Skip to main content
SpringerLink
Log in

Timing of Adjuvant Radioimmunotherapy after Cytoreductive Surgery in Experimental Peritoneal Carcinomatosis of Colorectal Origin

  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Treatment of patients with peritoneal carcinomatosis (PC) of colorectal cancer (CRC) includes cytoreductive surgery (CS) in combination with (hyperthermic) intraperitoneal chemotherapy (HIPEC), resulting in a limited survival benefit with high morbidity and mortality rates. Radioimmunotherapy (RIT) as adjuvant therapy after CS of CRC has been shown to prolong survival in preclinical studies. However, the optimal setting of RIT remains to be determined.

Methods

PC was induced by intraperitoneal inoculation of CC-531 colon carcinoma cells in Wag/Rij rats. Animals were subjected to exploratory laparotomy (Sham), CS only or CS + RIT at different time points after surgery. RIT consisted of 55 MBq lutetium-177-labelled anti-CC531 antibody MG1 (183 μg). The primary endpoint was survival.

Results

Cytoreductive surgery with or without RIT was well tolerated. Median survival of animals in the Sham and CS group was 29 days and 39 days, respectively (P < 0.04). Compared to CS alone, median survival of rats after adjuvant RIT was 77 days (P < 0.0001), 52 days (P < 0.0001) and 45 days (P < 0.0001) when given directly, 4 and 14 days after surgery, respectively.

Conclusion

The efficacy of adjuvant RIT after CS for the treatment of PC of colonic origin decreases when the administration of the radiolabelled MAbs is postponed. This study shows that adjuvant RIT should be given as early as possible after surgery.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

FIG. 1.
FIG. 2.
FIG. 3.
FIG. 4.
FIG. 5.

Similar content being viewed by others

References

  1. Sugarbaker PH, Cunliffe WJ, Belliveau J, et al. Rationale for integrating early postoperative intraperitoneal chemotherapy into the surgical treatment of gastrointestinal cancer. Semin Oncol 1989; 16:83–97

    PubMed  CAS  Google Scholar 

  2. Sugarbaker PH. Colorectal carcinomatosis: a new oncologic frontier. Curr Opin Oncol 2005; 17:397–9

    Article  PubMed  Google Scholar 

  3. Culliford AT, Brooks AD, Sharma S, et al. Surgical debulking and intraperitoneal chemotherapy for established peritoneal metastases from colon and appendix cancer. Ann Surg Oncol 2001; 8:787–95

    Article  PubMed  Google Scholar 

  4. Koppe MJ, Boerman OC, Oyen WJ, et al. Peritoneal carcinomatosis of colorectal origin: incidence and current treatment strategies. Ann Surg 2006; 243:212–22

    Article  PubMed  Google Scholar 

  5. Verwaal VJ, Boot H, Aleman BM, et al. Recurrences after peritoneal carcinomatosis of colorectal origin treated by cytoreduction and hyperthermic intraperitoneal chemotherapy: location, treatment, and outcome. Ann Surg Oncol 2004; 11:375–9

    Article  PubMed  Google Scholar 

  6. Monneuse O, Mestrallet JP, Quash G, et al. Intraperitoneal treatment with dimethylthioampal (DIMATE) combined with surgical debulking is effective for experimental peritoneal carcinomatosis in a rat model. J Gastrointest Surg 2005; 9:769–74

    Article  PubMed  Google Scholar 

  7. Mahteme H, Sundin A, Larsson B, et al. 5-FU uptake in peritoneal metastases after pretreatment with radioimmunotherapy or vasoconstriction: an autoradiographic study in the rat. Anticancer Res 2005; 25:917–22

    PubMed  CAS  Google Scholar 

  8. Koppe MJ, Soede AC, Pels W, et al. Experimental radioimmunotherapy of small peritoneal metastases of colorectal origin. Int J Cancer 2003; 106:965–72

