Strahlentherapie und Onkologie

, Volume 185, Issue 6, pp 371–378 | Cite as

Molecular targeted treatment and radiation therapy for rectal cancer

  • Friederike Marquardt
  • Franz Rödel
  • Gianni Capalbo
  • Christian Weiss
  • Claus Rödel
Original Article


EGFR (epidermal growth factor receptor) and VEGF (vascular endothelial growth factor) inhibitors confer clinical benefit in metastatic colorectal cancer when combined with chemotherapy. An emerging strategy to improve outcomes in rectal cancer is to integrate biologically active, targeted agents as triple therapy into chemoradiation protocols.

Material and Methods:

Cetuximab and bevacizumab have now been incorporated into phase I–II studies of preoperative chemoradiation therapy (CRT) for rectal cancer. The rationale of these combinations, early efficacy and toxicity data, and possible molecular predictors for tumor response are reviewed. Computerized bibliographic searches of Pubmed were supplemented with hand searches of reference lists and abstracts of ASCO and ASTRO meetings.


The combination of cetuximab and CRT can be safely applied without dose compromises of the respective treatment components. Disappointingly low rates of pathologic complete remission have been noted in several phase II studies. The K-ras mutation status and the gene copy number of EGFR may predict tumor response. The toxicity pattern (radiation-induced enteritis, perforations) and surgical complications (wound healing, fistula, bleeding) observed in at least some of the clinical studies with bevacizumab and CRT warrant further investigations.


Longer follow-up (and, finally, randomized trials) is needed to draw any firm conclusions with respect to local and distant failure rates, and toxicity associated with these novel treatment approaches.

Key Words:

Cetuximab Bevacizumab Chemoradiotherapy Rectal cancer 

Molekular-zielgerichtete Therapie und Bestrahlung zur Behandlung des Rektumkarzinoms


EGFR-(epidermaler Wachstumsfaktor-Rezeptor) und VEGF-Inhibitoren (vaskulärer endothelialer Wachstumsfaktor) zeigen beim metastasierten kolorektalen Karzinom in Kombination mit Chemotherapie einen klinischen Vorteil. Diese biologisch aktiven, zielgerichteten Substanzen werden als Dreifachtherapie zunehmend auch bei der Radiochemotherapie des Rektumkarzinoms eingesetzt.

Material und Methodik:

Cetuximab und Bevacizumab sind in Phase-I–II-Studien zur präoperativen Radiochemotherapie des Rektumkarzinoms getestet worden. Die Rationale für diese Kombination, erste Wirksamkeits- und Toxizitätsdaten sowie mögliche molekulare Responsemarker werden dargestellt. Dazu diente eine Suchabfrage in Pubmed, in Referenzlisten publizierter Arbeiten sowie Abstracts von ASCO- und ASTRO-Konferenzen.


Cetuximab und Radiochemotherapie können ohne Dosiskompromisse sicher miteinander kombiniert werden. Zahlreiche Phase-II-Studien ergaben allerdings enttäuschende Raten an pathologisch bestätigten kompletten Remissionen. Der K-ras-Mutationsstatus und die Anzahl an Genkopien des EGFR scheinen die Tumorantwort zu prädizieren. Das bei Kombination von Bevacizumab mit einer Radiochemotherapie beobachtete Toxizitätsspektrum (Enteritis, Perforationen) sowie die postoperativen Komplikationen (Wundheilungsstörungen, Fistelbildung, Blutungen) erfordern weitere Untersuchungen.


Längere Nachbeobachtungszeiten (und schließlich randomisierte Studien) sind nötig, um Daten zu Lokalrezidiv- und Fernmetastasenraten sowie zur Toxizität dieser Kombinationstherapien zu erhalten.


