Top

Published in:

Open Access 01-05-2016 | Colorectal Cancer

Angiogenesis-Related Markers and Prognosis After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Metastatic Colorectal Cancer

Authors: E. M. V. de Cuba, MD, I. H. J. T. de Hingh, MD, PhD, N. R. Sluiter, BSc, R. Kwakman, MD, V. M. H. Coupé, PhD, J. A. M. Beliën, PhD, V. J. Verwaal, MD, PhD, W. J. H. J. Meijerink, MD, PhD, P. M. Delis-van Diemen, BSc, H. J. Bonjer, MD, PhD, G. A. Meijer, MD, PhD, E. A. te Velde, MD, PhD

Published in: Annals of Surgical Oncology | Issue 5/2016

Abstract

Background

Patients presenting with peritoneal metastases (PM) of colorectal cancer (CRC) can be curatively treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Angiogenesis is under control of multiple molecules of which HIF1a, SDF1, CXCR4, and VEGF are key players. We investigated these angiogenesis-related markers and their prognostic value in patients with PM arising from CRC treated with CRS and HIPEC.

Patients and Methods

Clinicopathological data and tissue specimens were collected in 2 tertiary referral centers from 52 patients who underwent treatment for isolated PM of CRC. Whole tissue specimens were subsequently analyzed for protein expression of HIF1a, SDF1, CXCR4, and VEGF by immunohistochemistry. Microvessel density (MVD) was analyzed by CD31 immunohistochemistry. The relationship between overall survival (OS) and protein expression as well as other clinicopathological characteristics was analyzed.

Results

Univariate analysis showed that high peritoneal cancer index (PCI), resection with residual disease and high expression of VEGF were negatively correlated with OS after treatment with CRS and HIPEC (P < 0.01, P < 0.01, and P = 0.02, respectively). However, no association was found between the other markers and OS (P > 0.05). Multivariate analysis showed an independent association between OS and PCI, resection outcome and VEGF expression (multivariate HR: 6.1, 7.8 and 3.8, respectively, P ≤ 0.05).

Conclusions

An independent association was found between high VEGF expression levels and worse OS after CRS and HIPEC. The addition of VEGF expression to the routine clinicopathological workup could help to identify patients at risk for early treatment failure. Furthermore, VEGF may be a potential target for adjuvant treatment in these patients.

Available only for authorised users

Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.CrossRefPubMed

Koppe MJ, Boerman OC, Oyen WJG, Bleichrodt RP. Peritoneal carcinomatosis of colorectal origin. Ann Surg. 2006;243:212–22. doi:10.1097/01.sla.0000197702.46394.16.CrossRefPubMedPubMedCentral

Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30. doi:10.3322/caac.21166.CrossRefPubMed

Elias D, Lefevre JH, Chevalier J, et al. Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin. J Clin Oncol. 2009;27(5):681–685. doi:10.1200/JCO.2008.19.7160.CrossRefPubMed

Carpizo DR, Are C, Jarnagin W, et al. Liver resection for metastatic colorectal cancer in patients with concurrent extrahepatic disease: results in 127 patients treated at a single center. Ann Surg Oncol. 2009;16:2138–46. doi:10.1245/s10434-009-0521-6.CrossRefPubMed

Sugarbaker PH. Peritonectomy procedures. Ann Surg. 1995;221:29–42.CrossRefPubMedPubMedCentral

Verwaal VJ. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol. 2003;21:3737–43. doi:10.1200/JCO.2003.04.187.CrossRefPubMed

Maggiori L, Elias D. Curative treatment of colorectal peritoneal carcinomatosis: current status and future trends. Eur J Surg Oncol. 2010;36:599–603. doi:10.1016/j.ejso.2010.05.007.CrossRefPubMed

Cao Y, Tan A, Gao F, Liu L, Liao C, Mo Z. A meta-analysis of randomized controlled trials comparing chemotherapy plus bevacizumab with chemotherapy alone in metastatic colorectal cancer. Int J Colorectal Dis. 2009;24:677–85. doi:10.1007/s00384-009-0655-9.CrossRefPubMed

10.

