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Annals of Surgical Oncology

, Volume 22, Issue 12, pp 4029–4037 | Cite as

Detection of Circulating Tumor Cells at Surgery and at Follow-Up Assessment to Predict Survival After Two-Stage Liver Resection of Colorectal Liver Metastases

  • Kristoffer Watten BrudvikEmail author
  • Lars Thomas Seeberg
  • Harald Hugenschmidt
  • Anne Renolen
  • Cecilie Bendigtsen Schirmer
  • Cathrine Brunborg
  • Bjørn Atle Bjørnbeth
  • Elin Borgen
  • Bjørn Naume
  • Anne Waage
  • Gro Wiedswang
Hepatobiliary Tumors

Abstract

Background

The presence of circulating tumor cells (CTCs) is negatively associated with survival after resection of colorectal liver metastases (CLM). The current study aimed to determine the prognostic value of CTCs and disseminated tumor cells (DTCs) at the time of surgery and the prognostic value of CTCs at follow-up assessment, for patients scheduled to undergo two-stage hepatectomy with portal vein embolization (PVE) for CLM.

Methods

Samples were collected at surgery (blood and bone marrow) and at follow-up assessment (blood) for the period 2008 through 2011. In this study, CTCs were detected with the CellSearch system, and DTCs were detected using standard immunocytochemical analysis.

Results

Of 24 patients, 18 completed both stages, and no patients were lost to follow-up. The median overall survival (OS) was 37 months, and the median recurrence-free survival (RFS) was 7 months. At surgery, CTCs were found in nine patients (38 %), and their presence was associated with reduced OS (p < 0.001) and RFS (p = 0.006). Follow-up CTC status was available for 11 patients. All eight patients with positive CTC status experienced recurrence. Two of three patients with negative CTC status remained recurrence free. In seven patients (32 %), DTCs were detected but were not associated with OS or RFS.

Conclusions

The presence of CTCs at surgery is associated with worse OS and RFS for patients undergoing two-stage hepatectomy with PVE for CLM. Analysis of CTCs should be explored further for their potential to assist in treatment decisions and monitoring for CLM patients.

Keywords

Overall Survival Liver Resection Circulate Tumor Cell Colorectal Liver Metastasis Portal Vein Embolization 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgment

Kristoffer Watten Brudvik was awarded the Unger-Vetlesen Medical Fund for 2014, and Lars Thomas Seeberg received founding from The Eckbo Foundation, The Finn Wilhelmsen Foundation, and The Blix Family Foundation.

Conflict of interest

There are no conflicts of interest.

