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Published in: BMC Cancer 1/2017

Open Access 01-12-2017 | Research article

Prognostic and clinicopathological significance of circulating tumor cells detected by RT-PCR in non-metastatic colorectal cancer: a meta-analysis and systematic review

Authors: Chaogang Yang, Kun Zou, Liang Zheng, Bin Xiong

Published in: BMC Cancer | Issue 1/2017

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Abstract

Background

Circulating tumor cells (CTCs) have been accepted as a prognostic marker in patients with metastatic colorectal cancer (mCRC, UICC stage IV). However, the prognostic value of CTCs in patients with non-metastatic colorectal cancer (non-mCRC, UICC stage I-III) still remains in dispute. A meta-analysis was performed to investigate the prognostic significance of CTCs detected by the RT-PCR method in patients diagnosed with non-mCRC patients.

Methods

A comprehensive literature search for relevant articles was performed in the EmBase, PubMed, Ovid, Web of Science, Cochrane library and Google Scholar databases. The studies were selected according to predetermined inclusion/exclusion criteria. Using the random-effects model of Stata software, version12.0 (2011) (Stata Corp, College Station, TX, USA), to conduct the meta-analysis, and the hazard ratio (HR), risk ratio (RR) and their 95% confidence intervals (95% CIs) were regarded as the effect measures. Subgroup analyses and meta-regression were also conducted to clarify the heterogeneity.

Results

Twelve eligible studies, containing 2363 patients with non-mCRC, were suitable for final analyses. The results showed that the overall survival (OS) (HR = 3.07, 95% CI: [2.05–4.624], P < 0.001; I2 = 55.7%, P = 0.008) and disease-free survival (DFS) (HR = 2.58, 95% CI: [2.00–3.32], P < 0.001; I2 = 34.0%, P = 0.085) were poorer in patients with CTC-positive, regardless of the sampling time, adjuvant therapy and TNM stage. CTC-positive was also significantly associated with regional lymph nodes (RLNs) metastasis (RR = 1.62, 95% CI: [1.17–2.23], P = 0.003; I2 = 74.6%, P<0.001), depth of infiltration (RR = 1.41, 95% CI: [1.03–1.92], P = 0.03; I2 = 38.3%, P = 0.136), vascular invasion (RR = 1.66, 95% CI: [1.17–2.36], P = 0.004; I2 = 46.0%, P = 0.135), tumor grade (RR = 1.19, 95% CI: [1.02–1.40], P = 0.029; I2 = 0%, P = 0.821) and tumor-node-metastasis (TNM) stage(I, II versus III) (RR = 0.76, 95% CI 0.71–0.81, P < 0.001; I2 = 0%, P = 0.717). However, there was no significant relationship between CTC-positive and tumor size (RR = 1.08, 95% CI: [0.94–1.24], P = 0.30; I2 = 0%, P = 0.528).

Conclusions

Detection of CTCs by RT-PCR method has prognostic value for non-mCRC patients, and CTC-positive was associated with poor prognosis and poor clinicopathological prognostic factors. However, the prognostic value of CTCs supports the use of CTCs as an indicator of metastatic disease prior to the current classification of mCRC meaning it is detectable by CT/MRI.