Verwaal VJ, Zoetmulder FAN. Follow-up of patients treated by cytoreduction and chemotherapy for peritoneal carcinomatosis of colorectal origin. Eur J Surg Oncol. 2004;30:280–5. doi:10.1016/j.ejso.2003.12.003.CrossRefPubMed

11.

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74. doi:10.1016/j.cell.2011.02.013.CrossRefPubMed

12.

Nieves BJ, D’Amore PA, Bryan BA. The function of vascular endothelial growth factor. Biofactors. 2009;35:332–7. doi:10.1002/biof.46.CrossRefPubMed

13.

Hong X, Jiang F, Kalkanis SN, et al. SDF-1 and CXCR4 are up-regulated by VEGF and contribute to glioma cell invasion. Cancer Lett. 2006;236:39–45. doi:10.1016/j.canlet.2005.05.011.CrossRefPubMed

14.

Chen L, Endler A, Shibasaki F. Hypoxia and angiogenesis: regulation of hypoxia-inducible factors via novel binding factors. Exp Mol Med. 2009;41:849–57. doi:10.3858/emm.2009.41.12.103.CrossRefPubMedPubMedCentral

15.

Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol. 2002;20:4368–80.CrossRefPubMed

16.

Wu Y, Jin M, Xu H, Shimin Z, He S, Wang L, Zhang Y. Clinicopathologic significance of HIF-1α, CXCR4, and VEGF expression in colon cancer. Clin Dev Immunol. 2010;2010. doi:10.1155/2010/537531.

17.

Barresi V, Di Gregorio C, Regiani-Bonetti L, Ponz-De Leon M, Barresi G, Vitarelli E. Stage I colorectal carcinoma: VEGF immunohistochemical expression, microvessel density, and their correlation with clinical outcome. Virchows Archiv. 2010;457:11–9. doi:10.1007/s00428-010-0933-5.CrossRefPubMed

18.

Kuijpers AM, Mirck B, Aalbers AGJ, et al. Cytoreduction and HIPEC in the Netherlands: nationwide long-term outcome following the Dutch protocol. Ann Surg Oncol. 2013;20:4224–30. doi:10.1245/s10434-013-3145-9.CrossRefPubMedPubMedCentral

19.

Kerkhof MH, Ruiz-Zapata AM, Bril H, Bleeker MC, Belien JA, Stoop R, Helder MN. Changes in tissue composition of the vaginal wall of premenopausal women with prolapse. Am J Obstet Gynecol. 2014;210:168.e1–.e9. doi:10.1016/j.ajog.2013.10.881.

20.

McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM; Statistics Subcommittee of the NCI-EORTC Working Group on Cancer Diagnostics. REporting recommendations for tumour MARKer prognostic studies (REMARK). Br J Cancer. 2005;93:387–91. doi:10.1038/sj.bjc.6602678.CrossRefPubMedPubMedCentral

21.

Portilla AG, Shigeki K, Dario B, Marcello D. The intraoperative staging systems in the management of peritoneal surface malignancy. J Surg Oncol. 2008;98:228–31. doi:10.1002/jso.21068.CrossRefPubMed

22.

Avital I, Brücher BL, Nissan A, Stojadinovic A. Randomized clinical trials for colorectal cancer peritoneal surface malignancy. Surg Oncol Clin N Am. 2012;21:665–88. doi:10.1016/j.soc.2012.07.004.CrossRefPubMed

23.

de Cuba EMV, Kwakman R, Knol DL, Bonjer HJ, Meijer GA, Velde te EA. Cytoreductive surgery and HIPEC for peritoneal metastases combined with curative treatment of colorectal liver metastases: Systematic review of all literature and meta-analysis of observational studies. Cancer Treat Rev. 2013:39:321–7. doi:10.1016/j.ctrv.2012.11.003.CrossRefPubMed

24.

