Interventions for cognitive deficits in patients with a brain tumor: an update

Figures & data

Table 1. Recent and novel studies of targeted brain tumor treatments.

Investigators (year; trial no.)	Design	n	Population	Intervention	Relevant outcome measures	Timing of assessments	Statistical analyses	Relevant results	Attrition/toxicities	Comments	Ref.
Gondi et al. (2010) in preparation of RTOG 0933 trial	Retrospective risk estimation	371	Patients with ≤10 BMs	None; estimation of perihippocampal metastasis risk in preparation of trial HA-WBRT	Axial images from pretreatment, postcontrast MRIs	NA	Correlations, backward logistic regression	Metastases within 5 mm of the hippocampus in 8.6% of patients, intracranial volume of metastatic disease predicted perihippocampal metastases	NA	HA-WBRT is safe for clinical testing	[49]
Anscher et al. (NCT00581113)	Phase III, randomized, open label	30	1–6 BMs	Neural stem cell-preserving WBRT vs standard WBRT	Cognitive tests	Until 12 months after completion of WBRT	NA	Study start: December 2007 Current status: terminated due to new research priorities	NA	No publication	[202]
Eisai Inc. (NJ, USA) (NCT00525590)	Phase II, no control group	75	1 BM	Surgery plus gliadel wafers	Cognitive tests	Unknown	NA	Study start: September 2007 Expected primary completion: March 2011 Current status: recruiting	NA	Estimated enrollment adjusted from 75 to 59 patients	[203]
Correa et al. (2009)	Phase II, prospective, no control group	12	Immunocompetent patients with newly diagnosed, histologically confirmed B-cell PCNSL	Induction CTX, reduced-dose WBRT and consolidation CTX	Cognitive tests, Q on depression and QoL; MRI	Baseline, postinduction CTX and prior to WBRT, 6, 12, 18 and 24 months after treatment	T-tests, correlations	No cognitive decline over 2 years post-treatment; mild increase of white matter disease until 18-month follow-up	7 drop-outs within 12 months and 3 drop-outs thereafter, with various reasons, among them 2 who declined cognitive testing		[50]

BM: Brain metastasis; CTX: Chemotherapy; HA-WBRT: Hippocampal avoidance during whole-brain radiation therapy; NA: Not applicable; PCNSL: Primary CNS lymphoma; Q: Questionnaire; QoL: Quality of life; RTOG: Radiation Therapy Oncology Group; WBRT: Whole-brain radiation therapy.

Table 2. Recent and novel studies of pharmacological prevention of cognitive deficits in patients with brain tumors.

Investigators (trial no.)	Design	n	Population	Intervention	Relevant outcome measures	Timing of assessments	Statistical analyses	Relevant results	Attrition/toxicities	Ref.
Brown et al. (NCT00566852)	Phase III, randomized, placebo-controlled, double-blind	536	BMs from solid tumors	Memantine during, and until 24 weeks after, WBRT	Cognitive tests, Q on QoL	BL, weeks 8, 16 and 24 of treatment, then every 4 months for 1 year, every 6 months for 2 years and every year thereafter	NA	Study start: March 2008 Estimated primary completion: June 2012 Current status: recruiting	NA	[205]
Lu et al.(NCT00469937)	Phase I, open label, no control group	24	Multiple BMs	Lithium 7 days before and during WBRT	Mental status and Q on QoL	BL, days 1, 8 and 15, 1 month after treatment and periodically thereafter	NA	Study start: February 2006 Current status: data collection completed March 2009	NA	[204]

BL: Baseline; BM: Brain metastasis; NA: Not applicable; Q: Questionnaire; QoL: Quality of life; WBRT: Whole-brain radiation therapy.

Table 3. Recent and novel studies of pharmacological treatment of cognitive deficits in patients with brain tumors.

Investigators (year; trial no.)	Design	n	Population	Intervention	Relevant outcome measures	Timing of assessments	Statistical analyses	Relevant results	Attrition/toxicities	Ref.
Wefel et al. (NCT00418691); Patwardhan et al. (2010)	Phase III, open label, randomized, no control group	24 out of 75	Primary or metastatic BT, postsurgery and post-RTX, reported cognitive decline	Methylphenidate (IR or SR) or modafinil, all for 4 weeks	Cognitive tests, Qs on symptoms such as fatigue and depression	BL, week 4	Likelihood ratio statistic, controlled for baseline performance, adjusted for multiple comparisons	Terminated owing to poor accrual (n = 24); methylphenidate improved psychomotor processing speed but not memory or executive function. No effect of modafinil	NV	[206] [52]
Levin et al. (NCT00488644); Wefel et al. (2009)	Open label, no control group	10 out of 26	BT, hypothyroidism, post-RTX^†	Liothyronine added to levothyroxine for 8 weeks	Cognitive tests, Qs on QoL and mood	BL, day 1 of treatment, and after 8 weeks	Paired t-tests, effect sizes	Terminated owing to slow accrual (n = 10); improved psychomotor processing speed, but not memory	NV	[207] [53]
Gesell et al.^† (NCT00087815)	Pilot randomized, single blind, active control (CC)	30	BT, RN with progressive neurological symptoms, managed with steroid therapy^†	CC plus hyperbaric oxygen therapy for ∼3 months	Mental status, Q on QoL	BL, every month during treatment, end of treatment, and months 1, 2 and 4 thereafter	NA	Study start: September 2003 Expected primary completion: June 2005 Current status: ongoing, but not recruiting	NA	[208]
Loghin et al.^† (NCT00492089)	Phase II, randomized, placebo controlled, crossover, double blind	16	Irradiated primary BT and head and neck cancer, RN with progressive neurological symptoms^†	Bevacizumab for 6–12 weeks	Cognitive tests and QoL as secondary outcomes	BL, periodically during treatment, and weeks 12 and 24 after completion	NA	Study start: February 2007 Expected primary completion: September 2007 Current status: ongoing but not recruiting	NA	[209]
Rapp et al.^† (NCT00369785)	Phase III, randomized, double blind, placebo controlled	200	Primary or metastatic BT, post-RTX, radiographically stable^†	Donepezil for 24 weeks	Cognitive tests, Qs on subjective cognitive function, fatigue, mood and QoL	BL, weeks 12 and 24	NA	Study start: January 2008 Estimated primary Completion: June 2010 Current status: recruiting	NA	[210]
Correa et al.^† (NCT00594633)	Open label, no control group	30	BT, mild–moderate cognitive deficits, previous RTX, CTX or both	Donepezil for 24 weeks	Cognitive tests	BL, weeks 12 and 24, and 6 months after end of treatment	NA	Study start: October 2004 Estimated primary completion: October 2010 Current status: ongoing, but not recruiting	Estimated enrollment adjusted from 30 to 25 patients	[211]
Shaw et al. (NCT01032200)	Randomized, placebo controlled, double blind	54	Patients with primary BT undergoing RTX^†	Armodafinil or placebo for 9–11 weeks	Cognitive tests, Qs on fatigue and QoL	BL and periodically during the study	NA	Study start: March 2010 Estimated primary completion: May 2011 Current status: not yet recruiting	NA	[212]

