Skip to main content

Advertisement

SpringerLink
Log in

ACE Inhibitor Therapy Does Not Influence the Survival Outcomes of Patients with Colorectal Liver Metastases Following Liver Resection

  • Original Research
  • Published:
Journal of Gastrointestinal Cancer Aims and scope Submit manuscript

Abstract

Background

Angiotensin-converting enzyme (ACE) inhibitors have been shown to possibly influence the survival outcomes in certain cancers. The aim of this study was to evaluate the impact of ACE inhibitors on the outcomes of patients undergoing liver resection for colorectal liver metastases (CRLM). The secondary aim was to determine whether ACE inhibitors influenced histopathological changes in CRLM.

Methods

Patients treated with liver resection for CRLM over a 13-year period were identified from a prospectively maintained database. Data including demographics, primary tumour treatment, surgical data, histopathology analysis and clinical outcome were collated and analysed.

Results

A total of 586 patients underwent primary hepatic resections for CRLM during this period including 100 patients on ACE inhibitors. The median follow-up period was 23 (range: 12–96) months, in which 267 patients developed recurrent disease and 131 patients died. Independent predictors of disease-free survival on multivariate analysis included synchronous presentation, neoadjuvant chemotherapy, major liver resection, tumour size and number, extent of hepatic steatosis, R0 resection and presence of perineural invasion. Poorer overall survival was associated with neoadjuvant treatment, major liver resection, presence of multiple metastases, perineural invasion and positive resection margins on multivariate analysis. ACE inhibitors did not influence the survival outcome or histological presentation in CRLM.

Conclusion

The use of ACE inhibitors did not affect the survival outcome or tumour biology in patients with CRLM following liver resection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Torre LA, Siegel RL, Ward EM, Jemal A. Global cancer incidence and mortality rates and trends—an update. Cancer Epidemiol Biomarkers Prev. 2016;25(1):16–27.

    Article  Google Scholar 

  2. Cummings LC, Payes JD, Cooper GS. Survival after hepatic resection in metastatic colorectal cancer: a population-based study. Cancer. 2007;109(4):718–26.

    Article  Google Scholar 

  3. van der Geest LG, Koopman M, Verhoef C, Elferink MA, de Wilt JH. Nationwide trends in incidence, treatment and survival of colorectal cancer patients with synchronous metastases. Clin Exp Metastasis. 2015;32(5):457–65.

    Article  Google Scholar 

  4. Kanas GP, Taylor A, Primrose JN, Langeberg WJ, Kelsh MA, Mowat FS, et al. Survival after liver resection in metastatic colorectal cancer: review and meta-analysis of prognostic factors. Clin Epidemiol. 2012;4:283.

    PubMed  PubMed Central  Google Scholar 

  5. Landreau P, Drouillard A, Launoy G, Ortega-Deballon P, Jooste V, Lepage C, et al. Incidence and survival in late liver metastases of colorectal cancer. J Gastroenterol Hepatol. 2015;30(1):82–5.

    Article  Google Scholar 

  6. Adam R, de Gramont A, Figueras J, Kokudo N, Kunstlinger F, Loyer E, et al. Managing synchronous liver metastases from colorectal cancer: a multidisciplinary international consensus. Cancer Treat Rev. 2015;41(9):729–41.

    Article  Google Scholar 

  7. Peng H, Carretero OA, Vuljaj N, Liao T-D, Motivala A, Peterson EL, et al. Angiotensin-converting enzyme inhibitors: a new mechanism of action. Circulation. 2005;112(16):2436–45.

    Article  CAS  Google Scholar 

  8. Lever AF, Hole DJ, Gillis CR, McCallum IR, McInnes GT, MacKinnon PL, et al. Do inhibitors of angiotensin-I-converting enzyme protect against risk of cancer? Lancet. 1998;352(9123):179–84.

    Article  CAS  Google Scholar 

  9. Miyajima A, Yazawa S, Kosaka T, Tanaka N, Shirotake S, Mizuno R, et al. Prognostic impact of renin–angiotensin system blockade on renal cell carcinoma after surgery. Ann Surg Oncol. 2015;22(11):3751–9.

    Article  Google Scholar 

  10. Sun H, Li T, Zhuang R, Cai W, Zheng Y. Do renin-angiotensin system inhibitors influence the recurrence, metastasis, and survival in cancer patients?: Evidence from a meta-analysis including 55 studies. Medicine (Baltimore). 2017;96(13):e6394. https://doi.org/10.1097/MD.0000000000006394.

  11. George AJ, Thomas WG, Hannan RD. The renin–angiotensin system and cancer: old dog, new tricks. Nat Rev Cancer. 2010;10(11):745–59.

