Advertisement

Angiogenic regeneration defines loco-regional recurrence following pre-operative radio-chemotherapy for rectal cancer: a pilot study

  • Michael I. KoukourakisEmail author
  • Ioannis M. Koukourakis
  • Stella Arelaki
  • Maria Kouroupi
  • Spyros Domoxoudis
  • Alexandra Giatromanolaki
Original Article

Abstract

Previous studies from our group have brought forward the concept of angiogenic regeneration during radiotherapy (RT), as a major cause of RT failure. This process was examined herein in rectal cancer patients undergoing preoperative chemo-radiotherapy. Out of 25 patients with stage II/III rectal adenocarcinoma, 15 had incomplete response (pIR) after preoperative chemo-radiotherapy. The MIB1 proliferation index, the vascular density (VD) assessed with the anti-CD31 antibody and the Hypoxia Inducible Factor HIF1α was assessed. High VD before RT was related with poor local relapse free survival LRFS (p = 0.04), in cases with pIR. Pre-RT values of MIB1 and of HIF1α were not related with LRFS. High MIB1 index and intensification of VD beyond pre-treatment levels in post-RT samples, features indicative of angiogenic regeneration, defined poor LRFS (p = 0.04 and p = 0.0008, respectively). Angiogenic regeneration is strongly related to failure of RT and surgery to control loco-regional disease in rectal cancer patients. Addition of anti-angiogenic agents in the preoperative chemo-radiotherapy regimens may prove beneficial in subgroups of patients.

Keywords

Rectal cancer MIB1 index Vascular density HIF1α Angiogenic regeneration 

Notes

Acknowledgements

The study has been financially supported by the Tumour and Angiogenesis Research Group (Grant No. 0017).

Compliance with ethical standards

Conflict of interest

There are no conflicts of interest to report.

Supplementary material

11033_2019_4668_MOESM1_ESM.tif (132 kb)
Supplementary material 1 (TIF 132 KB). Supplemental Figure 1s MIB1 score in patients with pIR and intensified angiogenic activity (VD intensified) in post-radiotherapy biopsies vs. in patients without angiogenic intensification (VD stable)

