Abstract
Background
Tumor markers are commonly utilized in the diagnostic evaluation, treatment decision making, and surveillance of appendiceal tumors. In this study, we aimed to determine the prognostic significance of elevated preoperative tumor markers in patients with pseudomyxoma peritonei secondary to low-grade appendiceal mucinous neoplasm who underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
Methods
Using a multi-institutional database, eligible patients with measured preoperative tumor markers [carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), or cancer antigen 125 (CA-125)] were identified. Univariate and multivariate Cox-proportional hazards regression analysis assessed relationships between normal and elevated serum tumor markers with progression-free and overall survival in the context of multiple clinicopathologic variables.
Results
zTwo hundred and sixty-four patients met criteria. CEA was the most commonly measured tumor marker (97%). Patients who had any elevated tumor marker had a higher peritoneal carcinomatosis index (PCI) as compared to those with normal range markers. Elevated CEA and CA 19-9 levels were individually associated with longer inpatient length of stay, requirement for intraoperative transfusion, and incomplete cytoreduction. Utilization of neoadjuvant chemotherapy, increased PCI score, elevated CA 19-9 (p = 0.007), and CA-125 levels (p = 0.01) were predictive of decreased progression-free survival on univariate analysis. However, in a multivariate model, only elevated PCI was a statistically significant predictor of progression-free survival.
Conclusion
Elevated preoperative tumor markers indicate a higher burden of disease but are not independently associated with survival in this retrospective multi-institutional cohort. Further prospective studies are needed to clarify the utility of these markers in this patient population.
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References
Tirumani SH, Fraser-Hill M, Auer R, Shabana W, Walsh C, Lee F, et al. Mucinous neoplasms of the appendix: a current comprehensive clinicopathologic and imaging review. Cancer Imaging Off Publ Int Cancer Imaging Soc. 2013 Feb 22;13(1):14–25.
Ramaswamy V. Pathology of Mucinous Appendiceal Tumors and Pseudomyxoma Peritonei. Indian J Surg Oncol. 2016 Jun;7(2):258–67.
Carr NJ, Cecil TD, Mohamed F, Sobin LH, Sugarbaker PH, Gonzalez-Moreno S, et al. A Consensus for Classification and Pathologic Reporting of Pseudomyxoma Peritonei and Associated Appendiceal Neoplasia: The Results of the Peritoneal Surface Oncology Group International (PSOGI) Modified Delphi Process. Am J Surg Pathol. 2016 Jan;40(1):14–26.
Kelly KJ. Management of Appendix Cancer. Clin Colon Rectal Surg. 2015 Dec;28(4):247–55.
Misdraji J, Yantiss RK, Graeme-Cook FM, Balis UJ, Young RH. Appendiceal mucinous neoplasms: a clinicopathologic analysis of 107 cases. Am J Surg Pathol. 2003 Aug;27(8):1089–103.
Foster JM, Sleightholm RL, Wahlmeier S, Loggie B, Sharma P, Patel A. Early identification of DPAM in at-risk low-grade appendiceal mucinous neoplasm patients: a new approach to surveillance for peritoneal metastasis. World J Surg Oncol. 2016 Sep 13;14(1):243.
Haslinger M, Francescutti V, Attwood K, McCart JA, Fakih M, Kane III JM, et al. A contemporary analysis of morbidity and outcomes in cytoreduction/hyperthermic intraperitoneal chemoperfusion. Cancer Med. 2013;2(3):334–42.
Choudry MHA, Shuai Y, Jones HL, Pai RK, **pank JF, Ahrendt SS, et al. Postoperative complications independently predict cancer-related survival in peritoneal malignancies. Ann Surg Oncol. 2018;25(13):3950–9.
Bast JR. Status of tumor markers in ovarian cancer screening. J Clin Oncol Off J Am Soc Clin Oncol. 2003;21(10 Suppl):200s–5s.
Duffy MJ. Tumor markers in clinical practice: a review focusing on common solid cancers. Med Princ Pract. 2013;22(1):4–11.
Saito H, Kono Y, Murakami Y, Kuroda H, Matsunaga T, Fukumoto Y, et al. Influence of prognostic nutritional index and tumor markers on survival in gastric cancer surgery patients. Langenbecks Arch Surg. 2017 May;402(3):501–7.
Ryu T, Takami Y, Wada Y, Tateishi M, Matsushima H, Mikagi K, et al. Double- and Triple-Positive Tumor Markers Predict Early Recurrence and Poor Survival in Patients with Hepatocellular Carcinoma within the Milan Criteria and Child-Pugh Class A. J Gastrointest Surg Off J Soc Surg Aliment Tract. 2017 Jun;21(6):957–66.
Zhou B, Fang B, Yan S, Wang W. Comparison of Tumor Markers for Predicting Disease-Free Survival in Surgically Resected Pancreatic Neuroendocrine Tumors. Clin Lab. 2017 Jul 1;63(7):1251–9.
Nummela P, Leinonen H, Jarvinen P, Thiel A, Jarvinen H, Lepisto A, et al. Expression of CEA, CA19-9, CA125, and EpCAM in pseudomyxoma peritonei. Hum Pathol. 2016 Aug;54:47–54.
Group CCW, Schuitevoerder D, Plana A, Izquierdo FJ, Votanopoulos KI, Cusack Jr JC, et al. The Chicago Consensus on peritoneal surface malignancies: Management of appendiceal neoplasms. Cancer. 2020;126(11):2525–33.
