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Neurocognitive function impairment after whole brain radiotherapy for brain metastases: actual assessment.

ABSTRACT: Whole brain radiation therapy (WBRT) is an effective treatment in brain metastases and, when combined with local treatments such as surgery and stereotactic radiosurgery, gives the best brain control. Nonetheless, WBRT is often omitted after local treatment due to its potential late neurocognitive effects. Publications on radiation-induced neurotoxicity have used different assessment methods, time to assessment, and definition of impairment, thus making it difficult to accurately assess the rate and magnitude of the neurocognitive decline that can be expected. In this context, and to help therapeutic decision making, we have conducted this literature review, with the aim of providing an average incidence, magnitude and time to occurrence of radio-induced neurocognitive decline. We reviewed all English language published articles on neurocognitive effects of WBRT for newly diagnosed brain metastases or with a preventive goal in adult patients, with any methodology (MMSE, battery of neurcognitive tests) with which baseline status was provided. We concluded that neurocognitive decline is predominant at 4 months, strongly dependant on brain metastases control, partially solved at later time, graded 1 on a SOMA-LENT scale (only 8% of grade 2 and more), insufficiently assessed in long-term survivors, thus justifying all efforts to reduce it through irradiation modulation.

SUBMITTER: Tallet AV

PROVIDER: S-EPMC3403847 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Neurocognitive function impairment after whole brain radiotherapy for brain metastases: actual assessment.

Tallet Agnes V AV Azria David D Barlesi Fabrice F Spano Jean-Philippe JP Carpentier Antoine F AF Gonçalves Antony A Metellus Philippe P

Radiation oncology (London, England) 20120528

Whole brain radiation therapy (WBRT) is an effective treatment in brain metastases and, when combined with local treatments such as surgery and stereotactic radiosurgery, gives the best brain control. Nonetheless, WBRT is often omitted after local treatment due to its potential late neurocognitive effects. Publications on radiation-induced neurotoxicity have used different assessment methods, time to assessment, and definition of impairment, thus making it difficult to accurately assess the rate ...[more]

PMID: 22640600

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Project description:To prospectively evaluate the association between hippocampal dose and long-term neurocognitive function (NCF) impairment for benign or low-grade adult brain tumors treated with fractionated stereotactic radiotherapy (FSRT).Adult patients with benign or low-grade adult brain tumors were treated with FSRT per institutional practice. No attempt was made to spare the hippocampus. NCF testing was conducted at baseline and 18 months follow-up, on a prospective clinical trial. Regression-based standardized z scores were calculated by using similar healthy control individuals evaluated at the same test-retest interval. NCF impairment was defined as a z score ?-1.5. After delineation of the bilateral hippocampi according to the Radiation Therapy Oncology Group contouring atlas, dose-volume histograms were generated for the left and right hippocampi and for the composite pair. Biologically equivalent doses in 2-Gy fractions (EQD(2)) assuming an ?/? ratio of 2 Gy were computed. Fisher's exact test and binary logistic regression were used for univariate and multivariate analyses, respectively. Dose-response data were fit to a nonlinear model.Of 29 patients enrolled in this trial, 18 completed both baseline and 18-month NCF testing. An EQD(2) to 40% of the bilateral hippocampi >7.3 Gy was associated with impairment in Wechsler Memory Scale-III Word List (WMS-WL) delayed recall (odds ratio [OR] 19.3; p = 0.043). The association between WMS-WL delayed recall and EQD(2) to 100% of the bilateral hippocampi >0.0 Gy trended to significance (OR 14.8; p = 0.068).EQD(2) to 40% of the bilateral hippocampi greater than 7.3 Gy is associated with long-term impairment in list-learning delayed recall after FSRT for benign or low-grade adult brain tumors. Given that modern intensity-modulated radiotherapy techniques can reduce the dose to the bilateral hippocampi below this dosimetric threshold, patients should be enrolled in ongoing prospective trials of hippocampal sparing during cranial irradiation to confirm these preliminary results.

