neurocognitive decline along with the development of novel assessment and intervention strategies may further enhance functioning and general well-being in this patient population.

Management for Different Glioma Subtypes: Are All Low-Grade Gliomas Created Equal?

Following the identification of key molecular alterations that provided superior prognostication and led to the updated 2016 World Health Organization (WHO) Central Nervous System (CNS) Tumor Classification, the understanding of glioma behavior has rapidly evolved. Mutations in isocitrate dehydrogenase (IDH) 1 and 2 are present in the majority of adult grade 2 and 3 gliomas, and when used in conjunction with 1p/19q codeletion for classification, the prognostic distinction between grade 2 versus grade 3 is diminished. As such, the previously often used term of "low-grade glioma," which referred to grade 2 gliomas, has now been replaced by the phrase "lower-grade glioma" to encompass both grade 2 and 3 tumors. Additional molecular characterization is ongoing to even further classify this heterogeneous group of tumors. With such a colossal shift in the understanding of lower-grade gliomas, management of disease is being redefined in the setting of emerging molecular-genetic biomarkers. In this article, we review recent progress and future directions regarding the surgical, radiotherapeutic, chemotherapeutic, and long-term management of adult lower-grade gliomas.

Pharmacologic management of cognitive impairment induced by cancer therapy.

Cognitive dysfunction is a challenging adverse effect of chemotherapy and radiotherapy that has limited treatment options. Clinical trials for proposed pharmacotherapeutic interventions to help manage these cognitive symptoms have had conflicting results and no standard of care has yet been established. Pharmacotherapeutic approaches for cancer therapy-induced cognitive symptoms include CNS stimulants (eg, methylphenidate and modafinil), medications used in patients with memory impairment (eg, donepezil, memantine, and ginkgo biloba), and bone marrow supporting agents (eg, erythropoietin). Whilst the beneficial effects of CNS stimulants have been mainly reported in children, efficacy in adults has been varied. Antidementia drugs have emerged as promising compounds in the management of cognitive dysfunction, but clinical experience of their use remains limited. Therefore, large clinical trials for these putative memory-enhancing drugs are needed to establish their clinical value in an oncology setting. Several clinical trials testing novel pharmacotherapeutic interventions for the management of cognitive dysfunction are ongoing, as well as numerous preclinical studies. With an increasing understanding of the molecular and cellular mechanisms underlying cognitive deficits in patients with cancer, novel treatment strategies are emerging.

Validation of computerized episodic memory measures in a diverse clinical sample referred for neuropsychological assessment.

OBJECTIVE: To examine the convergent and discriminant validity of two brief computerized episodic memory measures in a large, diverse clinical sample of adults undergoing neuropsychological assessment. METHOD: Computerized measures of word and face memory were administered to 233 adults (age 30 and over) who also completed comprehensive neuropsychological testing. RESULTS: Moderate correlations were observed between the computerized memory tests and a wide range of traditional neuropsychological measures of episodic memory (e.g. word-list learning, story recall, face recognition, design recall). Select measures of visuomotor processing speed and language were also related to performance on the computerized tasks. In contrast, the computerized memory tests showed weak correlations with tests in other cognitive domains (i.e. visuospatial skills, attention/working memory, executive function, motor dexterity, academic skills) and self-report screening measures of mood and anxiety. Similar to traditional measures of episodic memory, the computerized memory measures were sensitive to effects of age and gender. CONCLUSIONS: Computerized measures of word and face memory showed good convergent and discriminant validity in this diverse clinical sample supporting the construct validity of these measures. This indicates that it may be feasible to measure memory function in clinical settings using brief, well-designed computerized memory measures.