Annals of Surgical Oncology

, 15:2120 | Cite as

Persistent Presence of Postoperative Circulating Tumor Cells is a Poor Prognostic Factor for Patients with Stage I–III Colorectal Cancer after Curative Resection

  • Yih-Huei Uen
  • Chien-Yu Lu
  • Hsiang-Lin Tsai
  • Fang-Jung Yu
  • Ming-Yii Huang
  • Tian-Lu Cheng
  • Shiu-Ru Lin
  • Jaw-Yuan Wang
Gastrointestinal Oncology

Abstract

Aim

To detect pre- and postoperative circulating tumor cells (CTCs) in stage I–III colorectal cancer (CRC) patients undergoing curative resection and so identify a subgroup of patients who are at high risk for relapse.

Methods

Four mRNA molecular markers including human telomerase reverse transcriptase, cytokeratin-19, cytokeratin-20, and carcinoembryonic antigen mRNA were used to detect CTCs in 438 CRC patients underwent curative resection.

Results

Out of 438 patients, 80 CRC patients were classified to preoperative (−)/postoperative (−), 221 patients were preoperative (+)/postoperative (−), while 137 patients were preoperative (+)/postoperative (+). Univariately, postoperative relapse was significantly correlated with depth of invasion (P = 0.032), lymph node metastasis (P < 0.001), vascular invasion (P = 0.001), perineural invasion (P = 0.013), and persistent presence of CTCs (P < 0.001). Using a multivariate proportional hazards regression analysis, the presence of lymph node metastasis (P = 0.012; HR, 7.652; 95% CI: 4.162–14.827), vascular invasion (P = 0.033; HR, 4.360; 95% CI: 2.793–10.847), and the persistent presence of CTCs (P < 0.001; HR, 29.486; 95% CI: 10.281–87.792) were demonstrated to be independent predictors for postoperative relapse. Combination of these three independent predictors showed that patients with any one positive predictor had a hazard ratio of sevenfold to develop postoperative relapse (P < 0.001; HR, 7.064; 95% CI: 4.354–11.464). Furthermore, the persistent presence of CTCs was strongly correlated with poorer relapse-free survival rates (all P < 0.001).

Conclusion

The promising results of this study suggest that persistent presence of postoperative CTCs may be a crucial prognostic factor adjuvant to conventional tumor markers in CRC patients who have undergone curative resection. Identification of these high-risk patients of persistent CTCs positivity is important and thus could help to define patients for adjuvant therapy with this tumor entity.

Keywords

Circulating tumor cells Molecular markers Colorectal cancer Prognosis Postoperative surveillance 

Notes

Acknowledgements

The authors would like to thank Drs. Jan-Sing Hsieh, Deng-Chyang Wu, Yu-Chung Su, Jeng-Yih Wu, and Che-Jen Huang for contributing materially to the paper. This study was supported by a grant from the Chi Mei Medical Center and Kaohsiung Medical University Research Foundation (97CM-KMU-03).

