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Zentralbl Chir 2008; 133(2): 101-106
DOI: 10.1055/s-2008-1004741
Übersicht

© Georg Thieme Verlag Stuttgart · New York

Antikörpertherapie beim metastasierten kolorektalen Karzinom - was der Chirurg wissen sollte

Antibody Treatment in Colorectal Cancer - What the Surgeon Needs to KnowA. Thalheimer1 , B. Illert1 , P. Reimer2 , M. Bueter1 , A. Thiede1 , M. Gasser1 , M. Fein1 , A.-M. Waaga-Gasser1 , D. Meyer1
  • 1Chirurgische Klinik und Poliklinik I, Zentrum Operative Medizin der Universitätsklinik Würzburg
  • 2Medizinische Klinik und Poliklinik II der Universitätsklinik Würzburg
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Publication History

Publication Date:
15 April 2008 (online)

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Zusammenfassung

Fortschritte in der medikamentösen Therapie des kolorektalen Karzinoms haben in den letzten Jahren durch die Einführung neuer zytotoxischer Präparate zu einer signifikanten Verbesserung der Behandlung von betroffenen Patienten geführt. Neue Erkenntnisse in der molekularen Tumorbiologie führten zusätzlich zur Entwicklung einer Reihe von zielgerichteten, tumorspezifischen monoklonalen Antikörpern, die sich nun in verschiedenen Stadien der klinischen Erprobung befinden. Zwei dieser Antikörper, Cetuximab (Erbitux®) und Bevacizumab (Avastin®), gerichtet gegen den Epidermal Growth Factor Receptor (EGFR) bzw. den Vascular Epithelial Growth Factor (VEGF), wurden in der Zwischenzeit für die Behandlung des metastasierten kolorektalen Karzinoms zugelassen. Die Kombination von altbekannten und neuentwickelten Zytostatika mit monoklonalen Antikörpern hat die medikamentöse Behandlung des kolorektalen Karzinoms zwar wesentlich komplexer gemacht, bietet aber gerade Patienten mit Metastasen einen zusätzlichen Therapieansatz.

Abstract

Advances in the medical treatment of colorectal cancer patients have resulted in considerable improvements through the introduction of new cytotoxic drugs. The significant progress in molecular and tumour biology has produced a great number of targeted, tumour-specific, monoclonal antibodies that are now in various stages of clinical development. Two of these antibodies, cetuximab (Erbitux®) und bevacizumab (Avastin®), directed against the epidermal growth factor receptor (EGFR) and the vascular epithelial growth factor (VEGF), respectively, have recently been approved for use in metastatic colorectal cancer. The combination of well-known and newly developed cytotoxic agents with monoclonal antibodies makes the medical treatment of colorectal cancer patients considerably more complex, but also provides additional therapeutic strategies for patients in advanced stages of disease.