    Article  CAS  Google Scholar 

  12. Chauhan VP, Martin JD, Liu H, Lacorre DA, Jain SR, Kozin SV, et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat Commun. 2013;4:2516.

    Article  Google Scholar 

  13. Murphy JE, Wo JY-L, Ferrone C, Jiang W, Yeap BY, Blaszkowsky LS, et al. TGF-B1 inhibition with losartan in combination with FOLFIRINOX (F-NOX) in locally advanced pancreatic cancer (LAPC): preliminary feasibility and R0 resection rates from a prospective phase II study. J Clin Oncol. 2017;35(4):386.

  14. Liu H, Naxerova K, Pinter M, Incio J, Lee H, Shigeta K, et al. Use of angiotensin system inhibitors is associated with immune activation and longer survival in nonmetastatic pancreatic ductal adenocarcinoma. Clin Cancer Res. 2017;23(19):5959–69.

    Article  CAS  Google Scholar 

  15. Osumi H, Matsusaka S, Wakatsuki T, Suenaga M, Shinozaki E, Mizunuma N. Angiotensin II type-1 receptor blockers enhance the effects of bevacizumab-based chemotherapy in metastatic colorectal cancer patients. Mol Clin Oncol. 2015;3(6):1295–300.

    Article  CAS  Google Scholar 

  16. Kim ST, Park KH, Oh SC, Seo JH, Kim JS, Shin SW, et al. How does inhibition of the renin-angiotensin system affect the prognosis of advanced gastric cancer patients receiving platinum-based chemotherapy? Oncology. 2012;83(6):354–60.

    Article  CAS  Google Scholar 

  17. Miao L, Chen W, Zhou L, Wan H, Gao B, Feng Y. Impact of angiotensin I-converting enzyme inhibitors and angiotensin II type-1 receptor blockers on survival of patients with NSCLC. Sci Rep. 2016;6:21359.

    Article  CAS  Google Scholar 

  18. Smith T, Noble M, Noble S, Wright G, McLennan D, Plunkett E. The English indices of deprivation 2015. London: Department for Communities and Local Government; 2015.

    Google Scholar 

  19. Boyd-Carson H, Irving G, Navarro A, Cameron I, Gomez D, Group NHS. Anti-platelet therapy does not influence the outcome of patients undergoing hepatic resection for colorectal liver metastases, an observational study. Int J Surg. 2018;53:59–64.

    Article  CAS  Google Scholar 

  20. Gomez D, Morris-Stiff G, Toogood GJ, Lodge JPA, Prasad KR. Interaction of tumour biology and tumour burden in determining outcome after hepatic resection for colorectal metastases. HPB. 2010;12(2):84–93.

    Article  Google Scholar 

  21. Gomez D, Zaitoun AM, De Rosa A, Hossaini S, Beckingham IJ, Brooks A, et al. Critical review of the prognostic significance of pathological variables in patients undergoing resection for colorectal liver metastases. HPB. 2014;16(9):836–44.

    Article  Google Scholar 

  22. Gomez D, Morris-Stiff G, Wyatt J, Toogood GJ, Lodge JPA, Prasad KR. Surgical technique and systemic inflammation influences long-term disease-free survival following hepatic resection for colorectal metastasis. J Surg Oncol. 2008;98(5):371–6.

    Article  Google Scholar 

  23. Gomez D, Malik H, Bonney G, Wong V, Toogood G, Lodge J, et al. Steatosis predicts postoperative morbidity following hepatic resection for colorectal metastasis. Br J Surg. 2007;94(11):1395–402.

    Article  CAS  Google Scholar 

  24. Egami K, Murohara T, Shimada T, Sasaki K-I, Shintani S, Sugaya T, et al. Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth. J Clin Invest. 2003;112(1):67–75.

    Article  CAS  Google Scholar 

  25. Bodor C, Nagy JP, Végh B, Németh A, Jenei A, MirzaHosseini S, et al. Angiotensin II increases the permeability and PV-1 expression of endothelial cells. Am J Phys Cell Phys. 2012;302(1):C267–76.

  26. Oh E, Kim JY, Cho Y, An H, Lee N, Jo H, et al. Overexpression of angiotensin II type 1 receptor in breast cancer cells induces epithelial–mesenchymal transition and promotes tumor growth and angiogenesis. Biochim Biophys Acta Mol Cell Res. 2016;1863(6):1071–81.

    Article  CAS  Google Scholar 

  27. Okamoto K, Tajima H, Nakanuma S, Sakai S, Makino I, Kinoshita J, et al. Angiotensin II enhances epithelial-to-mesenchymal transition through the interaction between activated hepatic stellate cells and the stromal cell-derived factor-1/CXCR4 axis in intrahepatic cholangiocarcinoma. Int J Oncol. 2012;41(2):573–82.

