Development and Validation of a Prognostic Nomogram Based on the Systemic Immune-Inflammation Index for Resectable Gallbladder Cancer to Predict Survival and Chemotherapy Benefit

Lin Li, Tai Ren, Ke Liu, Mao-Lan Li, Ya-Jun Geng, Yang Yang, Huai-Feng Li, Xue-Chuan Li, Run-Fa Bao, Yi-Jun Shu, Hao Weng, Wei Gong, Wan Yee Lau, Xiang-Song Wu, Ying-Bin Liu, Lin Li, Tai Ren, Ke Liu, Mao-Lan Li, Ya-Jun Geng, Yang Yang, Huai-Feng Li, Xue-Chuan Li, Run-Fa Bao, Yi-Jun Shu, Hao Weng, Wei Gong, Wan Yee Lau, Xiang-Song Wu, Ying-Bin Liu

Abstract

Objectives: To investigate the prognostic significance of the systemic immune-inflammation index (SII) in patients after radical cholecystectomy for gallbladder cancer (GBC) using overall survival (OS) as the primary outcome measure.

Methods: Based on data from a multi-institutional registry of patients with GBC, significant prognostic factors after radical cholecystectomy were identified by multivariate Cox proportional hazards model. A novel staging system was established, visualized as a nomogram. The response to adjuvant chemotherapy was compared between patients in different subgroups according to the novel staging system.

Results: Of the 1072 GBC patients enrolled, 691 was randomly selected in the discovery cohort and 381 in the validation cohort. SII>510 was found to be an independent predictor of OS (hazard ratio [HR] 1.90, 95% confidence interval [CI] 1.42-2.54). Carbohydrate antigen 199(CA19-9), tumor differentiation, T stage, N stage, margin status and SII were involved in the nomogram. The nomogram showed a superior prediction compared with models without SII (1-, 3-, 5-year integrated discrimination improvement (IDI):2.4%, 4.1%, 5.4%, P<0.001), and compared to TNM staging system (1-, 3-, 5-year integrated discrimination improvement (IDI):5.9%, 10.4%, 12.2%, P<0.001). The C-index of the nomogram in predicting OS was 0.735 (95% CI 0.683-0.766). The novel staging system based on the nomogram showed good discriminative ability for patients with T2 or T3 staging and with negative lymph nodes after R0 resection. Adjuvant chemotherapy offered significant survival benefits to these patients with poor prognosis.

Conclusions: SII was an independent predictor of OS in patients after radical cholecystectomy for GBC. The new staging system identified subgroups of patients with T2 or T3 GBC with negative lymph nodes who benefited from adjuvant chemotherapy.

Clinical trial registration: ClinicalTrials.gov, identifier (NCT04140552).

Keywords: chemotherapy; gallbladder carcinoma; nomogram; prognostic marker; systemic immune-inflammation index.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Li, Ren, Liu, Li, Geng, Yang, Li, Li, Bao, Shu, Weng, Gong, Lau, Wu and Liu.

Figures

Figure 1
Figure 1
Forest plot of the association between systemic immune-inflammation index (SII) and overall survival (OS), according to different subgroups.
Figure 2
Figure 2
Nomogram for predicting overall survival in GBC patients.
Figure 3
Figure 3
Kaplan-Meier curves of overall survival for patients classified by TNM staging system and the novel staging system. (A) discovery cohort classified by TNM system, (B) validation cohort classified by TNM system, (C) total cohort classified by TNM system, and (D) discovery cohort classified by the novel staging system, (E) validation cohort classified by the novel staging system, (F) total cohort classified by the novel staging system.
Figure 4
Figure 4
Kaplan-Meier curves of overall survival for patients with surgery only versus surgery and chemotherapy. (A) T2N0 patients with good prognosis, (B) T3N0 patients with good prognosis, (C) T2N0 and T3N0 patients with good prognosis, and (D) T2N0 patients with poor prognosis, (E) T3N0 patients with poor prognosis, (F) T2N0 and T3N0 patients with poor prognosis.

