Der Klinikarzt 2006; 35(3): 109-114
DOI: 10.1055/s-2006-939737
In diesem Monat

© Georg Thieme Verlag Stuttgart · New York

Klinischer Nutzen und Perspektive - EGF-Rezeptorinhibitoren in der Tumortherapie

Clinical Benefits and Perspectives - EGF Receptor Inhibitors in Tumour TherapyS. Peinert1 , D. Arnold1
  • 1Klinik für Innere Medizin IV, Martin-Luther-Universität, Halle-Wittenberg (Direktor: Prof. Dr. H.-J. Schmoll)
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
24. März 2006 (online)

Zusammenfassung

Die Therapie mit molekularen, gegen den EGF-Rezeptor gerichteten Therapien ist bereits heute bei mehreren Tumorentitäten Standard. Aufgrund der Bedeutung des EGFR für die maligne Signaltransduktion und die Differenzierung bei vielen Tumorarten ist davon auszugehen, dass beide Wirkprinzipien, sowohl die extrazelluläre Blockade durch monoklonale Antikörper wie die intrazelluläre Inhibition der Tyrosinkinase des Rezeptors durch „small molecules”, bei zahlreichen weiteren Tumorentitäten einen Wirksamkeitsnachweis zeigen. Sie verbessern damit bei vielen Patienten die Prognose und geben sogar manchen die Chance auf Heilung ihres metastasierten Krankheitsstadiums.

Summary

Treatment employing molecular therapies directed against the EGF receptor has already become a standard procedure for several tumour entities. On account of the significance of the EGF receptor for the malignant signal transduction and the differentiation in a great variety of tumours we can assume that in numerous other tumour entities both active principles will be effective, namely, the extracellular blockade by monoclonal antibodies as well as the intracellular inhibition of tyrosine kinase of the receptor by "small molecules". Thus, prognosis will be improved for many patients and in quite a number of cases there is a chance that the metastasized stage of their disease may be cured.