Schlüsselwörter

zielgerichtete Therapie - kolorektales Karzinom - EGFR - VEGF

Key words

targeted therapy - colorectal cancer - EGFR - VEGF

Literatur

  • 1 Akbulut H, Altuntas F, Akbulut K G, Ozturk G, Cindoruk M, Unal E, Icli F. Prognostic role of serum vascular endothelial growth factor, basic fibroblast growth factor and nitric oxide in patients with colorectal carcinoma.  Cytokine. 2002;  20 184-190
    CrossrefPubMedGoogle Scholar
  • 2 Baselga J. The EGFR as a target for anticancer therapy - focus on cetuximab.  Eur J Cancer. 2001;  37 Suppl 4 S16-S22
    PubMedGoogle Scholar
  • 3 Chaudhary V K, Fitzgerald D J, Adhya S, Pastan I. Activity of a recombinant fusion protein between transforming growth factor type alpha and Pseudomonas toxin.  Proc Natl Acad Sci USA. 1987;  84 4538-4542
    CrossrefPubMedGoogle Scholar
  • 4 Ciardiello F, Caputo R, Troiani T, Borriello G, Kandimalla E R, Agrawal S, Mendelsohn J, Bianco A R, Tortora G. Antisense oligonucleotides targeting the epidermal growth factor receptor inhibit proliferation, induce apoptosis, and cooperate with cytotoxic drugs in human cancer cell lines.  Int J Cancer. 2001;  93 172-178
    CrossrefPubMedGoogle Scholar
  • 5 Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer.  N Engl J Med. 2004;  351 337-345
    CrossrefPubMedGoogle Scholar
  • 6 de Gramont A, Bosset J F, Milan C, Rougier P, Bouche O, Etienne P L, Morvan F, Louvet C, Guillot T, Francois E, Bedenne L. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study.  J Clin Oncol. 1997;  15 808-815
    PubMedGoogle Scholar
  • 7 Ellerbroek S M, Halbleib J M, Benavidez M, Warmka J K, Wattenberg E V, Stack M S, Hudson L G. Phosphatidylinositol 3-kinase activity in epidermal growth factor-stimulated matrix metalloproteinase-9 production and cell surface association.  Cancer Res. 2001;  61 1855-1861
    PubMedGoogle Scholar
  • 8 Fan Z, Lu Y, Wu X, Mendelsohn J. Antibody-induced epidermal growth factor receptor dimerization mediates inhibition of autocrine proliferation of A 431 squamous carcinoma cells.  J Biol Chem. 1994;  269 27595-27602
    PubMedGoogle Scholar
  • 9 Ferrara N, Gerber H P, LeCouter J. The biology of VEGF and its receptors.  Nat Med. 2003;  9 669-676
    CrossrefPubMedGoogle Scholar
  • 10 Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease.  Nat Med. 1995;  1 27-31
    CrossrefPubMedGoogle Scholar
  • 11 Gordon M S, Cunningham D. Managing patients treated with bevacizumab combination therapy.  Oncology. 2005;  69 Suppl 3 25-33
    CrossrefPubMedGoogle Scholar
  • 12 Gordon M S, Margolin K, Talpaz M, Sledge Jr G W, Holmgren E, Benjamin R, Stalter S, Shak S, Adelman D. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer.  J Clin Oncol. 2001;  19 843-850
    PubMedGoogle Scholar
  • 13 Gross M E, Zorbas M A, Danels Y J, Garcia R, Gallick G E, Olive M, Brattain M G, Boman B M, Yeoman L C. Cellular growth response to epidermal growth factor in colon carcinoma cells with an amplified epidermal growth factor receptor derived from a familial adenomatous polyposis patient.  Cancer Res. 1991;  51 1452-1459
    PubMedGoogle Scholar
  • 14 Grothey A, Sargent D, Goldberg R M, Schmoll H J. 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 1209-1214
    CrossrefPubMedGoogle Scholar
  • 15 Heinzerling J H, Huerta S. Bowel perforation from Bevacizumab for the treatment of metastatic colon cancer: incidence, etiology, and management.  Curr Surg. 2006;  63 334-337
    CrossrefPubMedGoogle Scholar
  • 16 Hochster H S, Hart L L, Ramanathan R K, Hainsworth J D, Hedrick I I, Childs B H. Safety and efficacy of oxaliplatin / fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: final analysis of the TREE-study.  J Clin Oncol. 2006;  24 3510 ,  ASCO Annual Meeting Proceedings Part I Vol 24 No 18 S (June 20 supplement)