Cetuximab Bevacizumab Radiochemotherapie Rektumkarzinom 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Azria D, Bibeau F, Barbier N, et al. Prognostic impact of epidermal growth factor receptor (EGFR) expression on loco-regional recurrence after preoperative radiotherapy in rectal cancer. BMC Cancer 2005;5:62.PubMedCrossRefGoogle Scholar
  2. 2.
    Bengala C, Bettelli S, Bertolini F, et al. Predictive value of EGFR gene copy number and K-ras mutation for pathological response to preoperative cetuximab, 5FU, and radiation therapy in locally advanced rectal cancer (LARC). J Clin Oncol 2008;26:4125.abstract.Google Scholar
  3. 3.
    Bertolini F, Bengala C, Losi L, et al. Prognostic and predictive value of baseline and posttreatment molecular marker expression in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy. Int J Radiat Oncol Biol Phys 2007;68:1455–61.PubMedGoogle Scholar
  4. 4.
    Bertolini F, Zironi S, Malavasi N, et al. Phase II study of pre-operative cetuximab, fluorouracil (5FU), and radiotherapy (RT) in patients with rectal cancer (RC). ASCO Gastrointestinal Cancers Symposium, Orlando, FL, USA, 19.1.2007.abstract 308.Google Scholar
  5. 5.
    Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354:567–78.PubMedCrossRefGoogle Scholar
  6. 6.
    Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006;355:1114–23.PubMedCrossRefGoogle Scholar
  7. 7.
    Cabebe EC, Kuo T, Koong A, et al. Phase I trial of preoperative cetuximab in combination with oxaliplatin, capecitabine, and radiation therapy for locally advanced rectal cancer. J Clin Oncol 2008;26:15019.abstract.Google Scholar
  8. 8.
    Cascinu S, Graziano F, Catalano V, et al. An analysis of p53, BAX and vascular endothelial growth factor expression in node-positive rectal cancer. Relationships with tumour recurrence and event-free survival of patients treated with adjuvant chemoradiation. Br J Cancer 2002;86:744–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Chung KY, Minsky B, Schrag D, et al. Phase I trial of preoperative cetuximab with concurrent continuous infusion 5-fluorouracil and pelvic radiation in patients with local-regionally advanced rectal cancer. J Clin Oncol 2006;24:3560.abstract.Google Scholar
  10. 10.
    Crane CH, Eng CB, Feig W, et al. Phase II trial of neoadjuvant bevacizumab (BEV), capecitabine (CAP), and radiotherapy (XRT) for locally advanced rectal cancer. J Clin Oncol 2008;26:4091.abstract.Google Scholar
  11. 11.
    Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337–45.PubMedCrossRefGoogle Scholar
  12. 12.
    Czito BG, Bendell JC, Willett CG, et al. Bevacizumab, oxaliplatin, and capecitabine with radiation therapy in rectal cancer: phase I trial results. Int J Radiat Oncol Biol Phys 2007;68:472–8.PubMedGoogle Scholar
  13. 13.
    De Roock W, Piessevaux H, De Schutter J, et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol 2008;19:508–15.PubMedCrossRefGoogle Scholar
  14. 14.
    DiPetrillo TA, Pricolo V, Sikov WM, et al. Neoadjuvant bevacizumab, oxaliplatin, 5-fluorouracil, and radiation in clinical stage II-III rectal cancer. J Clin Oncol 2008;26:15041.abstract.Google Scholar
  15. 15.
    Gerard JP, Conroy T, Bonnetain F, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 2006;24:4620–5.PubMedCrossRefGoogle Scholar
  16. 16.
    Giralt J, de las Heras M, Cerezo L, et al. The expression of epidermal growth factor receptor results in a worse prognosis for patients with rectal cancer treated with preoperative radiotherapy: a multicenter, retrospective analysis. Radiother Oncol 2005;74:101–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Giralt J, Eraso A, Armengol M, et al. Epidermal growth factor receptor is a predictor of tumor response in locally advanced rectal cancer patients treated with preoperative radiotherapy. Int J Radiat Oncol Biol Phys 2002;54:1460–5.PubMedGoogle Scholar
  18. 18.
    Giralt J, Navalpotro B, Hermosilla E, et al. Prognostic significance of vascular endothelial growth factor and cyclooxygenase-2 in patients with rectal cancer treated with preoperative radiotherapy. Oncology 2006;71:312–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Gorski DH, Beckett MA, Jaskowiak NT, et al. Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res 1999;59:3374–8.PubMedGoogle Scholar
  20. 20.
    Haustermans K, Roels S, Verstraete J, et al. Adaptive RT in rectal cancer: superior to 3D-CRT? A simple question, a complex answer. Strahlenther Onkol 2007;183:Special Issue 2:21–3.CrossRefGoogle Scholar
  21. 21.
    Hofheinz RD, Horisberger K, Woernle C, et al. Phase I trial of cetuximab in combination with capecitabine, weekly irinotecan, and radiotherapy as neoadjuvant therapy for rectal cancer. Int J Radiat Oncol Biol Phys 2006;66:1384–90.PubMedGoogle Scholar
  22. 22.
    Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335–42.PubMedCrossRefGoogle Scholar
  23. 23.
    Kim JS, Kim JM, Li S, et al. Epidermal growth factor receptor as a predictor of tumor downstaging in locally advanced rectal cancer patients treated with preoperative chemoradiotherapy. Int J Radiat Oncol Biol Phys 2006;66:195–200.PubMedGoogle Scholar
  24. 24.
    Kopp R, Rothbauer E, Mueller E, et al. Reduced survival of rectal cancer patients with increased tumor epidermal growth factor receptor levels. Dis Colon Rectum 2003;46:1391–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Lee CG, Heijn M, di Tomaso E, et al. Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res 2000;60:5565–70.PubMedGoogle Scholar