References

    1. Song X, Hu Y, Li Y, Shao R, Liu F, Liu Y. Overview of Current Targeted Therapy in Gallbladder Cancer. Signal Transduct Target Ther (2020) 5(1):230. 10.1038/s41392-020-00324-2
    1. Li H, Hu Y, Jin Y, Zhu Y, Hao Y, Liu F, et al. . Long Noncoding RNA lncGALM Increases Risk of Liver Metastasis in Gallbladder Cancer Through Facilitating N-cadherin and IL-1β-Dependent Liver Arrest and Tumor Extravasation. Clin Transl Med (2020) 10(7):e201. 10.1002/ctm2.201
    1. Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, et al. . AJCC Cancer Staging Manual. Chicago, IL: American Joint Committee on Cancer: Springer; (2017).
    1. Cai ZQ, Guo P, Si SB, Geng ZM, Chen C, Cong LL. Analysis of Prognostic Factors for Survival After Surgery for Gallbladder Cancer Based on a Bayesian Network. Sci Rep (2017) 7(1):293. 10.1038/s41598-017-00491-3
    1. Agrawal S, Lawrence A, Saxena R. Does CA 19-9 Have Prognostic Relevance in Gallbladder Carcinoma (Gbc)? J Gastrointest Cancer (2018) 49(2):144–9. 10.1007/s12029-016-9914-5
    1. Gukovsky I, Li N, Todoric J, Gukovskaya A, Karin M. Inflammation, Autophagy, and Obesity: Common Features in the Pathogenesis of Pancreatitis and Pancreatic Cancer. Gastroenterology (2013) 144(6):1199–209.e4. 10.1053/j.gastro.2013.02.007
    1. Yang L, Karin M. Roles of Tumor Suppressors in Regulating Tumor-Associated Inflammation. Cell Death Differ (2014) 21(11):1677–86. 10.1038/cdd.2014.131
    1. Roxburgh CS, McMillan DC. Role of Systemic Inflammatory Response in Predicting Survival in Patients With Primary Operable Cancer. Future Oncol (2010) 6(1):149–63. 10.2217/fon.09.136
    1. Mady M, Prasai K, Tella SH, Yadav S, Hallemeier CL, Rakshit S, et al. . Neutrophil to Lymphocyte Ratio as a Prognostic Marker in Metastatic Gallbladder Cancer. HPB (Oxford) (2020) 22(10):1490–5. 10.1016/j.hpb.2020.02.002
    1. Jansson H, Cornillet M, Björkström NK, Sturesson C, Sparrelid E. Prognostic Value of Preoperative Inflammatory Markers in Resectable Biliary Tract Cancer - Validation and Comparison of the Glasgow Prognostic Score and Modified Glasgow Prognostic Score in a Western Cohort. Eur J Surg Oncol (2020) 46(5):804–10. 10.1016/j.ejso.2019.12.008
    1. Saqib R, Pathak S, Smart N, Nunes Q, Rees J, Finch Jones M, et al. . Prognostic Significance of Pre-Operative Inflammatory Markers in Resected Gallbladder Cancer: A Systematic Review. ANZ J Surg (2018) 88(6):554–9. 10.1111/ans.14300
    1. Hu B, Yang XR, Xu Y, Sun YF, Sun C, Guo W, et al. . Systemic Immune-Inflammation Index Predicts Prognosis of Patients After Curative Resection for Hepatocellular Carcinoma. Clin Cancer Res (2014) 20(23):6212–22. 10.1158/1078-0432.CCR-14-0442
    1. Sun L, Jin Y, Hu W, Zhang M, Jin B, Xu H, et al. . The Impacts of Systemic Immune-Inflammation Index on Clinical Outcomes in Gallbladder Carcinoma. Front Oncol (2020) 10:554521. 10.3389/fonc.2020.554521
    1. Kattan MW, Scardino PT. Evidence for the Usefulness of Nomograms. Nat Clin Pract Urol (2007) 4(12):638–9. 10.1038/ncpuro0968
    1. Han DS, Suh YS, Kong SH, Lee HJ, Choi Y, Aikou S, et al. . Nomogram Predicting Long-Term Survival After D2 Gastrectomy for Gastric Cancer. J Clin Oncol (2012) 30(31):3834–40. 10.1200/JCO.2012.41.8343
    1. Wang Y, Li J, Xia Y, Gong R, Wang K, Yan Z, et al. . Prognostic Nomogram for Intrahepatic Cholangiocarcinoma After Partial Hepatectomy. J Clin Oncol (2013) 31(9):1188–95. 10.1200/JCO.2012.41.5984
