Hippocampal avoidance in WBRT better preserves cognitive function without compromising survival

Hippocampal avoidance during whole-brain radiotherapy (HA-WBRT), together with memantine, better preserves cognitive function vs WBRT plus memantine in patients with brain metastases, without compromising survival, a multi-institutional phase III trial has shown.

In the NRG Oncology CC001 trial, 518 adult patients (median age, 61.5 years; primary lung cancer, 57.7 percent) with brain metastases outside a 5 mm margin around either hippocampus were randomized to receive HA-WBRT (n=257) or WBRT (n=261), together with memantine. HA-WBRT was delivered using intensity-modulated radiotherapy (IMRT) technique. In both groups, the prescribed WBRT dose was 30 Gy in 10 fractions. [J Clin Oncol 2020;38:1019-1029]

After a median follow-up of 7.9 months for patients who remained alive, the primary analysis showed a significantly lower risk of cognitive failure (defined as decline determined by reliable change index on ≥1 cognitive test) in the HA-WBRT vs WBRT arm (hazard ratio [HR], 0.76; 95 percent confidence interval [CI], 0.60 to 0.98; p=0.03). A significant treatment effect in favour of HA-WBRT plus memantine (HR, 0.74; 95 percent CI, 0.58 to 0.95; p=0.02) was found in the adjusted cause-specific analysis.

The better preservation of cognitive function with HA-WBRT vs WBRT was attributable to lower rates of deterioration in executive function at 4 months (23.3 percent vs 40.4 percent; p=0.01), as well as learning (11.5 percent vs 24.7 percent; p=0.049) and memory (16.4 percent vs 33.3 percent; p=0.02) at 6 months.

Importantly, overall survival (OS) and intracranial progression-free survival (PFS) did not differ significantly between the HA-WBRT and WBRT arms. Median OS was 6.3 months vs 7.6 months (HR, 1.13; 95 percent CI, 0.90 to 1.41; p=0.31), while median intracranial PFS was 5.0 months vs 5.3 months (HR, 1.14; 95 percent CI, 0.93 to 1.41; p=0.21).

Of note, there were fewer HA regional relapses in the HA-WBRT vs WBRT arm (11 vs 16).

No significant difference in grade ≥3 toxicity was reported between the HA-WBRT and WBRT arms.

In terms of symptom burden and quality of life, patients in the HA-WBRT arm experienced fewer cognitive symptoms (p=0.01) and less interference of neurologic symptoms in daily activities (p=0.008) at 6 months than those in the WBRT arm.

At 6 months, patients in the HA-WBRT arm reported less difficulty in remembering things (p=0.01), less difficulty in speaking (p=0.049), and less fatigue (p=0.04) than those in the WBRT arm.

“To our knowledge, this trial provides the first definitive clinical evidence that the hippocampal neuroregenerative niche is important to the pathophysiology of RT-induced cognitive decline,” the investigators wrote. “Our results provide confirmation that conformal avoidance of the hippocampal neuroregenerative stem-cell niche using IMRT during WBRT better preserves cognitive function and [reduces] patient-reported symptoms, with no significant difference observed in toxicity, intracranial PFS or OS.”

In the trial, the benefit of HA-WBRT emerged robustly with ≥4 months of follow-up, the investigators noted. For patients with life spans <4 months, previous trials showed that cognitive decline likely resulted from disease progression or other factors that contributed to shorter survival. [JAMA 2016;316:401-409; J Clin Oncol 2014;32:3810-3816] “Therefore, it seems reasonable to forgo HA during WBRT in patients with expected survival of <4 months,” they suggested.

“With these findings, HA-WBRT plus memantine 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,” they concluded.