Skip to main content

Advertisement

SpringerLink
Log in

Efficacy and toxicity of adding cetuximab to chemotherapy in the treatment of metastatic colorectal cancer: a meta-analysis from 12 randomized controlled trials

  • Research Article
  • Published:
Tumor Biology

Abstract

Cetuxiamb, a monoclonal antibody against epidermal growth factor receptor (EGFR), has been used in combination with chemotherapy for patients with metastatic colorectal cancer (mCRC). However, the efficacy of combined therapies of cetuximab and different chemotherapy regimens remains controversial. Therefore, we conducted a meta-analysis to evaluate the efficacy and toxicity of adding cetuximab to oxaliplatin-based or irinotecan-based chemotherapeutic regimens for the treatment of patients with mCRC with wild-type/mutated KRAS tumors. Randomized controlled trials (RCTs), published in Pubmed and Embase were systematically reviewed to assess the survival benefits and toxicity profile mCRC patients treated with cetuximab plus chemotherapy. Outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and toxicities. Results were expressed as the hazard ratio (HR) with 95 % confidence intervals (CI). Pooled estimates were generated by using a fixed-effects model or a randomized-effects model, depending on the heterogeneity among studies. A total of 12 trials involving 6,297 patients met the inclusion criteria and were included in this meta-analysis. All patients were administered oxaliplatin-based or irinotecan-based chemotherapy with or without cetuximab. Pooled results showed that the addition of cetuximab did not significantly improve the OS (HR = 0.99, 95 % CI = 0.89–1.09; Z = 0.28, P = 0.78) or PFS (HR = 0.94, 95 % CI = 0.81–1.10; Z = 0.76, P = 0.49), but did improve ORR (RR = 1.34, 95 % CI = 1.08–1.65; Z = 2.72, P = 0.00), when compared with chemotherapy alone. Subgroup analysis showed the highest PFS benefit in patients with wild-type KRAS tumors (HR = 0.80, 95 % CI = 0.65–0.99; Z = 2.1, P = 0.04) or wild-type KRAS/BRAF tumors (HR = 0.64, 95 % CI = 0.52–0.79; Z = 4.15, P = 0.00). When combined with cetuximab, irinotecan-based chemotherapy was significantly associated with prolonged PFS (HR = 0.79, 95 % CI = 0.66–0.96; Z = 2.36, P = 0.02) for all patients with differing gene-status. The incidence of grade 3/4 adverse events, including skin toxicity, diarrhea, hypertension, anorexia, and mucositis/stomatitis, was slightly higher in the combined therapy group than in the chemotherapy-only group. Based on the current evidence, the addition of cetuximab to chemotherapy significantly improves the PFS in patients with wild-type KRAS or wild-type KRAS/BRAF tumors as well as the ORR in all patients. In addition, irinotecan-based combination therapy showed a beneficial effect on the PFS in all patients. These findings confirm the use of cetuximab in combination with chemotherapy for the treatment of patients with mCRC with wild-type KRAS tumors. Further multi-center RCTs are needed to indentify these findings.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    PubMed  Google Scholar 

  2. Kopetz S, Chang GJ, Overman MJ, Eng C, Sargent DJ, Larson DW, et al. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol. 2009;27:3677–83.

    PubMed  PubMed Central  Google Scholar 

  3. Chau I, Cunningham D. Treatment in advanced colorectal cancer: what, when and how? Br J Cancer. 2009;100:1704–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Wolpin BM, Mayer RJ. Systemic treatment of colorectal cancer. Gastroenterology. 2008;134:1296–310.

    CAS  PubMed  Google Scholar 

  5. O’Neil BH, Goldberg RM. Innovations in chemotherapy for metastatic colorectal cancer: an update of recent clinical trials. Oncologist. 2008;13:1074–83.

    PubMed  Google Scholar 

  6. Simmonds PC. Palliative chemotherapy for advanced colorectal cancer: systematic review and meta-analysis. Colorectal cancer collaborative group. BMJ. 2000;321:531–5.

    CAS  PubMed  Google Scholar 

  7. Labianca RF, Beretta GD, Pessi MA. Disease management considerations: disease management considerations. Drugs. 2001;61:1751–64.

    CAS  PubMed  Google Scholar 

  8. Labianca R, Pessi MA, Zamparelli G. Treatment of colorectal cancer. Current guidelines and future prospects for drug therapy. Drugs. 1997;53:593–607.

