The baseline characteristics of the patients are summarized in Table 2. A total of 358 patients who were diagnosed with AC and underwent the Whipple procedure as curative resection were included in the final analysis. The median age was 58 years (range: 25 to 85) and there were 216 (60.3%) male patients and 142 (39.7%) female patients in the whole study cohort. Additionally, according to the TNM staging criteria, 165 patients (46.1%) were in stage I, 138 patients (38.6%) were in stage II, and 55 patients (15.4%) were in stage III. Furthermore, 159 (44.4%) patients were sorted into the lymphatic metastasis group. The median values of lymphocytes, neutrophils, and platelets were 1.60×109/L (range: 0.4×109/L to 4.7×109/L), 4.4×109/L (range: 1.3×109/L to 9.6×109/L) and 305.56×109/L (range: 84×109/L to 720×109/L), respectively. Moreover, the tumour differentiation degree was classified into well (7, 2.0%), moderate (188, 52.5%) and poor (163, 45.5%) differentiation,166 (46.4%) patients underwent chemotherapy.
The NLR, PLR and dNLR scores were divided into two groups: ≤ 3.32 and >3.32, ≤ 99.02 and > 99.02, and ≤ 1.94 and > 1.94, respectively. Among the 358 patients, 132 (36.9%) patients had an elevated NLR score; 327 (91.3%) patients had an elevated PLR score; 154 (43.0%) patients had an elevated dNLR score; 136 (38%) patients had an mGPS > 0; 277 (77.4%) patients had PNI ≥45; and 142 (39.6%) patients were allocated to PI 1 or 2.
OS and prognostic factors
The median OS for the entire cohort was 44.3 months and the estimated 1-, 2-, and 3-year OS rates were 83.9%, 65.8%, and 55.2%, respectively. The long-term survival rates were significantly higher for patients with lower NLR values than for those with higher NLR values (P<0.05, Fig.1a). Moreover, patients with dNLR ≤ 1.94 also had better long-term survival than patients with dNLR >1.94 (P<0.05, Fig.1b). However, other inflammatory indexes, including PLR, PI, mGPS and PNI, cannot be used to distinguish the long-term survival rates of patients in either of the respective groups (Fig. 1c-f).
In univariate survival analysis, NLR and dNLR were significantly associated with OS (NLR: hazard ratio (HR) 1.599, 95% CI 1.104-2.317, P<0.05; dNLR: HR 1.451, 95% CI 1.002-2.101, P<0.05). Other significant prognostic parameters included age, neutrophilic granulocyte count, IBIL, tumour differentiation, macrovascular or microvascular invasion, lymph node metastasis, TNM stage, CEA, CA19-9 and lymph node metastasis stage. According to the multivariate Cox proportional hazards model, tumour differentiation can be viewed as an independent prognostic indicator of OS (HR 1.669, 95% CI 1.126-2.476, P<0.05) (Table 3).
DFS and prognostic factors
The estimated 1-, 2-, and 3-year DFS rates for all patients were 58.0%, 42.8%, and 37.8%, respectively. The median DFS was 16.9 months. The correlations between the inflammation-based indexes and DFS are shown in Fig. 2. Elevated NLR (P<0.05, Fig. 2a) and PLR (P<0.05, Fig. 2c) were associated with reduced DFS. Nevertheless, dNLR, PI, mGPS and PNI failed to distinguish patients with longer DFS from those with shorter DFS (Fig. 2b, 2d-f).
Univariate survival analysis for DFS revealed significant associations between unfavourable DFS and higher pretreatment NLR (HR 1.406, 95% CI 1.051-1.879, P < 0.05) and PLR (HR 2.432, 95% CI 1.197-4.942, P < 0.05). Other significant prognostic parameters related to DFS included tumour differentiation, macrovascular invasion, lymph node metastasis, TNM stage, lymph node metastasis stage, CEA, CA19-9 and whether subsequent chemotherapy was administered. Multivariate Cox proportional hazards analysis showed that tumour differentiation (HR 1.593, 95% CI 1.185-2.141, P < 0.05) and whether subsequent chemotherapy was administered (HR 1.427, 95% CI 1.056-1.928, P < 0.05) were independent predictors of DFS (Table 4).
Prognostic value of inflammatory indexes
Moreover, the prognostic values of the inflammation-based indexes for both OS and DFS were compared by analysing the AUROC values. The ROC curves for OS and DFS prediction were calculated for the patients at 1, 2, and 3 years of follow-up. More specifically, for OS, the AUROC values of the NLR and dNLR scores were consistently higher than those of most of the other inflammatory indexes; in addition, the NLR and dNLR scores were higher in patients at 1 year, and the NLR and PLR scores were higher in patients at 2 and 3 years of follow-up for DFS (Fig. 3)(Table 5).
However, NLR or other factors alone only showed a moderate ability in predicting the prognosis of patients with AC after pancreaticoduodenectomy. From an overall perspective, in addition to NLR, PI had a higher AUROC values regardless of OS or DFS. To further enhance the diagnostic efficiency, a new inflammation-based scoring system was generated by combining NLR with PI. The NLR-PI score was defined as follows: (1) NLR-PI=1: NLR=0 and PI=0; (2) NLR-PI=2: NLR=0 and PI=1 or 2 or NLR=1 and PI=0; and (3) NLR-PI=3: NLR=1 and PI=1or 2. Among the 358 patients, 217 (60.6%) patients had a low NLR-PI score (NLR-PI=1) and 141 (39.4%) patients had an NLR-PI score of 2 or 3. In terms of the survival differences in patients with NLR-PI scores of 2 and 3, the median survival times for patients with NLR-PI scores of 2 and 3 were 16.5 and 32 months , respectively, and the survival differences were significant (P < 0.05). As shown in Table 5, the AUROC value of NLR-PI is the maximal among these indexes mentioned above under any conditions, which means that the NLR-PI score showed a better distinguishing power for predicting the prognosis of patients with AC who were treated with the Whipple procedure than the other inflammation-based indexes alone. In other words, with regard to both OS and DFS, the NLR-PI score divided patients into subgroups more precisely. Additionally, the concordance index (C-index) of each inflammatory parameter was calculated (Table 6) and compared with each other (Table 7). These results also verified that the NLR-PI score had a superior discriminative capacity.
Furthermore, patients with low NLR-PI scores also had better long-term survival and DFS than patients with high NLR-PI scores (P<0.05, Fig. 4). In univariate survival analysis, the NLR-PI score was also significantly associated with OS and DFS (OS: HR 1.570, 95% CI 1.192-2.068, P < 0.05; DFS:HR 1.304, 95% CI 1.047-1.624, P < 0.05). In multivariate Cox proportional hazards analysis, the NLR-PI score was also viewed as an independent predictor of both OS and DFS (OS: HR 1.684, 95% CI 1.015-2.2.796, P < 0.05; DFS: HR 1.285, 95% CI 1.014-1.630, P < 0.05) (Tables 3 and 4).