ABSTRACT
AIM: To determine the long-term prognosis of immune-related response profiles (pseudoprogression and dissociated response), not covered by conventional PERCIST criteria, in patients with non-small-cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICPIs). METHODS: 109 patients were prospectively included and underwent [18F]FDG-PET/CT at baseline, after 7 weeks (PETinterim1), and 3 months (PETinterim2) of treatment. On PETinterim1, tumor response was assessed using standard PERCIST criteria. In the event of PERCIST progression at this time-point, the study design provided for continued immunotherapy for 6 more weeks. Additional response patterns were then considered on PETinterim2: pseudo-progression (PsPD, subsequent metabolic response); dissociated response (DR, coexistence of responding and non-responding lesions), and confirmed progressive metabolic disease (cPMD, subsequent homogeneous progression of lesions). Patients were followed up for at least 12 months. RESULTS: Median follow-up was 21 months. At PETinterim1, PERCIST progression was observed in 60% (66/109) of patients and ICPI was continued in 59/66. At the subsequent PETinterim2, 14% of patients showed PsPD, 11% DR, 35% cPMD, and 28% had a sustained metabolic response. Median overall survival (OS) and progression-free-survival (PFS) did not differ between PsPD and DR (27 vs 29 months, p = 1.0; 17 vs 12 months, p = 0.2, respectively). The OS and PFS of PsPD/DR patients were significantly better than those with cPMD (29 vs 9 months, p < 0.02; 16 vs 2 months, p < 0.001), but worse than those with sustained metabolic response (p < 0.001). This 3-group prognostic stratification enabled better identification of true progressors, outperforming the prognostic value of standard PERCIST criteria (p = 0.03). CONCLUSION: [18F]FDG-PET/CT enables early assessment of response to immunotherapy. The new wsPERCIST ("wait and see") PET criteria proposed, comprising immune-related atypical response patterns, can refine conventional prognostic stratification based on PERCIST criteria. TRIAL REGISTRATION: HDH F20230309081206. Registered 20 April 2023. Retrospectively registered.
ABSTRACT
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 18F-fluoro-deoxy-glucose PET (18F-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. 18F-FDG-PET studies were performed before the start of immunotherapy (PETbaseline), after 6-8 weeks (PETinterim1) and after 12-16 weeks (PETinterim2) 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 (ΔSUVmax, ΔTMTV and ΔTLG). 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 PETinterim1 and PETinterim2, all metabolic parameters were predictive for 12M-OS and 6M-PFS, the residual TMTV on PETinterim1 (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 cm3; 0-57 cm3; >57 cm3), 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 PETinterim1, low residual tumor volume (<57 cm3) 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. TRIAL REGISTRATION NUMBER: 2018-A02116-49; NCT03584334.
