Journal Mobile Options
Table of Contents
Vol. 77, No. 2, 2009
Issue release date: August 2008

Risk of High-Grade Skin Rash in Cancer Patients Treated with Cetuximab – an Antibody against Epidermal Growth Factor Receptor: Systemic Review and Meta-Analysis

Su X. · Lacouture M.E. · Jia Y. · Wu S.
To view the fulltext, log in and/or choose pay-per-view option

Individual Users: Register with Karger Login Information

Please create your User ID & Password





Contact Information











I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in

Abstract

Background: Cetuximab, a chimeric antibody against epidermal growth factor receptor has emerged as an effective therapy for advanced colorectal cancer (CRC) and head-neck cancer. However, severe skin toxicity may limit its use. Its efficacy in the treatment of other cancers is also undergoing extensive investigation. We performed a systemic review and meta-analysis of published clinical trials to quantify the overall incidence and risk of severe skin rash. Methods: Databases Medline (OVID 1998 to July 2008), Web of Science, and abstracts presented at the American Society of Clinical Oncology conferences from 2004 through July 2008 were searched to identify relevant studies. Eligible studies include phase II and III clinical trials in which patients were treated with a single agent, i.e. cetuximab at 400 mg/m2 as initial dose followed by 250 mg/m2 weekly. Incidence, relative risk (RR), and 95% confidence intervals (CI) were calculated using a fixed-effects or random-effects model based on the heterogeneity of included studies. Results: A total of 2,037 patients with a variety of solid tumors from 16 trials were included for analysis. The overall incidence of all-grade skin rash was 88.2% (95% CI: 84.8–91.0%), with11.3% (95% CI: 8.8–14.3%) being high-grade (grade 3 or above). The overall incidence of all-grade acne-like skin rash was 81.6% (95% CI: 75.4–86.6%) with 6.5% (95% CI: 4.1–10.0%) being high-grade. Notably, patients with CRC exhibited a significantly higher incidence of high-grade skin rash (12.6%, 95% CI: 9.7–16.4%) than those with non-CRC (6.6%, 95% CI: 3.6–11.8%) with a risk ratio of 1.9 (95% CI: 1.0–3.6, p = 0.049). From randomized controlled studies, patients who received cetuximab had a significantly increased risk of developing high-grade skin rash in comparison with controls (RR 21.8, 95% CI: 6.9–68.8, p < 0.001). Conclusion: Cancer patients who received cetuximab have a substantial risk of developing high-grade skin rash. The risk may be particularly increased in patients with CRC. Further studies are strongly recommended for the prevention and treatment of high-grade skin rash.



Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Bianco R, Gelardi T, Damiano V, Ciardiello F, Tortora G: Rational bases for the development of EGFR inhibitors for cancer treatment. Int J Biochem Cell Biol 2007;39:1416–1431.
  2. Higashiyama S, Iwabuki H, Morimoto C, Hieda M, Inoue H, Matsushita N: Membrane-anchored growth factors, the epidermal growth factor family: beyond receptor ligands. Cancer Sci 2008;99:214–220.
  3. Normanno N, De Luca A, Bianco C, Strizzi L, Mancino M, Maiello MR, Carotenuto A, De Feo G, Caponigro F, Salomon DS: Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 2006;366:2–16.
  4. Ritter CA, Arteaga CL: The epidermal growth factor receptor-tyrosine kinase: a promising therapeutic target in solid tumors. Semin Oncol 2003;30:3–11.
  5. Sibilia M, Kroismayr R, Lichtenberger BM, Natarajan A, Hecking M, Holcmann M: The epidermal growth factor receptor: from development to tumorigenesis. Differentiation 2007;75:770–787.
  6. Brabender J, Danenberg KD, Metzger R, Schneider PM, Park J, Salonga D, Holscher AH, Danenberg PV: Epidermal growth factor receptor and HER2-neu mRNA expression in non-small cell lung cancer is correlated with survival. Clin Cancer Res 2001;7:1850–1855.
  7. Galizia G, Lieto E, Ferraraccio F, De Vita F, Castellano P, Orditura M, Imperatore V, La Mura A, La Manna G, Pinto M, Catalano G, Pignatelli C, Ciardiello F: Prognostic significance of epidermal growth factor receptor expression in colon cancer patients undergoing curative surgery. Ann Surg Oncol 2006;13:823–835.
  8. Yarden Y, Sliwkowski MX: Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001;2:127–137.
  9. Herbst RS, Shin DM: Monoclonal antibodies to target epidermal growth factor receptor-positive tumors: a new paradigm for cancer therapy. Cancer 2002;94:1593–1611.
  10. 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.
  11. Inoue K, Slaton JW, Perrotte P, Davis DW, Bruns CJ, Hicklin DJ, McConkey DJ, Sweeney P, Radinsky R, Dinney CP: Paclitaxel enhances the effects of the anti-epidermal growth factor receptor monoclonal antibody ImClone C225 in mice with metastatic human bladder transitional cell carcinoma. Clin Cancer Res 2000;6:4874–4884.
  12. Perrotte P, Matsumoto T, Inoue K, Kuniyasu H, Eve BY, Hicklin DJ, Radinsky R, Dinney CP: Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clin Cancer Res 1999;5:257–265.
  13. 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.
  14. Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J, Mayer RJ: 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.
  15. Souglakos J, Kalykaki A, Vamvakas L, Androulakis N, Kalbakis K, Agelaki S, Vardakis N, Tzardi M, Kotsakis AP, Gioulbasanis J, Tsetis D, Sfakiotaki G, Chatzidaki D, Mavroudis D, Georgoulias V: Phase II trial of capecitabine and oxaliplatin (CAPOX) plus cetuximab in patients with metastatic colorectal cancer who progressed after oxaliplatin-based chemotherapy. Ann Oncol 2007;18:305–310.
  16. Jonker DJ, O’Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R, Langer C, Moore MJ: Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007;357:2040–2048.
  17. Folprecht G, Lutz MP, Schoffski P, Seufferlein T, Nolting A, Pollert P, Kohne CH: Cetuximab and irinotecan/5-fluorouracil/folinic acid is a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing metastatic colorectal carcinoma. Ann Oncol 2006;17:450–456.
  18. Tabernero J, Van Cutsem E, Diaz-Rubio E, Cervantes A, Humblet Y, André T, Van Laethem JL, Soulie P, Casado E, Verslype C, Valera JS, Tortora G, Ciardiello F, Kisker O, de Gramont A: Phase II trial of cetuximab in combination with fluorouracil, leucovorin, and oxaliplatin in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2007;25:5225–5232.
  19. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, Ove R, Kies MS, Baselga J, Youssoufian H, Amellal N, Rowinsky EK, Ang KK: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354:567–578.
  20. Rosell R, Robinet G, Szczesna A, Ramlau R, Constenla M, Mennecier BC, Pfeifer W, O‘Byrne KJ, Welte T, Kolb R, Pirker R, Chemaissani A, Perol M, Ranson MR, Ellis PA, Pilz K, Reck M: Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer. Ann Oncol 2008;19:362–369.
  21. Burtness B: The role of cetuximab in the treatment of squamous cell cancer of the head and neck. Expert Opin Biol Ther 2005;5:1085–1093.
  22. Lordick F, Lorenzen S, Hegewisch-Becker S, Folprecht G, Wöll E, Decker T, Endlicher E, Röthling N, Fend F, Peschel C: Cetuximab plus weekly oxaliplatin/5FU/FA (FUFOX) in 1st line metastatic gastric cancer. Final results from a multicenter phase II study of the AIO upper GI Study Group. 2007 ASCO Annu Meet Proc. J Clin Oncol 2007;25:4526.
  23. Lacouture ME, Melosky BL: Cutaneous reactions to anticancer agents targeting the epidermal growth factor receptor: a dermatology-oncology perspective. Skin Therapy Lett 2007;12:1–5.
  24. Segaert S, Van Cutsem E: Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol 2005;16:1425–1433.
  25. Perez-Soler R, Saltz L: Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining? J Clin Oncol 2005;23:5235–5246.
  26. NCI: Common terminology criteria for adverse events (CTCAE) of National Cancer Institute 2006, http://ctep.cancer.gov/reporting/ctc_archive.html.
  27. Hanna N, Lilenbaum R, Ansari R, Lynch T, Govindan R, Janne PA, Bonomi P: Phase II trial of cetuximab in patients with previously treated non-small-cell lung cancer. J Clin Oncol 2006;24:5253–5258.
  28. Pessino A, Artale S, Sciallero S, Guglielmi A, Fornarini G, Andreotti IC, Mammoliti S, Comandini D, Caprioni F, Bennicelli E, Andretta V, Siena S, Sobrero A: First-line single-agent cetuximab in patients with advanced colorectal cancer. Ann Oncol 2008;19:711–716.
  29. Vermorken JB, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, Rolland F, Knecht R, Amellal N, Schueler A, Baselga J: Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol 2007;25:2171–2177.
  30. Gold PJ, Goldman B, Iqbal S, Leichman LP, Lenz HJ, Blanke CD: Cetuximab as second-line therapy in patients with metastatic esophageal cancer: A phase II Southwest Oncology Group Study. J Clin Oncol 2008;26: 222s (abstr 4536).
  31. Gruenwald V, Wilkens L, Gebel M, Wirth T, Greten T, Kubicka S, Manns MP, Ganser A, Malek NP: A phase II open-label study of cetuximab in unresectable hepatocellular carcinoma. 2006 ASCO Annu Meet Proc. J Clin Oncol 2006;24:14079.
  32. Lenz HJ, Mayer RJ, Mirtsching B, Cohn AL, Pippas A, Windt P, Cutsem Ev: Consistent response to treatment with cetuximab monotherapy in patients with metastatic colorectal cancer. 2005 ASCO Annu Meet Proc. J Clin Oncol 2005;23:3536.
  33. Licitra LF, Locati LD, Potepan P, Crippa F, Bossi P, Bergamini C, Rinaldi G, Liberatoscioli C, Perrone F, Losa M, Pilotti S: Cetuximab (C225) in recurrent and/or metastatic salivary gland carcinomas (RMSGCS): a monoinstitutional phase II study. 2006 ASCO Annu Meet Proc. J Clin Oncol 2006;24:5547.