Literatur

  • 1 Arnold D, Peinert S, Voigt W, Schmoll -J H.. Epidermal growth factor receptor tyrosine kinase inhibitors: present and future role in gastrointestinal cancer treatment. The Oncologist 2006
  • 2 Bailey R, Kris M, Wolf M. et al. . Tumor EGFR membrane staining is not clinically relevant for predicting response in patients receiving gefitinib ('Iressa', ZD 1839) monotherapy for pretreated advanced non-small-cell lung cancer: IDEAL 1 and 2.  Proc Am Assoc Cancer Res. 2003;  44 1362
  • 3 Baselga J, Pfister D, Cooper MR. et al. . Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin.  J Clin Oncol. 2000;  18 904-914
  • 4 Baselga J, Trigo JM, Bourhis J. et al. . Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck.  J Clin Oncol. 2005;  23 5568-5577
  • 5 Blaszkowsky LS, Kulke KH, Ryan DP. et al. . A phase II study of erlotinib in combination with capecitabine in previously treated patients with metastatic pancreatic cancer.  Proc Am Soc Clin Oncol. 2005;  23 4099
  • 6 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;  354 567-578
  • 7 Bos M, Mendelsohn J, Kim YM. et al. . PD153035, a tyrosine kinase inhibitor, prevents epidermal growth factor receptor activation and inhibits growth of cancer cells in a receptor number-dependent manner.  Clin Cancer Res. 1997;  3 2099-2106
  • 8 Burtness BA, Li Y, Flood W. et al. . Phase III randomized trial of cisplatin + placebo versus cisplatin + C225, a monoclonal antibody directed to the epidermal growth factor-receptor: An Eastern Cooperative Oncology Group trial.  Proc Am Assoc Cancer Res. 2003;  77
  • 9 Cerny T, Barnes DM, Hasleton P. et al. . Expression of epidermal growth factor receptor (EGF-R) in human lung tumors.  Br J Cancer. 1986;  54 265-259
  • 10 Chen YJ, Lin SC, Kao T. et al. . Genome-wide profiling of oral squamous cell carcinoma.  J Pathol. 2004;  204 326-332
  • 11 Chung KY, Shia J, Kemeny NE. et al. . Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry.  J Clin Oncol. 2005;  23 1803-1810
  • 12 Ciardiello F, Bianco R, Damiano V. et al. . Antitumor activity of sequential treatment with topotecan and anti-epidermal growth factor receptor monoclonal antibody C225.  Clin Cancer Res. 1999;  5 909-916
  • 13 Cohen EE, Haraf DJ, Stenson KM. et al. . Integration of gefitinib (G), into a concurrent chemoradiation (CRT) regimen followed by G adjuvant therapy in patients with locally advanced head and neck cancer (HNC) - a Phase II Trial.  Proc Am Soc Clin Oncol. 2005;  23 5506
  • 14 Cohen EE, Kane MA, List M. et al. . Phase II trial of gefitinib 250mg daily in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.  Clin Cancer Res. 2005;  11 8418-8424
  • 15 Cohen EE, Rosen F, Stadler WM. et al. . Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck.  J Clin Oncol. 2003;  21 1980-1987
  • 16 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;  351 337-345
  • 17 Diaz-Rubio E, Tabernero J, van Cutsem E. et al. . Cetuximab in combination with oxaliplatin/5-fluorouracil (5-FU)/folinic acid (FA) (FOLFOX-4) in the first-line treatment of patients with epidermal growth factor receptor (EGFR) - expressing metastatic colorectal cancer: An international phase II study.  Proc Am Soc Clin Oncol. 2005;  23 3535
  • 18 Fan Z, Lu Y, Wu X. et al. . Antibody-induced epidermal growth factor dimerization mediates inhibition of autocrine proliferation of A431 squamous carcinoma cells.  J Biol Chem. 1994;  269 27595-27602
  • 19 Fisher GA, Cho CD, Halsey J. et al. . A phase II study of gefitinib in combination with FOLFOX-4 (IFOX) in patients with metastatic colorectal cancer.  Proc Am Soc Clin Oncol. 2004;  22 187
  • 20 Folprecht G, Lutz MP, Soffski P. et al. . Cetuximab and irinotecan/5-fluorouracil/folinic acid is a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing colorectal carcinoma.  Ann Oncol. 2006;  17 450-456
  • 21 Forastiere AA, Metch B, Schuller DE. et al. . Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study.  J Clin Oncol. 1992;  10 1245-1251
  • 22 Fukuoka M, Yano S, Giaccone G. et al. . Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer.  J Clin Oncol. 2003;  21 2237-2246
  • 23 Gatzemeier U, Pluzanska A, Szczesna A. et al. . Results of a phase III trial of erlotinib (OSI-774) combined with cisplatin and gemcitabine (GC) chemotherapy in advanced non-small-cell lung cancer (NSCLC).  Proc Am Soc Clin Oncol. 2004;  22 7010
  • 24 Giaccone G, Herbst RS, Manegold C. et al. . Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial-INTACT 1.  J Clin Oncol. 2004;  22 777-784
  • 25 Goldstein NS, Armin M. Epidermal growth factor receptor immunohistochemical reactivity in patients with American Joint Committee on Cancer stage IV colon adenocarcinoma: implications for a standardized scoring system.  Cancer. 2001;  92 13311346
