Preservation of Neurocognitive Function (NCF) with Conformal Avoidance of the Hippocampus during Whole-Brain Radiotherapy (HA-WBRT) for Brain Metastases: Preliminary Results of Phase III Trial NRG Oncology CC001

PURPOSE Radiation dose to the neuroregenerative zone of the hippocampus has been found to be associated with cognitive toxicity. Hippocampal avoidance (HA) using intensity-modulated radiotherapy during whole-brain radiotherapy (WBRT) is hypothesized to preserve cognition. METHODS This phase III trial enrolled adult patients with brain metastases to HA-WBRT plus memantine or WBRT plus memantine. The primary end point was time to cognitive function failure, defined as decline using the reliable change index on at least one of the cognitive tests. Secondary end points included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported symptom burden. RESULTS Between July 2015 and March 2018, 518 patients were randomly assigned. Median follow-up for alive patients was 7.9 months. Risk of cognitive failure was significantly lower after HA-WBRT plus memantine versus WBRT plus memantine (adjusted hazard ratio, 0.74; 95% CI, 0.58 to 0.95; P = .02). This difference was attributable to less deterioration in executive function at 4 months (23.3% v 40.4%; P = .01) and learning and memory at 6 months (11.5% v 24.7% [ P = .049] and 16.4% v 33.3% [ P = .02], respectively). Treatment arms did not differ significantly in OS, intracranial PFS, or toxicity. At 6 months, using all data, patients who received HA-WBRT plus memantine reported less fatigue ( P = .04), less difficulty with remembering things ( P = .01), and less difficulty with speaking ( P = .049) and using imputed data, less interference of neurologic symptoms in daily activities ( P = .008) and fewer cognitive symptoms ( P = .01). CONCLUSION HA-WBRT plus memantine better preserves cognitive function and patient-reported symptoms, with no difference in intracranial PFS and OS, and should be considered a standard of care for patients with good performance status who plan to receive WBRT for brain metastases with no metastases in the HA region.

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Whole brain radiotherapy after local treatment of brain metastases in melanoma patients - a randomised phase III trial

BMC Cancer ◽

10.1186/1471-2407-11-142 ◽

2011 ◽

Vol 11 (1) ◽

Cited By ~ 46

Author(s):

Gerald Fogarty ◽

Rachael L Morton ◽

Janette Vardy ◽

Anna K Nowak ◽

Catherine Mandel ◽

...

Keyword(s):

New Zealand ◽

Brain Metastases ◽

Local Treatment ◽

Whole Brain Radiotherapy ◽

Neurocognitive Function ◽

Cerebral Metastases ◽

Phase Iii ◽

Leptomeningeal Disease ◽

Whole Brain ◽

Brain Radiotherapy

Abstract Background Cerebral metastases are a common cause of death in patients with melanoma. Systemic drug treatment of these metastases is rarely effective, and where possible surgical resection and/or stereotactic radiosurgery (SRS) are the preferred treatment options. Treatment with adjuvant whole brain radiotherapy (WBRT) following neurosurgery and/or SRS is controversial. Proponents of WBRT report prolongation of intracranial control with reduced neurological events and better palliation. Opponents state melanoma is radioresistant; that WBRT yields no survival benefit and may impair neurocognitive function. These opinions are based largely on studies in other tumour types in which assessment of neurocognitive function has been incomplete. Methods/Design This trial is an international, prospective multi-centre, open-label, phase III randomised controlled trial comparing WBRT to observation following local treatment of intracranial melanoma metastases with surgery and/or SRS. Patients aged 18 years or older with 1-3 brain metastases excised and/or stereotactically irradiated and an ECOG status of 0-2 are eligible. Patients with leptomeningeal disease, or who have had previous WBRT or localised treatment for brain metastases are ineligible. WBRT prescription is at least 30 Gy in 10 fractions commenced within 8 weeks of surgery and/or SRS. Randomisation is stratified by the number of cerebral metastases, presence or absence of extracranial disease, treatment centre, sex, radiotherapy dose and patient age. The primary endpoint is the proportion of patients with distant intracranial failure as determined by MRI assessment at 12 months. Secondary end points include: survival, quality of life, performance status and neurocognitive function. Discussion Accrual to previous trials for patients with brain metastases has been difficult, mainly due to referral bias for or against WBRT. This trial should provide the evidence that is currently lacking in treatment decision-making for patients with melanoma brain metastases. The trial is conducted by the Australia and New Zealand Melanoma Trials Group (ANZMTG-study 01-07), and the Trans Tasman Radiation Oncology Group (TROG) but international participation is encouraged. Twelve sites are open to date with 43 patients randomised as of the 31st March 2011. The target accrual is 200 patients. Trial registration Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12607000512426

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Faculty Opinions recommendation of A European Organisation for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life results.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717969214.793469111 ◽

2013 ◽

Author(s):

Marc Chamberlain

Keyword(s):

Quality Of Life ◽

Brain Metastases ◽

Solid Tumors ◽

Surgical Resection ◽

Whole Brain Radiotherapy ◽

Phase Iii ◽

Phase Iii Trial ◽

European Organisation ◽

Brain Radiotherapy

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A Dutch phase III randomized multicenter trial: whole brain radiotherapy vs. stereotactic radiotherapy for 4-10 brain metastases

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab021 ◽

2021 ◽

Author(s):

Dianne Hartgerink ◽

Anna Bruynzeel ◽

Danielle Eekers ◽

Ans Swinnen ◽

Coen Hurkmans ◽

...