    CrossrefPubMedGoogle Scholar
  • 17 Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.  N Engl J Med. 2004;  350 2335-2342
    CrossrefPubMedGoogle Scholar
  • 18 Italiano A. Targeting the epidermal growth factor receptor in colorectal cancer: advances and controversies.  Oncology. 2006;  70 161-167
    CrossrefPubMedGoogle Scholar
  • 19 Kabbinavar F, Hurwitz H I, Fehrenbacher L, Meropol N J, Novotny W F, Lieberman G, Griffing S, Bergsland E. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU) / leucovorin (LV) with FU / LV alone in patients with metastatic colorectal cancer.  J Clin Oncol. 2003;  21 60-65
    CrossrefPubMedGoogle Scholar
  • 20 Kang S M, Maeda K, Onoda N, Chung Y S, Nakata B, Nishiguchi Y, Sowa M. Combined analysis of p53 and vascular endothelial growth factor expression in colorectal carcinoma for determination of tumor vascularity and liver metastasis.  Int J Cancer. 1997;  74 502-507
    CrossrefPubMedGoogle Scholar
  • 21 Khorana A A, Ryan C K, Cox C, Eberly S, Sahasrabudhe D M. Vascular endothelial growth factor, CD 68, and epidermal growth factor receptor expression and survival in patients with Stage II and Stage III colon carcinoma: a role for the host response in prognosis.  Cancer. 2003;  97 960-968
    CrossrefPubMedGoogle Scholar
  • 22 Koenders P G, Peters W H, Wobbes T, Beex L V, Nagengast F M, Benraad T J. Epidermal growth factor receptor levels are lower in carcinomatous than in normal colorectal tissue.  Br J Cancer. 1992;  65 189-192
    PubMedGoogle Scholar
  • 23 Kohne C H, Folprecht G. Current perspectives in the treatment of metastatic colorectal cancer.  Ann Oncol. 2004;  15 Suppl 4 iv 43-iv 53
    PubMedGoogle Scholar
  • 24 Lee J C, Chow N H, Wang S T, Huang S M. Prognostic value of vascular endothelial growth factor expression in colorectal cancer patients.  Eur J Cancer. 2000;  36 748-753
    CrossrefPubMedGoogle Scholar
  • 25 Lin Y S, Nguyen C, Mendoza J L, Escandon E, Fei D, Meng Y G, Modi N B. Preclinical pharmacokinetics, interspecies scaling, and tissue distribution of a humanized monoclonal antibody against vascular endothelial growth factor.  J Pharmacol Exp Ther. 1999;  288 371-378
    PubMedGoogle Scholar
  • 26 Lockhart A C, Berlin J D. The epidermal growth factor receptor as a target for colorectal cancer therapy.  Semin Oncol. 2005;  32 52-60
    CrossrefPubMedGoogle Scholar
  • 27 McKay J A, Murray L J, Curran S, Ross V G, Clark C, Murray G I, Cassidy J, McLeod H L. Evaluation of the epidermal growth factor receptor (EGFR) in colorectal tumours and lymph node metastases.  Eur J Cancer. 2002;  38 2258-2264
    CrossrefPubMedGoogle Scholar
  • 28 Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer.  J Clin Oncol. 2003;  21 2787-2799
    CrossrefPubMedGoogle Scholar
  • 29 Meropol N J, Berlin J D, Hecht J R, Croghan G A, Patnaik A, Weiner L M, Sweed M, Wiens B L, Caron D, Visonneau S. Multicenter study of ABX-EGF monotherapy in patients with metastatic colorectal cancer.  Proc Am Soc Clin Oncol. 2003;  22 (abstr 1026)
    PubMedGoogle Scholar
  • 30 National Institute for Health and Clinical Excellence .Final appraisal determination, Bevacizumab and cetuximab for metastatic colorectal cancer.  www.nice.org.uk 2006
    Google Scholar
  • 31 Ozawa S, Ueda M, Ando N, Abe O, Minoshima S, Shimizu N. Selective killing of squamous carcinoma cells by an immunotoxin that recognizes the EGF receptor.  Int J Cancer. 1989;  43 152-157
    CrossrefPubMedGoogle Scholar
  • 32 Peeters M, Van Cutsem E, Siena S, Humblet Y, Hendlisz A, Neyns J, Canon J, Van Laethem M, Amado R. A phase 3, multicenter, randomized controlled trial of panitumumab plus best supportive care (BSC) vs. BSC alone in patients with metastatic colorectal cancer.  Proc Am Soc Clin Oncol. 2006;  abstr 3548