Literature
  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.View ArticlePubMed
  2. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–32.View ArticlePubMed
  3. Edwards BK, Ward E, Kohler BA, Eheman C, Zauber AG, Anderson RN, Jemal A, Schymura MJ, Lansdorp-Vogelaar I, Seeff LC, et al. Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer. 2010;116(3):544–73.View ArticlePubMedPubMed Central
  4. Hayashi M, Inoue Y, Komeda K, Shimizu T, Asakuma M, Hirokawa F, Miyamoto Y, Okuda J, Takeshita A, Shibayama Y, et al. Clinicopathological analysis of recurrence patterns and prognostic factors for survival after hepatectomy for colorectal liver metastasis. BMC Surg. 2010;10:27.View ArticlePubMedPubMed Central
  5. Fidler IJ. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev Cancer. 2003;3(6):453–8.View ArticlePubMed
  6. Ashworth T. A case of cancer in which cells similar to those in the tumours were seen in the blood after death. Aust Med J. 1869;14(3):146–9.
  7. Engell HC. Cancer cells in the circulating blood; a clinical study on the occurrence of cancer cells in the peripheral blood and in venous blood draining the tumour area at operation. Acta chirurgica Scandinavica Supplementum. 1955;201:1–70.PubMed
  8. Pantel K, Alix-Panabieres C. Circulating tumour cells in cancer patients: challenges and perspectives. Trends Mol Med. 2010;16(9):398–406.View ArticlePubMed
  9. Tibbe AG, Miller MC, Terstappen LW. Statistical considerations for enumeration of circulating tumor cells. Cytometry Part A. 2007;71(3):154–62.View Article
  10. Paterlini-Brechot P, Benali NL. Circulating tumor cells (CTC) detection: clinical impact and future directions. Cancer Lett. 2007;253(2):180–204.View ArticlePubMed
  11. Seeberg LT, Waage A, Brunborg C, Hugenschmidt H, Renolen A, Stav I, Bjornbeth BA, Brudvik KW, Borgen EF, Naume B, et al. Circulating tumor cells in patients with colorectal liver metastasis predict impaired survival. Ann Surg. 2015;261(1):164–71.View ArticlePubMed
  12. Aggarwal C, Meropol NJ, Punt CJ, Iannotti N, Saidman BH, Sabbath KD, Gabrail NY, Picus J, Morse MA, Mitchell E, et al. Relationship among circulating tumor cells, CEA and overall survival in patients with metastatic colorectal cancer. Ann Oncol. 2013;24(2):420–8.View ArticlePubMed
  13. Sotelo MJ, Sastre J, Maestro ML, Veganzones S, Vieitez JM, Alonso V, Gravalos C, Escudero P, Vera R, Aranda E, et al. Role of circulating tumor cells as prognostic marker in resected stage III colorectal cancer. Ann Oncol. 2015;26(3):535–41.View ArticlePubMed
  14. Kuboki Y, Matsusaka S, Minowa S, Shibata H, Suenaga M, Shinozaki E, Mizunuma N, Ueno M, Yamaguchi T, Hatake K. Circulating tumor cell (CTC) count and epithelial growth factor receptor expression on CTCs as biomarkers for cetuximab efficacy in advanced colorectal cancer. Anticancer Res. 2013;33(9):3905–10.PubMed
  15. Bork U, Rahbari NN, Scholch S, Reissfelder C, Kahlert C, Buchler MW, Weitz J, Koch M. Circulating tumour cells and outcome in non-metastatic colorectal cancer: a prospective study. Br J Cancer. 2015;112(8):1306–13.View ArticlePubMedPubMed Central
  16. Zhe X, Cher ML, Bonfil RD. Circulating tumor cells: finding the needle in the haystack. Am J Cancer Res. 2011;1(6):740–51.PubMedPubMed Central
  17. Riethdorf S, Fritsche H, Muller V, Rau T, Schindlbeck C, Rack B, Janni W, Coith C, Beck K, Janicke F, et al. Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: a validation study of the CellSearch system. Clin Cancer Res. 2007;13(3):920–8.View ArticlePubMed
  18. Allard WJ, Matera J, Miller MC, Repollet M, Connelly MC, Rao C, Tibbe AG, Uhr JW, Terstappen LW. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res. 2004;10(20):6897–904.View ArticlePubMed
  19. Shimada R, Iinuma H, Akahane T, Horiuchi A, Watanabe T. Prognostic significance of CTCs and CSCs of tumor drainage vein blood in Dukes' stage B and C colorectal cancer patients. Oncol Rep. 2012;27(4):947–53.View ArticlePubMedPubMed Central
  20. Kust D, Samija I, Kirac I, Radic J, Kovacevic D, Kusic Z. Cytokeratin 20 positive cells in blood of colorectal cancer patients as an unfavorable prognostic marker. Acta Clin Belg. 2016;71(4):235–43.View ArticlePubMed
  21. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:16.View ArticlePubMedPubMed Central
  22. Smith T, Smith B, Ryan MA. Survival analysis using Cox proportional hazards modeling for single and multiple event time data. In: Proceedings of the twenty-eighth annual SAS users group international conference, SAS Institute, inc, Cary, paper; 2003. p. 228–54.
  23. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603–5.View ArticlePubMed
  24. Schmidt FL, Oh IS, Hayes TL. Fixed- versus random-effects models in meta-analysis: model properties and an empirical comparison of differences in results. The British journal of mathematical and statistical psychology. 2009;62(Pt 1):97–128.View ArticlePubMed
  25. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539.View ArticlePubMed
  26. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34.View ArticlePubMedPubMed Central
  27. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50(4):1088–101.View ArticlePubMed
  28. Liu Y, Qian J, Feng JG, Ju HX, Zhu YP, Feng HY, Li DC. Detection of circulating tumor cells in peripheral blood of colorectal cancer patients without distant organ metastases. Cell Oncol. 2013;36(1):43–53.View Article
