The correlation between the levels of tissue inhibitor of metalloproteinases 1 in plasma and tumour response and survival after preoperative radiochemotherapy in patients with rectal cancer

Open access

Background. The aim of this study was to analyse whether the level of tissue inhibitor of metalloproteinases (TIMP) 1 is associated with the tumour response and survival to preoperative radiochemotherapy in rectal cancer patients.

Patients and methods. Ninety-two patients with histologically confirmed non-metastatic rectal cancer of clinical stage I- III were treated with preoperative radiochemotherapy, surgery and postoperative chemotherapy. Plasma TIMP-1 concentrations were measured prior to the start of the treatment with an enzyme-linked immunosorbent assay (ELISA).

Results. Median follow-up time was 68 months (range: 3-93 months) while in survivors it was 80 months (range: 68-93 months). The 5-year locoregional control (LRC), disease-free survival (DFS), disease-specific survival (DSS) and overall survival (OS) rates for all patients were 80.2%, 56.4%, 63.7% and 52.2%, respectively. The median TIMP-1 level was 185 ng/mL (range: 22-523 ng/mL) and the mean level (±standard deviation) was 192 (±87) ng/mL. Serum TIMP-1 levels were found to be significantly increased in patients with preoperative CRP>12 mg/L and in those who died from rectal cancer or had cT4 tumours. No correlation was established for age, gender, carcinoembriogenic antigene (CEA) level, platelets count, histopathological grade, response to preoperative therapy, resectability and disease reappearance. On univariate analysis, various parameters favourably influenced one or more survival endpoints: TIMP-1 <170 ng/mL, CRP <12 mg/L, platelets count <290 10E9/L, CEA <3.4mg/L, age <69 years, male gender, early stage disease (cN0 and/or cT2-3), radical surgery (R0) and response to preoperative radiochemotherapy. In multivariate model, LRC was favourably influenced by N-downstage, DFS by lower CRP and N-downstage, DSS by lower CRP and N-downstage and OS by lower TIMP-1 level, lower CRP and N-downstage.

Conclusions. Although we did not find any association between pretreatment serum TIMP-1 levels and primary tumour response to preoperative radiochemotherapy in our cohort of patients with rectal cancer, TIMP-1 levels were recognized as an independent prognostic factor for OS in these patients.

1. Kim DY, Jung KH, Kim TH, Kim DW, Chang HJ, Jeong JY, et al. Comparison of 5-fluorouracil/leucovorin and capecitabine in preoperative chemoradiotherapy for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2007; 67: 378-84.

2. Chan AK, Wong AO, Jenken DA. Preoperative capecitabine and pelvic radiation in locally advanced rectal cancer-is it equivalent to 5-FU infusion plus leucovorin and radiotherapy? Int J Radiat Oncol Biol Phys 2010; 76: 1413-9.

3. Velenik V, Ocvirk J, Oblak I, Anderluh F. Cetuximab in preoperative treatment of rectal cancer - term outcome of the XERT trial. Radiol Oncol 2012; 46: 252-7.

4. Pesta M, Topolcan O, Holubec L Jr, Rupert K, Cerna M, Holubec LS, et al. Clinicopathological assesment and quantitative estimation of the matrix metalloproteinases MMP-2 and MMP-7 and the inhibitors TIMP-1 and TIMP-2 in colorectal carcinoma tissue samples. Anticancer Res 2007; 27: 1863-7.

5. Li M, Yamamoto H, Adachi Y, Maruyama Y, Shinomura Y. Role of matrix metaloproteinase-7 (matrilysin) in human cancer invasion, apoptosis, growth and angiogenesis. Exp Biol Med 2006; 231: 20-7.

6. Giaginis C, Nikiteas N, Margeli A, Tzanakis N, Rallis G, Kouraklis G, et al. Serum tissue inhibitor of metalloproteinase 1 and 2 (TIMP-1 and TIMP-2) levels in colorectal cancer patients: association with clinicopathological variables and patients survival. Int J Biol Markers 2009; 24: 245-52.

7. Alo-Aho R, Kahari VM: Colagenases in cancer. Biochemie 2005; 87: 273-86.

8. Sørensen NM, Sørensen IV, Wűrtz SØ, Schrohl AS, Dowell B, Davis G, et al. Biology and potential clinical implications of tissue inhibitor of metalloproteinases-1 in colorectal cancer treatment. Scan J Gastroenterol 2008; 43: 774-86.

9. Frederiksen CB, Lomholt AF, Lottenburger T, Davis GJ, Dowell BL, Blankenstein MA, et al. Assesment of the biological variation of plasma tissue inhibitor of metalloproteinase-1. Int J of Biological Markers 2008; 23: 42-7.

10. Wass ET, Hendriks T, Lomme RM, Woblles T. Plasma levels of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 correlate with disease stage and survival in colorectal cancer patients. Dis Colon Rectum 2005; 48: 700-10.

