Skip to main content

Advertisement

SpringerLink
Log in

Clinical significance of VEGFR-2 and 18F-FDG PET/CT SUVmax pretreatment score in predicting the long-term outcome of patients with locally advanced rectal cancer treated with neoadjuvant therapy

  • Original Article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Vascular endothelial growth factor receptor-2 (VEGFR-2), epidermal growth factor receptor-1 (EGFR), and cyclooxygenase-2 (COX-2) stimulate key processes involved in tumor progression and are important targets for cancer drugs. 18F-FDG maximum standardized uptake value (SUVmax) is a marker of tumor metabolic activity. The purpose of this study was to measure SUVmax combined with VEGFR-2, EGFR and COX-2 proteins in pretreatment tumor biopsies from patients with locally advanced rectal cancer receiving intensive neoadjuvant treatment and to correlate the findings with clinical outcome.

Methods

VEGFR-2, EGFR and COX-2 were measured using the immunoreactive score (IRS). SUVmax (median 8.4) was quantified in tumors with molecular overexpression (IRS ≥3 + SUVmax ≥ 8.4 indicating active tumors; SUVmax <8.4 indicating inactive tumors). The Cox proportional hazards model was used to explore associations between tumor markers, disease-free survival (DFS) and overall survival (OS).

Results

The study group comprised 38 patients with a median follow-up of 69.3 months (range 4.5 – 92 months). Multivariate analysis showed that active tumors (overexpressing VEGFR-2, high SUVmax) were associated with worse DFS (HR 4.73, 95 % CI 1.18  – 22.17; p = 0.04) and OS (HR 4.28, 95 % CI 1.04 – 20.12; p = 0.05).

Conclusion

Active tumors overexpressing VEGFR-2 are associated with a worse overall outcome in patients with rectal cancer treated with induction chemotherapy followed by pelvic chemoradiation and surgery. The optimal diagnostic cut-off level for this novel biomarker association should be investigated. Evaluation in a clinical trial is required to determine whether selected patients could benefit from a VEGFR-targeting drug.

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

Similar content being viewed by others

References

  1. Heald RJ, Ryall RD. Recurrence and survival after total mesorectal excision for rectal cancer. Lancet. 1986;1:1479–82.

    Article  PubMed  CAS  Google Scholar 

  2. Smith N, Brown G. Preoperative staging of rectal cancer. Acta Oncol. 2008;47:20–31.

    Article  PubMed  Google Scholar 

  3. Nagtegaal ID, van Krieken JH. The role of pathologists in the quality control of diagnosis and treatment of rectal cancer – an overview. Eur J Cancer. 2002;38:964–72.

    Article  PubMed  CAS  Google Scholar 

  4. Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006;355:1114–23.

    Article  PubMed  CAS  Google Scholar 

  5. van Gijn W, Marijnen CA, Nagtegaal ID, Kranenbarg EM, Putter H, Wiggers T, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-Year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. 2011;12:575–82.

    Article  PubMed  Google Scholar 

  6. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Michalski W, Bebenek M, Pudełko M, et al. Sphincter preservation following preoperative radiotherapy for rectal cancer: report of a randomised trial comparing short-term radiotherapy vs. conventionally fractionated radiochemotherapy. Radiother Oncol. 2004;72:15–24.

    Article  PubMed  CAS  Google Scholar 

  7. Blomqvist L, Glimelius B. The “good”, the “bad”, and the “ugly” rectal cancers. Acta Oncol. 2008;47:5–8.

    Article  PubMed  Google Scholar 

  8. Roth AD, Delorenzi M, Tejpar S, Yan P, Klingbiel D, Fiocca R, et al. Integrated analysis of molecular and clinical prognostic factors in stage II/III colon cancer. J Natl Cancer Inst. 2012;104:1635–46.

    Google Scholar 

  9. Kuremsky JG, Tepper JE, McLeod HL. Biomarkers for response to neoadjuvant chemoradiation for rectal cancer. Int J Radiat Oncol Biol Phys. 2009;74:673–88.

    Article  PubMed  CAS  Google Scholar 

  10. McShane L, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM, et al. REporting recommendations for tumor MARKer prognostic studies (REMARK). Eur J Cancer. 2005;41:1690–6.