References

  1. 1.
    Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, Becker H, Raab HR, Villanueva MT, Witzigmann H, Wittekind C, Beissbarth T, Rödel C (2012) Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol 30:1926–1933CrossRefGoogle Scholar
  2. 2.
    Park JH, Yoon SM, Yu CS, Kim JH, Kim TW, Kim JC (2011) Randomized phase 3 trial comparing preoperative and postoperative chemoradiotherapy with capecitabine for locally advanced rectal cancer. Cancer 117:3703–3712CrossRefGoogle Scholar
  3. 3.
    Swedish Rectal Cancer Trial, Cedermark B, Dahlberg M, Glimelius B, Påhlman L et al (1997) Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 336:980–987CrossRefGoogle Scholar
  4. 4.
    Erlandsson J, Holm T, Pettersson D, Berglund Å, Cedermark B, Radu C, Johansson H, Machado M, Hjern F, Hallböök O, Syk I, Glimelius B, Martling A (2017) Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial. Lancet Oncol 18:336–346CrossRefGoogle Scholar
  5. 5.
    Koukourakis MI, Simopoulos C, Pitiakoudis M, Lyratzopoulos N, Romanidis K, Giatromanolaki A, Polychronidis A, Kouklakis G, Sivridis E, Minopoulos G, Manolas K (2008) Hypofractionated accelerated radiotherapy, cytoprotection and capecitabine in the treatment of rectal cancer: a feasibility study. Anticancer Res 28:3035–3040Google Scholar
  6. 6.
    Valentini V, van Stiphout RG, Lammering G, Gambacorta MA, Barba MC, Bebenek M, Bonnetain F, Bosset JF, Bujko K, Cionini L, Gerard JP, Rödel C, Sainato A, Sauer R, Minsky BD, Collette L, Lambin P (2011) 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 29:3163–3172CrossRefGoogle Scholar
  7. 7.
    Gérard JP, Azria D, Gourgou-Bourgade S, Martel-Lafay I, Hennequin C, Etienne PL, Vendrely V, François E, de La Roche G, Bouché O, Mirabel X, Denis B, Mineur L, Berdah JF, Mahé MA, Bécouarn Y, Dupuis O, Lledo G, Seitz JF, Bedenne L, Juzyna B, Conroy T (2012) Clinical outcome of the ACCORD 12/0405 PRODIGE 2 randomized trial in rectal cancer. J Clin Oncol 30:4558–4565CrossRefGoogle Scholar
  8. 8.
    Lin S, Lai H, Qin Y, Chen J, Lin Y (2015) Thymidine phosphorylase and hypoxia-inducible factor 1-α expression in clinical stage II/III rectal cancer: association with response to neoadjuvant chemoradiation therapy and prognosis. Int J Clin Exp Pathol 8:10680–10688Google Scholar
  9. 9.
    Peng Y, Wang L, Du C, Gu J (2012) Expression of vascular endothelial growth factor can predict distant metastasis and disease-free survival for clinical stage III rectal cancer following 30-Gy/10-f preoperative radiotherapy. Int J Colorectal Dis 27:1555–1560CrossRefGoogle Scholar
  10. 10.
    Willett CG, Warland G, Hagan MP, Daly WJ, Coen J, Shellito PC, Compton CC (1995) Tumor proliferation in rectal cancer following preoperative irradiation. J Clin Oncol 13:1417–1424CrossRefGoogle Scholar
  11. 11.
    Koukourakis MI, Giatromanolaki A, Sivridis E, Simopoulos K, Pissakas G, Gatter KC, Harris AL (2001) Squamous cell head and neck cancer: evidence of angiogenic regeneration during radiotherapy. Anticancer Res 21:4301–4309Google Scholar
  12. 12.
    Koukourakis MI (2001) Tumour angiogenesis and response to radiotherapy. Anticancer Res 21:4285–4300Google Scholar
  13. 13.
    Koukourakis MI, Giatromanolaki A, Fountzilas G, Sivridis E, Gatter KC, Harris AL (2000) Angiogenesis, thymidine phosphorylase, and resistance of squamous cell head and neck cancer to cytotoxic and radiation therapy. Clin Cancer Res 6:381–389Google Scholar
  14. 14.
    Glynne-Jones R, Anyemene N (2009) Histologic response grading after chemoradiation in locally advanced rectal cancer: a proposal for standardized reporting. Int J Radiat Oncol Biol Phys 73:971–973CrossRefGoogle Scholar
  15. 15.
    Giatromanolaki A, Koukourakis MI, Sivridis E, Chlouverakis G, Vourvouhaki E, Turley H, Harris AL, Gatter KC (2007) Activated VEGFR2/KDR pathway in tumour cells and tumour associated vessels of colorectal cancer. Eur J Clin Invest 37:878–886CrossRefGoogle Scholar
  16. 16.
