Introduction: A new pattern of response, so-called hyper-progressive disease (HPD), is emerging during treatment with immune checkpoint inhibitors (ICI). Our aim was to investigate the prevalence of such phenomenon and to assess its association with clinical variables and metabolic parameters by ¹⁸F-fludeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT). Methods: Data from 50 patients (34 male, 16 female, median age 73) with non-small cell lung carcinoma (NSCLC) and treated with ICI were prospectively collected. All patients underwent contrast-enhanced CT, ¹⁸F-FDG PET/CT, and complete peripheral blood sample at baseline before ICI. HPD was defined according to clinical and radiologic criteria. Because of the rapid disease progression or worsening of clinic conditions, radiologic response assessment was available for 46 patients. OS were analyzed using the Kaplan–Meier method and the log-rank test. A Cox proportional hazards regression analysis was used to evaluate factors independently associated with OS. Median follow-up was 12.4 months (9.7-15.2 months). Results: We identified the following response categories: 10 cases as complete/partial response (CR/PR), 17 cases with stable disease (SD), 5 patients with progressive disease (PD), and 14 with HPD. Among metabolic parameters we observed a statistically significant association between HPD status and tumor burden, expressed by both MTV (756.1ml for HPD vs 475.6ml for non-HPD, P = 0.011) and TLG (287.3 for HPD vs 62.1 for non-HPD, P = 0.042). Among clinical variables, 12/14 patients (85.7%) within the HPD group compared with 8/32 patients (25%) in the non-HDP group had more than two metastatic sites (p<0.001). In addition, the derived neutrophil-to-lymphocyte ratio (dNLR) and platelet counts was significantly associated with HPD status (P = 0.038, P = 0.025, respectively). Survival analysis showed a median OS of 4 months for HPD group compared with 15 months within non-HPD patients (P = 0.003). Likewise, median OS was significantly different when we considered all the response categories: CR/PR, SD, PD, and HPD (P = 0.001). Finally, Multivariate analysis identified MTV and dNLR as independent predictors for OS. Conclusion: Our results suggest that the use of ICI might represent a concern in patients with high metabolic tumor burden and inflammatory indexes at baseline. However Additional studies are needed.

Circulating tumor cells (CTC) count and characterization have been associated with poor prognosis in recent studies. Our aim was to examine CTC count and its association with metabolic parameters and clinical outcomes in non-small cell lung carcinoma (NSCLC) patients treated with immune checkpoint inhibitors (ICI). For this prospective study, data from 35 patients (23 males, 12 females) were collected and analyzed. All patients underwent an 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) scan and CTC detection through Isolation by Size of Tumor/Trophoblastic Cells (ISET) from peripheral blood samples obtained at baseline and 8 weeks after ICI initiation. Association of CTC count with clinical and metabolic characteristics was studied. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan–Meier method and the log-rank test. Median follow-up was 13.2 months (range of 4.9–21.6). CTC were identified in 16 out of 35 patients (45.7%) at baseline and 10 out of 24 patients at 8 weeks (41.7%). Mean CTC numbers before and after 8 weeks were 15 ± 28 and 11 ± 19, respectively. Prior to ICI, the mean CTC number was significantly higher in treatment-naïve patients (34 ± 39 vs. 9 ± 21, p = 0.004). CTC count variation (ΔCTC) was significantly associated with tumor metabolic response set by European Organization for Research and Treatment of Cancer (EORTC) criteria (p = 0.033). At the first restaging, patients with a high tumor burden, that is, metabolic tumor volume (MTV) and total lesion glycolysis (TLG), had a higher CTC count (p = 0.009). The combination of mean CTC and median MTV at 8 weeks was associated with PFS (p < 0.001) and OS (p = 0.024). Multivariate analysis identified CTC count at 8 weeks as an independent predictor for PFS and OS, whereas ΔMTV and maximum standardized uptake value variation (ΔSUVmax) was predictive for PFS and OS, respectively. Our study confirmed that CTC number is modulated by previous treatments and correlates with metabolic response during ICI. Moreover, elevated CTC count, along with metabolic parameters, were found to be prognostic factors for PFS and OS.