^†Presence of cognitive deficits not an inclusion criterion.

BL: Baseline; BT: Brain tumor; CC: Conventional care; CTX: Chemotherapy; IR: Immediate release; NA: Not applicable; NV: Not available; Q: Questionnaire; QoL: Quality of life; RN: Radionecrosis; RTX: Radiotherapy; SR: Sustained release.

Table 4. Recent and novel studies of cognitive rehabilitation for cognitive deficits in patients with brain tumors.

Investigators (year; trial no.)	Design	n	Population	Intervention	Relevant outcome measures	Timing of assessments	Statistical analyses	Relevant results	Attrition/toxicities	Comments	Ref.
Duval et al. (2008)	Case study	1	Man with resection of ganglioglioma grade 2 in left temporal lobe	Rehabilitation of central-executive component of working memory, consisting of information, cognitive and ecological sessions, several per week, for 6 months	Cognitive and ecological tests, Q on subjective cognitive functioning	Complex time-frame, with 15 different evaluation points, until 3 months after completion of rehabilitation	Both comparison to normative groups, and nonparametric χ^2 tests	Improvement of working memory deficits, subjective cognitive functioning and on ecological tasks. Effects on cognitive tests and subjective cognitive functioning maintained at 3-month follow-up	NA		[55]
Locke et al. (2008)	Pilot open label, randomized controlled for first 16 dyads, another three assigned to intervention group	19	Dyads of patients with newly diagnosed primary BT, during RTX, having mild–moderate cognitive deficits, and their caregivers	12 sessions of cognitive-rehabilitation and problem-solving therapy intervention (n = 12) vs standard medical care (n = 7) over 2 weeks	Qs on compensation techniques, intervention feedback, QoL, and functional status, cognitive tests	Baseline, postintervention, and 3-month follow-up	Wilcoxon signed-rank test	88% used compensation strategies and 88% found intervention helpful (n = 13); no significant intervention-related improvement in QoL and functional status; no analysis of cognitive data	Low accrual, 5 pairs dropped out before postintervention assessment, 1 pair did not complete follow-up	Feasibility and tolerability study	[56]
Hassler et al. (2010)	Pilot, no control group	11	Patients with grade 3 gliomas and glioblastomas multiforme, postsurgery RTX and CTX; KPS: 80–100^†	Ten sessions of holistic mnemonic group training of attention, verbal and memory skills over 12 weeks	Three cognitive tests	Pre- and postintervention	Paired t-tests	Significant improvement in a verbal memory test	None		[57]
Brigidi et al. (NCT00849498)	Open-label, randomized, controlled	20	Dyads of patients with high-grade glioma, and depression, fatigue, sleep problems and/or cognitive impairment, and their caregivers	Coping skills training including problem solving, communication skills and managing activities for 3 months vs usual care	Adherence, cognitive tests, Qs on cognitive functioning and symptoms	Baseline, postintervention, and every 4 months thereafter up to 2 years	NA	Study start: December 2008 Estimated study completion date: December 2011 Current status: recruiting	NA	Coping skills include cognitive rehabilitation strategies	[213]
Taphoorn et al. (NCT00256425); Gehring et al. (2009)	Open label, randomized, controlled	140	Low-grade gliomas, anaplastic gliomas (age <50 years and KPS >70), subjective and objective cognitive symptoms	Six sessions of cognitive rehabilitation (retraining and compensation) in 7 weeks	Cognitive tests, Qs on cognitive functioning, mental fatigue, community integration and QoL	Baseline, immediately after training and 6-month follow-up	Doubly multivariate repeated measures ANCOVAs	Postintervention improvement of subjective cognitive functioning, longer term improvement in attention, verbal memory and mental fatigue	13 patients dropped out between baseline and follow-up		[214] [48]

^†Presence of cognitive deficits not an inclusion criterion.

ANCOVA: Analysis of covariance; BT: Brain tumor; CTX: Chemotherapy; KPS: Karnofsky performance score; NA: Not applicable; Q: Questionnaire; QoL: Quality of life; RTX: Radiotherapy.

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