    External Resources

  34. Maubec E, Petrow P, Duvillard P, Certain A, Duval X, Kerob D, Bagot M, Faivre S, Mentré F, Avril M: Cetuximab as first-line monotherapy in patients with unresectable squamous cell carcinoma of the skin: Preliminary results of a phase II multicenter study. J Clin Oncol 2008;26:493s (abstr 9042).
  35. Neyns B, Sadones J, Joosens E, Bouttens F, Verbeke L, Baurain JF, D’Hondt L, Chaskis C, Michotte A, Greve JD: A multicenter stratified phase II study of cetuximab for the treatment of patients with recurrent high-grade glioma. 2008 ASCO Annu Meet Proc. J Clin Oncol 2008;26:2017.

    External Resources

  36. Schilder RJ, Lokshin AE, Holloway RW, Alvarez RD, Pathak H, Aghajanian C, Drescher CW, Godwin AK: Phase II trial of single-agent cetuximab in patients with persistent or recurrent epithelial ovarian or primary peritoneal carcinoma with the potential for dose escalation to rash. 2007 ASCO Annu Meet Proc. J Clin Oncol 2007;25:5577.
  37. Wierzbicki R, Jonker DJ, Moore MJ, Berry SR, Loehrer PJ, Fox F, Katz T, Rowinsky EK, Youssoufian H: A phase II multicenter study of cetuximab monotherapy in patients with EGFR-undetectable refractory metastatic colorectal carcinoma (MCRC). J Clin Oncol 2008;26:194s (abstr 4065).
  38. Zhu AX, Blaszkowsky L, Enzinger PC, Bhargava P, Ryan DP, Meyerhardt J, Horgan K, Hale K, Sheehan S, Stuart K: Phase II study of cetuximab in patients with unresectable or metastatic hepatocellular carcinoma. 2006 ASCO Annu Meet Proc. J Clin Oncol 2006;24:14096.

    External Resources

  39. Nanney LB, Stoscheck CM, King LE Jr, Underwood RA, Holbrook KA: Immunolocalization of epidermal growth factor receptors in normal developing human skin. J Invest Dermatol 1990;94:742–748.
  40. Jost M, Kari C, Rodeck U: The EGF recep- tor – an essential regulator of multiple epidermal functions. Eur J Dermatol 2000;10:505–510.
  41. Lacouture ME: Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer 2006;6:803–812.
  42. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, Patterson SD, Chang DD: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008;26:1626–1634.
  43. De Roock W, Piessevaux H, De Schutter J, Janssens M, De Hertogh G, Personeni N, Biesmans B, Van Laethem JL, Peeters M, Humblet Y, Van Cutsem E, Tejpar S: KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol 2008;19:508–515.
  44. Di Fiore F, Blanchard F, Charbonnier F, Le Pessot F, Lamy A, Galais MP, Bastit L, Killian A, Sesboue R, Tuech JJ, Queuniet AM, Paillot B, Sabourin JC, Michot F, Michel P, Frebourg T: Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer 2007;96:1166–1169.
  45. Lièvre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, Côté JF, Tomasic G, Penna C, Ducreux M, Rougier P, Penault-Llorca F, Laurent-Puig P: KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 2006;66:3992–3995.
  46. Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR: K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008;359:1757–1765.
  47. Scope A, Agero AL, Dusza SW, Myskowski PL, Lieb JA, Saltz L, Kemeny NE, Halpern AC: Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption. J Clin Oncol 2007;25:5390–5396.
  48. Davies JM, Goldberg RM: First-line therapeutic strategies in metastatic colorectal cancer. Oncology (Williston Park) 2008;22:1470–1479; discussion 1479–1483.
  49. Giusti RM, Shastri K, Pilaro AM, Fuchs C, Cordoba-Rodriguez R, Koti K, Rothmann M, Men AY, Zhao H, Hughes M, Keegan P, Weiss KD, Pazdur R: US Food and Drug Administration approval: Panitumumab for epidermal growth factor receptor-expressing metastatic colorectal carcinoma with progression following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. Clin Cancer Res 2008;14:1296–1302.
  50. Saif MW, Cohenuram M: Role of panitumumab in the management of metastatic colorectal cancer. Clin Colorectal Cancer 2006;6:118–124.
  51. Cartwright TH, Genther R: Successful administration of panitumumab alone after severe infusion reaction to cetuximab in a patient with metastatic colorectal cancer. Clin Colorectal Cancer 2008;7:202–203.
  52. Heun J, Holen K: Treatment with panitumumab after a severe infusion reaction to cetuximab in a patient with metastatic colorectal cancer: A case report. Clin Colorectal Cancer 2007;6:529–531.
  53. Saif MW, Peccerillo J, Potter V: Successful re-challenge with panitumumab in patients who developed hypersensitivity reactions to cetuximab: Report of three cases and review of literature. Cancer Chemother Pharmacol 2009;63:1017–1022.


Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50