References

  1. 1.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.CrossRefPubMedGoogle Scholar
  2. 2.
    Manfredi S, Lepage C, Hatem C, Coatmeur O, Faivre J, Bouvier AM. Epidemiology and management of liver metastases from colorectal cancer. Ann Surg. 2006;244:254–9.PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Adam R, De Gramont A, Figueras J, et al. The oncosurgery approach to managing liver metastases from colorectal cancer: a multidisciplinary international consensus. Oncologist. 2012;17:1225–39.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Alberts SR, Poston GJ. Treatment advances in liver-limited metastatic colorectal cancer. Clin Colorect Cancer. 2011;10:258–65.CrossRefGoogle Scholar
  5. 5.
    Gallagher DJ, Kemeny N. Improving response and outcomes for patients with liver-limited metastatic colorectal cancer. Clin Colorect Cancer. 2010;9(Suppl 1):S36–43.CrossRefGoogle Scholar
  6. 6.
    Adam R, Laurent A, Azoulay D, Castaing D, Bismuth H. Two-stage hepatectomy: a planned strategy to treat irresectable liver tumors. Ann Surg. 2000;232:777–85.PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Narita M, Oussoultzoglou E, Jaeck D, et al. Two-stage hepatectomy for multiple bilobar colorectal liver metastases. Br J Surg. 2011;98:1463–75.CrossRefPubMedGoogle Scholar
  8. 8.
    Aloia TA, Vauthey JN. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): what is gained and what is lost? Ann Surg. 2012;256:e9; author reply e16–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Schadde E, Ardiles V, Slankamenac K, et al. ALPPS offers a better chance of complete resection in patients with primarily unresectable liver tumors compared with conventional-staged hepatectomies: results of a multicenter analysis. World J Surg. 2014;38:1510–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Pantel K, Alix-Panabieres C, Riethdorf S. Cancer micrometastases. Nat Rev Clin Oncol. 2009;6:339–51.CrossRefPubMedGoogle Scholar
  11. 11.
    Cohen SJ, Punt CJ, Iannotti N, et al. Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:3213–21.CrossRefPubMedGoogle Scholar
  12. 12.
    Allen JE, El-Deiry WS. Circulating tumor cells and colorectal cancer. Curr Colorect Cancer Rep. 2010;6:212–20.CrossRefGoogle Scholar
  13. 13.
    Rahbari NN, Aigner M, Thorlund K, et al. Meta-analysis shows that detection of circulating tumor cells indicates poor prognosis in patients with colorectal cancer. Gastroenterology. 2010;138:1714–26.CrossRefPubMedGoogle Scholar
  14. 14.
    Tol J, Koopman M, Miller MC, et al. Circulating tumour cells early predict progression-free and overall survival in advanced colorectal cancer patients treated with chemotherapy and targeted agents. Ann Oncol. 2010;21:1006–12.CrossRefPubMedGoogle Scholar
  15. 15.
    Koerkamp BG, 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;20:2156–65.CrossRefGoogle Scholar
  16. 16.
    Negin BP, Cohen SJ. Circulating tumor cells in colorectal cancer: past, present, and future challenges. Curr Treat Options oncol. 2010;11:1–13.CrossRefPubMedGoogle Scholar
  17. 17.
    Seeberg LT, Waage A, Brunborg C, et al. Circulating tumor cells in patients with colorectal liver metastasis predict impaired survival. Ann Surg. 2015;261:164–71.CrossRefPubMedGoogle Scholar
  18. 18.
    Sharif S, O’Connell MJ, Yothers G, Lopa S, Wolmark N. FOLFOX and FLOX regimens for the adjuvant treatment of resected stage II and III colon cancer. Cancer Invest. 2008;26:956–63.PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Blazer DG III, Kishi Y, Maru DM, et al. Pathologic response to preoperative chemotherapy: a new outcome end point after resection of hepatic colorectal metastases. J Clin Oncol. 2008;6:5344–51.CrossRefGoogle Scholar
  20. 20.
    Rubbia-Brandt L, Giostra E, Brezault C, et al. Importance of histological tumor response assessment in predicting the outcome in patients with colorectal liver metastases treated with neo-adjuvant chemotherapy followed by liver surgery. Ann Oncol. 2007;18:299–304.CrossRefPubMedGoogle Scholar
  21. 21.
    Shindoh J, Loyer EM, Kopetz S, et al. Optimal morphologic response to preoperative chemotherapy: an alternate outcome end point before resection of hepatic colorectal metastases. J Clin Oncol. 2012;30:4566–72.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Riethdorf S, Fritsche H, Muller V, 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;13:920–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Allard WJ, Matera J, Miller MC, et al. 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;10:6897–904.CrossRefPubMedGoogle Scholar
  24. 24.
    Wiedswang G, Borgen E, Karesen R, et al. Detection of isolated tumor cells in bone marrow is an independent prognostic factor in breast cancer. J Clin Oncol. 2003;21:3469–78.CrossRefPubMedGoogle Scholar
  25. 25.
    Borgen E, Naume B, Nesland JM, et al. Use of automated microscopy for the detection of disseminated tumor cells in bone marrow samples. Cytometry. 2001;46:215–21.CrossRefPubMedGoogle Scholar
  26. 26.
    Borgen E, Naume B, Nesland JM, et al. Standardization of the immunocytochemical detection of cancer cells in BM and blood: I. establishment of objective criteria for the evaluation of immunostained cells. Cytotherapy. 1999;1:377–88.CrossRefPubMedGoogle Scholar
  27. 27.
    Fehm T, Braun S, Muller V, et al. A concept for the standardized detection of disseminated tumor cells in bone marrow from patients with primary breast cancer and its clinical implementation. Cancer. 2006;107:885–92.CrossRefPubMedGoogle Scholar
  28. 28.
    Cohen SJ, Punt CJ, Iannotti N, et al. Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer. Ann Oncol. 2009;20:1223–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Zakaria S, Donohue JH, Que FG, et al. Hepatic resection for colorectal metastases: value for risk scoring systems? Ann Surg. 2007;246:183–91.PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Spolverato G, Ejaz A, Azad N, Pawlik TM. Surgery for colorectal liver metastases: the evolution of determining prognosis. World J Gastrointest Oncol. 2013;5:207–21.PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Katz SC, Pillarisetty V, Bamboat ZM, et al. T cell infiltrate predicts long-term survival following resection of colorectal cancer liver metastases. Ann Surg Oncol. 2009;16:2524–30.CrossRefPubMedGoogle Scholar
  32. 32.
    Vauthey JN, Zimmitti G, Kopetz SE, et al. RAS mutation status predicts survival and patterns of recurrence in patients undergoing hepatectomy for colorectal liver metastases. Ann Surg. 2013;258:619–26; discussion 26–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Kaifi JT, Kunkel M, Zhu J, et al. Circulating tumor cells are associated with diffuse spread in stage IV colorectal cancer patients. Cancer Biol Ther. 2013;14:1174–81.PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Pamecha V, Levene A, Grillo F, Woodward N, Dhillon A, Davidson BR. Effect of portal vein embolisation on the growth rate of colorectal liver metastases. Br J Cancer. 2009;100:617–22.PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Alix-Panabieres C, Pantel K. Challenges in circulating tumour cell research. Nat Rev Cancer. 2014;0(14):623–31.CrossRefGoogle Scholar
  36. 36.
    Kokudo N, Tada K, Seki M, et al. Proliferative activity of intrahepatic colorectal metastases after preoperative hemihepatic portal vein embolization. Hepatology. 2001;34:267–72.CrossRefPubMedGoogle Scholar
  37. 37.
    Hoekstra LT, van Lienden KP, Doets A, Busch OR, Gouma DJ, van Gulik TM. Tumor progression after preoperative portal vein embolization. Ann Surg. 2012;256:812–7; discussion 7–8.CrossRefPubMedGoogle Scholar
  38. 38.
    Abdalla EK. Portal vein embolization (prior to major hepatectomy) effects on regeneration, resectability, and outcome. J Surg Oncol. 2010;102:960–7.CrossRefPubMedGoogle Scholar
  39. 39.
    van Gulik TM, van den Esschert JW, de Graaf W, et al. Controversies in the use of portal vein embolization. Dig Surg. 2008;25:436–44.CrossRefPubMedGoogle Scholar
  40. 40.
    Wallwiener M, Riethdorf S, Hartkopf AD, et al. Serial enumeration of circulating tumor cells predicts treatment response and prognosis in metastatic breast cancer: a prospective study in 393 patients. BMC Cancer. 2014;14:512.PubMedCentralCrossRefPubMedGoogle Scholar
  41. 41.
    Gazzaniga P, Raimondi C, Gradilone A, et al. Circulating tumor cells in metastatic colorectal cancer: do we need an alternative cutoff? J Cancer Res Clin Oncol. 2013;139:1411–6.CrossRefPubMedGoogle Scholar