11. Kahlert C, Bandapalli OR, Schirmacher P, Weitz J, Brand K. Invasion frontspecific overexpression of tissue inhibitor of metalloproteinase-1 in liver metastases from colorectal cancer. Anticancer Res 2008; 28: 1459-66.

12. Oblak I, Anderluh F, Velenik V, Mozina B, Ocvirk J, Ciric E, et al. Differences in plasma TIMP-1 levels between healthy people and patients with rectal cancer stage II-III. Radiol Oncol 2011; 45: 209-12.

13. Sørensen NM, Byström P, Christensen IJ, Berglund A, Nielsen HJ, Brüner N, et al. TIMP-1 is significantly associated with objective response and survival in metastatic colorectal cancer patients reciving combination of irinotecan, 5-fluorouracil, and folinic acid. Clin Cancer Res 2007; 13: 4117-22.

14. Unsal D, Under A, Akyurek N, Erpolat P, Dursun A, Pak Y. Matrix metalloproteinase-9 expression correlates with tumor response in patients with locally advanced rectal cancer undergoing preoperative chemoradiotherapy. Int JRadiol Oncol Biol Phys 2007; 67: 196-203.

15. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457-81.

16. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples. Br J Cancer 1977; 35: 1-39.

17. Cox DR. Regression models and life-tables. J R Stat Soc Bull 1972; 34: 187-220.

18. Holten-Andersen MN, Nielsen HJ, Sørensen S, Jensen V, Brűner N, Christensen IJ. Tissue inhibitor of metalloproteinases-1 in the postoperative monitoring of colorectal cancer. Eur J Cancer 2006; 42: 1886-96.

19. Yakawa N, Yoshikawa T, Akaike M, Sugimasa Y, Rino Y, Masuda M, et al. Impact of plasma tissue inhibitor of matrix metalloproteinase-1 on longterm survival in patients with colorectal cancer. Oncology 2007; 72: 205-8.

20. Velenik V, Oblak I, Anderluh F. Long-term results from a randomized phase II trial of neoadjuvant combined-modality therapy for locally advanced rectal cancer. Radiat Oncol 2010; 5: 88-96.

21. Dunst J, Debus J, Rudat V, Wulf J, Budach W, Hoelscher T, et al. Neoadjuvant capecitabine combined with standard radiotherapy in patients with locally advanced rectal cancer: mature results of a phase II trial. StrachlentherOncol 2008; 184: 450-6.

22. Holten-Anderson MN, Christensen IJ, Nielsen HJ, Lilja H, Murphy G, Jensen V, et al. Measurement of the non-complex free fraction of tissue inhibitor of metalloproteinases I in plasma by immunoassay. Clin Chem 2002; 48: 1305-13.

23. Holten-Anderson M, Christensen IJ, Nilberg M, Bendahl PO, Nielsen HJ, Brűnner N, et al. Association between preoperative plasma levels of tissue inhibitor of metalloproteinases 1 and rectal cancer patient survival: a validation study. Eur J of Cancer 2004; 40: 64-72.

24. Ishida H, Murata N, Hayashi Y, Tada M, Hashimoto D. Serum levels of tissue inhibitor of metalloproteinases-1 (TIMP- 1) in colorectal cancer patients. Surg Today 2003; 33: 885-92.

25. Tayebjee MH, Lip GYH, Blann AD, MacFadyen RJ. Effects of age, gender, ethnicity, diurnal variations and exercise on circulating levels of matrix metalloproteinases (MMP)-2 and-9, and their inhibitors, tissue inhibitors of matrix metalloproteinases (TIMP)-1 and -2. Thromb Res 2005; 115: 205-10.

26. Duffy MJ, van Dalen A, Haglund C, Hansson L, Klapdor R, Lamerz R, et al. Clinical utility of biochemical markers in colorectal cancer: European Group on Tumour Markers (EGTM) guidelines. Eur J Cancer 2003; 39: 718-27.

27. Sprenger T, Rothe H, Jung K, Christiansen H, Conradi LC, Ghadimi BM, et al. Stage II/III rectal cancer with intermediate response to preoperative radiochemotherapy: do we have indications for individual risk stratification? World J Surg Oncol 2010; 8: 27.

28. Laohavinij S, Maneechavakaiorn J, Techatanol P. Prognostic factors for survival in colorectal cancer patients. J Med Assoc Thai 2010; 93: 1156-66.

Radiology and Oncology

The Journal of Association of Radiology and Oncology

Journal Information

IMPACT FACTOR 2017: 1.722
5-year IMPACT FACTOR: 1.729

CiteScore 2017: 1.84

SCImago Journal Rank (SJR) 2017: 0.574
Source Normalized Impact per Paper (SNIP) 2017: 0.814

Cited By


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 122 122 10
PDF Downloads 18 18 2