Hope drives quality of life in patients with brain metastases, but the hope center remains elusive: An analysis of NRG-CC003.
Authors: Corn Benjamin W. , Paulus Rebecca , Gondi Vinai , Mehta Minesh P. , Fogh Shannon E. , Wefel Jeffrey Scott , Videtic Gregory M.M. , Sun Alexander , Yoon Harold , Heinzerling John H , McGarry Ronald C , Kundapur Vijayananda , Devisetty Kiran , Wu Abraham Jing-Ching , Kanner Andrew A , Pugh Stephanie L. , Movsas Benjamin , Kachnic Lisa A. 
Published: August 2024

12011 Background: NRG-CC003, a phase II/III study, randomized 393 patients with small cell lung cancer to prophylactic cranial irradiation (PCI) with or without Hippocampal Avoidance (HA). “Hopefulness” is a cognitive construct based on 3 components: goals; pathways to reach those goals; and agency (i.e., motivation to embark on the pathway). Hope can be measured with validated instruments. Since hope is cognitive in nature, the existence of a “hope center” in the brain -- most likely in the hippocampus -- has been hypothesized. One exploratory objective of NRG-CC003 posited that if hope levels (measured pre- and post-PCI) were better maintained in patients randomized to PCI+HA (in comparison to patients treated by PCI without hippocampal protection), then the hippocampus would, indeed, be implicated as part of the mechanism of hopefulness. Methods: In both arms, PCI consisted of 10 fractions of 2.5 Gy. The Adult Hope Scale (AHS) was administered at time-zero and at 6-months. With regard to patient reported outcome (PRO) measures, the EORTC QLQ-C30 was administered at baseline and then at 3, 6-, 12-, 18- and 24-month intervals. Comparisons of AHS scores by arm were made using Wilcoxon-Mann-Whitney tests, and correlation of AHS with EORTC QLQ-C30 by Pearson correlation coefficients. Results: Approximately 95% of patients completed the AHS at baseline and 67% filled out the questionnaire at 6-months which paralleled the completion rates of the conventional tools for QOL and neurocognition that were employed in the study. When comparing hope levels (change from baseline to 6 months) there was no significant difference (p > 0.05) between the two arms of the trial (PCI vs PCI + HA). There was a significant correlation for the components of hopefulness with QOL; specifically, between change in agency score and QLQ-C30 global health status (p < 0.0001) as well as between change in pathways score and QLQ-C30 global health status (p = 0.022). Conclusions: It is feasible to study hopefulness in the context of prospective trials conducted within the NCTN. The hippocampus could not be implicated as a critical structure in a central pathway that coordinates hopefulness. Whether these data categorically refute the “hope-hippocampal hypothesis” will be discussed vis-à-vis several caveats (e.g., selection of AHS; presence of sufficient cognitive reserve post-irradiation; adequacy of the dose-delta between the 2 arms to cause differential levels of damage to the purported hope center). For the first time, a validated tool prospectively established a relationship between hope and quality of life among patients with cancer. Given previous NRG studies correlating QOL with oncologic endpoints (e.g., local control and survival), modelling will be carried out to determine if hope mediates, results from, or is associated with these endpoints. Clinical trial information: NCT02635009 .