Du C, Yao Y, Xue W, Zhu W, Peng Y, Gu J. The expression of chemokine receptors CXCR3 and CXCR4 in predicting postoperative tumour progression in stages I-II colon cancer: a retrospective study. BMJ Open. 2014;1–6. doi:10.1136/bmjopen-2014-005012.

25.

Chandler B, Detsika M, Khoo SH, Williams J, Back DJ, Owen A. Factors impacting the expression of membrane-bound proteins in lymphocytes from HIV-positive subjects. J Antimicrob Chemother. 2007;60:685–9. doi:10.1093/jac/dkm230.CrossRefPubMed

26.

Furlan D, Sahnane N, Carnevali I, et al. Up-regulation and stabilization of HIF-1alpha in colorectal carcinomas. Surg Oncol. 2007;16 Suppl 1:S25–7. doi:10.1016/j.suronc.2007.10.014.CrossRefPubMed

27.

Blancher C, Moore JW, Talks KL, Houlbrook S, Harris AL. Relationship of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression to vascular endothelial growth factor induction and hypoxia survival in human breast cancer cell lines. Cancer Res. 2000;60(24):7106–7113.PubMed

28.

Beasley NJ, Leek R, Alam M, et al. Hypoxia-inducible factors HIF-1alpha and HIF-2alpha in head and neck cancer: relationship to tumor biology and treatment outcome in surgically resected patients. Cancer Res. 2002;62:2493–7.PubMed

29.

Rohwer N, Dame C, Haugstetter A, Wiedenmann B, Detjen K, Schmitt CA, Cramer T. Hypoxia-inducible factor 1alpha determines gastric cancer chemosensitivity via modulation of p53 and NF-kappaB. PLoS One. 2010;5:e12038. doi:10.1371/journal.pone.0012038.CrossRefPubMedPubMedCentral

30.

Koh MY, Spivak-Kroizman TR, Powis G. HIF-1alpha and cancer therapy. Recent Results Cancer Res. 2010;180:15–34. doi:10.1007/978-3-540-78281-0_3.CrossRefPubMed

31.

Goos JA, de Cuba EM, Coupé VM, et al. Glucose transporter 1 (SLC2A1) and vascular endothelial growth factor A (VEGFA) predict survival after resection of colorectal cancer liver metastasis. Ann Surg. 2015. doi:10.1097/SLA.0000000000001109.

32.

Wehler TC, Graf C, Altherr K, et al. SDF1β expression in renal cell carcinoma correlates with grading and infiltration by CD8 + T-cells. Anticancer Res. 2011;31:2797–803.PubMed

33.

Mirisola V, Zuccarino A, Bachmeier BE, Sormani MP, Falter J, Nerlich A, Pfeffer U. CXCL12/SDF1 expression by breast cancers is an independent prognostic marker of disease-free and overall survival. Eur J Cancer. 2009;45:2579–87. doi:10.1016/j.ejca.2009.06.026.CrossRefPubMed

34.

Bird NC, Mangnall D, Majeed AW. Biology of colorectal liver metastases: a review. J Surg Oncol. 2006;94:68–80. doi:10.1002/jso.20558.CrossRefPubMed

35.

Diniz Bizzo SM, Meira DD, Lima JM, Mororó JDS, Casali-da-Rocha JC, Ornellas MHF. Peritoneal VEGF burden as a predictor of cytoreductive surgery outcome in women with epithelial ovarian cancer. Int J Gynaecol Obstet. 2010;109:113–7. doi:10.1016/j.ijgo.2009.11.021.CrossRefPubMed

36.

Logan-Collins JM, Lowy AM, Robinson-Smith TM, Kumar S, Sussman JJ, James LE, Ahmad SA. VEGF expression predicts survival in patients with peritoneal surface metastases from mucinous adenocarcinoma of the appendix and colon. Ann Surg Oncol. 2007;15:738–44. doi:10.1245/s10434-007-9699-7.CrossRefPubMed

37.

