Annals of Surgical Oncology

, Volume 14, Issue 9, pp 2577–2590 | Cite as

Update of Carcinoembryonic Antigen Radioimmunotherapy with 131I-Labetuzumab After Salvage Resection of Colorectal Liver Metastases: Comparison of Outcome to a Contemporaneous Control Group

  • Torsten Liersch
  • Johannes Meller
  • Michael Bittrich
  • Bettina Kulle
  • Heinz Becker
  • David M. Goldenberg



We tested whether adjuvant radioimmunotherapy (RAIT) given after R0 resection of liver metastases (LM) of colorectal cancer is safe and can improve survival. Resection of LM from colorectal cancer is the standard of care in this setting, yet two thirds will eventually relapse, and adjuvant systemic chemotherapy has failed to improve survival.


Twenty-three patients who underwent R0 resection for LM of colorectal cancer received a dose of 40 to 60 mCi/m2131I-labetuzumab, a humanized monoclonal antibody against carcinoembryonic antigen. Safety (n = 23), disease-free survival, and overall survival (n = 19) were analyzed, and efficacy was then compared retrospectively with a similar contemporaneous group of control patients (n = 19) treated at the same institution during the same time period but without RAIT.


At a median follow-up of 91 months (95% confidence interval [CI], 68.0 months to infinity), the median overall survival for RAIT patients was 58.0 months (95% CI, 55.0 months to infinity), versus 31.0 months (95% CI, 26.0 months to infinity) at a 51-month median follow-up for the controls (P = .032). The median disease-free survival for RAIT patients was 18.0 months (95% CI, 11.0–31.0 months), versus 12.0 months (95% CI, 6.5–27.0 months) for the controls (P = .565). Corresponding survival rates (Kaplan-Meier analyses) were estimated to be 94.7% at 1 year, 78.9% at 2 years, 68.4% at 3 years, and 42.1% at 5 years with RAIT and 94.7%, 68.4%, 36.8%, and 15.8%, respectively, for the controls. RAIT was beneficial independently of bilobar involvement, size and number of LM, or resection margins. Transient myelosuppression was the principal adverse effect.


This first evidence of a promising survival advantage of adjuvant RAIT after long-term follow-up of colorectal cancer patients given salvage resection of LM warrants confirmation in a prospective randomized trial.


Colorectal liver metastases Carcinoembryonic antigen radioimmunotherapy Salvage resection 


