Purpose: Adding losartan (LOS) to FOLFIRINOX (FFX) chemotherapy followed by chemoradiation (CRT) resulted in 61% R0 surgical resection in our phase II trial in patients with locally advanced pancreatic cancer (LAPC). Here we identify potential mechanisms of benefit by assessing the effects of neoadjuvant LOS on the tumor microenvironment. Experimental Design: We performed a gene expression and immunofluorescence (IF) analysis using archived surgical samples from patients treated with LOS+FFX+CRT (NCT01821729), FFX+CRT (NCT01591733), or surgery upfront, without any neoadjuvant therapy. We also conducted a longitudinal analysis of multiple biomarkers in the plasma of treated patients. Results: In comparison with FFX+CRT, LOS+FFX+CRT downregulated immunosuppression and pro-invasion genes. Overall survival (OS) was associated with dendritic cell (DC) and antigen presentation genes for patients treated with FFX+CRT, and with immunosuppression and invasion genes or DC- and blood vessel–related genes for those treated with LOS+FFX+CRT. Furthermore, LOS induced specific changes in circulating levels of IL-8, sTie2, and TGF-β. IF revealed significantly less residual disease in lesions treated with LOS+FFX+CRT. Finally, patients with a complete/near complete pathologic response in the LOS+FFX+CRT–treated group had reduced CD4+FOXP3+ regulatory T cells (Tregs), fewer immunosuppressive FOXP3+ cancer cells (C-FOXP3), and increased CD8+ T cells in pancreatic ductal adenocarcinoma lesions. Conclusions: Adding LOS to FFX+CRT reduced pro-invasion and immunosuppression–related genes, which were associated with improved OS in patients with LAPC. Lesions from responders in the LOS+FFX+CRT–treated group had reduced Tregs, decreased C-FOXP3 and increased CD8+ T cells. These findings suggest that LOS may potentiate the benefit of FFX+CRT by reducing immunosuppression.

To describe the outcomes and toxicities of the largest cohort to date of patients with anal squamous cell carcinoma uniformly treated with concurrent chemoradiation using dose-painted intensity modulated radiation therapy (DP-IMRT) according to RTOG 0529. We identified 99 eligible patients with anal cancer who were treated at our institution with definitive chemoradiation using DP-IMRT between 2005 and 2015 per RTOG 0529 dosing guidelines. Primary study endpoints included event-free survival (defined as recurrence, colostomy, or death) and overall survival. Secondary endpoints were treatment duration and acute and late toxicity. At a median follow-up of 49 months (range, 2-114 months), 92% of patients had a clinical complete response. Fifteen percent underwent colostomy, including 4 pretreatment colostomies, 6 planned abdominoperineal resections (APRs), 4 salvage APRs, and 1 APR for treatment-related complications. Thirteen patients developed local recurrence, of whom 6 developed synchronous metastatic disease. The 4-year overall survival was 85.8%, and 4-year event-free survival was 75.5%. Median treatment duration was 43 days (range, 10-68 days). The overall rate of non-hematologic grade 3+ acute and grade 2+ late toxicities was 20% and 15%, respectively. Long-term outcomes and tolerability were excellent In the largest cohort to date of patients with anal cancer who received DP-IMRT prescribed per RTOG 0529.