| Part I Comparison of prognostic evaluation of pancreatic neuroendocrine neoplasms in different TNM stagesObjective: The TNM staging system is widely used in pancreatic neuroendocrine neoplasms(pan NENs).However,there is no unanimously recognized TNM staging system currently.Various versions of the TNM staging system have been used,but the standards in use are inconsistent.The American Joint Committee on Cancer(AJCC)has partially updated and improved the eighth version of the AJCC staging system,but the multicenter studies to compare the eighth version of the AJCC staging system with other existing TNM staging systems on the prognosis evaluation value are lacking.In this study,pan NENs patients were classified and assessed by different TNM stages,and the prognostic evaluation value of different TNM staging systems for pan NENs was compared and verified.Methods: We collected a multicenter data set(n=1086)to evaluate the prognostic value of different TNM staging systems for well-differentiated(G1/G2)pan NENs patients using population characteristics analysis,survival analysis,and univariate and multivariate risk analysis.Results: AJCC 7 showed that only 12 patients(1.1%)of the total population were classified as stage III.In the survival analysis,patients with stage III showed a comparable hazard ratio(HR)to patients of stage IA(compared with stage IA patients,HR=2.076,95% CI=0.265-16.232,P=0.486).Compared with other TNM staging systems,patients with European Neuroendocrine Tumor Society(ENETS)stage IIB had a higher risk of death than patients with stage IIIA(compared with stage I patients,stage IIB:HR=4.376,95% CI=2.130-8.990;Stage IIIA: HR=4.322,95% CI=1.563-11.984).Patients with stage IIIA showed a lower expected mean survival time(78.9 vs 107.3months)than patients with stage IIIB.For the modified ENETS staging system,patients with stage IIB disease had higher risks of death than patients with stage III(compared with stage IA patients,stage IIB: HR=6.078,95% CI=3.077-12.044;stage III: HR=5.341,95% CI=2.248-12.563).According to the 8th AJCC staging system,after limiting the application population to well-differentiated pan NENs patients and combining the subgroups of the ENETS staging system(stage IIA and IIB combined into stage II,while stage IIIA and IIIB combined into stage III),the proportions of patients with stage I,stage II,stage III and stage V in the total population were 25.7%,40.3%,23.6% and 10.4%,respectively.Moreover,as the stage advanced,the median survival time decreased(the estimated median survival time for stage I,stage II,stage III,and stage V are NA,144.7,100.8,and 72.0 months,respectively,P<0.001),and the risk of death increased(compared with stage I patients,stage II: HR=3.145,95% CI=1.617-6.119;stage III:HR=5.925,95% CI=3.033-11.573;stage IV: HR=8.762,95% CI=4.417-17.379,P<0.001).Conclusion: The 8th AJCC staging system was more reasonable for patients’ distribution at different stages,which were more closely related to prognostic survival.Compared with the 7th AJCC staging system,the ENETS staging system and the m ENETS staging system,the 8th AJCC staging system may be more suitable for pan NENs staging and may bring greater value to clinical practice.Part II Establishment of TNMG staging of pancreatic neuroendocrine neoplasmsObjective: Based on the clinical staging information and pathological grading information,the AJCC TNM stage and WHO grade(G)are two widely used separate classification systems for pan NENs.However,both stage systems have their limitations and confuse in application standard.We integrate TNM stage and G grade into a novel staging system(TNMG)to evaluate its clinical practice in guiding the clinical management.Methods: The SEER database(n=3907)and the multi-center database(n=1347)were used to compare the prognosis ability of TNM stage and G grade to the patients with pan NENs,and to develop and validate the applicability of TNMG to pan NENs.The decision curve analysis(DCA)was used to verify the clinical applicability of the new TNMG stage.The calibration curve analysis,c-index and the time-dependent area under ROC curve were used to compare and evaluate the accuracy of stratification and prognosis prediction between the new TNMG staging system and independent staging systems in the pan NENs patients.Results: TNM stage and G grade were independent risk factors(all P<0.05)for overall survival(OS)in both the SEER and multicenter series.The interaction effect between TNM stage and G grade was significant(P interaction <0.05).In addition,the TNMG stage including twelve subgroups was combined the TNM stage and G grade,which was classified into five stages(TNMG)basing on median survival time and hazard ratios in the SEER series.According to the TNMG stage,in the SEER series,40.7%,25.6%,8.1%,20.3%,and 5.3% patients were classified into stages I,II,III,IV,and V,respectively.The estimated median survival time for stages I,II,III,IV,and V was 203.0,174.0,112.0,61.0,and 8.0,respectively(all P<0.05).Compared with stage I disease,the HRs of stages II,III,IV,and V were 1.6,2.7,4.9,and 16.2,respectively,in multivariable analyses(all P<0.05).Furthermore,the TNMG stage obtained consistent results with the SEER series group in the multicenter series and the validation series.The DCA analysis suggests that the TNMG staging system may bring greater benefits than the traditional staging grading system in clinical applications.Calibration curve analysis shows that the new TNMG staging system was well-performing in the prediction of the 3-year,5-year,and 10-year survival rate of patients with pan NENs.The c-index of different staging systems showed that TNMG staging model was more reliable in predicting the prognosis of pan NENs.The predictive accuracy of TNMG stage was higher than that of TNM stage and G grade used independently(average area under the ROC curve of each staging system,SEER database: 0.71,0.70,0.59;multi-center database: 0.72,0.71,0.60).Conclusion: The TNMG stage classification was more accurate in predicting prognosis than either the TNM stage or G grade alone among pan NEN patients,which suggests that the TNMG is a feasible and accurate staging model.The new TNMG staging model will promote to make precise treatment decisions in individualized treatment,and provide reliable risk stratification in future clinical trials. |
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