Summary It has become increasingly apparent that cytotoxic drugs given systemically for non-CNS tumours might have cognitive side-effects, but many fundamental questions require further elucidation, ...and large samples from several institutions are needed. Two working groups brought together by the International Cognition and Cancer Task Force (ICCTF) developed recommendations for a core set of neuropsychological tests, common criterion for defining cognitive impairment and cognitive changes, and common approaches to improve the homogeneity of study methods. These recommendations will improve research design and facilitate study combinations, between-study comparisons, and meta-analyses, which will allow more accurate estimates of incidence, severity, individual risk factors, and causes of cognitive problems associated with chemotherapy for non-CNS tumours.
To conduct a controlled trial of bevacizumab for the treatment of symptomatic radiation necrosis of the brain.
A total of 14 patients were entered into a placebo-controlled randomized double-blind ...study of bevacizumab for the treatment of central nervous system radiation necrosis. All patients were required to have radiographic or biopsy proof of central nervous system radiation necrosis and progressive neurologic symptoms or signs. Eligible patients had undergone irradiation for head-and-neck carcinoma, meningioma, or low- to mid-grade glioma. Patients were randomized to receive intravenous saline or bevacizumab at 3-week intervals. The magnetic resonance imaging findings 3 weeks after the second treatment and clinical signs and symptoms defined the response or progression.
The volumes of necrosis estimated on T(2)-weighted fluid-attenuated inversion recovery and T(1)-weighted gadolinium-enhanced magnetic resonance imaging scans demonstrated that although no patient receiving placebo responded (0 of 7), all bevacizumab-treated patients did so (5 of 5 randomized and 7 of 7 crossover) with decreases in T(2)-weighted fluid-attenuated inversion recovery and T(1)-weighted gadolinium-enhanced volumes and a decrease in endothelial transfer constant. All bevacizumab-treated patients-and none of the placebo-treated patients-showed improvement in neurologic symptoms or signs. At a median of 10 months after the last dose of bevacizumab in patients receiving all four study doses, only 2 patients had experienced a recurrence of magnetic resonance imaging changes consistent with progressive radiation necrosis; one patient received a single additional dose of bevacizumab and the other patient received two doses.
The Class I evidence of bevacizumab efficacy from the present study in the treatment of central nervous system radiation necrosis justifies consideration of this treatment option for people with radiation necrosis secondary to the treatment of head-and-neck cancer and brain cancer.
An estimated 20% of patients with cancer will develop brain metastases. Approximately 200,000 individuals in the United States alone receive whole-brain radiotherapy (WBRT) each year to treat brain ...metastases. Historically, the prognosis of patients with brain metastases has been poor; however, with new therapies, this is changing. Because patients are living longer following the diagnosis and treatment of brain metastases, there has been rising concern about treatment-related toxicities associated with WBRT, including neurocognitive toxicity. In addition, recent clinical trials have raised questions about the use of WBRT. To better understand this rapidly changing landscape, this review outlines the treatment roles and toxicities of WBRT and alternative therapies for the management of brain metastases.
Various tumor characteristics have been associated with neurocognitive functioning (NCF), though the role of tumor grade has not been adequately examined.
Seventy-two patients with histologically ...confirmed grade IV glioma (n = 37), grade III glioma (n = 20), and grade II glioma (n = 15) in the left temporal lobe completed preoperative neuropsychological assessment. Rates of impairment and mean test performances were compared by tumor grade with follow-up analysis of the influence of other tumor- and patient-related characteristics on NCF.
NCF impairment was more frequent in patients with grade IV tumor compared with patients with lower-grade tumors in verbal learning, executive functioning, as well as language abilities. Mean performances significantly differed by tumor grade on measures of verbal learning, processing speed, executive functioning, and language, with the grade IV group exhibiting worse performances than patients with lower-grade tumors. Group differences in mean performances remained significant when controlling for T1-weighted and fluid attenuated inversion recovery MRI-based lesion volume. Performances did not differ by seizure status or antiepileptic and steroid use.