  1. 1.
    Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin 2004; 54:8–29PubMedGoogle Scholar
  2. 2.
    Ferlay J, Bray F, Pisani P, et al. GLOBOCAN 2002: cancer incidence, mortality and prevalence worldwide. IARC CancerBase No. 5, version 2.0. Lyon, France: IARC Press, 2004. Available at:
  3. 3.
    Steele G Jr, Ravikumar TS. Resection of hepatic metastases from colorectal cancer: biologic perspective. Ann Surg 1989; 210:127–38PubMedCrossRefGoogle Scholar
  4. 4.
    Ekberg H, Tranberg KG, Andersson R, et al. Determinants of survival in liver resection for colorectal secondaries. Br J Surg 1986; 73:727–31PubMedCrossRefGoogle Scholar
  5. 5.
    Blumgart LH, Fong Y. Surgical options in the treatment of hepatic metastasis from colorectal cancer. Curr Probl Surg 1995; 32:333–421PubMedCrossRefGoogle Scholar
  6. 6.
    Wagner JS, Adson MA, van Heerden JA, et al. The natural history of hepatic metastases from colorectal cancer. Ann Surg 1984; 199:502–8PubMedCrossRefGoogle Scholar
  7. 7.
    Fong Y, Kemeny N, Paty P, et al. Treatment of colorectal cancer: hepatic metastasis. Semin Surg Oncol 1996; 12:219–52PubMedCrossRefGoogle Scholar
  8. 8.
    Doci R, Bignami P, Montalto F, et al. Prognostic factors for survival and disease-free survival in hepatic metastases from colorectal cancer treated by resection. Tumori 1995; 81:143–6PubMedGoogle Scholar
  9. 9.
    Abdalla EK, Vauthey JN, Ellis LM, et al. Recurrence and outcome following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg 2004; 239:818–25PubMedCrossRefGoogle Scholar
  10. 10.
    Folprecht G, Grothey A, Alberts S, et al. Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol 2005; 16:1311–9PubMedCrossRefGoogle Scholar
  11. 11.
    Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004; 22:23–30PubMedCrossRefGoogle Scholar
  12. 12.
    Grothey A, Sargent D, Goldberg RM, Schmoll HJ. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 2004; 22:1209–14PubMedCrossRefGoogle Scholar
  13. 13.
    Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy. A model to predict long-term survival. Ann Surg 2004; 240:644–58PubMedCrossRefGoogle Scholar
  14. 14.
    Kato T, Yasui K, Hirai T, et al. Therapeutic results for hepatic metastasis of colorectal cancer with special reference to effectiveness of hepatectomy: analysis of prognostic factors for 763 cases recorded at 18 institutions. Dis Colon Rectum 2003;46 (Suppl):S22–31PubMedGoogle Scholar
  15. 15.
    Leonard GD, Brenner B, Kemeny NE. Neoadjuvant chemotherapy before liver resection for patients with unresectable liver metastases from colorectal carcinoma. J Clin Oncol 2005; 23:2038–48PubMedCrossRefGoogle Scholar
  16. 16.
    Doci R, Gennari L, Bignami P, et al. Morbidity and mortality after hepatic resection of metastases from colorectal cancer. Br J Surg 1995; 82:377–81PubMedCrossRefGoogle Scholar
  17. 17.
    Birkmeyer JD, Siewers AE, Finlayson EV, et al. Hospital volume and surgical mortality in the United States. N Engl J Med 2002; 346:1128–37PubMedCrossRefGoogle Scholar
  18. 18.
    Scheele J, Stangl R, Altendorf-Hofmann A, et al. Resection of colorectal liver metastases. World J Surg 1995; 19:59–71PubMedCrossRefGoogle Scholar
  19. 19.
    Nordlinger B, Guiguet M, Vaillant JC, et al. Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Association Francaise de Chirurgie. Cancer 1996; 77:1254–62Google Scholar
  20. 20.
    Fong Y, Fortner J, Sun RL, et al. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999; 230:309–18PubMedCrossRefGoogle Scholar