  • 26 Graeven U, Vogel I, Killing B. et al. . Phase I study of the humanized IgG1 anti EGFR monoclonal antibody EMD 72000 plus Gemcitabine in advanced pancreatic cancer.  Proc Am Soc Clin Oncol. 2004;  23 210
  • 27 Hecht J, Patnaik A, Malik I. et al. . ABX-EGF monotherapy in patients (pts) with metastatic colorectal cancer (mCRC): An updated analysis.  Proc Am Soc Clin Oncol. 2004;  22 3511
  • 28 Hecht. ASCO GI 2006
  • 29 Hemming AW, Davis NL, Kluftinger A. et al. . Prognostic markers of colorectal cancer: an evaluation of DNA content, epidermal growth factor receptor, and Ki-67.  J Surg Oncol. 1992;  51 147-152
  • 30 Herbst RS, Arquette M, Shin DM. et al. . Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck.  J Clin Oncol. 2005;  23 5440-5442
  • 31 Herbst RS, Giaccone G, Schiller JH. et al. . Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial - INTACT 2.  J Clin Oncol. 2004;  22 785-794
  • 32 Herbst RS, Prager D, Hermann R. et al. . TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer.  J Clin Oncol. 2005;  23 5892
  • 33 Huang SM, Bock JM, Harari PM. Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck.  Cancer Res. 1999;  59 1935-1940
  • 34 Huang SM, Li J, Harari PM. Molecular inhibition of angiogenesis and metastatic potential in human squamous cell carcinomas after epidermal growth factor receptor blockade.  Mol Cancer Ther. 2002;  1 507-514
  • 35 Jacobs C, Lyman G, Velez-Garcia E. et al. . A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carconoma of the head and neck.  J Clin Oncol. 1992;  10 257-263
  • 36 Keilholz U, Arnold D, Niederle N. et al. . Erlotinib ans 2nd and 3rd line monotherapy in patients with metastatic colorectal cancer. Results of a multicenter two-cohort phase II trial.  Proc Am Soc Clin Oncol. 2005;  23 3575
  • 37 Kim ES, Kies M, Sabichi A. et al. . Phase II study of combination cisplatin, docetaxel and erlotinib in patients with metastatic/recurrent head and neck squamous cell carcinoma (HNSCC).  Proc Am Soc Clin Oncol. 2005;  23 5546
  • 38 Kim ES, Mauer AM, Tran HT. et al. . A phase II study of cetuximab, an epidermal growth factor receptor (EGFR) blocking antibody, in combination with docetaxel in chemotherapy refractory/resistant patients with advanced non-small cell lung cancer: final report.  Proc Am Soc Clin Oncol. 2003;  22 642
  • 39 Kobayashi S, Boggon TJ, Dayaram T. et al. . EGFR mutation and resistance of NSCLC to gefitinib.  N Engl J Med. 2005;  352 786-792
  • 40 Kris MG, Matale RB, Herbst RS. et al. . Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial.  JAMA. 2003;  290 2149-2158
  • 41 Lemoine NR, Hughes CM, Barton CM. et al. . The epidermal growth factor receptor in human pancreatic cancer.  J Pathol. 1992;  166 7-12
  • 42 Lenz H. ASCO 2005
  • 43 Lordick F, Arnold D, Hoehler T. et al. . Cetuximab in Combination with 5-fluorouracil (5-FU)/folinic acid (FA) plus weekly oxaliplatin (L-OHP) (FUFOX) in the first-line treatment of patients with metastatic colorectal cancer (mCRC) expressing epidermal growth factor receptor (EGFR). Results of a multicenter phase I/II study.  Proc Am Soc Clin Oncol GI Cancer Symposium. 2005;  23 247
  • 44 Lynch TJ, Bell DW, Sordella R. et al. . Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.  N Engl J Med. 2004;  350 2129-2139
  • 45 Masui H, Kawamoto T, Sato JD. et al. . Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies.  Cancer Res. 1984;  44 1002-1007
  • 46 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
  • 47 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;  6 701-708
  • 48 Moore MJ, Goldstein D, Hamm J. et al. . Erlotinib plus gemcitabine compared to gemcitabine alone in patients with advanced pancreatic cancer. A phase III trial of the National Cancer Institute of Canada Trials Group [NCIC-CTG].  Proc Am Soc Clin Oncol. 2005;  23 1
  • 49 Muthuswamy SK, Gilman M, Brugge JS. Controlled dimerization of ErbB receptors provides evidence for differential signalling by homo- and heterodimers.  Mol Cell Biol. 1999;  19 6845-6857
  • 50 Normanno N, Bianco C, De Luca A. et al. . Target-based agents against ErbB receptors and their ligands: a novel approach to cancer treatment.  Endocr Relat Cancer. 2003;  10 1-21
  • 51 Overholser JP, Prewett AC, Hooper AT. et al. . EGFR blockade by antibody C225 inhibits growth of human pancreatic xenograft in nude mice.  Cancer. 2000;  89 74-82
  • 52 Oza A, Townsley C, Siu L. et al. . Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer.  Proc Am Soc Clin Oncol. 2003;  22 785
  • 53 Paez JG, Janne PA, Lee JC. et al. . EGFR mutation in lung cancer: correlation with clinical response to gefitinib therapy.  Science. 2004;  304 1497-1500
