Patient demographics
The study included 46 patients with a median age of 74 years (range, 60–85 years). Table 1 shows the patient demographics according to 18F-FDG uptake on PET. The performance status (PS) was 0, 1, 2, 3, and 4 in 15 (32.6%), 24 (52.2%), 4 (8.6%), 2 (4.4%), and 1 (2.2%) patient, respectively. Forty-four patients (95.6%) had extensive disease at initial presentation, and two (4.4%) had recurrence after chemoradiotherapy at the limited stage. The IMpower133 regimen [1] was administered to 30 patients and the CASPIAN [2] regimen was used in 16.
Clinical features based on 18F-FDG accumulation on PET
The median period from 18F-FDG-PET to initial chemotherapy was 14 days (range; 0–119 days). The median follow-up period was 293 days (range 54–976 days). The median values for SUVmax, MTV, and TLG on 18F-FDG uptake before initial treatment were 8.0 (range 2.7–37.4), 201.7 cm3/mL (range 0.2–2636.7), and 879.1 cm3/mL (range 0.6–10957.4), respectively. The optimal cutoff values for SUVmax, MTV, and TLG, as determined by ROC curve analyses were 11.1 (sensitivity,33%; specificity,84%), 374.6 cm3/mL (sensitivity:40%; specificity:74%), and 1433.2 cm3/mL (sensitivity:47%], specificity:74%), respectively. The area under the curve for the ROC analysis was 0.548 for SUVmax, 0.620 for MTV, and 0.613 for TLG. The relationship between different variables and the uptake of 18F-FDG depicted that high MTV was significantly associated with poor PS and low albumin level, and a significant association was observed between low albumin level and high TLG (Table 1). Using Pearson’s rank tests, SUVmax was significantly correlated with TLG (γ = 0.356, p = 0.015) but not with MTV (γ = 0.270, p = 0.070). Moreover, some blood markers reflecting inflammatory changes (leukocytes, neutrophils, and C-reactive protein) and nutrition (albumin) correlated with the uptake of 18F-FDG. The Pearson’s rank test revealed that C-reactive protein closely correlated with MTV (γ = 0.423, p = 0.003) and TLG (γ = 0.440, p = 0.002) on 18F-FDG uptake, but not SUVmax (γ = 0.124, p = 0.411), and the correlation of the statistical borderline was observed between MTV (γ =-0.274, p = 0.065) or TLG (γ = -0.270, p = 0.069) and albumin, but not SUVmax (γ =-0.212, p = 0.158). Progastrin-releasing peptide correlated with MTV (γ =-0.334, p = 0.023), but not with SUVmax (γ =-0.053, p = 0.729) or TLG (γ =-0.267, p = 0.073). However, no statistically significant correlation was observed between 18F-FDG uptake and leukocytes, neutrophils, and lymphocytes. The representative imaging was showing in Fig. 1.
Effects and survival analysis according to 18F-FDG-PET
Among 46 patients, complete response, partial response (PR), stable disease (SD), and progressive disease (PD) were observed in 0, 38, 2, and 5 patients, respectively. One patient was not evaluated. The objective response and disease control rates were 84.4% (95% confidence interval 70.5–93.5%) and 88.9% (95% confidence interval 75.9–96.3%), respectively. The median SUVmax, MTV, and TLG values were not significantly different between patients with PR and SD/PD. After induction chemotherapy with platinum regimens plus PD-L1 antibody, a median of two cycles were administered as PD-L1 antibody maintenance, ranging from 0 to 24. The median SUVmax, MTV, and TLG values were not significantly different between patients receiving < three and ≥ three maintenance treatments with PD-L1 antibody monotherapy.
Median PFS and OS were 178 and 344 days, respectively. Thirty-four patients experienced tumor recurrence, and 28 died due to PD. Univariate and multivariate survival analyses were performed for all patients (Table 2). Univariate analysis identified sex, Brinkman index, and MTV as significant predictors of PFS, and sex, SUVmax, MTV, and TLG as significant factors of OS (Table 2). For the multivariate analysis, fundamental factors such as age, sex, Brinkman index, PS, and 18F-FDG uptake were chosen for further examination. Since MTV or TLG were calculated based on the SUV, individual 18F-FDG uptake markers were assessed as a multivariate analysis, separate from each 18F-FDG uptake marker. Multivariate analysis revealed that sex, Brinkman index, and MTV were independent prognostic factors for PFS, and sex, SUVmax, MTV, and TLG were identified as significant predictors of OS (Table 2). Kaplan–Meier survival curves for PFS and OS according to the uptake of 18F-FDG (Fig. 2).
Relationship between 18F-FDG uptake and tumor microimmune environment:
Immunohistochemical assessment was performed in 36 of the 46 primary sites before first-line treatment (all patients with biopsy specimens). The remaining 10 primary sites were not available because of inadequate tissue and cytological specimens. In the tumor, the median values of different biomarkers were 0.0 (0–12.2) for PD-L1, 0.0 (0–20.9) for CD4, 1.5 (0–37.8) for CD8, 0.9 (0–201.6) for Foxp3, and 0.0 (0–104.4) for PD-1. The positive percentage of PD-L1, CD4, CD8, Foxp3, and PD-1 was 22.2% (8/36), 30.5% (11/36), 69.4% (25/36), 66.7% (24/36), and 30.5% (11/36), respectively. The expression levels of SUVmax, MTV, and TLG on 18F-FDG uptake were compared between positive and negative PD-L1 expression and TILs (Fig. 3). SUVmax was significantly higher in patients with positive PD-L1 expression than in those with negative expression but was not significantly different between positive and negative TILs (Fig. 3). Moreover, the levels of MTV and TLG were not closely associated with the levels of PD-L1 and TILs (Fig. 3). Next, patients with clinical benefit were defined as those with an OS of > 180 days in the 36 patients in this study. The clinical benefit was significantly related to high MTV and TLG, but not SUVmax, CD4, CD8, Foxp3, or PD-1 (Table 3).
Table 3
Clinical benefit with OS > 180 days according to different biomarkers
Different variables | Clinical benefit (OS > 180 days) | p-value |
Yes (N = 25) | No (N = 11) |
SUVmax | High/Low | 17 / 8 | 7 / 4 | > 0.999 |
MTV | High/Low | 5 / 20 | 7 / 4 | 0.019 |
TLG | High/Low | 5 / 20 | 7 / 4 | 0.019 |
PD-1 | Positive/Negative | 7 / 18 | 4 / 7 | 0.703 |
PD-L1 | Positive/Negative | 7 / 18 | 5 / 6 | 0.445 |
CD4 | Positive/Negative | 8 / 17 | 3 / 8 | > 0.999 |
CD8 | Positive/Negative | 16 / 9 | 9 / 2 | 0.438 |
Foxp3 | Positive/Negative | 17 / 8 | 7 / 4 | > 0.999 |
Abbreviations: PD-L1, programmed death ligand-1; PD-1, programmed death-1; SUVmax, the maximum of standardized uptake value; MTV, metabolic tumor volume; TLG, total lesion glycolysis; OS, overall survival; bold type, statistically significance. |