  21. 21.
    Figueras J. Changing strategies in surgical treatment of colorectal liver metastases: state of the art. Clin Transl Oncol 2005; 7:229–31PubMedGoogle Scholar
  22. 22.
    Poston GJ, Adam R, Alberts S, et al. OncoSurge: a strategy for improving resectability with curative intent in metastatic colorectal cancer. J Clin Oncol 2005; 23:7125–34PubMedCrossRefGoogle Scholar
  23. 23.
    Adam R, Pascal G, Azoulay D, et al. Liver resection for colorectal metastases: the third hepatectomy. Ann Surg 2003; 238:871–83PubMedCrossRefGoogle Scholar
  24. 24.
    Fernandez FG, Drebin JA, Linehan DC, et al. Five-year survival after resection of hepatic metastases from colorectal cancer in patients screened by positron emission tomography with F-18 fluorodeoxyglucose (FDG-PET). Ann Surg 2004; 240:438–47PubMedCrossRefGoogle Scholar
  25. 25.
    Liersch T, Becker H, Goldenberg DM. In reply. J Clin Oncol 2006; 24:2680–1CrossRefGoogle Scholar
  26. 26.
    Alberts SR, Horvath WL, Sternfeld WC, et al. Oxaliplatin, fluorouracil, and leucovorin for patients with unresectable liver-only metastases from colorectal cancer: a North Central Cancer Treatment Group Phase II study. J Clin Oncol 2005; 23:9243–9PubMedCrossRefGoogle Scholar
  27. 27.
    Aloia T, Sebagh M, Plasse M, et al. Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases. J Clin Oncol 2006; 24:4983–90PubMedCrossRefGoogle Scholar
  28. 28.
    Nordlinger B, Benoist S. Benefits and risks of neoadjuvant therapy for liver metastases. J Clin Oncol 2006; 24:4954–5PubMedCrossRefGoogle Scholar
  29. 29.
    Bartlett DL, Berlin J, Lauwers GY, et al. Chemotherapy and regional therapy of hepatic colorectal metastases: expert consensus statement. Ann Surg Oncol 2006; 13:1284–92PubMedCrossRefGoogle Scholar
  30. 30.
    Guimbaud R. What are the roles of neoadjuvant, adjuvant and palliative chemotherapy in the management of hepatic metastasis of colorectal origin? Gastroenterol Clin Biol 2003; 27:B14–15, B63–79PubMedGoogle Scholar
  31. 31.
    Van Cutsem E, Nordlinger B, Adam R, et al. European Colorectal Metastases Treatment Group. Towards a pan-Europe consensus on the treatment of patients with colorectal liver metastases. Eur J Cancer 2006; 42:2212–21PubMedCrossRefGoogle Scholar
  32. 32.
    Hebbar M. Chemotherapy in patients with resectable liver metastases from colorectal cancer. Curr Colorectal Cancer Rep 2005; 1:34–40CrossRefGoogle Scholar
  33. 33.
    Kemeny NE, Gonen M. Hepatic arterial infusion after liver resection. N Engl J Med 2005; 352:734–5PubMedCrossRefGoogle Scholar
  34. 34.
    Goldenberg DM. Advancing role of radiolabeled antibodies in the therapy of cancer. Cancer Immunol Immunother 2003; 52:281–96PubMedGoogle Scholar
  35. 35.
    Sharkey RM, Goldenberg DM. Perspectives on cancer therapy with radiolabeled monoclonal antibodies. J Nucl Med 2005; 46:115S–127SPubMedGoogle Scholar
  36. 36.
    Blumenthal RD, Osorio L, Hayes MK, et al. Carcinoembryonic antigen antibody inhibits metastasis and augments chemotherapy in a human colonic carcinoma xenograft. Cancer Immunol Immunother 2005; 54:315–27PubMedCrossRefGoogle Scholar
  37. 37.
    Liersch T, Meller J, Kulle B, et al. Phase II trial of carcinoembryonic antigen radioimmunotherapy with 131I-labetuzumab after resection of colorectal metastases in the liver: five-year safety and efficacy results. J Clin Oncol 2005; 23:6763–70PubMedCrossRefGoogle Scholar
  38. 38.