    CAS  PubMed  Google Scholar 

  9. Midgley R, Kerr D. Colorectal cancer. Lancet. 1999;353:391–9.

    CAS  PubMed  Google Scholar 

  10. Karapetis CS, Yip D, Harper PG. The treatment of metastatic colorectal cancer. Int J Clin Pract. 1999;53:287–94.

    CAS  PubMed  Google Scholar 

  11. Cunningham D, Pyrhonen S, James RD, Punt CJ, Hickish TF, Heikkila R, et al. Randomised trial of irinotecan plus supportive care versus supportive care aloneafter fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998;352:1413–8.

    CAS  PubMed  Google Scholar 

  12. Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004;22:23–30.

    CAS  PubMed  Google Scholar 

  13. Rougier P, Van Cutsem E, Bajetta E, Niederle N, Possinger K, Labianca R, et al. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet. 1998;352:1407–12.

    CAS  PubMed  Google Scholar 

  14. Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW, Burgess AW. Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res. 2003;284:31–53.

    CAS  PubMed  Google Scholar 

  15. Holbro T, Civenni G, Hynes NE. The erbb receptors and their role in cancer progression. Exp Cell Res. 2003;284:99–110.

    CAS  PubMed  Google Scholar 

  16. Normanno N, De Luca A, Bianco C, Strizzi L, Mancino M, Maiello MR, et al. Epidermal growth factor receptor (egfr) signaling in cancer. Gene. 2006;366:2–16.

    CAS  PubMed  Google Scholar 

  17. Ciardiello F, Tortora G. Egfr antagonists in cancer treatment. N Engl J Med. 2008;358:1160–74.

    CAS  PubMed  Google Scholar 

  18. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337–45.

    CAS  PubMed  Google Scholar 

  19. Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757–65.

    CAS  PubMed  Google Scholar 

  20. Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (folfiri) compared with folfiri alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28:4706–13.

    CAS  PubMed  Google Scholar 

  21. Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, et al. Wild-type braf is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008;26:5705–12.

    PubMed  Google Scholar 

  22. Tol J, Nagtegaal ID, Punt CJ. Braf mutation in metastatic colorectal cancer. N Engl J Med. 2009;361:98–9.

    CAS  PubMed  Google Scholar 

  23. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1–12.

    CAS  PubMed  Google Scholar 

  24. Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet. 1998;352:609–13.

    CAS  PubMed  Google Scholar 

  25. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:16.

    PubMed  PubMed Central  Google Scholar 

  26. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22:719–48.

    CAS  PubMed  Google Scholar 

  27. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.

    CAS  PubMed  Google Scholar 

  28. Cochran WG. The combination of estimates from different experiments. Biometrics. 1954;10:101–29.

    Google Scholar 

  29. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.

    PubMed  PubMed Central  Google Scholar 

  30. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–101.

    CAS  PubMed  Google Scholar 

  31. Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27:663–71.

    CAS  PubMed  Google Scholar 

  32. Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang CC, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408–17.

    PubMed  Google Scholar 

  33. Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, et al. Efficacy according to biomarker status of cetuximab plus folfox-4 as first-line treatment for metastatic colorectal cancer: the opus study. Ann Oncol. 2011;22:1535–46.

    CAS  PubMed  Google Scholar 

  34. Van Cutsem E, Kohne CH, Lang I, Folprecht G, Nowacki MP, Cascinu S, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor kras and braf mutation status. J Clin Oncol. 2011;29:2011–9.

    PubMed  Google Scholar 

  35. Borner M, Koeberle D, Von Moos R, Saletti P, Rauch D, Hess V, et al. Adding cetuximab to capecitabine plus oxaliplatin (xelox) in first-line treatment of metastatic colorectal cancer: a randomized phase II trial of the swiss group for clinical cancer research sakk. Ann Oncol. 2008;19:1288–92.

    CAS  PubMed  Google Scholar 

  36. Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011;377:2103–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Alberts SR, Sargent DJ, Nair S, Mahoney MR, Mooney M, Thibodeau SN, et al. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. JAMA. 2012;307:1383–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Stintzing S, Fischer VWL, Decker T, Vehling-Kaiser U, Jager E, Heintges T, et al. Folfiri plus cetuximab versus folfiri plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer-subgroup analysis of patients with kras: mutated tumours in the randomised german aio study krk-0306. Ann Oncol. 2012;23:1693–9.

    CAS  PubMed  Google Scholar 

  39. Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360:563–72.

    CAS  PubMed  Google Scholar 

  40. Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, et al. Randomized controlled trial of cetuximab plus chemotherapy for patients with kras wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013;31:1931–8.