  26. 26.
    Li S, Kim JS, Kim JM, et al. Epidermal growth factor receptor as a prognostic factor in locally advanced rectal-cancer patients treated with preoperative chemoradiation. Int J Radiat Oncol Biol Phys 2006;65:705–12.PubMedGoogle Scholar
  27. 27.
    Lordick F, Geinitz H, Theisen J, et al. Increased risk of ischemic bowel complications during treatment with bevacizumab after pelvic irradiation: report of three cases. Int J Radiat Oncol Biol Phys 2006;64:1295–8.PubMedGoogle Scholar
  28. 28.
    Machiels JH, Debucquoy A, Gevaert O, et al. Prediction of pathological response to preoperative chemoradiotherapy with cetuximab in rectal cancer. J Clin Oncol 2008;26:4095.abstract.CrossRefGoogle Scholar
  29. 29.
    Machiels JP, Sempoux C, Scalliet P, et al. Phase I/II study of preoperative cetuximab, capecitabine, and external beam radiotherapy in patients with rectal cancer. Ann Oncol 2007;18:738–44.PubMedCrossRefGoogle Scholar
  30. 30.
    Marijnen CA. Preoperative chemoradiotherapy regimen with capecitabine and bevacizumab in locally advanced rectal cancer: a feasibility study of the Dutch Colorectal Cancer Group (DCCG). Proc Am Soc Clin Oncol 2008;27:abstract 15040.Google Scholar
  31. 31.
    Milani V, Pazos M, Issels RD, et al. Radiochemotherapy in combination with regional hyperthermia in preirradiated patients with recurrent rectal cancer. Strahlenther Onkol 2008;184:163–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Milas L, Mason K, Hunter N, et al. In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody. Clin Cancer Res 2000;6:701–8.PubMedGoogle Scholar
  33. 33.
    Moosmann N, Heinemann V. Cetuximab plus oxaliplatin-based chemotherapy in the treatment of colorectal cancer. Expert Rev Anticancer Ther 2008;8:319–29.PubMedCrossRefGoogle Scholar
  34. 34.
    Morelli MP, Cascone T, Troiani T, et al. Sequence-dependent antiproliferative effects of cytotoxic drugs and epidermal growth factor receptor inhibitors. Ann Oncol 2005;16:Suppl 4:iv61–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Negri FV, Campanini N, Camisa R, et al. Biological predictive factors in rectal cancer treated with preoperative radiotherapy or radiochemotherapy. Br J Cancer 2008;98:143–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Paris F, Fuks Z, Kang A, et al. Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science 2001;293:293–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Rhomberg W, Hammer J, Sedlmayer F, et al. Irradiation with and without razoxane in the treatment of incompletely resected or inoperable recurrent rectal cancer. Results of a small randomized multicenter study. Strahlenther Onkol 2007;183:380–4.PubMedCrossRefGoogle Scholar
  38. 38.
    Rödel C, Arnold D, Hipp M, et al. Phase I-II trial of cetuximab, capecitabine, oxaliplatin, and radiotherapy as preoperative treatment in rectal cancer. Int J Radiat Oncol Biol Phys 2008;70:1081–6.PubMedGoogle Scholar
  39. 39.
    Rödel C, Sauer R. Integration of novel agents into combined-modality treatment for rectal cancer patients. Strahlenther Onkol 2007;183:227–35.PubMedCrossRefGoogle Scholar
  40. 40.
    Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731–40.PubMedCrossRefGoogle Scholar
  41. 41.
    Spindler KL, Nielsen JN, Lindebjerg J, et al. Prediction of response to chemoradiation in rectal cancer by a gene polymorphism in the epidermal growth factor receptor promoter region. Int J Radiat Oncol Biol Phys 2006;66:500–4.PubMedGoogle Scholar
  42. 42.
    Valentini V, De Paoli A, Gambacorta MA, et al. Infusional 5-fluorouracil and ZD1839 (fefitinib-IRESSA) in combination with preoperative radiotherapy in patients with locally advanced rectal cancer: a phase I and II trial (1839IL/0092). Int J Radiat Oncol Biol Phys 2008;72:644–9.PubMedGoogle Scholar
  43. 43.
    Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 2004;10:145–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Willett CG, Boucher Y, Duda DG, et al. 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 2005;23:8136–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Willett CG, Duda DG, Xu L, et al. Correlation of blood and physiologic markers with effect of bevacizumab (BV) with chemoradiation therapy in rectal cancer (RC). J Clin Oncol 2008;26:4096.abstract.Google Scholar
  46. 46.
    Wollman R, Yahalom J, Maxy R, et al. Effect of epidermal growth factor on the growth and radiation sensitivity of human breast cancer cells in vitro. Int J Radiat Oncol Biol Phys 1994;30:91–8.PubMedGoogle Scholar
  47. 47.
    Zlobec I, Vuong T, Compton CC, et al. Combined analysis of VEGF and EGFR predicts complete tumour response in rectal cancer treated with preoperative radiotherapy. Br J Cancer 2008;98:450–6.PubMedCrossRefGoogle Scholar

Copyright information

© Urban & Vogel, Muenchen 2009

Authors and Affiliations

  • Friederike Marquardt
  • Franz Rödel
  • Gianni Capalbo
  • Christian Weiss
  • Claus Rödel
    • 1
    • 2
  1. 1.Department of Radiation TherapyUniversity of Frankfurt/MainFrankfurt/MainGermany
  2. 2.Klinik für Strahlentherapie und OnkologieGoethe-Universität Frankfurt/MainFrankfurt/MainGermany

Personalised recommendations