    Hansen HJ, Goldenberg DM, Newman ES, et al. Characterization of second generation monoclonal antibodies against carcinoembryonic antigen. Cancer 1993; 71:3478–85PubMedCrossRefGoogle Scholar
  39. 39.
    Behr TM, Salib AL, Liersch T, et al. Radioimmunotherapy of small volume disease of colorectal cancer metastatic to the liver preclinical evaluation in comparison to standard chemotherapy and initial results of a phase I clinical study. Clin Cancer Res 1999; 5:3232s–3242sPubMedGoogle Scholar
  40. 40.
    Hajjar G, Sharkey RM, Burton J, et al. Phase I radioimmunotherapy trial with iodine-131-labelled humanized MN-14 anti-carcinoembryonic antigen monoclonal antibody in patients with metastatic gastrointestinal and colorectal cancer. Clin Colorectal Cancer 2002; 2:31–42PubMedGoogle Scholar
  41. 41.
    Goldenberg DM. Targeted therapy of cancer with radiolabeled antibodies. J Nucl Med 2002; 43:693–713PubMedGoogle Scholar
  42. 42.
    Dunn RM, Juweid M, Sharkey RM, Behr TM, Goldenberg DM. Can occult metastases be treated by radioimmunotherapy? Cancer 1997; 80(Suppl):2656–49PubMedCrossRefGoogle Scholar
  43. 43.
    Sobin LH, Wittekind C, eds. UICC: TNM Classification of Malignant Tumors. 5th ed. New York: Wiley, 1997Google Scholar
  44. 44.
    Gayowski TJ, Iwatsuki S, Madariaga JR, et al. Experience in hepatic resection for metastatic colorectal cancer: analysis of clinical and pathologic risk factors. Surgery 1994; 116:703–10PubMedGoogle Scholar
  45. 45.
    Jaeck D, Bachellier P, Guiguet M, et al. Long-term survival following resection of colorectal hepatic metastases. Association Francaise de Chirurgie. Br J Surg 1997;84:977–80PubMedCrossRefGoogle Scholar
  46. 46.
    Bismuth H, Adam R, Lévi F, et al. Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg 1996; 224:509–22PubMedCrossRefGoogle Scholar
  47. 47.
    Penna C, Nordlinger B. Surgery of liver metastases from colorectal cancer: new promises. Br Med Bull 2002; 64:127–40PubMedCrossRefGoogle Scholar
  48. 48.
    Lorenz M, Müller HH, Schramm H, et al. Randomized trial of surgery versus surgery followed by adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal cancer. German Cooperative on Liver Metastases (Arbeitsgruppe Lebermetastasen). Ann Surg 1998; 28:756–62CrossRefGoogle Scholar
  49. 49.
    Fong Y, Cohen AM, Fortner JG, et al. Liver resection for colorectal metastases. J Clin Oncol 1997; 15:938–46PubMedGoogle Scholar
  50. 50.
    Weber SM, Jarnagin WR, DeMatteo RP, et al. Survival after resection of multiple hepatic colorectal metastases. Ann Surg Oncol 2000; 7:643–50PubMedCrossRefGoogle Scholar
  51. 51.
    Weitz J, Koch M, Kienle P, et al. Detection of hematogenic tumor cell dissemination in patients undergoing resection of liver metastases of colorectal cancer. Ann Surg 2000; 232:66–72PubMedCrossRefGoogle Scholar
  52. 52.
    Koch M, Kienle P, Hinz U, et al. Detection of hematogenous tumor cell dissemination predicts tumor relapse in patients undergoing surgical resection of colorectal liver metastases. Ann Surg 2005; 241:199–205PubMedCrossRefGoogle Scholar
  53. 53.
    Topal B, Aerts JL, Roskams T, et al. Cancer cell dissemination during curative surgery for colorectal liver metastases. Eur J Surg Oncol 2005; 31:506–11PubMedCrossRefGoogle Scholar
  54. 54.
    Kemeny N, Huang Y, Cohen AM, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 1999; 341:2039–48PubMedCrossRefGoogle Scholar
  55. 55.
    Clancy TE, Dixon E, Perlis R, et al. Hepatic arterial infusion after curative resection of colorectal cancer metastases: a meta-analysis of prospective clinical trials. J Gastrointest Surg 2005; 9:198–206PubMedCrossRefGoogle Scholar