    Article  CAS  Google Scholar 

  28. Fujimoto Y, Sasaki T, Tsuchida A, Chayama K. Angiotensin II type 1 receptor expression in human pancreatic cancer and growth inhibition by angiotensin II type 1 receptor antagonist. FEBS Lett. 2001;495(3):197–200.

    Article  CAS  Google Scholar 

  29. Uemura H, Ishiguro H, Nagashima Y, Sasaki T, Nakaigawa N, Hasumi H, et al. Antiproliferative activity of angiotensin II receptor blocker through cross-talk between stromal and epithelial prostate cancer cells. Mol Cancer Ther. 2005;4(11):1699–709.

    Article  CAS  Google Scholar 

  30. Fujita M, Hayashi I, Yamashina S, Fukamizu A, Itoman M, Majima M. Angiotensin type 1a receptor signaling-dependent induction of vascular endothelial growth factor in stroma is relevant to tumor-associated angiogenesis and tumor growth. Carcinogenesis. 2005;26(2):271–9.

    Article  CAS  Google Scholar 

  31. Miyajima A, Kosaka T, Asano T, Asano T, Seta K, Kawai T, et al. Angiotensin II type I antagonist prevents pulmonary metastasis of murine renal cancer by inhibiting tumor angiogenesis. Cancer Res. 2002;62(15):4176–9.

    CAS  PubMed  Google Scholar 

  32. Fujita M, Hayashi I, Yamashina S, Itoman M, Majima M. Blockade of angiotensin AT1a receptor signaling reduces tumor growth, angiogenesis, and metastasis. Biochem Biophys Res Commun. 2002;294(2):441–7.

    Article  CAS  Google Scholar 

  33. Carl-McGrath S, Ebert MP, Lendeckel U, Rocken C. Expression of the local angiotensin II system in gastric cancer may facilitate lymphatic invasion and nodal spread. Cancer Biol Ther. 2007;6(8):1229–37.

    Article  Google Scholar 

  34. Fryzek JP, Poulsen AH, Lipworth L, Pedersen L, Nørgaard M, McLaughlin JK, et al. A cohort study of antihypertensive medication use and breast cancer among Danish women. Breast Cancer Res Treat. 2006;97(3):231–6.

    Article  Google Scholar 

  35. Sipahi I, Chou J, Mishra P, Debanne SM, Simon DI, Fang JC. Meta-analysis of randomized controlled trials on effect of angiotensin-converting enzyme inhibitors on cancer risk. Am J Cardiol. 2011;108(2):294–301.

    Article  CAS  Google Scholar 

  36. Neo JH, Malcontenti-Wilson C, Muralidharan V, Christophi C. Effect of ACE inhibitors and angiotensin II receptor antagonists in a mouse model of colorectal cancer liver metastases. J Gastroenterol Hepatol. 2007;22(4):577–84.

    Article  CAS  Google Scholar 

  37. Neo JH, Ager EI, Angus PW, Zhu J, Herath CB, Christophi C. Changes in the renin angiotensin system during the development of colorectal cancer liver metastases. BMC Cancer. 2010;10(1):134.

    Article  Google Scholar 

  38. Wen SW, Ager EI, Neo J, Christophi C. The renin angiotensin system regulates Kupffer cells in colorectal liver metastases. Cancer Biol Ther. 2013;14(8):720–7.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hepatobiliary and Pancreatic Surgery, Queen’s Medical Centre, Nottingham University Hospitals NHS Trust, Derby Rd, Nottingham, NG7 2UH, UK

    Sudip Sanyal, Edward Alabraba, Hussain Ibrahim, Adina Olaru, Iain Cameron & Dhanny Gomez

  2. NIHR Nottingham Digestive Disease Biomedical Research Uni, University of Nottingham, Nottingham, UK

    Dhanny Gomez

Authors
  1. Sudip Sanyal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Edward Alabraba
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hussain Ibrahim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Adina Olaru
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Iain Cameron
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dhanny Gomez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dhanny Gomez.

Ethics declarations

Conflict of Interest

The authors confirm that they have no conflicts of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sanyal, S., Alabraba, E., Ibrahim, H. et al. ACE Inhibitor Therapy Does Not Influence the Survival Outcomes of Patients with Colorectal Liver Metastases Following Liver Resection. J Gastrointest Canc 52, 106–112 (2021). https://doi.org/10.1007/s12029-019-00350-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12029-019-00350-6

Keywords

Search

Navigation