Mid-Treatment FDG-PET in HPV-Related Oropharyngeal Squamous Cell Carcinoma: Is It a Gateway to the Use of Adaptive Radiotherapy and Immunotherapy in Viral Induced Cancers and Is Abscopal Effect at Play

Abstract

To evaluate whether biomarkers derived from FDG-PET-CT performed prior to (prePET) and during the third week (iPET) of radiotherapy can predict treatment outcomes in oropharyngeal squamous-cell-carcinoma (OPC). Seventy-nine consecutive patients with newly diagnosed OPC from 2009 to 2015 treated with radical radiotherapy and underwent pre-PET and iPET were included in the study. This analysis included fifty-eight patients with available tissue blocks that have been independently prepared and P16 immunohistochemistry re-validated to ensure standardization. The median follow-up was 42.5 months. HPV status was positive (HPV+OPC) in 46 patients based on p16 status. The maximum-standardized-uptake-value (SUV), metabolic-tumor-volume (MTV) and total-lesional-glycolysis (TLG) of primary tumor, index-node (IN) (node with highest TLG) and “total-lymph-nodes” (TN), and their median % (≥50%) reductions in iPET were analyzed, and correlated with 5-year Kaplan–Meier and multivariable analyses including local-failure-free, regional-failure-free, loco-regional-failure-free, distant-metastatic-failure-free, disease-free, and overall-survival (LFFS, RFFS, LRFFS, DMFFS, DFS and OS). At the time of analysis, 22 patients (38%) had treatment failure. Seventeen patients had loco-regional failures (local failure: 6, regional failure: 14, and combined: 3), and eleven patients had distant failure, of which 5 had distant failure only and 6 had concurrent loco-regional failure There was no association of outcomes with pre-PET parameters, except for IN-TLG and DMFFS in HPV+OPC patients: 94.4% vs. 57.8%, (p=0.04, HR=6.81, CI 0.82-56.78). Complete metabolic response of primary tumor was seen in 13 HPV+OPC patients, and negative-predictive-value for local failure was 100%. More than 50% reduction in TN-MTV provided the best predictor of favorable outcomes in HPV+OPC patients, including LRFFS (88% vs. 47.1%, p=0.006, HR=0.153, CI 0.033-0.711) and DFS (78.2% vs. 41.2%, p=0.01, HR=0.234, CI 0.07-0.782). More than 50% reduction in IN-TLG predicted better DMFFS outcome in HPV-negative-OPC (83.3% vs. 33.3%, p=0.017), but was inversely related to DMFFS (66.7% vs. 100%, p=0.005, HR 3.0, CI 1.32-6.83) in HPV+OPC patients. Our research suggests that volumetric nodal metabolic response during the week 3 of radiotherapy can potentially identify a subgroup of HPV+OPC patients at low risk of loco-regional-failure but inversely at higher risk of distant-metastatic-failure, and may have a role in individualized adaptive radiotherapy and systemic immunotherapy. This clinical finding can be consistent with the current radiobiology understanding that Abscopal responses are not induced by high dose radiation, and are dependent on the critical balance between Trex1 induction and systolic DNA accumulations that were induced by fractionated radiation doses between 12-18 Gy.