Total metabolic tumor volume on 18F-FDG PET/CT is a game-changer for patients with metastatic lung cancer treated with immunotherapy

Purpose Because of atypical response imaging patterns in patients with metastatic non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICPIs), new biomarkers are needed for a better monitoring of treatment efficacy. The aim of this prospective study was to evaluate the prognostic value of volume-derived positron-emission tomography (PET) parameters on baseline and follow-up F-18-fluoro-deoxy-glucose PET (F-18-FDG-PET) scans and compare it with the conventional PET Response Criteria in Solid Tumors (PERCIST). Methods Patients with metastatic NSCLC were included in two different single-center prospective trials. F-18-FDG-PET studies were performed before the start of immunotherapy (PETbaseline), after 6-8 weeks (PET(interim)1) and after 12-16 weeks (PET(interim)2) of treatment, using PERCIST criteria for tumor response assessment. Different metabolic parameters were evaluated: absolute values of maximum standardized uptake value (SUVmax) of the most intense lesion, total metabolic tumor volume (TMTV), total lesion glycolysis (TLG), but also their percentage changes between PET studies (Delta SUVmax, Delta TMTV and Delta TLG). The median follow-up of patients was 31 (7.3-31.8) months. Prognostic values and optimal thresholds of PET parameters were estimated by ROC (Receiver Operating Characteristic) curve analysis of 12-month overall survival (12M-OS) and 6-month progression-free survival (6M-PFS). Tumor progression needed to be confirmed by a multidisciplinary tumor board, considering atypical response patterns on imaging. Results 110 patients were prospectively included. On PETbaseline, TMTV was predictive of 12M-OS [AUC (Area Under Curve) =0.64; 95% CI: 0.61 to 0.66] whereas SUVmax and TLG were not. On PET(interim)1 and PET(interim)2, all metabolic parameters were predictive for 12M-OS and 6M-PFS, the residual TMTV on PET(interim)1 (TMTV1) being the strongest prognostic biomarker (AUC=0.83 and 0.82; 95% CI: 0.74 to 0.91, for 12M-OS and 6M-PFS, respectively). Using the optimal threshold by ROC curve to classify patients into three TMTV1 subgroups (0 cm(3); 0-57 cm(3); >57 cm(3)), TMTV1 prognostic stratification was independent of PERCIST criteria on both PFS and OS, and significantly outperformed them. Subgroup analysis demonstrated that TMTV1 remained a strong prognostic biomarker of 12M-OS for non-responding patients (p=0.0003) according to PERCIST criteria. In the specific group of patients with PERCIST progression on PET(interim)1, low residual tumor volume (<57 cm(3)) was still associated with a very favorable patients' outcome (6M-PFS=73%; 24M-OS=55%). Conclusion The absolute value of residual metabolic tumor volume, assessed 6-8 weeks after the start of ICPI, is an optimal and independent prognostic measure, exceeding and complementing conventional PERCIST criteria. Oncologists should consider it in patients with first tumor progression according to PERCIST criteria, as it helps identify patients who benefit from continued treatment.