    Article  PubMed  Google Scholar 

  11. Altman DG, McShane LM, Sauerbrei W, Taube SE. Reporting recommendations for tumor marker prognostic studies (REMARK): explanation and elaboration. PLoS Med. 2012;9:e1001216.

    Article  PubMed  Google Scholar 

  12. Ali HR, Dawson SJ, Blows FM. A Ki67/BCL2 index based on immunohistochemistry is highly prognostic in ER-positive breast cancer. J Pathol. 2012;226:97–107.

    Article  PubMed  CAS  Google Scholar 

  13. Calvo FA, Sole CV, de la Mata D, Cabezón L, Gómez-Espí M, Alvarez E, et al. 18F-FDG PET/CT-based treatment response evaluation in locally advanced rectal cancer: a prospective validation of long-term outcomes. Eur J Nucl Med Mol Imaging. 2013;40:657–67.

    Article  PubMed  CAS  Google Scholar 

  14. Calvo FA, Cabezón L, González C, Soria A, de la Mata D, Gómez-Espí M, et al. 18F-FDG PET bio-metabolic monitoring of neoadjuvant therapy effects in rectal cancer: focus on nodal disease characteristics. Radiother Oncol. 2010;97:212–6.

    Article  PubMed  Google Scholar 

  15. Calvo FA, Serrano FJ, Diaz-González JA, Gomez-Espi M, Lozano E, Garcia R, et al. Improved incidence of pT0 downstaged surgical specimens in locally advanced rectal cancer (LARC) treated with induction oxaliplatin plus 5-fluorouracil and preoperative chemoradiation. Ann Oncol. 2006;17:1103–10.

    Article  PubMed  CAS  Google Scholar 

  16. Quirke P, Durdey P, Dixon MF, Williams NS. Local recurrence of rectal adenocarcinoma due to inadequate surgical resection. Histopathological study of lateral tumor spread and surgical excision. Lancet. 1986;2:996–9.

    Article  PubMed  CAS  Google Scholar 

  17. American Joint Committee on Cancer. General information on cancer staging and end-results reporting. In: Cancer Staging Handbook. Seventh edition, Heidelberg: Springer; 2007. p.1–39.

  18. Rödel C, Martus P, Papadoupolos T, Füzesi L, Klimpfinger M, Fietkau R, et al. Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol. 2005;23:8688–96.

    Article  PubMed  Google Scholar 

  19. Beaulieu S, Kinahan P, Tseng J, Dunnwald LK, Schubert EK, Pham P, et al. SUV varies with time after injection in (18)F-FDG PET of breast cancer: characterization and method to adjust for time differences. J Nucl Med. 2003;44:1044–50.

    PubMed  Google Scholar 

  20. Boellaard R, Krak NC, Hoekstra OS, Lammertsma AA. Effects of noise, image resolution, and ROI definition on the accuracy of standard uptake values: a simulation study. J Nucl Med. 2004;45:1519–27.

    PubMed  Google Scholar 

  21. Remmele W, Stegner HE. Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe. 1987;8:138–40.

    PubMed  CAS  Google Scholar 

  22. Shields AF. Positron emission tomography measurement of tumor metabolism and growth: its expanding role in oncology. Mol Imaging Biol. 2006;8:141–50.

    Article  PubMed  Google Scholar 

  23. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407:249–57.

    Article  PubMed  CAS  Google Scholar 

  24. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996;86:353–64.

    Article  PubMed  CAS  Google Scholar 

  25. Bouck N, Stellmach V, Hsu S. How tumors become angiogenic. Adv Cancer Res. 1996;69:135–74.

    Article  PubMed  CAS  Google Scholar 

  26. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–6.

    Article  PubMed  CAS  Google Scholar 

  27. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9:669–76.

    Article  PubMed  CAS  Google Scholar 

  28. Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol. 2002;20(21):4368–80.

    Article  PubMed  CAS  Google Scholar 

  29. Veeravagu A, Hsu AR, Cai W, Hou LC, Tse VC, Chen X. Vascular endothelial growth factor and vascular endothelial growth factor receptor inhibitors as anti-angiogenic agents in cancer therapy. Recent Patents Anticancer Drug Discov. 2007;2:59–71.

    Article  CAS  Google Scholar 

  30. Longo R, Gasparini G. Challenges for patient selection with VEGF inhibitors. Cancer Chemother Pharmacol. 2007;60:151–70.