    1. Mariani L, Miceli R, Kattan MW, Brennan MF, Colecchia M, Fiore M, et al. . Validation and Adaptation of a Nomogram for Predicting the Survival of Patients With Extremity Soft Tissue Sarcoma Using a Three-Grade System. Cancer (2005) 103(2):402–8. 10.1002/cncr.20778
    1. Tang LQ, Li CF, Li J, Chen WH, Chen QY, Yuan LX, et al. . Establishment and Validation of Prognostic Nomograms for Endemic Nasopharyngeal Carcinoma. J Natl Cancer Inst (2015) 108(1):djv291. 10.1093/jnci/djv291
    1. Liang W, Zhang L, Jiang G, Wang Q, Liu L, Liu D, et al. . Development and Validation of a Nomogram for Predicting Survival in Patients With Resected non-Small-Cell Lung Cancer. J Clin Oncol (2015) 33(8):861–9. 10.1200/JCO.2014.56.6661
    1. Karakiewicz PI, Briganti A, Chun FK, Trinh QD, Perrotte P, Ficarra V, et al. . Multi-Institutional Validation of a New Renal Cancer-Specific Survival Nomogram. J Clin Oncol (2007) 25(11):1316–22. 10.1200/JCO.2006.06.1218
    1. Aloia TA, Járufe N, Javle M, Maithel SK, Roa JC, Adsay V, et al. . Gallbladder Cancer: Expert Consensus Statement. HPB (2015) 17(8):681–90. 10.1111/hpb.12444
    1. Benson AB, D’Angelica MI, Abbott DE, Anaya DA, Anders R, Are C, et al. . Hepatobiliary Cancers, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw (2021) 19(5):541–65. 10.6004/jnccn.2021.0022
    1. Ren T, Li Y, Zhang X, Geng Y, Shao Z, Li M, et al. . Protocol for a Gallbladder Cancer Registry Study in China: The Chinese Research Group of Gallbladder Cancer (CRGGC) Study. BMJ Open (2021) 11(2):e038634. 10.1136/bmjopen-2020-038634
    1. Collins GS, Ogundimu EO, Altman DG. Sample Size Considerations for the External Validation of a Multivariable Prognostic Model: A Resampling Study. Stat Med (2016) 35(2):214–26. 10.1002/sim.6787
    1. Aziz MH, Sideras K, Aziz NA, Mauff K, Haen R, Roos D, et al. . The Systemic-Immune-Inflammation Index Independently Predicts Survival and Recurrence in Resectable Pancreatic Cancer and its Prognostic Value Depends on Bilirubin Levels: A Retrospective Multicenter Cohort Study. Ann Surg (2019) 270(1):139–46. 10.1097/SLA.0000000000002660
    1. Strom BL, Maislin G, West SL, Atkinson B, Herlyn M, Saul S, et al. . Serum CEA and CA 19-9: Potential Future Diagnostic or Screening Tests for Gallbladder Cancer? Int J Cancer (1990) 45(5):821–4. 10.1002/ijc.2910450505
    1. Jarnagin WR, Ruo L, Little SA, Klimstra D, D’Angelica M, DeMatteo RP, et al. . Patterns of Initial Disease Recurrence After Resection of Gallbladder Carcinoma and Hilar Cholangiocarcinoma: Implications for Adjuvant Therapeutic Strategies. Cancer (2003) 98(8):1689–700. 10.1002/cncr.11699
    1. Edeline J, Benabdelghani M, Bertaut A, Watelet J, Hammel P, Joly JP, et al. . Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (Prodige 12-ACCORD 18-UNICANCER Gi): A Randomized Phase Iii Study. J Clin Oncol (2019) 37(8):658–67. 10.1200/JCO.18.00050
    1. Horgan AM, Amir E, Walter T, Knox JJ. Adjuvant Therapy in the Treatment of Biliary Tract Cancer: A Systematic Review and Meta-Analysis. J Clin Oncol (2012) 30(16):1934–40. 10.1200/JCO.2011.40.5381
    1. Gold DG, Miller RC, Haddock MG, Gunderson LL, Quevedo F, Donohue JH, et al. . Adjuvant Therapy for Gallbladder Carcinoma: The Mayo Clinic Experience. Int J Radiat Oncol Biol Phys (2009) 75(1):150–5. 10.1016/j.ijrobp.2008.10.052