Govaerts K, Lurvink RJ, De Hingh IHJT, et al. Appendiceal tumours and pseudomyxoma peritonei: Literature review with PSOGI/EURACAN clinical practice guidelines for diagnosis and treatment. Eur J Surg Oncol. 2021;47(1):11–35. https://doi.org/10.1016/j.ejso.2020.02.012
Fournier K, Rafeeq S, Taggart M, Kanaby P, Ning J, Chen H-C, et al. Low-grade Appendiceal Mucinous Neoplasm of Uncertain Malignant Potential (LAMN-UMP): Prognostic Factors and Implications for Treatment and Follow-up. Ann Surg Oncol. 2017 Jan;24(1):187–93.
Reghunathan M, Kelly KJ, Valasek MA, Lowy AM, Baumgartner JM. Histologic Predictors of Recurrence in Mucinous Appendiceal Tumors with Peritoneal Dissemination after HIPEC. Ann Surg Oncol. 2018 Mar;25(3):702–8.
Solomon D, Bekhor E, Leigh N, et al. Surveillance of Low-Grade Appendiceal Mucinous Neoplasms With Peritoneal Metastases After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Are 5 Years Enough? A Multisite Experience [published correction appears in Ann Surg Oncol. 2019 Dec;26(Suppl 3):890]. Ann Surg Oncol. 2020;27(1):147–153. https://doi.org/10.1245/s10434-019-07678-0
Pablo Carmignani C, Hampton R, Sugarbaker CE, Chang D, Sugarbaker PH. Utility of CEA and CA 19-9 tumor markers in diagnosis and prognostic assessment of mucinous epithelial cancers of the appendix. J Surg Oncol. 2004;87(4):162–6.
Beal EW, Ahmed A, Grotz T, Leiting J, Fournier KF, Lee AJ, et al. Trends in the indications for and short-term outcomes of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. Am J Surg. 2020 Mar;219(3):478–83.
Edge SB, Byrd DR, Carducci MA, Compton CC, Fritz AG, Greene FL. AJCC cancer staging manual. Vol. 649. Springer New York; 2010.
Sugarbaker PH. Management of peritoneal-surface malignancy: the surgeon’s role. Langenbecks Arch Surg. 1999;384(6):576–87.
Van Eden WJ, Kok NFM, Snaebjornsson P, et al. Factors influencing long-term survival after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for pseudomyxoma peritonei originating from appendiceal neoplasms. BJS Open. 2019;3(3):376–386. Published 2019 Feb 19. https://doi.org/10.1002/bjs5.50134
Gupta A, Chandrakumaran K, Cecil TD, Mohamed F, Moran BJ, Gupta A. Tumour grade and complete tumour removal affects survival after cytoreductive surgery and HIPEC for Pseudomyxoma Peritonei (PMP) of appendiceal origin. PMI Basingstoke Basingstoke North Hamps Hosp. 2014;
Chua TC, Moran BJ, Sugarbaker PH, Levine EA, Glehen O, Gilly FN, et al. Early- and long-term outcome data of patients with pseudomyxoma peritonei from appendiceal origin treated by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. J Clin Oncol Off J Am Soc Clin Oncol. 2012 Jul 10;30(20):2449–56.
Tu Y, Tian Y, Fang Z, Ruan Q, Tang H, Zhang X, et al. Cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion for the treatment of gastric cancer: A single-centre retrospective study. Int J Hyperth Off J Eur Soc Hyperthermic Oncol North Am Hyperth Group. 2016 Sep;32(6):587–94.
Zaidi MY, Lee RM, Gamboa AC, Speegle S, Cloyd JM, Kimbrough C, et al. Preoperative Risk Score for Predicting Incomplete Cytoreduction: A 12-Institution Study from the US HIPEC Collaborative. Ann Surg Oncol. 2020 Jan;27(1):156–64.
Wagner PL, Austin F, Sathaiah M, Magge D, Maduekwe U, Ramalingam L, et al. Significance of serum tumor marker levels in peritoneal carcinomatosis of appendiceal origin. Ann Surg Oncol. 2013 Feb;20(2):506–14.
Kyang LS, Alzahrani NA, Alshahrani MS, Rahman MK, Liauw W, Morris DL. Early recurrence in peritoneal metastasis of appendiceal neoplasm: Survival and prognostic factors. Eur J Surg Oncol. 2019;45(12):2392–2397. https://doi.org/10.1016/j.ejso.2019.06.015
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The authors would like to thank local database managers that were involved in data collection and maintenance of this large database.
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W. N.: substantial contributions towards the conception and design of study, acquisition, analysis, and interpretation of data for the work, drafted the work, made revisions, and final approval of manuscript.
N. F.: substantial contributions towards the conception and design of study, acquisition, analysis, and interpretation of data for the work, made revisions, and final approval of manuscript.
B. P., B. K., J. M. C., T. G., K. F., S. D., J. V., J. M. B., C. C., S. H. P., G. C. W., L. L., D. E. A., K. A. V. W., B. L., M. R., S. K. M., M. C. R., M. Y. Z., F. M. J., and J. B. G. made substantial contributions to the acquisition of data for the work, interpretation and analysis of results, critical review of manuscript, and final approval of manuscript.
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Nizam, W., Fackche, N., Pessoa, B. et al. Prognostic Significance of Preoperative Tumor Markers in Pseudomyxoma Peritonei from Low-Grade Appendiceal Mucinous Neoplasm: a Study from the US HIPEC Collaborative. J Gastrointest Surg 26, 414–424 (2022). https://doi.org/10.1007/s11605-021-05075-1
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DOI: https://doi.org/10.1007/s11605-021-05075-1