The Influence of the Pretreatment Host Immune State on Response to Radiation Therapy in High Risk Adenocarcinoma of the Prostate: A Validation Study from NRG Oncology/RTOG 0521 (Updated)

Abstract

The immuno-inflammatory state has been shown in several retrospective series to be associated with poor outcomes following radiation therapy (RT) for high risk prostate cancer (PCA). We conducted an a priori designed validation study using prospectively banked serum specimens from the phase III clinical trial RTOG 0521. It was hypothesized the pre-treatment inflammatory state would correlate with clinical outcomes. Patients enrolled on RTOG 0521 had serum samples banked for future biomarker validation. This study was designed to validate previous findings (Hall 2013) showing an association between elevations in CRP levels and shorter biochemical failure-free survival after RT. CRP levels were measured in pre-treatment samples using a widely available, clinical grade assay. A panel of serum inflammatory cytokines were also measured including: monocyte chemotactic protein-1 (MCP-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon gamma (IFN-γ), IL-1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17A, IL-23, and tumor necrosis factor (TNFα). The primary endpoint examined in this a priori designed validation study was disease-free survival (DFS), defined as the time from randomization to the development of biochemical failure, local progression, distant metastases, or death from PCA, whichever occurred first. Additional endpoints included correlation with cytokine levels and toxicity events attributed to RT, namely: pollakiuria ≥grade (g) 2, cystitis ≥g 2, diarrhea ≥g 2, erectile dysfunction (ED) ≥g 2, proctitis≥g 2. Of 563 patients who enrolled in RTOG 0521, 202 had banked serum samples available. In the subsample, median age was 66 years (range 48-83), 90% of patients were white and 10% African-American. There was not an association between CRP and DFS ([HR] = 1.07 per one log increase in CRP, 95% CI: 0.84 - 1.38, p = 0.58). Pre-treatment IL-10 was significantly associated with worse DFS, both unadjusted (HR = 1.60 per log increase, p = 0.0029) and following co-variate adjustment (HR = 1.44 per log increase, p = 0.019). IL-10 was also associated with increased distant metastases (HR = 1.55 per log increase, p = 0.028). Pretreatment levels of IFN-γ, IL-1b, IL-2, IL-13, IL-23 were negatively associated with g 2 or higher pollakiuria (adjusted OR = 0.64, 0.65, 0.71, 0.72, and 0.74, respectively, all p<0.05) and IL-6 was negatively associated with g 2 or higher ED (OR = 0.62, p = 0.027). Pretreatment CRP was not associated with a poorer DFS following RT. Higher baseline levels of IL-10 were significantly associated with lower rates of DFS and higher rates of distant metastases, a novel finding that warrants further exploration. Multiple cytokines were associated with the development of RT-specific toxicities, which may help with the design of precision strategies to mitigate RT-induced toxicities.