Compared with patients with grade II or III left temporal lobe glioma, patients with grade IV tumors exhibit greater difficulty with verbal learning, processing speed, executive functioning, and language. Differences in NCF associated with glioma grade were independent of lesion volume, seizure status, and antiepileptic or steroid use, lending support to the concept of "lesion momentum" as a primary contributor to deficits in NCF of newly diagnosed patients prior to surgery.
The addition of bevacizumab to temozolomide and radiotherapy did not improve overall survival in patients with glioblastoma. Patients receiving bevacizumab had more symptoms, a worse quality of life, ...and more cognitive impairment than did those receiving placebo.
Glioblastoma is the most common primary malignant brain tumor in adults. After maximal surgical tumor resection, the current standard of care is based on a phase 3, randomized clinical trial conducted by the European Organization for Research and Treatment of Cancer and the National Cancer Institute of Canada, which showed that concurrent treatment with daily temozolomide and radiotherapy followed by maintenance temozolomide was superior to radiotherapy alone.
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Despite the improvement in outcomes with this combined chemoradiotherapy approach, few patients survive beyond 5 years; therefore, new therapeutic strategies are needed.
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Angiogenesis is a prominent feature of glioblastoma, most commonly attributed . . .
Radiotherapy with concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma (GBM). O(6)-methylguanine-DNA methyltransferase (MGMT) methylation status may be an ...important determinant of treatment response. Dose-dense (DD) temozolomide results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial tested whether DD temozolomide improves overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed GBM.
This phase III trial enrolled patients older than age 18 years with a Karnofsky performance score of ≥ 60 with adequate tissue. Stratification included clinical factors and tumor MGMT methylation status. Patients were randomly assigned to standard temozolomide (arm 1) or DD temozolomide (arm 2) for 6 to 12 cycles. The primary end point was OS. Secondary analyses evaluated the impact of MGMT status.
A total of 833 patients were randomly assigned to either arm 1 or arm 2 (1,173 registered). No statistically significant difference was observed between arms for median OS (16.6 v 14.9 months, respectively; hazard ratio HR, 1.03; P = .63) or median PFS (5.5 v 6.7 months; HR, 0.87; P = .06). Efficacy did not differ by methylation status. MGMT methylation was associated with improved OS (21.2 v 14 months; HR, 1.74; P < .001), PFS (8.7 v 5.7 months; HR, 1.63; P < .001), and response (P = .012). There was increased grade ≥ 3 toxicity in arm 2 (34% v 53%; P < .001), mostly lymphopenia and fatigue.
This study did not demonstrate improved efficacy for DD temozolomide for newly diagnosed GBM, regardless of methylation status. However, it did confirm the prognostic significance of MGMT methylation. Feasibility of large-scale accrual, prospective tumor collection, and molecular stratification was demonstrated.
Patients with glioma frequently suffer from deficits of neurocognitive functioning (NCF), though few studies have assessed NCF in localized glioma patients prior to surgery. One hundred and three ...patients (M age = 52.0; M education = 14.6 years) with histologically confirmed glioma in the right (RTL: n = 30; 57 % glioblastoma) or left temporal lobe (LTL: n = 73; 49 % glioblastoma) completed presurgical neuropsychological assessment. Impairment of NCF was identified in 75 % of all patients. Notably, patients with RTL glioma were most frequently impaired on measures of verbal memory and executive functioning, and at similar rates as the LTL group. Nonetheless, χ
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tests revealed that impairment rates were significantly higher in the LTL group on attention and object naming tests (p ≤ .05). Independent-samples t-tests revealed that mean performances of patients with LTL glioma were also significantly below RTL patients on measures of attention (p = .01), verbal learning and memory (p = .05), and language (p < .03). A trend was observed in which anterior LTL tumors were associated with reduced verbal learning and medial LTL lesions with delayed recall problems, though patients with lesions involving multiple LTL regions exhibited the greatest difficulty across all verbal memory measures. Significant group differences in NCF performances remained so after controlling for FLAIR volume and tumor histology. These findings indicate that temporal lobe glioma frequently present with impaired NCF, though impairments are often milder in RTL compared to LTL patients. Nonetheless, the relatively frequent verbal memory impairment in the RTL group underscores the bilaterality of verbal memory processes.