References

  1. 1.
    http://www.doh.gov.tw/statistic/index.htm; last accessed: September 2007
  2. 2.
    Byers T, Levin B, Rothenberger D, et al. American Cancer Society guidelines for screening and surveillance for early detection of colorectal polyps and cancer: update 1997. American Cancer Society Detection and Treatment Advisory Group on Colorectal Cancer. CA Cancer J Clin 1997; 47:154–60PubMedCrossRefGoogle Scholar
  3. 3.
    Mandel JS, Church TR, Bond JH, et al. The effect of fecal occult-blood screening on the incidence of colorectal cancer. N Engl J Med 2000; 343:1603–7PubMedCrossRefGoogle Scholar
  4. 4.
    Smith RA, Cokkinides V, Eyre HJ. Cancer screening in the United States, 2007: a review of current guidelines, practices, and prospects. CA Cancer J Clin 2007; 57:90–104PubMedGoogle Scholar
  5. 5.
    Castells A, Bessa X, Daniels M, et al. Value of postoperative surveillance after radical surgery for colorectal cancer: results of a cohort study. Dis Colon Rectum 1998; 41:714–23PubMedCrossRefGoogle Scholar
  6. 6.
    Ghossein RA, Bhattacharya S. Molecular detection and characterisation of circulating tumour cells and micrometastases in solid tumours. Eur J Cancer 2000; 36:1681–94PubMedCrossRefGoogle Scholar
  7. 7.
    Ghossein RA, Bhattacharya S, Rosai J. Molecular detection of micrometastases and circulating tumor cells in solid tumors. Clin Cancer Res 1999; 5:1950–60PubMedGoogle Scholar
  8. 8.
    Weitz J, Kienle P, Lacroix J, et al. Dissemination of tumor cells in patients undergoing surgery for colorectal cancer. Clin Cancer Res 1998; 4:343–8PubMedGoogle Scholar
  9. 9.
    Wharton RQ, Jonas SK, Glover C, et al. Increased detection of circulating tumor cells in the blood of colorectal carcinoma patients using two reverse transcription-PCR assays and multiple blood samples. Clin Cancer Res 1999; 5:4158–63PubMedGoogle Scholar
  10. 10.
    Yamaguchi K, Takagi Y, Aoki S, et al. Significant detection of circulating cancer cells in the blood by reverse transcriptase-polymerase chain reaction during colorectal cancer resection. Ann Surg 2000; 232:58–65PubMedCrossRefGoogle Scholar
  11. 11.
    Patel H, Le Marer N, Wharton RQ, et al. Clearance of circulating tumor cells after excision of primary colorectal cancer. Ann Surg 2002; 235:226–31PubMedCrossRefGoogle Scholar
  12. 12.
    Wang JY, Wu CH, Lu CY, et al. Molecular detection of circulating tumor cells in the peripheral blood of patients with colorectal cancer using RT-PCR: significance in the prediction of postoperative metastasis. World J Surg 2006; 30:1007–13PubMedCrossRefGoogle Scholar
  13. 13.
    Hoon DS, Wang Y, Dale PS, et al. Detection of occult melanoma cells in blood with a multiple-marker polymerase chain reaction assay. J Clin Oncol 1995; 13:2109–16PubMedGoogle Scholar
  14. 14.
    Racila E, Euhus D, Weiss AJ, et al. Detection and characterization of carcinoma cells in the blood. Proc Natl Acad Sci USA 1998; 95:4589–94PubMedCrossRefGoogle Scholar
  15. 15.
    Baker MK, Mikhitarian K, Osta W, et al. Molecular detection of breast cancer cells in the peripheral blood of advanced-stage breast cancer patients using multimarker real-time reverse transcription-polymerase chain reaction and a novel porous barrier density gradient centrifugation technology. Clin Cancer Res 2003; 9:4865–71PubMedGoogle Scholar
  16. 16.
    Sher YP, Shih JY, Yang PC, et al. Prognosis of non-small cell lung cancer patients by detecting circulating cancer cells in the peripheral blood with multiple marker genes. Clin Cancer Res 2005; 11:173–9PubMedGoogle Scholar
  17. 17.
    Chen YF, Wang JY, Wu CH, et al. Detecting circulating cancer cells with K-ras oncogene using membrane array. Cancer Lett 2005; 229:115–22PubMedCrossRefGoogle Scholar
  18. 18.
    Wang JY, Yeh CS, Chen YF, et al. Development and evaluation of a colorimetric membrane-array method for the detection of circulating tumor cells in the peripheral blood of Taiwanese patients with colorectal cancer. Int J Mol Med 2006; 17:737–47PubMedGoogle Scholar
  19. 19.
    Yeh CS, Wang JY, Wu CH, et al. Molecular detection of circulating cancer cells in the peripheral blood of patients with colorectal cancer by using membrane array with a multiple mRNA marker panel. Int J Oncol 2006; 28:411–20PubMedGoogle Scholar
  20. 20.
    Wang JY, Lin SR, Wu DC, et al. Multiple molecular markers as predictors of colorectal cancer in patients with normal peri-operative serum CEA levels. Clin Cancer Res 2007; 13:2406–13PubMedCrossRefGoogle Scholar
  21. 21.
    International Union Against Cancer. TNM classification of malignant tumors, 6th edition. New York: Wiley-Liss, Inc., 2002Google Scholar
  22. 22.
    Wu CH, Lin SR, Yu FJ, et al. Development of a high-throughput membrane-array method for molecular diagnosis of circulating tumor cells in patients with gastric cancers. Int J Cancer 2006; 119:373–9PubMedCrossRefGoogle Scholar
  23. 23.
    Uen YH, Lin SR, Wu DC, et al. Prognostic significance of multiple molecular markers for patients with stage II colorectal cancer undergoing curative resection. Ann Surg 2007; 246:1040–6PubMedCrossRefGoogle Scholar
  24. 24.
    Iinuma H, Okinaga K, Egami H, et al. Usefulness and clinical significance of quantitative real-time RT-PCR to detect isolated tumor cells in the peripheral blood and tumor drainage blood of patients with colorectal cancer. Int J Oncol 2006; 28:297–306PubMedGoogle Scholar
  25. 25.
    Guller U, Zajac P, Schnider A, et al. Disseminated single tumor cells as detected by real-time quantitative polymerase chain reaction represent a prognostic factor in patients undergoing surgery for colorectal cancer. Ann Surg 2002; 236:768–75PubMedCrossRefGoogle Scholar
  26. 26.
    Liefers GJ, Cleton-Jansen AM, van de Velde CJ, et al. Micrometastases and survival in stage II colorectal cancer. N Engl J Med 1998; 339:223–8PubMedCrossRefGoogle Scholar
  27. 27.
    Koch M, Kienle P, Kastrati D, et al. Prognostic impact of hematogenous tumor cell dissemination in patients with stage II colorectal cancer. Int J Cancer 2006; 118:3072–7PubMedCrossRefGoogle Scholar
  28. 28.
    Bessa X, Elizalde JI, Boix L, et al. Lack of prognostic influence of circulating tumor cells in peripheral blood of patients with colorectal cancer. Gastroenterology 2001; 120:1084–92PubMedCrossRefGoogle Scholar
  29. 29.
    Bosch B, Guller U, Schnider A, et al. Perioperative detection of disseminated tumor cells is an independent prognostic factor in patients with colorectal cancer. Br J Surg 2003; 90:882–8PubMedCrossRefGoogle Scholar
  30. 30.
    Khair G, Monson JR, Greenman J. Epithelial molecular markers in the peripheral blood of patients with colorectal cancer. Dis Colon Rectum 2007; 50:1188–203PubMedCrossRefGoogle Scholar
  31. 31.
    Fidler IJ. Metastasis: quantitative analysis of distribution and fate of tumor emboli labeled with 125 I-5-iodo–2′-deoxyuridine. J Natl Cancer Inst 1970; 45:773–82PubMedGoogle Scholar
  32. 32.
    Sadahiro S, Suzuki T, Maeda Y, et al. Detection of carcinoembryonic antigen messenger RNA-expressing cells in peripheral blood 7 days after curative surgery is a novel prognostic factor in colorectal cancer. Ann Surg Oncol 2007; 14:1092–8PubMedCrossRefGoogle Scholar
  33. 33.
    Allen-Mersh TG, McCullough TK, Patel H, et al. Role of circulating tumour cells in predicting recurrence after excision of primary colorectal carcinoma. Br J Surg 2007; 94:96–105PubMedCrossRefGoogle Scholar
  34. 34.
    Silva JM, Rodriguez R, Garcia JM, et al. Detection of epithelial tumour RNA in the plasma of colon cancer patients is associated with advanced stages and circulating tumour cells. Gut 2002; 50:530–4PubMedCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2008