    Article  PubMed  CAS  Google Scholar 

  31. Mandrekar SJ, Sargent DJ. Clinical trial designs for predictive biomarker validation: theoretical considerations and practical challenges. J Clin Oncol. 2009;27:4027–34.

    Article  PubMed  Google Scholar 

  32. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:3584–90.

    Article  PubMed  CAS  Google Scholar 

  33. Hurwitz HI, Fehrenbacher L, Hainsworth JD, Heim W, Berlin J, Holmgren E, et al. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol. 2005;23:3502–8.

    Article  PubMed  CAS  Google Scholar 

  34. Chen Z, Duldulao MP, Li W, Lee W, Kim J, Garcia-Aguilar J. Molecular diagnosis of response to neoadjuvant chemoradiation therapy in patients with locally advanced rectal cancer. J Am Coll Surg. 2011;212:1008–17.

    Article  PubMed  Google Scholar 

  35. Glynne-Jones R, Anyamene N. Just how useful an endpoint is complete pathological response after neoadjuvant chemoradiation in rectal cancer? Int J Radiat Oncol Biol Phys. 2006;66:319–20.

    Article  PubMed  Google Scholar 

  36. Sanghera P, Wong DW, McConkey CC, Geh JI, Hartley A. Chemoradiotherapy for rectal cancer: an updated analysis of factors affecting pathological response. Clin Oncol (R Coll Radiol). 2008;20:176–86.

    Article  CAS  Google Scholar 

  37. Glynne-Jones R, Hughes R. Critical appraisal of the ‘wait and see’ approach in rectal cancer for clinical complete responders after chemoradiation. Br J Surg. 2012;99:897–909.

    Article  PubMed  CAS  Google Scholar 

  38. Valentini V, van Stiphout R, Lammering G, Gambacorta MA, Barba MC, Bebenek M, et al. Nomograms for predicting local recurrence, distant metastases, and overall survival for patients with locally advanced rectal cancer on the basis of European randomized clinical trials. J Clin Oncol. 2011;29:3163–72.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was financed in part by a research grant from Mutua Madrileña Biomedical, Foundation Institute Health Research Marañon, study code CMF, FMM 06–02.

Conflicts of Interest

None.

Author information

Authors and Affiliations

  1. Department of Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain

    Claudio V. Sole & Felipe A. Calvo

  2. School of Medicine Complutense University, Madrid, Spain

    Claudio V. Sole, Felipe A. Calvo, Emilio Alvarez, Isabel Peligros & Jose L. Carreras

  3. Service of Radiation Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain

    Rafael Herranz

  4. Service of Medical Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain

    Pilar Garcia-Alfonso

  5. Department of Pathology, Hospital General Universitario Gregorio Marañón, Madrid, Spain

    Emilio Alvarez & Isabel Peligros

  6. Institute for Sanitary Research, Hospital General Universitario Gregorio Marañón, Madrid, Spain

    Claudio V. Sole, Felipe A. Calvo, Emilio Alvarez, Isabel Peligros, Pilar Garcia-Alfonso & Rafael Herranz

  7. Institute of Oncology, Hospital Provincial de Castellon, Castellon de la Plana, Spain

    Carlos Ferrer & Enrique Ochoa

  8. Department of Radiology and Medical Physics, Hospital General Universitario Gregorio Marañón, Madrid, Spain

    Jose L. Carreras

  9. Hospital General Universitario Gregorio Marañon, C/ Doctor Esquerdo, 46, 28007, Madrid, Spain

    Claudio V. Sole

Authors
  1. Claudio V. Sole
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Felipe A. Calvo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Emilio Alvarez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Isabel Peligros
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pilar Garcia-Alfonso
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carlos Ferrer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Enrique Ochoa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rafael Herranz
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jose L. Carreras
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Claudio V. Sole.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 85 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sole, C.V., Calvo, F.A., Alvarez, E. et al. Clinical significance of VEGFR-2 and 18F-FDG PET/CT SUVmax pretreatment score in predicting the long-term outcome of patients with locally advanced rectal cancer treated with neoadjuvant therapy. Eur J Nucl Med Mol Imaging 40, 1635–1644 (2013). https://doi.org/10.1007/s00259-013-2479-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-013-2479-7

Keywords

Search

Navigation