Project description:Whole brain radiotherapy (WBRT) has been the treatment of choice for patients with brain metastases. However, change/decline of neurocognitive functions (NCFs) resulting from impaired hippocampal neurogenesis might occur after WBRT. It is reported that conformal hippocampal sparing would provide the preservation of NCFs. Our study aims to investigate the hippocampal dosimetry and to demonstrate the correlation between hippocampal dosimetry and neurocognitive outcomes in patients receiving hippocampal sparing during WBRT (HS-WBRT).Forty prospectively recruited cancer patients underwent HS-WBRT for therapeutic or prophylactic purposes. Before receiving HS-WBRT, all participants received a battery of baseline neurocognitive assessment, including memory, executive functions and psychomotor speed. The follow-up neurocognitive assessment at 4 months after HS-WBRT was also performed. For the delivery of HS-WBRT, Volumetric Modulated Arc Therapy (VMAT) with two full arcs and two non-coplanar partial arcs was employed. For each treatment planning, dose volume histograms were generated for left hippocampus, right hippocampus, and the composite hippocampal structure respectively. Biologically equivalent doses in 2-Gy fractions (EQD2) assuming an alpha/beta ratio of 2 Gy were computed. To perform analyses addressing the correlation between hippocampal dosimetry and the change in scores of NCFs, pre- and post-HS-WBRT neurocognitive assessments were available in 24 patients in this study.Scores of NCFs were quite stable before and after HS-WBRT in terms of hippocampus-dependent memory. Regarding verbal memory, the corresponding EQD2 values of 0, 10, 50, 80 % irradiating the composite hippocampal structure with <12.60 Gy, <8.81, <7.45 Gy and <5.83 Gy respectively were significantly associated with neurocognitive preservation indicated by the immediate recall of Word List Test of Wechsler Memory Scale-III. According to logistic regression analyses, it was noted that dosimetric parameters specific to left sided hippocampus exerted an influence on immediate recall of verbal memory (adjusted odds ratio, 4.08; p-value, 0.042, predicting patients' neurocognitive decline after receiving HS-WBRT).Functional preservation by hippocampal sparing during WBRT is indeed achieved in our study. Providing that modern VMAT techniques can reduce the dose irradiating bilateral hippocampi below dosimetric threshold, patients should be recruited in prospective trials of hippocampal sparing during cranial irradiation to accomplish neurocognitive preservation while maintaining intracranial control.Current Controlled Trials NCT02504788.

Project description:Abstract BACKGROUND: Patients with a large number of brain metastases (BM) and/or micrometastatic disease in the brain present a clinical challenge. While technical innovations in stereotactic radiosurgery (SRS) have extended the number of BM that can be effectively treated, SRS does not treat occult disease and distant brain failure (DBF) post-SRS remains high. Immuno- and targeted therapies show promise in treating metastatic disease to the brain, though response rates are variable. In contrast, whole-brain radiotherapy (WBRT) provides high rates of local control and, compared to SRS, reduces the risk of distant brain failure. Unfortunately, WBRT is also associated with substantial neurocognitive deficits and neither altered fractionation nor the use of available neuroprotectants has adequately addressed this issue. An agent that safely minimizes the adverse effects of WBRT while preserving or enhancing tumor control would provide meaningful clinical benefit. TRIAL DESIGN: BMX-001, a novel Mn-porphyrin superoxide dismutase mimetic, has been shown to protect normal tissues from ionizing radiation in preclinical trials, reducing neurocognitive adverse effects as well as enhancing tumor response. Based on the first-in-human trial of this agent in patients with high-grade gliomas, we have instituted a clinical trial of WBRT +/- BMX-001 in adult patients with more than 10 BM from melanoma, non-small-cell lung, breast and renal cancer. Following a safety lead-in of 5 patients, all of whom will receive WBRT and BMX-001, 69 patients will be randomized to WBRT (3Gy/fraction x 10 fractions) with or without BMX-001 administered subcutaneously before, twice weekly during and once after WBRT (6 injections total.) The primary endpoint is cognition, as measured by the Hopkins Verbal Learning, Trailmaking A/B and Controlled Oral Word Association tests. Secondary endpoints include health-related quality-of-life, overall and progression-free survival, rates of radiation necrosis, DBF and neurologic death. Enrollment began January 2019. (ClinicalTrials.gov Identifier: NCT03608020.)

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Neurocognitive function impairment after whole brain radiotherapy for brain metastases: actual assessment.

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Neurocognitive function impairment after whole brain radiotherapy for brain metastases: actual assessment.

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