Varghese S, Burness M, Xu H, Beresnev T, Pingpank J, Alexander HR. Site-specific gene expression profiles and novel molecular prognostic factors in patients with lower gastrointestinal adenocarcinoma diffusely metastatic to liver or peritoneum. Ann Surg Oncol. 2007;14:3460–71. doi:10.1245/s10434-007-9557-7.CrossRefPubMed

38.

Harris AL. Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2:38–47. doi:10.1038/nrc704.CrossRefPubMed

39.

Shaheen RM, Ahmad SA, Liu W, et al. Inhibited growth of colon cancer carcinomatosis by antibodies to vascular endothelial and epidermal growth factor receptors. Br J Cancer. 2001;85:584–9. doi:10.1054/bjoc.2001.1936.CrossRefPubMedPubMedCentral

40.

Zebrowski BK, Liu W, Ramirez K, Akagi Y, Mills GB, Ellis LM. Markedly elevated levels of vascular endothelial growth factor in malignant ascites. Ann Surg Oncol. 1999;6:373–8.CrossRefPubMed

41.

Yoshikawa T, Tsuburaya A, Miyagi Y, Sekiguchi H, Kimura M, Cho H, Kobayashi O. Up-regulation of hypoxia-inducible factor-1 alpha and VEGF mRNAs in peritoneal dissemination of patients with gastric cancer. Anticancer Res. 2006;26:3849–53.PubMed

42.

Gerber SA, Rybalko VY, Bigelow CE, Lugade AA, Foster TH, Frelinger JG, Lord EM. Preferential attachment of peritoneal tumor metastases to omental immune aggregates and possible role of a unique vascular microenvironment in metastatic survival and growth. Am J Pathol. 2006;169:1739–52. doi:10.2353/ajpath.2006.051222.CrossRefPubMedPubMedCentral

43.

Imaizumi T, Aoyagi K, Miyagi M, Shirouzu K. Suppressive effect of bevacizumab on peritoneal dissemination from gastric cancer in a peritoneal metastasis model. Surg Today. 2010;40:851–7. doi:10.1007/s00595-009-4154-y.CrossRefPubMed

44.

Bai Y, Deng H, Yang Y, et al. VEGF-targeted short hairpin RNA inhibits intraperitoneal ovarian cancer growth in nude mice. Oncology. 2009;77:385–94. doi:10.1159/000279385.CrossRefPubMed

45.

Williams E, Martin S, Moss R, Durrant L, Deen S. Co-expression of VEGF and CA9 in ovarian high-grade serous carcinoma and relationship to survival. Virchows Archiv. 2012;461:33–39. doi:10.1007/s00428-012-1252-9.CrossRefPubMed

46.

Kobold S, Hegewisch-Becker S, Oechsle K, Jordan K, Bokemeyer C, Atanackovic D. Intraperitoneal VEGF inhibition using bevacizumab: a potential approach for the symptomatic treatment of malignant ascites? Oncologist. 2009;14:1242–51. doi:10.1634/theoncologist.2009-0109.CrossRefPubMed

47.

Ninomiya S, Inomata M, Tajima M, Ali AT, Ueda Y, Shiraishi N, Kitano S. Effect of bevacizumab, a humanized monoclonal antibody to vascular endothelial growth factor, on peritoneal metastasis of MNK-45P human gastric cancer in mice. J Surg Res. 2009;154:196–202. doi:10.1016/j.jss.2008.08.017.CrossRefPubMed

48.

Shah DK, Shin BS, Veith J, Tóth K, Bernacki RJ, Balthasar JP. Use of an anti-vascular endothelial growth factor antibody in a pharmacokinetic strategy to increase the efficacy of intraperitoneal chemotherapy. J Pharmacol Exp Ther. 2009;329:580–91. doi:10.1124/jpet.108.149443.CrossRefPubMedPubMedCentral

49.