  56. 56.
    Meta-Analysis Group in Cancer. Reappraisal of hepatic arterial infusion in the treatment of nonresectable liver metastases from colorectal cancer. J Natl Cancer Inst 1996; 88:252–8CrossRefGoogle Scholar
  57. 57.
    Kemeny NE, Fong Y, Jarnagin W, et al. A phase I trial of systemic oxaliplatin combination with hepatic arterial infusion in patients with unresectable liver metastases from colorectal cancer. J Clin Oncol 2005; 23:4888–96PubMedCrossRefGoogle Scholar
  58. 58.
    Ducreux M, Ychou M, Laplanche A, et al. Combination of hepatic arterial oxaliplatin infusion and intravenous chemotherapy with leucovorin and fluorouracil in colorectal cancer patients with isolated inoperable hepatic metastases. J Clin Oncol 2005; 23:4881–7PubMedCrossRefGoogle Scholar
  59. 59.
    Faynsod M, Wagman LD, Longmate J, et al. Improved hepatic toxicity profile of adjuvant hepatic infusional chemotherapy utilizing the portal vein (PV) route. J Clin Oncol 2005; 23:4876–80PubMedCrossRefGoogle Scholar
  60. 60.
    Gill S, Thomas RR, Goldberg RM. New targeted therapies in gastrointestinal cancers. Curr Treat Options Oncol 2003; 4:393–403PubMedCrossRefGoogle Scholar
  61. 61.
    Hurwitz H. Integrating the anti-VEGF—a humanized monoclonal antibody bevacizumab with chemotherapy in advanced colorectal cancer. Clin Colorectal Cancer 2004; 4(Suppl 2):S62–8PubMedCrossRefGoogle Scholar
  62. 62.
    Portier G, Elias D, Bouche O, et al. Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. J Clin Oncol 2006; 24:4976–82PubMedCrossRefGoogle Scholar
  63. 63.
    Ellis LM, Curley SA, Grothey A. Surgical resection after downsizing of colorectal liver metastasis in the era of bevacizumab. J Clin Oncol 2005; 23:4853–5PubMedCrossRefGoogle Scholar
  64. 64.
    Curley SA. One surgeon’s unabashedly biased view on liver resection. J Clin Oncol 2005; 23:8286–8PubMedCrossRefGoogle Scholar
  65. 65.
    Kathri VP, Petrelli NJ, Belghiti J. Extending the frontiers of surgical therapy for hepatic colorectal metastases: is there a limit? J Clin Oncol 2005; 23:8490–9CrossRefGoogle Scholar
  66. 66.
    Mackay HJ, Billingsley K, Gallinger S, et al. A multicenter phase II study of “adjuvant” irinotecan following resection of colorectal hepatic metastases. Am J Clin Oncol 2005; 28:547–54PubMedCrossRefGoogle Scholar
  67. 67.
    Sharkey RM, Weadock KS, Natale A, et al. Successful radioimmunotherapy for lung metastasis of human colonic cancer in nude mice. J Natl Cancer Inst 1991; 83:627–32PubMedCrossRefGoogle Scholar
  68. 68.
    Behr TM, Blumenthal RD, Memtsoudis S, et al. Cure of metastatic human colonic cancer in mice with radiolabeled monoclonal antibody fragments. Clin Cancer Res 2000; 6:4900–7PubMedGoogle Scholar
  69. 69.
    Koppe MJ, Soede AC, Pels W, et al. Experimental radioimmunotherapy of small peritoneal metastases of colorectal origin. Int J Cancer 2003; 106:965–72PubMedCrossRefGoogle Scholar
  70. 70.
    Goldenberg DM, Sharkey RM, Primus FJ. Carcinoembryonic antigen in histopathology: immunoperoxidase staining of conventional tissue sections. J Natl Cancer Inst 1976; 57:11–22PubMedGoogle Scholar
  71. 71.
    Gold P, Goldenberg NA. The carcinoembryonic antigen (CEA): past, present, and future. McGill J Med 1997; 3:46–66Google Scholar
  72. 72.
    Goldenberg DM, Kim EE, DeLand FH, et al. Radioimmunodetection of cancer with radioactive antibodies to carcinoembryonic antigen. Cancer Res 1980; 40:2984–92PubMedGoogle Scholar
  73. 73.