  29. Yokobori T, Iinuma H, Shimamura T, Imoto S, Sugimachi K, Ishii H, Iwatsuki M, Ota D, Ohkuma M, Iwaya T, et al. Plastin3 is a novel marker for circulating tumor cells undergoing the epithelial-mesenchymal transition and is associated with colorectal cancer prognosis. Cancer Res. 2013;73(7):2059–69.View ArticlePubMed
  30. Iinuma H, Watanabe T, Mimori K, Adachi M, Hayashi N, Tamura J, Matsuda K, Fukushima R, Okinaga K, Sasako M, et al. Clinical significance of circulating tumor cells, including cancer stem-like cells, in peripheral blood for recurrence and prognosis in patients with Dukes' stage B and C colorectal cancer. J Clin Oncol. 2011;29(12):1547–55.View ArticlePubMed
  31. Uen YH, CY L, Tsai HL, FJ Y, Huang MY, Cheng TL, Lin SR, Wang JY. Persistent presence of postoperative circulating tumor cells is a poor prognostic factor for patients with stage I-III colorectal cancer after curative resection. Ann Surg Oncol. 2008;15(8):2120–8.View ArticlePubMed
  32. Barreto G, Neve R, Shrikhande SV, Shukla PJ. Role of circulating tumour cells in predicting recurrence after excision of primary colorectal carcinoma (Br J Surg 2007; 94: 96-105). Br J Surg. 2007;94(5):644. author reply 644-645View ArticlePubMed
  33. Koch M, Kienle P, Kastrati D, Antolovic D, Schmidt J, Herfarth C, von Knebel Doeberitz M, Weitz J. Prognostic impact of hematogenous tumor cell dissemination in patients with stage II colorectal cancer. Int J Cancer. 2006;118(12):3072–7.View ArticlePubMed
  34. Lloyd JM, McIver CM, Stephenson SA, Hewett PJ, Rieger N, Hardingham JE. Identification of early-stage colorectal cancer patients at risk of relapse post-resection by immunobead reverse transcription-PCR analysis of peritoneal lavage fluid for malignant cells. Clin Cancer Res. 2006;12(2):417–23.View ArticlePubMed
  35. Sadahiro S, Suzuki T, Ishikawa K, Saguchi T, Maeda Y, Yasuda S, Makuuchi H, Yurimoto S, Murayama C. Detection of carcinoembryonic antigen messenger RNA-expressing cells in portal and peripheral blood during surgery does not influence relapse in colorectal cancer. Ann Surg Oncol. 2005;12(12):988–94.View ArticlePubMed
  36. Bessa X, Pinol V, Castellvi-Bel S, Piazuelo E, Lacy AM, Elizalde JI, Pique JM, Castells A. Prognostic value of postoperative detection of blood circulating tumor cells in patients with colorectal cancer operated on for cure. Ann Surg. 2003;237(3):368–75.PubMedPubMed Central
  37. Ito S, Nakanishi H, Hirai T, Kato T, Kodera Y, Feng Z, Kasai Y, Ito K, Akiyama S, Nakao A, et al. Quantitative detection of CEA expressing free tumor cells in the peripheral blood of colorectal cancer patients during surgery with real-time RT-PCR on a LightCycler. Cancer Lett. 2002;183(2):195–203.View ArticlePubMed
  38. Treanor D, Quirke P. Pathology of colorectal cancer. Clin Oncol. 2007;19(10):769–76.View Article
  39. Sargent D, Sobrero A, Grothey A, O'Connell MJ, Buyse M, Andre T, Zheng Y, Green E, Labianca R, O'Callaghan C, et al. Evidence for cure by adjuvant therapy in colon cancer: observations based on individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol. 2009;27(6):872–7.View ArticlePubMedPubMed Central
  40. Gunderson LL, Jessup JM, Sargent DJ, Greene FL, Stewart A. Revised tumor and node categorization for rectal cancer based on surveillance, epidemiology, and end results and rectal pooled analysis outcomes. J Clin Oncol. 2010;28(2):256–63.View ArticlePubMed
  41. Groot Koerkamp B, Rahbari NN, Buchler MW, Koch M, Weitz J. Circulating tumor cells and prognosis of patients with resectable colorectal liver metastases or widespread metastatic colorectal cancer: a meta-analysis. Ann Surg Oncol. 2013;20(7):2156–65.View ArticlePubMed
  42. Peach G, Kim C, Zacharakis E, Purkayastha S, Ziprin P. Prognostic significance of circulating tumour cells following surgical resection of colorectal cancers: a systematic review. Br J Cancer. 2010;102(9):1327–34.View ArticlePubMedPubMed Central
  43. Huang X, Gao P, Song Y, Sun J, Chen X, Zhao J, Xu H, Wang Z. Meta-analysis of the prognostic value of circulating tumor cells detected with the CellSearch system in colorectal cancer. BMC Cancer. 2015;15:202.View ArticlePubMedPubMed Central
  44. Weitz J, Kienle P, Lacroix J, Willeke F, Benner A, Lehnert T, Herfarth C, von Knebel Doeberitz M. Dissemination of tumor cells in patients undergoing surgery for colorectal cancer. Clin Cancer Res. 1998;4(2):343–8.PubMed
  45. Ikeguchi M, Kaibara N. Detection of circulating cancer cells after a gastrectomy for gastric cancer. Surg Today. 2005;35(6):436–41.View ArticlePubMed
  46. Wicha MS, Hayes DF. Circulating tumor cells: not all detected cells are bad and not all bad cells are detected. J Clin Oncol. 2011;29(12):1508–11.View ArticlePubMed
  47. Pham B, Klassen TP, Lawson ML, Moher D. Language of publication restrictions in systematic reviews gave different results depending on whether the intervention was conventional or complementary. J Clin Epidemiol. 2005;58(8):769–76.View ArticlePubMed
Metadata
Title
Prognostic and clinicopathological significance of circulating tumor cells detected by RT-PCR in non-metastatic colorectal cancer: a meta-analysis and systematic review
Authors
Chaogang Yang
Kun Zou
Liang Zheng
Bin Xiong
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3704-8

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