    Toiyama Y, Inoue Y, Saigusa S, Okugawa Y, Yokoe T, Tanaka K, Miki C, Kusunoki M (2010) Gene expression profiles of epidermal growth factor receptor, vascular endothelial growth factor and hypoxia-inducible factor-1 with special reference to local responsiveness to neoadjuvant chemoradiotherapy and disease recurrence after rectal cancer surgery. Clin Oncol (R Coll Radiol) 22:272–280CrossRefGoogle Scholar
  17. 17.
    Korkeila EA, Sundström J, Pyrhönen S, Syrjänen K (2011) Carbonic anhydrase IX, hypoxia-inducible factor-1α, ezrin and glucose transporter-1 as predictors of disease outcome in rectal cancer: multivariate Cox survival models following data reduction by principal component analysis of the clinicopathological predictors. Anticancer Res 31:4529–4535Google Scholar
  18. 18.
    Havelund BM, Sørensen FB, Pløen J, Lindebjerg J, Spindler KL, Jakobsen A (2013) Immunohistological expression of HIF-1α, GLUT-1, Bcl-2 and Ki-67 in consecutive biopsies during chemoradiotherapy in patients with rectal cancer. APMIS 121:127–138CrossRefGoogle Scholar
  19. 19.
    Lee-Kong SA, Ruby JA, Chessin DB, Pucciarelli S, Shia J, Riedel ER, Nitti D, Guillem JG (2012) Hypoxia-related proteins in patients with rectal cancer undergoing neoadjuvant combined modality therapy. Dis Colon Rectum 55:990–995CrossRefGoogle Scholar
  20. 20.
    Inoue Y, Ojima E, Watanabe H, Hiro J, Toiyama Y, Kobayashi M, Miki C, Kusunoki M (2007) Does preoperative chemo-radiotherapy enhance the expression of vascular endothelial growth factor in patients with rectal cancer? Oncol Rep 18:369–375Google Scholar
  21. 21.
    Solberg TD, Nearman J, Mullins J, Li S, Baranowska-Kortylewicz J (2008) Correlation between tumor growth delay and expression of cancer and host VEGF, VEGFR2, and osteopontin in response to radiotherapy. Int J Radiat Oncol Biol Phys 72:918–926CrossRefGoogle Scholar
  22. 22.
    Sofia Vala I, Martins LR, Imaizumi N, Nunes RJ, Rino J, Kuonen F, Carvalho LM, Rüegg C, Grillo IM, Barata JT, Mareel M, Santos SC (2010) Low doses of ionizing radiation promote tumor growth and metastasis by enhancing angiogenesis. PLoS ONE 5:e11222CrossRefGoogle Scholar
  23. 23.
    Kim JS, Son Y, Bae MJ, Lee M, Lee CG, Jo WS, Kim SD, Yang K (2015) Administration of granulocyte colony-stimulating factor with radiotherapy promotes tumor growth by stimulating vascularization in tumor-bearing mice. Oncol Rep 34:147–154CrossRefGoogle Scholar
  24. 24.
    Hess C, Vuong V, Hegyi I, Riesterer O, Wood J, Fabbro D, Glanzmann C, Bodis S, Pruschy M (2001) Effect of VEGF receptor inhibitor PTK787/ZK222584 [correction of ZK222548] combined with ionizing radiation on endothelial cells and tumour growth. Br J Cancer 85:2010–2016CrossRefGoogle Scholar
  25. 25.
    Willett CG, Boucher Y, Duda DG, di Tomaso E, Munn LL, Tong RT, Kozin SV, Petit L, Jain RK, Chung DC, Sahani DV, Kalva SP, Cohen KS, Scadden DT, Fischman AJ, Clark JW, Ryan DP, Zhu AX, Blaszkowsky LS, Shellito PC, Mino-Kenudson M, Lauwers GY (2005) Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a phase I trial in rectal cancer patients. J Clin Oncol 23:8136–8139CrossRefGoogle Scholar
  26. 26.
    Koukourakis MI, Giatromanolaki A, Tsoutsou P, Lyratzopoulos N, Pitiakoudis M, Kouklakis G, Chloropoulou PA, Manolas K, Sivridis E (2011) Bevacizumab, capecitabine, amifostine, and preoperative hypofractionated accelerated radiotherapy (HypoARC) for rectal cancer: a Phase II study. Int J Radiat Oncol Biol Phys 80:492–498CrossRefGoogle Scholar
  27. 27.
    Salazar R, Capdevila J, Laquente B, Manzano JL, Pericay C, Villacampa MM, López C, Losa F, Safont MJ, Gómez A, Alonso V, Escudero P, Gallego J, Sastre J, Grávalos C, Biondo S, Palacios A, Aranda E (2015) A randomized phase II study of capecitabine-based chemoradiation with or without bevacizumab in resectable locally advanced rectal cancer: clinical and biological features. BMC Cancer 15:60CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department Radiotherapy/OncologyDemocritus University of ThraceAlexandroupolisGreece
  2. 2.Department of PathologyDemocritus University of ThraceAlexandroupolisGreece

Personalised recommendations