A total of 644 eligible patients with pathologically confirmed pNECs were identified from the SEER database. And 75 cases were excluded for unknown cancer stage at diagnosis, 1 for unknown follow-up information. In total, 568 patients were included in the study. Table 1 shows frequency distributions of selected characteristics for the full study cohort.
The median age at diagnosis was 63.0 years (mean 62.0 years). Male patients account for a slightly higher proportion than female patients (a male to female ratio of 1.4:1.0). More than three quarters of the patients were white. In addition, 41.5% of the patients had tumors located at the head of the pancreas. A total of 418 patients died of their cancer. The estimated median overall survival (OS) was 10.0 months.
ENETS Staging Classification and Survival
According to the ENETS staging classification, only 1.2% (7 of 568) of patients had stage I tumors and 6.0% (34 of 568) of patients had stage II tumors (Table 2). Overlap was noticed for the ENETS classification of stage II and III disease (Fig. 1A-1B). In addition, median OS uniformly decreased from class I to II, was longer in class III, and decreased further in class IV. The median OS for stage I, II, III and IV were 90.0, 40.0, 48.0 and 7.0 months, respectively (Table 2). Compared with stage I disease, the HR of stage II was comparable to that of stage III (stage II and III HRs, 3.27 and 2.23, respectively) by multivariable analyses(Table 3).
The 8th AJCC Staging Classification and Survival
It is notable that overlap existed between the 8th AJCC classification of stage I and II disease (Fig. 1C-1D). The median OS, in more detail, for stage I, II, III and IV were 62, 138, 15.0 and 7.0 months, respectively (Table 2). No statistical significance was observed for HR between stage I and stage II disease by multivariable analyses (stage I served as the reference; stage II HR, 0.74; P = 0.32; Table 3).
The 7th AJCC Staging Classification and Survival
For the 7th AJCC staging system, the median OS uniformly decreased from class I to IV (Table 2), although overlap was also noticed for the 7th AJCC classification of stage I and II disease (Fig. 2A-2B). Furthermore, the median OS of the patients with the same tumor stage varied widely between the different substages. Within stage II of the current AJCC staging system, the median OS for T3N0M0 and T1-3N1M0 were 20.0 and 78.0 months, respectively. The death risk of the patients increased from stage I to IV by multivariable analyses (stage I served as the reference; stage II HR of death = 1.08, 95% CI = 0.60 to 1.94, P = 0.80; stage III HR of death = 2.06, 95% CI = 0.94 to 4.52, P=0.07; stage IV HR of death = 4.62, 95% CI = 2.73 to 7.83, P <0.001; Table 3).
Comparison of Survival Outcomes Based on the Current and Modified 7th AJCC Staging Systems
Considering the shortcomings of the AJCC and ENETS systems cited previously, a m7th AJCC staging classification was proposed by maintaining the T and M definitions of the 7th AJCC staging system and adopting a new staging definition system. Stage IV is the same across all systems defined as disease with distant metastasis. The proportion of patients with stage I disease using the m7th AJCC staging system was higher than that of the 7th AJCC system (8.8% vs 5.8%; Table 1). Better separation of survival curves was found among stages for the m7th AJCC classification (Fig. 2C-2D). There was the expected worsening in survival as tumor stage increased (Table 2). In addition, an increase in HRs was observed in the m7th AJCC staging classification by multivariable analyses, although statistically significant difference was not observed between stages I and II(compared with stage I disease; HR for stage II =1.23, 95% CI= 0.73-2.06, P =0.44; HR for stage III =2.20, 95% CI =1.06-4.56, P=0.03; HR for stage IV =4.95, 95% CI =3.20-7.65, P < 0.001; Table 3).
Two types of C-indices of different staging systems for pNECs were presented in
Table 4. One was for local disease only, and the other was for the entire cohort. The respective C- indices using the 7th and m7th staging systems for patients with local disease (stages I–III) were 0.57 (95% CI 0.51-0.63) and 0.59 (95% CI 0.53-0.66), respectively. Also, for the entire cohort, the C- indices based on the 7th staging system (0.626, 95% CI 0.599-0.653), and the m7th staging system (0.627, 95% CI 0.600-0.654) were similar.