Patient characteristics
The mean (± standard deviation) and median (range) CXI values were, respectively, 9.35 (± 6.18) and 7.65 (0.47 – 34.15) for males and 7.76 (± 6.32) and 5.90 (1.18 – 30.57) for females. The area under the curve (AUC) (calculated using time-dependent ROC data) was 0.651 for males and 0.602 for females (Supplementary Fig. 1). The CXI cutoffs were 5.23 (sensitivity 41.4% and specificity 85.9%) for males and 6.79 (sensitivity 72.6% and specificity 58.4%) for females. In total, 208 and 94 patients were assigned to the high- and low-CXI groups, respectively.
Patient baseline characteristics are presented in Table 1. The median age was 68 years (range 40 – 86 years). Most patients were male (88.4%) and of Eastern Cooperative Oncology Group (ECOG) PS 0 – 1 (78.5%). The low-CXI group had a higher proportion of patients with a poor PS (ECOG PS 2 – 3, 37.2% vs. 14.4%, p < 0.001), more advanced-stage disease (ED, 73.4% vs. 53.4%, p = 0.001), and received prophylactic cranial irradiation less frequently (25.5% vs. 49.0%, p < 0.001), compared to the high-CXI group. As expected, the BMI was lower in the low-CXI group than in the high-CXI group (median 21.3 vs. 23.2 kg/m2, p < 0.001).
Treatment response
Of 302 patients, 285 were available for the assessment of treatment response (Table 2). The objective response rates [ORRs; complete response (CR) + partial response (PR)] were 71.3% and 89.4% in the low- and high-CXI groups, respectively (p < 0.001). Only one (1.1%) patient in the low-CXI group achieved a CR, compared to 35 of 208 (16.8%) patients in the high-CXI group (p < 0.001). All 36 patients who achieved CRs completed their planned treatments. When 60 patients who discontinued treatment early (because of toxicity or patient decision) or for whom treatment response was not assessed were excluded from the analysis, the ORR remained lower in the low-CXI group compared to the high-CXI group (78.3% vs. 91.2%, p = 0.008).
Treatment-related toxicity
Adverse treatment-related events are listed in Table 3. Neutropenia of grade ≥ 3 was more frequently observed in the high-CXI group than in the low-CXI group (p = 0.033). However, low-CXI patients received fewer cycles of chemotherapy (median 5 vs. 6 cycles, p < 0.001) and more frequently discontinued treatment early because of treatment-related toxicity (20.2% vs. 6.3%, p < 0.001) compared to high-CXI patients. TRM occurred in 8 of 94 (8.5%) patients in the low-CXI group but in only six (2.9%) patients in the high-CXI group (p = 0.031).
Survival
The median follow-up duration was 41 months. PFS was significantly shorter in the low-CXI group than in the high-CXI group (median 5.8 vs. 6.9 months, p < 0.001; Fig. 1A). OS was also shorter in the former group (median 8.3 vs. 15.6 months, p < 0.001; Fig. 1B). Similar findings were obtained following subgroup analyses by stage. In limited-stage disease (LD) patients, those with a low CXI had a shorter PFS (median 6.8 vs. 13.3 months, p < 0.001; Fig. 2A) and OS (median 8.3 vs. 23.9 months, p < 0.001; Fig. 2B) compared to those with a high CXI. In ED patients, those with a low CXI also had a shorter PFS (median 5.1 vs. 6.2 months, p = 0.014; Fig. 2C) and OS (median 8.1 vs. 12.9 months, p < 0.001; Fig. 2D) compared to those with a high CXI. On multivariate analysis, an ECOG PS of 2 – 3, ED, and a low CXI were independent poor prognostic factors for PFS [low CXI, hazard ratio (HR) 1.472, 95% confidence interval (CI) 1.107 – 1.958, p = 0.008] and OS (low CXI, HR 1.644, 95% CI 1.225 – 2.207, p = 0.001) (Table 4).