    Article  PubMed  CAS  Google Scholar 

  9. Kinuya S, Yokoyama K, Izumo M, et al. Locoreginal radioimmunotherapy with 186Re-labeled monoclonal antibody in treating small peritoneal carcinomatosis of colon cancer in mice in comparison with 131I-counterpart. Cancer Lett 2005; 219:41–8

    Article  PubMed  CAS  Google Scholar 

  10. Kinuya S, Li XF, Yokoyama K, et al. Intraperitoneal radioimmunotherapy in treating peritoneal carcinomatosis of colon cancer in mice compared with systemic radioimmunotherapy. Cancer Sci 2003; 94:650–4

    Article  PubMed  CAS  Google Scholar 

  11. Zedeck MS. A model system for studies of colon carcinogenesis: tumor induction by a single injection of methylazoxymethanol acetate. J Natl Cancer Inst 1974; 53:1419–21

    PubMed  CAS  Google Scholar 

  12. Lopes Cardozo AM, Gupta A, Koppe MJ, et al. Metastatic pattern of CC531 colon carcinoma cells in the abdominal cavity: an experimental model of peritoneal carcinomatosis in rats. Eur J Surg Oncol 2001; 27:359–63

    Article  PubMed  CAS  Google Scholar 

  13. Ruegg CL, nderson-Berg WT, Brechbiel MW, et al. Improved in vivo stability and tumor targeting of bismuth-labeled antibody. Cancer Res 1990; 50:4221–6

    PubMed  CAS  Google Scholar 

  14. Lindmo T, Boven E, Cuttitta F, et al. Determination of the immunoreactive fraction of radiolabeled monoclonal antibodies by linear extrapolation to binding at infinite antigen excess. J Immunol Methods 1984; 72:77–89

    Article  PubMed  CAS  Google Scholar 

  15. Steffens MG, Boerman OC, Oosterwijk-Wakka JC, et al. Targeting of renal cell carcinoma with iodine-131-labeled chimeric monoclonal antibody G250. J Clin Oncol 1997; 15:1529–37

    PubMed  CAS  Google Scholar 

  16. Koppe MJ, Hendriks T, Boerman OC, Oyen WJ, Bleichrodt RP. Radioimmunotherapy is an effective adjuvant treatment modality after cytoreductive surgery of peritoneal carcinomatosis of colonic origin. J Nucl Med 2006, in press

  17. Hagenaars M, Koelemij R, Ensink NG, et al. The development of novel mouse monoclonal antibodies against the CC531 rat colon adenocarcinoma. Clin Exp Metastasis 2000; 18:281–9

    Article  PubMed  CAS  Google Scholar 

  18. Reijnen MM, Bleichrodt RP, Van Goor H. Pathophysiology of intra-abdominal adhesion and abscess formation, and the effect of hyaluronan. Br J Surg 2003; 90:533–41

    Article  PubMed  CAS  Google Scholar 

  19. Nagy JA, Meyers MS, Masse EM, et al. Pathogenesis of ascites tumor growth: fibrinogen influx and fibrin accumulation in tissues lining the peritoneal cavity. Cancer Res 1995; 55:369–75

    PubMed  CAS  Google Scholar 

  20. Biggerstaff JP, Seth N, Amirkhosravi A, et al. Soluble fibrin augments platelet/tumor cell adherence in vitro and in vivo, and enhances experimental metastasis. Clin Exp Metastasis 1999; 17:723–30

    Article  PubMed  CAS  Google Scholar 

  21. Dijkstra FR, Nieuwenhuijzen M, Reijnen MM, et al. Recent clinical developments in pathophysiology, epidemiology, diagnosis and treatment of intra-abdominal adhesions. Scand J Gastroenterol Suppl 2000; 52–9

  22. Herrick SE, Mutsaers SE, Ozua P, et al. Human peritoneal adhesions are highly cellular, innervated, and vascularized. J Pathol 2000; 192:67–72

    Article  PubMed  CAS  Google Scholar 

  23. Dwivedi AJ, Kuwajerwala NK, Silva YJ, et al. Effects of surgical gloves on postoperative peritoneal adhesions and cytokine expression in a rat model. Am J Surg 2004; 188:491–4