Passot G, Dupré A, Rivoire M, Mohamed F, Bakrin N, Glehen O. Intraperitoneal bevacizumab combined with cytoreductive surgery: a pre-clinical study of tolerance and pharmacokinetics in an animal model. Clin Transl Oncol. 2012;14:931–6. doi:10.1007/s12094-012-0888-x.CrossRefPubMed

50.

Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42. doi:10.1056/NEJMoa032691.CrossRefPubMed

51.

Klaver YLB, Leenders BJM, Creemers G-J, Rutten HJ, Verwaal VJ, Lemmens VE, de Hingh IH. Addition of biological therapies to palliative chemotherapy prolongs survival in patients with peritoneal carcinomatosis of colorectal origin. Am J Clin Oncol. 2013;36:157–61. doi:10.1097/COC.0b013e3182438c55.CrossRefPubMed

52.

Ceelen W, Van Nieuwenhove Y, Putte DV, Pattyn P. Neoadjuvant chemotherapy with bevacizumab may improve outcome after cytoreduction and hyperthermic intraperitoneal chemoperfusion (HIPEC) for colorectal carcinomatosis. Ann Surg Oncol. 2014;21:3023–8. doi:10.1245/s10434-014-3713-7.CrossRefPubMed

53.

Eveno C, Passot G, Goeré D, et al. Bevacizumab doubles the early postoperative complication rate after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis of colorectal origin. Ann Surg Oncol. 2014;21:1792–800. doi:10.1245/s10434-013-3442-3.CrossRefPubMed

54.

van Dam GM, Themelis G, Crane LMA, et al. Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results. Nat Med. 2011;17:1315–9. doi:10.1038/nm.2472.CrossRefPubMed

55.

Terwisscha AGT, van Dam GM, Nagengast WB, et al. Intraoperative near-infrared fluorescence tumor imaging with vascular endothelial growth factor and human epidermal growth factor receptor 2 targeting antibodies. J Nucl Med. 2011;52:1778–85. doi:10.2967/jnumed.111.092833.CrossRefPubMed

56.

Gaykema SBM, Brouwers AH, Lub-de Hooge MN, et al. 89Zr-bevacizumab PET imaging in primary breast cancer. J Nucl Med. 2013;54:1014–8. doi:10.2967/jnumed.112.117218.CrossRefPubMed

Title: Angiogenesis-Related Markers and Prognosis After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Metastatic Colorectal Cancer
Authors: E. M. V. de Cuba, MD
I. H. J. T. de Hingh, MD, PhD
N. R. Sluiter, BSc
R. Kwakman, MD
V. M. H. Coupé, PhD
J. A. M. Beliën, PhD
V. J. Verwaal, MD, PhD
W. J. H. J. Meijerink, MD, PhD
P. M. Delis-van Diemen, BSc
H. J. Bonjer, MD, PhD
G. A. Meijer, MD, PhD
E. A. te Velde, MD, PhD
Publication date: 01-05-2016
Publisher: Springer International Publishing
Published in: Annals of Surgical Oncology / Issue 5/2016
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-015-5023-0

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Angiogenesis-Related Markers and Prognosis After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Metastatic Colorectal Cancer

Abstract

Background

Patients and Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Patients and Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 5/2016

Oncologic Outcomes of Colon Cancer Patients with Extraregional Lymph Node Metastasis: Comparison of Isolated Paraaortic Lymph Node Metastasis with Resectable Liver Metastasis

Impact of Time from Completion of Neoadjuvant Chemotherapy to Surgery on Survival Outcomes in Breast Cancer Patients

Risk of Local Recurrence of Benign and Borderline Phyllodes Tumors: A Danish Population-Based Retrospective Study

Patterns and Predictors of Weight Loss After Gastrectomy for Cancer

Prospective Randomized Study to Compare Lymphocele and Lymphorrhea Control Following Inguinal and Axillary Therapeutic Lymph Node Dissection With or Without the Use of an Ultrasonic Scalpel

Avoiding Diverting Ileostomy in Patients Requiring Complete Pelvic Peritonectomy