Copyright information

© Society of Surgical Oncology 2015

Authors and Affiliations

  • Kristoffer Watten Brudvik
    • 1
    • 2
    Email author
  • Lars Thomas Seeberg
    • 2
    • 6
  • Harald Hugenschmidt
    • 2
  • Anne Renolen
    • 3
  • Cecilie Bendigtsen Schirmer
    • 3
  • Cathrine Brunborg
    • 5
  • Bjørn Atle Bjørnbeth
    • 1
    • 2
  • Elin Borgen
    • 3
  • Bjørn Naume
    • 4
    • 7
  • Anne Waage
    • 1
  • Gro Wiedswang
    • 2
  1. 1.Department of Hepato-Pancreatico-Biliary SurgeryOslo University HospitalOsloNorway
  2. 2.Department of Gastrointestinal SurgeryOslo University HospitalOsloNorway
  3. 3.Department of PathologyOslo University HospitalOsloNorway
  4. 4.Department of OncologyOslo University HospitalOsloNorway
  5. 5.Department of Biostatistics and EpidemiologyOslo University HospitalOsloNorway
  6. 6.Department of Gastrointestinal SurgeryVestfold Hospital TrustTønsbergNorway
  7. 7.Institute of Clinical MedicineUniversity of OsloOsloNorway

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