    Article  PubMed  CAS  Google Scholar 

  24. Koppe MJ, Postema EJ, Aarts F, et al. Antibody-guided radiation therapy of cancer. Cancer Metastasis Rev 2005; 24:539–67

    Article  PubMed  CAS  Google Scholar 

  25. Uzunkoy A, Bolukbas C, Horoz M, et al. The optimal starting time of postoperative intraperitoneal mitomycin-C therapy with preserved intestinal wound healing. BMC Cancer 2005; 5:31

    Article  PubMed  Google Scholar 

  26. Jacquet P, Stuart OA, Dalton R, et al. Effect of intraperitoneal chemotherapy and fibrinolytic therapy on tumor implantation in wound sites. J Surg Oncol 1996; 62:128–34

    Article  PubMed  CAS  Google Scholar 

  27. Weiber S, Graf W, Glimelius B, et al. Experimental colonic healing in relation to timing of 5-fluorouracil therapy. Br J Surg 1994; 81:1677–80

    Article  PubMed  CAS  Google Scholar 

  28. van der Kolk BM, de Man BM, Wobbes T, et al. Is early post-operative treatment with 5-fluorouracil possible without affecting anastomotic strength in the intestine? Br J Cancer 1999; 79:545–50

    Article  PubMed  Google Scholar 

  29. Koppe MJ, Boerman OC, Oyen WJ, et al. Peritoneal carcinomatosis of colorectal origin: incidence and current treatment strategies. Ann Surg 2006; 243:212–22

    Article  PubMed  Google Scholar 

  30. Verheijen RH, Massuger LF, Benigno BB, et al. Phase III trial of intraperitoneal therapy with yttrium-90-labeled HMFG1 murine monoclonal antibody in patients with epithelial ovarian cancer after a surgically defined complete remission. J Clin Oncol 2006; 24:571–8

    Article  PubMed  CAS  Google Scholar 

  31. Kranenborg MH, Boerman OC, de Weijert MC, et al. The effect of antibody protein dose of anti-renal cell carcinoma monoclonal antibodies in nude mice with renal cell carcinoma xenografts. Cancer 1997; 80:2390–7

    Article  PubMed  CAS  Google Scholar 

  32. Koppe MJ, Soede AC, Pels W, et al. Experimental radioimmunotherapy of small peritoneal metastases of colorectal origin. Int J Cancer 2003; 106:965–72

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors wish to thank Ben de Man and Roger Lomme (Radboud University Nijmegen Medical Center, Surgical Research Laboratory) for their excellent assistence during the operative procedures, Gerry Grutters and Henny Eikholt (Radboud University Nijmegen Medical Center, Central Animal Laboratory) for their assistance in the animal experiments. Part of this study was supported by a grant from the Netherlands Organization for Health Research and Development (ZonMw); Grant number: 920–03-220

Author information

Authors and Affiliations

  1. 410 Department of Surgery, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands

    Frits Aarts MD, Manuel J. Koppe MD, Thijs Hendriks PhD & Robert P. Bleichrodt MD, PhD

  2. 444 Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands

    Julliëtte E. M. van Eerd PhD, Wim J. G. Oyen MD, PhD & Otto C. Boerman PhD

Authors
  1. Frits Aarts MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Manuel J. Koppe MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thijs Hendriks PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Julliëtte E. M. van Eerd PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wim J. G. Oyen MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Otto C. Boerman PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Robert P. Bleichrodt MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Frits Aarts MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Aarts, F., Koppe, M.J., Hendriks, T. et al. Timing of Adjuvant Radioimmunotherapy after Cytoreductive Surgery in Experimental Peritoneal Carcinomatosis of Colorectal Origin. Ann Surg Oncol 14, 533–540 (2007). https://doi.org/10.1245/s10434-006-9247-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-006-9247-x

Keywords

Search

Navigation