Neurocognitive function outcomes in NRG/RTOG 0534, the SPPORT trial.
Authors: Wefel Jeffrey Scott , Karrison Theodore , Pollack Alan , Balogh Alexander G. , Watkins-Bruner Deborah , Gomella Leonard G. , Michalski Jeff M. , Hallman Mark A , Rodrigues George , Seaward Samantha A. , Kuettel Michael R. , Barker Jerry L. , Camarata Andrew S , Hopkins Judith O. , Greenberg Michael , Jones James , Sandler Howard M. , Seiferheld Wendy , Movsas Benjamin 
Published: June 2023

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Background: RTOG 0534 established the benefit of adding of short term androgen deprivation therapy (PBRT+STADT, Arm 2) to prostate bed salvage radiotherapy (PBRT, Arm 1), and demonstrated that elective pelvic lymph node irradiation combined with STADT (PBRT+STADT+PLNRT, Arm 3) results in further reductions in progression. Longitudinal monitoring of neurocognitive function (NCF) was conducted to evaluate the hypothesis that patients treated with STADT will demonstrate greater decline in NCF compared to patients receiving PBRT alone. Methods: Patients were administered the Clinical Trial Battery [Hopkins Verbal Learning Test – Revised (HVLT-R), Trail Making Test (TMT), and the Controlled Oral Word Association (COWA) test] by certified test administrators at baseline, and at 6 weeks (6w), 1 year (1yr), and 5 years after the end of RT (5yr). Raw NCF tests scores were converted to standardized z-scores adjusted for age and education when necessary. Analyses included z-score change and reliable change index (RCI) determined decline compared to baseline, and longitudinal mixed effect regression models using z-scores. To control for multiplicity, p < 0.025 is required for statistical significance. Results: Among the 1716 analyzable patients, 429 consented to NCF monitoring. There were no significant differences in sociodemographic or clinical characteristics between arms. NCF test completion was 82, 76, 63 and 30% at baseline, 6w, 1yr, and 5yr, respectively. RCI-based NCF deterioration was more frequent in Arm 3 compared to Arm 1 at 6 weeks on Delayed Recall (16% vs. 7%, p = 0.023). Patients in Arm 3 evidenced greater z-score decline compared to patients in Arm 1 at 6w on HVLT-R Total Recall [M(SD) Z-score∆ = -0.1(1.0) vs 0.2(0.9), (p = 0.020)] and Delayed Recall [M(SD) Z-score∆ = -0.4(1.5) vs 0.1(1.2), (p = 0.012)]. Mixed effects models identified statistically significant differences in z-scores between Arm 3 and 1 at 6w on Delayed Recall [-0.541 (SE 0.178, p = 0.002)]. A statistically significant difference was observed between Arm 2 and 1 at 6w on TMTB [1.498 (SE 0.626, p = 0.017) favoring Arm 2]. Between arm differences were not seen at any other time point, or on other NCF outcomes. Conclusions: Compared to patients treated with PBRT alone, patients treated with PBRT+STADT+PLNRT exhibited greater worsening in episodic verbal learning and memory processes at 6 weeks after the end of RT, while patients treated with PBRT+STADT exhibited greater improvement in processing speed. The absence of long term or progressive cognitive decline associated with STADT-containing regimens is promising but limited by substantial missing data at year 5. FUNDING This project was supported by grants 10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), CTEP from the National Cancer Institute (NCI). Clinical trial information: NCT00567580 .