Avoiding Hippocampus in Brain RT May Help Preserve Cognitive Function

Avoiding hippocampal exposure during prophylactic cranial irradiation (PCI) helped preserve cognitive function with no increased risk of brain metastases in extensive-stage small-cell lung cancer (SCLC), according to a randomized trial.

Without hippocampal avoidance, four times as many patients had clinically significant declines in delayed free recall (DFR) at 3 months. Other measures of recall consistently favored hippocampal avoidance during PCI at all time points up to 24 months after treatment.

The incidence of brain metastasis, overall survival (OS) and quality of life (QoL) did not differ between patients who had PCI with hippocampal avoidance and those who did not, reported Núria Rodríguez de Dios, MD, PhD, of Hospital del Mar in Barcelona, and coauthors, writing in the Journal of Clinical Oncology.

“To our knowledge, this trial provides the first clinical evidence that sparing the hippocampus during PCI better preserves cognitive function,” the authors concluded. “No differences were observed with regard to brain failure, OS, and QoL compared with standard PCI. This approach should be considered standard of care for patients with SCLC who plan to receive PCI.”

The results must be considered within the context of another phase III trial of PCI with hippocampal avoidance (HA-PCI), which showed no difference in cognitive outcomes at 4 months but unexpectedly higher rates of cognitive failure over time in patients who had HA-PCI, stated authors of an accompanying editorial.

“It is difficult to reconcile the divergent cognitive outcome results of these two very similar trials,” wrote Paul D. Brown, MD, of the Mayo Clinic in Rochester, Minnesota, and coauthors.

Given the favorable effects of HA on cognitive outcomes in trials utilizing whole-brain radiation therapy (WBRT), the cognitive-preservation benefits observed in the Spanish study, and the safety demonstrated in both trials of HA-PCI, “it is reasonable to offer HA-PCI off trial as an alternative option to standard PCI or close observation with brain MR imaging,” Brown and coauthors continued. “However, for HA-PCI to potentially be a standard of care, further study is required.”

Ongoing randomized trials of HA with PCI and WBRT will provide additional data to inform decision-making about the use of HA for preservation of cognitive function after brain irradiation, they added.

PCI is considered standard of care for limited-stage SCLC, but the role in extensive-stage disease remains unresolved, Rodríguez de Dios and colleagues noted. Several trials of PCI for SCLC and non-small cell lung cancer have shown deterioration of cognitive function in patients without brain relapse. Emerging evidence suggests the deterioration results from radiation-induced injury to neuronal progenitor cells in the hippocampus.

The advent of intensity-modulated RT and volumetric modulated arc therapy has facilitated development of treatment protocols that limit radiation dose to the hippocampus, the authors continued. However, the attenuated dose to the hippocampus poses an increased risk of brain metastasis. To examine the safety and efficacy of HA-PCI in patients with SCLC, investigators at 13 Spanish cancer centers conducted a randomized phase III trial.

Patients with SCLC (limited- or extensive-stage disease) were randomized to standard PCI or to HA-PCI. The primary objective was the change in score on the DFR component of the Free and Cued Selective Reminding Test (FCSRT) at 3 months. A decrease of three or more points was considered a decline in DFR.

Data analysis included 150 randomized patients, whose baseline characteristics were well balanced between the two treatment groups. Median follow-up for patients still alive was 40.4 months.

The results showed that 23.5% of patients randomized to standard PCI had a decline in DFR at 3 months as compared with 5.8% of those allocated to HA-PCI (OR 5.0, 95% CI 1.57-15.86, P=0.003). Analysis of all FCSRT scores showed higher rates of deterioration in recall parameters among patients treated with standard PCI versus HA-PCI, respectively:

• Total recall (TR) at 3 months: 20.6% vs 8.7%
• DFR at 6 months: 33.3% vs 11.1%
• TR at 6 months: 38.9% vs 20.3%
• Total free recall at 6 months: 31.5% vs 14.8%
• TR at 24 months: 47.6% vs 14.2%

Brain metastases occurred in 17 patients randomized to HA-PCI and 14 in the PCI arm, a difference that did not achieve statistical significance. The incidence of brain metastases at 2 years was 22.8% with HA-PCI and 17.7% with PCI, also not significantly different, the authors reported. One patient in the HA-PCI arm developed an isolated brain metastasis in the hippocampal dentate gyrus, but no patient developed a metastasis in the hippocampal avoidance zone.

After survival follow-up of 60 months, 60% of patients in the HA-PCI arm had died compared with 65% in the PCI group. Median OS was 23.4 months with HA-PCI and 24.9 months with standard PCI. OS also did not differ between HA-PCI and PCI among patients with extensive-stage disease or limited-stage disease (71.3% of the study population).

QoL scores did not differ significantly between treatment groups at any time during follow-up or on any of the scales used to assess QoL.