Keyword(s):

Quality Of Life ◽

Side Effects ◽

Brain Metastases ◽

Survival Rates ◽

Whole Brain Radiotherapy ◽

Phase Iii ◽

Whole Brain ◽

Brain Radiotherapy ◽

One Year

Abstract Background The clinical value of whole brain radiotherapy (WBRT) for brain metastases (BM) is a matter of debate due to the significant side effects involved. Stereotactic radiosurgery (SRS) is an attractive alternative treatment option that may avoid these side effects and improve local tumor control. We initiated a randomized trial (NCT02353000) to investigate whether quality of life is better preserved after SRS compared with WBRT in patients with multiple brain metastases. Methods Patients with 4 to 10 BM were randomized between the standard arm WBRT (total dose 20 Gy in 5 fractions) or SRS (single fraction or 3 fractions). The primary endpoint was the difference in quality of life (QOL) at three months post-treatment. Results The study was prematurely closed due to poor accrual. A total of 29 patients (13%) were randomized, of which 15 patients have been treated with SRS and 14 patients with WBRT. The median number of lesions were 6 (range, 4-9) and the median total treatment volume was 13.0 cc 3 (range, 1.8-25.9 cc 3). QOL at three months decreased in the SRS group by 0.1 (SD=0.2), compared to 0.2 (SD=0.2) in the WBRT group (p=0.23). The actuarial one-year survival rates were 57% (SRS) and 31% (WBRT) (p=0.52). The actuarial one-year brain salvage-free survival rates were 50% (SRS) and 78% (WBRT) (p=0.22). Conclusion In patients with 4 to 10 BM, SRS alone resulted in one-year survival for 57% of patients while maintaining quality of life. Due to the premature closure of the trial, no statistically significant differences could be determined.

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Significant Preservation of Neurocognitive Function (NCF) and Patient-Reported Symptoms with Hippocampal Avoidance (HA) during Whole-Brain Radiotherapy (WBRT) for Brain Metastases: Final Results of Nrg Oncology CC001

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2019.06.402 ◽

2019 ◽

Vol 105 (1) ◽

pp. S12-S13 ◽

Cited By ~ 3

Author(s):

V. Gondi ◽

S. Pugh ◽

P.D. Brown ◽

J.S. Wefel ◽

W.A. Tome ◽

...

Keyword(s):

Brain Metastases ◽

Whole Brain Radiotherapy ◽

Neurocognitive Function ◽

Whole Brain ◽

Brain Radiotherapy ◽

Hippocampal Avoidance ◽

Patient Reported

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Hippocampal avoidance whole-brain radiotherapy without memantine in preserving neurocognitive function for brain metastases: a phase II blinded randomized trial

Neuro-Oncology ◽

10.1093/neuonc/noaa193 ◽

2020 ◽

Author(s):

Wen-Chi Yang ◽

Ya-Fang Chen ◽

Chi-Cheng Yang ◽

Pei-Fang Wu ◽

Hsing-Min Chan ◽

...

Keyword(s):

Brain Metastases ◽

Phase Ii ◽

Whole Brain Radiotherapy ◽

Neurocognitive Function ◽

Mean Difference ◽

Whole Brain ◽

Delayed Recall ◽

Brain Radiotherapy ◽

Hippocampal Avoidance

Abstract Background Hippocampal avoidance whole-brain radiotherapy (HA-WBRT) shows potential for neurocognitive preservation. This study aimed to evaluate whether HA-WBRT or conformal WBRT (C-WBRT) is better for preserving neurocognitive function. Methods This single-blinded randomized phase II trial enrolled patients with brain metastases and randomly assigned them to receive HA-WBRT or C-WBRT. Primary endpoint is decline of the Hopkins Verbal Learning Test–Revised (HVLT-R) delayed recall at 4 months after treatment. Neurocognitive function tests were analyzed with a mixed effect model. Brain progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Results From March 2015 to December 2018, seventy patients were randomized to yield a total cohort of 65 evaluable patients (33 in the HA-WBRT arm and 32 in the C-WBRT arm) with a median follow-up of 12.4 months. No differences in baseline neurocognitive function existed between the 2 arms. The mean change of HVLT-R delayed recall at 4 months was −8.8% in the HA-WBRT arm and +3.8% in the C-WBRT arm (P = 0.31). At 6 months, patients receiving HA-WBRT showed favorable perpetuation of HVLT-R total recall (mean difference = 2.60, P = 0.079) and significantly better preservation of the HVLT-R recognition-discrimination index (mean difference = 1.78, P = 0.019) and memory score (mean difference = 4.38, P = 0.020) compared with patients undergoing C-WBRT. There were no differences in Trail Making Test Part A or Part B or the Controlled Oral Word Association test between the 2 arms at any time point. There were no differences in brain PFS or OS between arms as well. Conclusion Patients receiving HA-WBRT without memantine showed better preservation in memory at 6-month follow-up, but not in verbal fluency or executive function.

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