    1. Kim Y, Amini N, Wilson A, Margonis GA, Ethun CG, Poultsides G, et al. . Impact of Chemotherapy and External-Beam Radiation Therapy on Outcomes Among Patients With Resected Gallbladder Cancer: A Multi-Institutional Analysis. Ann Surg Oncol (2016) 23(9):2998–3008. 10.1245/s10434-016-5262-8
    1. Kim K, Chie EK, Jang JY, Kim SW, Han SW, Oh DY, et al. . Postoperative Chemoradiotherapy for Gallbladder Cancer. Strahlenther Onkol (2012) 188(5):388–92. 10.1007/s00066-012-0074-7
    1. Cho SY, Kim SH, Park SJ, Han SS, Kim YK, Lee KW, et al. . Adjuvant Chemoradiation Therapy in Gallbladder Cancer. J Surg Oncol (2010) 102(1):87–93. 10.1002/jso.21544
    1. Bai Y, Liu ZS, Xiong JP, Xu WY, Lin JZ, Long JY, et al. . Nomogram to Predict Overall Survival After Gallbladder Cancer Resection in China. World J Gastroenterol (2018) 24(45):5167–78. 10.3748/wjg.v24.i45.5167
    1. Wang SJ, Lemieux A, Kalpathy-Cramer J, Ord CB, Walker GV, Fuller CD, et al. . Nomogram for Predicting the Benefit of Adjuvant Chemoradiotherapy for Resected Gallbladder Cancer. J Clin Oncol (2011) 29(35):4627–32. 10.1200/JCO.2010.33.8020
    1. Zhang W, Hong HJ, Chen YL. Establishment of a Gallbladder Cancer-Specific Survival Model to Predict Prognosis in Non-metastatic Gallbladder Cancer Patients After Surgical Resection. Digest Dis Sci (2018) 63(9):2251–8. 10.1007/s10620-018-5103-7
    1. Geng ZM, Cai ZQ, Zhang Z, Tang ZH, Xue F, Chen C, et al. . Estimating Survival Benefit of Adjuvant Therapy Based on a Bayesian Network Prediction Model in Curatively Resected Advanced Gallbladder Adenocarcinoma. World J Gastroenterol (2019) 25(37):5655–66. 10.3748/wjg.v25.i37.5655
    1. Hasegawa S, Eguchi H, Tomokuni A, Tomimaru Y, Asaoka T, Wada H, et al. . Pre-Treatment Neutrophil to Lymphocyte Ratio as a Predictive Marker for Pathological Response to Preoperative Chemoradiotherapy in Pancreatic Cancer. Oncol Lett (2016) 11(2):1560–6. 10.3892/ol.2015.4057
    1. Chen Y, Chen K, Xiao X, Nie Y, Qu S, Gong C, et al. . Pretreatment Neutrophil-to-Lymphocyte Ratio is Correlated With Response to Neoadjuvant Chemotherapy as an Independent Prognostic Indicator in Breast Cancer Patients: A Retrospective Study. BMC Cancer (2016) 16:320. 10.1186/s12885-016-2352-8
    1. Ferrucci PF, Ascierto PA, Pigozzo J, Del Vecchio M, Maio M, Antonini Cappellini GC, et al. . Baseline Neutrophils and Derived Neutrophil-to-Lymphocyte Ratio: Prognostic Relevance in Metastatic Melanoma Patients Receiving Ipilimumab. Ann Oncol (2016) 27(4):732–8. 10.1093/annonc/mdw016
    1. Kuzman JA, Stenehjem DD, Merriman J, Agarwal AM, Patel SB, Hahn AW, et al. . Neutrophil-Lymphocyte Ratio as a Predictive Biomarker for Response to High Dose Interleukin-2 in Patients With Renal Cell Carcinoma. BMC Urol (2017) 17(1):1. 10.1186/s12894-016-0192-0
    1. Johansson H, Andersson R, Bauden M, Hammes S, Holdenrieder S, Ansari D. Immune Checkpoint Therapy for Pancreatic Cancer. World J Gastroenterol (2016) 22(43):9457–76. 10.3748/wjg.v22.i43.9457
    1. Jomrich G, Paireder M, Kristo I, Baierl A, Ilhan-Mutlu A, Preusser M, et al. . High Systemic Immune-Inflammation Index is an Adverse Prognostic Factor for Patients With Gastroesophageal Adenocarcinoma. Ann Surg (2021) 273(3):532–41. 10.1097/SLA.0000000000003370

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する