    Moffat FL Jr, Pinsky CM, Hammershaimb L, et al. Clinical utility of external immunoscintigraphy with the IMMU-4 technetium-99m Fab′ antibody fragment in patients undergoing surgery for carcinoma of the colon and rectum: results of a pivotal, phase III trial. The Immunomedics Study Group. J Clin Oncol 1996; 14:2295–305PubMedGoogle Scholar
  74. 74.
    Goldenberg DM, DeLand F, Kim E, et al. Use of radiolabeled antibodies to carcinoembryonic antigen for the detection and localization of diverse cancers by external photoscanning. N Engl J Med 1978; 298:1384–6PubMedCrossRefGoogle Scholar
  75. 75.
    Moffat FL Jr, Gulec SA, Serafini AN, et al. A thousand points of light or just dim bulbs? Radiolabeled antibodies and colorectal cancer imaging. Cancer Invest 1999; 17:322–34PubMedGoogle Scholar
  76. 76.
    Fong Y. Surgical therapy of hepatic colorectal metastasis. CA Cancer J Clin 1999; 49:231–55PubMedCrossRefGoogle Scholar
  77. 77.
    Taieb J, Artru P, Paye F, et al. Intensive systemic chemotherapy combined with surgery for metastatic colorectal cancer: results of a phase II study. J Clin Oncol 2005; 23:502–9PubMedCrossRefGoogle Scholar
  78. 78.
    Junginger T, Hossfeld DK, Sauer R, Hermanek P. Adjuvante Therapie beim Kolon- und Rektumkarzinom. Dt Arztebl 1999; 96A:698–700Google Scholar
  79. 79.
    Sauer R, Becker H, Hohenberger W, et al. Preoperative compared with postoperative chemoradiotherapy for locally advanced rectal cancer. N Engl J Med 2004; 351:1731–40PubMedCrossRefGoogle Scholar
  80. 80.
    Abdalla EK, Vauthey JN, Ellis LM, et al. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg 2004; 239:818–25PubMedCrossRefGoogle Scholar
  81. 81.
    Aloia TA, Vauthey JN, Loyer EM, et al. Solitary colorectal liver metastasis: resection determines outcome. Arch Surg 2006; 141:460–466PubMedCrossRefGoogle Scholar
  82. 82.
    Pawlik TM, Scoggins CR, Zorzi D, et al. Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg 2005; 241:715–24PubMedCrossRefGoogle Scholar
  83. 83.
    Schnider A, Metzger U. Chirurgie der Lebermetastasen. Schweiz Med Forum 2002; 49:1171–6Google Scholar
  84. 84.
    Figueras J, Valls C, Rafecas A, et al. Resection rate and effect of postoperative chemotherapy on survival after surgery for colorectal liver metastases. Br J Surg 2001; 88:980–5PubMedCrossRefGoogle Scholar
  85. 85.
    Bramhall SR, Gur U, Coldham C. Liver resection for colorectal metastases. Ann R Coll Surg Engl 2003; 85:334–9PubMedCrossRefGoogle Scholar
  86. 86.
    Choti MA, Sitzmann JV, Tiburi MF, et al. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg 2002; 235:759–66PubMedCrossRefGoogle Scholar
  87. 87.
    Mann CD, Metcalfe MS, Leopardi LN, et al. The clinical risk score. Emerging as a reliable preoperative prognostic index in hepatectomy for colorectal metastases. Arch Surg 2004; 139:1168–72PubMedCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2007

Authors and Affiliations

  • Torsten Liersch
    • 1
  • Johannes Meller
    • 2
  • Michael Bittrich
    • 1
  • Bettina Kulle
    • 3
  • Heinz Becker
    • 1
  • David M. Goldenberg
    • 4
    • 5
  1. 1.Department of General SurgeryUniversity of GöttingenGöttingenGermany
  2. 2.Department of Nuclear MedicineUniversity of GöttingenGöttingenGermany
  3. 3.Department of Biostatistics and Department of MathematicsUniversity of OsloOsloNorway
  4. 4.Immunomedics, Inc.Morris PlainsUSA
  5. 5.Garden State Cancer CenterCenter for Molecular Medicine and ImmunologyBellevilleUSA

Personalised recommendations