Hippocampal dosimetry correlates with the change in neurocognitive function after hippocampal sparing during whole brain radiotherapy: a prospective study

Ping-Fang Tsai, Chi-Cheng Yang, Chi-Cheng Chuang, Ting-Yi Huang, Yi-Ming Wu, Ping-Ching Pai, Chen-Kan Tseng, Tung-Ho Wu, Yi-Liang Shen, Shinn-Yn Lin, Ping-Fang Tsai, Chi-Cheng Yang, Chi-Cheng Chuang, Ting-Yi Huang, Yi-Ming Wu, Ping-Ching Pai, Chen-Kan Tseng, Tung-Ho Wu, Yi-Liang Shen, Shinn-Yn Lin

Abstract

Background: Whole brain radiotherapy (WBRT) has been the treatment of choice for patients with brain metastases. However, change/decline of neurocognitive functions (NCFs) resulting from impaired hippocampal neurogenesis might occur after WBRT. It is reported that conformal hippocampal sparing would provide the preservation of NCFs. Our study aims to investigate the hippocampal dosimetry and to demonstrate the correlation between hippocampal dosimetry and neurocognitive outcomes in patients receiving hippocampal sparing during WBRT (HS-WBRT).

Methods: Forty prospectively recruited cancer patients underwent HS-WBRT for therapeutic or prophylactic purposes. Before receiving HS-WBRT, all participants received a battery of baseline neurocognitive assessment, including memory, executive functions and psychomotor speed. The follow-up neurocognitive assessment at 4 months after HS-WBRT was also performed. For the delivery of HS-WBRT, Volumetric Modulated Arc Therapy (VMAT) with two full arcs and two non-coplanar partial arcs was employed. For each treatment planning, dose volume histograms were generated for left hippocampus, right hippocampus, and the composite hippocampal structure respectively. Biologically equivalent doses in 2-Gy fractions (EQD2) assuming an alpha/beta ratio of 2 Gy were computed. To perform analyses addressing the correlation between hippocampal dosimetry and the change in scores of NCFs, pre- and post-HS-WBRT neurocognitive assessments were available in 24 patients in this study.

Results: Scores of NCFs were quite stable before and after HS-WBRT in terms of hippocampus-dependent memory. Regarding verbal memory, the corresponding EQD2 values of 0, 10, 50, 80 % irradiating the composite hippocampal structure with <12.60 Gy, <8.81, <7.45 Gy and <5.83 Gy respectively were significantly associated with neurocognitive preservation indicated by the immediate recall of Word List Test of Wechsler Memory Scale-III. According to logistic regression analyses, it was noted that dosimetric parameters specific to left sided hippocampus exerted an influence on immediate recall of verbal memory (adjusted odds ratio, 4.08; p-value, 0.042, predicting patients' neurocognitive decline after receiving HS-WBRT).

Conclusions: Functional preservation by hippocampal sparing during WBRT is indeed achieved in our study. Providing that modern VMAT techniques can reduce the dose irradiating bilateral hippocampi below dosimetric threshold, patients should be recruited in prospective trials of hippocampal sparing during cranial irradiation to accomplish neurocognitive preservation while maintaining intracranial control.

Trial registration: Current Controlled Trials NCT02504788.

Figures

Fig. 1
Fig. 1
An example of hippocampi contouring was demonstrated in (a) Axial, (b) Coronal and (c) Sagittal views. The bilateral hippocampal structures were contoured in yellow color. The zone for hippocampus avoidance (HA zone) was marked in orange. d Treatment planning was designed and arranged by four arcs in a VMAT plan, in which two full arcs and two non-coplanar partial arcs were employed
Fig. 2
Fig. 2
An example of 90 % isodose distribution in the display modes of color wash and dose volume histogram (DVH). a Axial, b Coronal, c agittal views and (d) The displayed DVH is in accordance with the prescription of 3000 cGy in physical dose. The yellow curve outlines where the bilateral hippocampal structures are, red for PTV, blue for CTV, and orange for the region of gross tumor or tumor bed
Fig. 3
Fig. 3
The isodose region without added color display represents the site of hippocampal sparing. The 40 % isodose displayed in color wash indicates where our VMAT treatment plan has attempted to achieve so-called hippocampal sparing
Fig. 4
Fig. 4
Scatter plots displaying the association between hippocampal dosimetry and neurocognitive functions. Each colored dot represents the change in the NCF scores obtained between before and after the HS-WBRT course for each individual patient. Horizontal axis indicates the hippocampal dosimetry irradiating left hippocampus in a unit of Gy converted to the equivalent dose in 2-Gy fractions (EQD2). Vertical axis represents the extent of the NCF change; negative values indicate that there is a specific neurocognitive decline in immediate recall of verbal memory (WLL-IR) after the course of HS-WBRT. Of note, a dotted vertical line in each panel stands for the median dose irradiating left hippocampus in a unit of Gy (EQD2). Moreover, the shadowed areas in each panel support the theoretical hypothesis that the higher EQD2 the hippocampus receives, the less likely the corresponding NCF is to be spared

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