One in three people will be diagnosed with cancer during their lifetime. The community of cancer patients is growing, and several common cancers are becoming increasingly chronic; thus, cancer ...survivorship is an important part of health care. A large body of research indicates that cancer and cancer therapies are associated with cognitive impairment. This research has mainly concentrated on chemotherapy-associated cognitive impairment but, with the arrival of immunotherapies, the focus is expected to widen and the number of studies investigating the potential cognitive effects of these new therapies is rising. Meanwhile, patients with cognitive impairment and their healthcare providers are eagerly awaiting effective approaches to intervene against the cognitive effects of cancer treatment. In this Review, we take stock of the progress that has been made and discuss the steps that need to be taken to accelerate research into the biology underlying cognitive decline following chemotherapy and immunotherapy and to develop restorative and preventive interventions. We also provide recommendations to clinicians on how to best help patients who are currently experiencing cognitive impairment.
Summary Background It is unclear whether the benefit of adding whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) for the control of brain-tumours outweighs the potential ...neurocognitive risks. We proposed that the learning and memory functions of patients who undergo SRS plus WBRT are worse than those of patients who undergo SRS alone. We did a randomised controlled trial to test our prediction. Methods Patients with one to three newly diagnosed brain metastases were randomly assigned using a standard permutated block algorithm with random block sizes to SRS plus WBRT or SRS alone from Jan 2, 2001, to Sept 14, 2007. Patients were stratified by recursive partitioning analysis class, number of brain metastases, and radioresistant histology. The randomisation sequence was masked until assignation, at which point both clinicians and patients were made aware of the treatment allocation. The primary endpoint was neurocognitive function: objectively measured as a significant deterioration (5-point drop compared with baseline) in Hopkins Verbal Learning Test–Revised (HVLT-R) total recall at 4 months. An independent data monitoring committee monitored the trial using Bayesian statistical methods. Analysis was by intention-to-treat. This trial is registered at www.ClinicalTrials.gov , number NCT00548756. Findings After 58 patients were recruited (n=30 in the SRS alone group, n=28 in the SRS plus WBRT group), the trial was stopped by the data monitoring committee according to early stopping rules on the basis that there was a high probability (96%) that patients randomly assigned to receive SRS plus WBRT were significantly more likely to show a decline in learning and memory function (mean posterior probability of decline 52%) at 4 months than patients assigned to receive SRS alone (mean posterior probability of decline 24%). At 4 months there were four deaths (13%) in the group that received SRS alone, and eight deaths (29%) in the group that received SRS plus WBRT. 73% of patients in the SRS plus WBRT group were free from CNS recurrence at 1 year, compared with 27% of patients who received SRS alone (p=0·0003). In the SRS plus WBRT group, one case of grade 3 toxicity (seizures, motor neuropathy, depressed level of consciousness) was attributed to radiation treatment. In the group that received SRS, one case of grade 3 toxicity (aphasia) was attributed to radiation treatment. Two cases of grade 4 toxicity in the group that received SRS alone were diagnosed as radiation necrosis. Interpretation Patients treated with SRS plus WBRT were at a greater risk of a significant decline in learning and memory function by 4 months compared with the group that received SRS alone. Initial treatment with a combination of SRS and close clinical monitoring is recommended as the preferred treatment strategy to better preserve learning and memory in patients with newly diagnosed brain metastases. Funding No external funding was received.
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