The results from a phase III clinical study provide the first clinical evidence that sparing the hippocampus during prophylactic cranial irradiation (PCI) better preserves cognitive function in patients with small-cell lung cancer (SCLC). Compared with standard PCI, no differences were observed in terms of failure in brain, overall survival (OS), and quality of life (QoL). Accirding to Prof. Núria Rodríguez de Dios of the Radiation Oncology, Hospital del Mar, Hospital del Mar Medical Research Institute, and Pompeu Fabra University in Barcelona, Spain and colleagues, who published their findings on 11 August 2021 in the JCO, hippocampal avoidance approach should be considered standard of care for patients with SCLC who need to receive PCI.

The authors explained in the background that introduction of intensity-modulated radiation therapy and volumetric modulated arc therapy enabled the reduction of radiation dose to the hippocampus in the delivery of PCI. Avoiding the hippocampus poses the risk of attenuating the benefit of PCI because of increased metastatic disease within the hippocampal conformal avoidance region.

They designed the phase III study to investigate the neurotoxicity of PCI and to assess in a randomised design the benefits and risks of sparing the hippocampus in patients with SCLC who receive PCI. The study enrolled 150 patients with SCLC of whom 71.3% were with limited disease. Patients were randomised to standard PCI of 25 Gy in 10 fractions or hippocampal avoidance during PCI.

The primary objective was the delayed free recall (DFR) on the Free and Cued Selective Reminding Test (FCSRT) at 3 months; a decrease of 3 points or greater from baseline was considered a decline. Secondary endpoints included other FCSRT scores, QoL, evaluation of the incidence and location of brain metastases, and OS.

Data were recorded at baseline, and 3, 6, 12, and 24 months after PCI. Baseline characteristics were well balanced between the two groups.

Decline on DFR from baseline to 3 months was lower in the hippocampal avoidance during PCI arm, 5.8% compared with 23.5% in the the PCI arm (odds ratio 5; 95% confidence interval, 1.57 to 15.86; p = 0.003).

Analysis of all FCSRT scores showed a decline on the total recall (TR; 8.7% versus 20.6%) at 3 months; DFR (11.1% versus 33.3%), TR (20.3% versus 38.9%), and total free recall (14.8% versus 31.5%) at 6 months, and TR (14.2% versus 47.6%) at 24 months.

The incidence of brain metastases, OS, and QoL were not significantly different.

The authors commented that a limitation of their study is the paucity of data available at 24 months of follow-up. Despite the long-term benefit reported in the FCSRT scores by patients who received hippocampal avoidance PCI, it is unknown whether the chronic changes (beyond 12 months) become more long term or permanent, or whether there is some recovery with more time. However, the available evidence has shown that the majority of neurocognitive impairment appears in the first months after brain irradiation.

They concluded that their study is an important step in introducing a new therapeutic approach to patients with SCLC who are candidates for PCI.

In accompanied editorial, Dr. Paul D. Brown of the Department of Radiation Oncology, Mayo Clinic in Rochester, MN, US and colleagues wrote that PCI for patients with SCLC continues to evolve with opportunities to prevent associated cognitive toxicity through improvements in radiation delivery and greater sensitivity of brain surveillance. Studies of hippocampal avoidance during PCI have contributed significantly to this evolution. Ongoing and future studies incorporating rigorous methodology and knowledge from cognitive neuroscience will continue to refine and personalise brain management strategies for patients with SCLC.


Rodríguez de Dios N, Couñago F, Murcia-Mejia M, et al. Randomized Phase III Trial of Prophylactic Cranial Irradiation With or Without Hippocampal Avoidance for Small-Cell Lung Cancer (PREMER): A GICOR-GOECP-SEOR Study. Journal of Clinical Oncology; Published online 11 August 2021. DOI: 10.1200/JCO.21.00639

Brown PD, Parsons MW, Rusthoven CG, et al. Hippocampal Avoidance Prophylactic Cranial Irradiation: A New Standard of Care? Journal of Clinical Oncology; Published online 11 August 2021. DOI: 10.1200/JCO.21.01632