  • 54 Pao W, Miller V, Zakowski M. et al. . EGF receptor gene mutations are common in lung cancers from „never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib.  Proc Natl Acad Sci USA. 2004;  10 13306-13311
  • 55 Perez-Soler R, Chachoua A, Huberman M. et al. . Final results from a phase II study of erlotinib (TarcevaTM) monotherapy in patients with advanced non-small cell lung cancer following failure of platinum-based chemotherapy.  Lung Cancer. 2003;  41 S246
  • 56 Pignon JP, Bourhis J, Domenge C. et al. . Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of chemotherapy on head and neck cancer.  Lancet. 2000;  355 949-955
  • 57 Robert F, Bumenschein G, Herbst RS. et al. .Phase I/Iia study of cetuximab with gemcitabine plus Carboplatin in patients with ehemotherapy-naïve advanced non-small-cell lung cancer. J Clin Oncol 2005: 9089-9096
  • 58 Rosell R, Daniel C, Ramlau R. et al. . Randomized phase II study of cetuximab in combination with cisplatin (C) and vinorelbine (V) vs. CV alone in first-line treatment of patients with epidermal growth factor receptor (EGFR) - expressing advanced non-small cell lung cancer (NSCLC).  Proc Am Soc Clin Oncol. 2004;  23 618
  • 59 Rothenberg M, Lafleur B, Washington M. et al. . Changes in epidermal growth factor receptor signalling in serum and tumor biopsies obtained from patients with progressive metastatic colorectal cancer (MCRC) treated with gefitinib (ZD1839): An Eastern Cooperative Oncology Group study.  Proc Am Soc Clin Oncol. 2004;  22 3000
  • 60 Rougier. ASCO 2005
  • 61 Salomon DS, Brandt R, Ciardiello F. et al. . Epidermal growth factor-related peptides and their receptors in human malignancies.  Crit Rev Oncol Hematol. 1995;  19 183-232
  • 62 Saltz LB, Meropol NJ, Loehrer Sr PJ. et al. . 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
  • 63 Sato JD, Kawamoto T, Le AD. et al. . Biological effect in vitro of monoclonal antibodies to human EGF receptors.  Mol Biol Med. 1983;  1 511-529
  • 64 Shepherd FA, Pereira J, Ciuleanu TE. et al. . Erlotinib in previously treated non-small-cell lung cancer.  N Engl J Med. 2005;  353 123-132
  • 65 Shibuya K, Mathers CD, Boschi-Pinto C. et al. . Global and regional estimates of cancer mortality and incidence by site: II. Results for the global burden of disease 2000.  BMC Cancer. 2002;  2 37
  • 66 Soulieres D, Senzer NN, Vokes EE. et al. . Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck.  J Clin Oncol. 2004;  22 77-85
  • 67 Thatcher N, Chang A, Parikh P. et al. .Results of a placebo-controlled study (ISEL) of gefitinib (Iressa) plus best supportive care (BSC) in patients with advanced non-squamous cell lung cancer who had received 1 or 2 prior chemotherapy regimen. Proc Am Assoc Cancer Res 2005: 46
  • 68 Thienelt CD, Bunn jr. PA, Hanna N. et al. . Multicenter phase I/II study of cetuximab with Paclitaxel and Carboplatin in untreated patients with stage IV non-small-cell lung cancer.  J Clin Oncol. 2005;  23 8786-8793
  • 69 Tokumo M, Toyooka S, Kiura K. et al. . The relationship between EGFR mutations and clinicopathologic features in NSCLC.  Clin Cancer Res. 2005;  11 1167-1173
  • 70 Trigo J, Hitt R, Koralewski P. et al. . Cetuximab monotherapy is active in patients (pts) with platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN): results of a phase II study.  Proc Am Soc Clin Oncol. 2004;  1221 5502
  • 71 Tsao MS, Sakurada A, Cutz JC. et al. . Erlotinib in lung cancer - clinical and molecular predictors of outcome.  N Engl J Med. 2005;  353 133-144
  • 72 Veale D, Kerr N, Gibson GJ. et al. . The relationship of quantitative epidermal growth factor receptor expression in non-small cell lung cancer to long term survival.  Br J Cancer. 1993;  68 162-165
  • 73 Wheeler RH, Jones D, Sharma P. et al. . Clinical and molecular phase II study of gefitinib in patients (pts) with recurrent squamous cell cancer of the head and neck (H&N Ca).  Proc Am Soc Clin Oncol. 2005;  23 5531
  • 74 Xiong HQ, Abbruzzese JL. Epidermal growth factor receptor-targeted therapy for pancreatic cancer.  Semin Oncol. 2002;  29 31-37
  • 75 Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network.  Nat Rev Mol Cell Biol. 2001;  2 127-137
  • 76 Zampino MG, Lorizzo K, Massacesi C. et al. . First-line gefitinib combined with simplified FOLFOX-6 in patients with epidermal growth factor receptor-positive advanced colorectal cancer.  Ann Oncol. 2004;  15 266PD

1 Bowel ONcology with Cetuximab AntiboDy

2 Pan-European Trials in Alimentary Tract Cancer

Anschrift für die Verfasser

Dr. Dirk Arnold

Klinik für Innere Medizin IV

Martin-Luther-Universität Halle-Wittenberg

Ernst-Grube-Str. 40

06120 Halle/Saale

    >