    PubMedGoogle Scholar
  • 33 Perrotte P, Matsumoto T, Inoue K, Kuniyasu H, Eve B Y, Hicklin D J, Radinsky R, Dinney C P. Anti-epidermal growth factor receptor antibody C 225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice.  Clin Cancer Res. 1999;  5 257-265
    PubMedGoogle Scholar
  • 34 Prewett M C, Hooper A T, Bassi R, Ellis L M, Waksal H W, Hicklin D J. Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C 225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts.  Clin Cancer Res. 2002;  8 994-1003
    PubMedGoogle Scholar
  • 35 Radinsky R, Risin S, Fan D, Dong Z, Bielenberg D, Bucana C D, Fidler I J. Level and function of epidermal growth factor receptor predict the metastatic potential of human colon carcinoma cells.  Clin Cancer Res. 1995;  1 19-31
    PubMedGoogle Scholar
  • 36 Raymond E, Faivre S, Armand J P. Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy.  Drugs. 2000;  60 Suppl 1 15-23
    CrossrefPubMedGoogle Scholar
  • 37 Rougier P, Raoul J VLM, Mueser M. Cetuximab and FOLFIRI as first-line treatment for metastatic colorectal CA.  J Clin Oncol. 2004;  22 3 , ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 145 (July 15 Supplement), 2004: 3
    PubMedGoogle Scholar
  • 38 Roy H, Bhardwaj S, Yla-Herttuala S. Biology of vascular endothelial growth factors.  FEBS Lett. 2006;  580 2879-2887
    CrossrefPubMedGoogle Scholar
  • 39 Saltz L B, Meropol N J, Loehrer Sr P J, Needle M N, Kopit J, Mayer R J. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor.  J Clin Oncol. 2004;  22 1201-1208
    CrossrefPubMedGoogle Scholar
  • 40 Tabernero J, Van Cutsem E, Sastre J, Cervantes A, Mueser M. An international phase II study of cetuximab in combination with oxaliplatin / 5-FU / folinic acid (FOLFOX 4) in the first-line treatment of patients with metastatic colorectal cancer expressing Epidermal Growth Factor Receptor. Preliminary results.  J Clin Oncol. 2004;  22 39 ,  ASCO Annual Meeting Proceedings (Post Meeting Edition) Vol 22, No 145 (July 15 Supplement), 2004: 39
    PubMedGoogle Scholar
  • 41 Takahashi Y, Kitadai Y, Bucana C D, Cleary K R, Ellis L M. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer.  Cancer Res. 1995;  55 3964-3968
    PubMedGoogle Scholar
  • 42 Thirion P, Michiels S, Pignon J P, Buyse M, Braud A C, Carlson R W, O'Connell M, Sargent P, Piedbois P. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: an updated meta-analysis.  J Clin Oncol. 2004;  22 3766-3775
    PubMedGoogle Scholar
  • 43 Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study.  J Clin Oncol. 2004;  22 229-237
    CrossrefPubMedGoogle Scholar
  • 44 Tyagi P. Vatalanib (PTK787 / ZK 222584) in combination with FOLFOX4 versus FOLFOX4 alone as first-line treatment for colorectal cancer: preliminary results from the CONFIRM-1 trial.  Clin Colorectal Cancer. 2005;  5 24-26
    PubMedGoogle Scholar
  • 45 Warren R S, Yuan H, Matli M R, Gillett N A, Ferrara N. Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis.  J Clin Invest. 1995;  95 1789-1797
    CrossrefPubMedGoogle Scholar
  • 46 Weiner L M. Updated results from a dose and schedule study of Panitumumab monotherapy in patients with advanced solid malignancies.  Proc Am Soc Clin Oncol. 2005;  abstr 3059
    PubMedGoogle Scholar
  • 47 Wu X, Fan Z, Masui H, Rosen N, Mendelsohn J. Apoptosis induced by an anti-epidermal growth factor receptor monoclonal antibody in a human colorectal carcinoma cell line and its delay by insulin.  J Clin Invest. 1995;  95 1897-1905
    CrossrefPubMedGoogle Scholar

Dr. med. A. Thalheimer

Chirurgische Klinik und Poliklinik I · Zentrum Operative Medizin der Universitätsklinik Würzburg

Oberdürrbacher Str. 6

97080 Würzburg

Phone: 09 31 / 20 11

Email: Thalheimer_A@chirurgie.uni-wuerzburg.de

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