Authors and Affiliations

  • Yih-Huei Uen
    • 1
  • Chien-Yu Lu
    • 2
  • Hsiang-Lin Tsai
    • 3
    • 4
  • Fang-Jung Yu
    • 2
  • Ming-Yii Huang
    • 5
    • 6
  • Tian-Lu Cheng
    • 7
  • Shiu-Ru Lin
    • 8
  • Jaw-Yuan Wang
    • 4
    • 6
  1. 1.Division of General Surgery, Department of SurgeryChi Mei Foundation Medical Center, Taipei Medical UniversityTaipeiTaiwan
  2. 2.Department of Internal MedicineKaohsiung Medical University Hospital, Kaohsiung Medical UniversityKaohsiungTaiwan
  3. 3.Department of Emergency MedicineKaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical UniversityKaohsiungTaiwan
  4. 4.Department of SurgeryKaohsiung Medical University Hospital, Kaohsiung Medical UniversityKaohsiungTaiwan
  5. 5.Department of Radiation OncologyKaohsiung Medical University Hospital, Kaohsiung Medical UniversityKaohsiungTaiwan
  6. 6.Faculty of Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
  7. 7.Faculty of Biomedical Science and Environmental Biology, College of Life ScienceKaohsiung Medical UniversityKaohsiungTaiwan
  8. 8.Department of Medical ResearchFooyin University HospitalKaohsiungTaiwan

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