    CAS  PubMed  Google Scholar 

  41. Saltz L, Badarinath S, Dakhil S, Bienvenu B, Harker WG, Birchfield G, et al. trial of cetuximab, bevacizumab, and 5-fluorouracil/leucovorin vs. Folfox-bevacizumab in colorectal cancer. Clin Colorectal Cancer. 2012;11:101–11.

    CAS  PubMed  Google Scholar 

  42. Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S, et al. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (nordic flox) versus flox alone in first-line treatment of metastatic colorectal cancer: the Nordic-VII study. J Clin Oncol. 2012;30:1755–62.

    CAS  PubMed  Google Scholar 

  43. Dewdney A, Cunningham D, Tabernero J, Capdevila J, Glimelius B, Cervantes A, et al. Multicenter randomized phase II clinical trial comparing neoadjuvant oxaliplatin, capecitabine, and preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in patients with high-risk rectal cancer (expert-c). J Clin Oncol. 2012;30:1620–7.

    CAS  PubMed  Google Scholar 

  44. Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, et al. Epic: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:2311–9.

    CAS  PubMed  Google Scholar 

  45. Bokemeyer C, Bondarenko I, Hartmann JT, De Braud FG, Volovat C, Nippgen J, et al. KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: the OPUS experience. Proc Am Soc Clin Oncol. 2008;26(suppl):abstr 4000.

    Google Scholar 

  46. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (folfox4) versus folfox4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the prime study. J Clin Oncol. 2010;28:4697–705.

    CAS  PubMed  Google Scholar 

  47. Tveit K, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S, et al. Randomized phase III study of 5-fluorouracil/folinate/oxaliplatin given continuously or intermittently with or without cetuximab, as first-line treatment of metastatic colorectal cancer: the NORDIC VII study (NCT00145314) by the Nordic Colorectal Cancer Biomodulation Group. Proc Am Soc Clin Oncol. 2011;29(suppl):abstr 365.

    Google Scholar 

  48. Park J, Park BB, Kim JY, Lee SH, Lee SI, Kim HY, et al. Gefitinib (zd1839) monotherapy as a salvage regimen for previously treated advanced non-small cell lung cancer. Clin Cancer Res. 2004;10:4383–8.

    CAS  PubMed  Google Scholar 

  49. Van Cutsem E, Mayer RJ, Gold P, Stella P, Cohn A, Pippas A. Correlation of acne rash and tumour response with cetuximab monotherapy in patients with colorectal cancer refractory to both irinotecan and oxaliplatin. Eur J Cancer Suppl. 2004;2:85.

    Google Scholar 

  50. Perez-Soler R, Chachoua A, Hammond LA, Rowinsky EK, Huberman M, Karp D, et al. Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol. 2004;22:3238–47.

    CAS  PubMed  Google Scholar 

  51. Zhou SW, Huang YY, Wei Y, Jiang ZM, Zhang YD, Yang Q, et al. No survival benefit from adding cetuximab or panitumumab to oxaliplatin-based chemotherapy in the first-line treatment of metastatic colorectal cancer in kras wild type patients: a meta-analysis. PLoS One. 2012;7:e50925.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Ibrahim EM, Zekri JM, Bin SB. Cetuximab-based therapy for metastatic colorectal cancer: a meta-analysis of the effect of kras mutations. Int J Colorectal Dis. 2010;25:713–21.

    PubMed  Google Scholar 

  53. Bokemeyer C, Bondarenko I, Hartmann J, Braud FD, Schuch G, Zubel A, Celik I, Koralewski P. Overall survival of patients with KRAS wild-type tumors treated with FOLFOX4±cetuximab as 1st-line treatment for metastatic colorectal cancer: The OPUS study. ECCO 15-ESMO 34 2009;Abstract No. 6.079 2009.

  54. Lang I, Köhne CH, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Zubel A, Cutsem EV. Quality of life (QoL) analysis of patients (pts) with KRAS wild-type (wt) tumors in the CRYSTAL trial. ECCO 15-ESMO 34 2009;Abstract No. 6.078 2009.

Download references

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. Department of Gastrointestinal Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University Medical College, Yantai, 264000, Shandong Province, China

    Zhong-chuan Lv, Jin-yao Ning & Hong-bing Chen

Authors
  1. Zhong-chuan Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jin-yao Ning
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hong-bing Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hong-bing Chen.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lv, Zc., Ning, Jy. & Chen, Hb. Efficacy and toxicity of adding cetuximab to chemotherapy in the treatment of metastatic colorectal cancer: a meta-analysis from 12 randomized controlled trials. Tumor Biol. 35, 11741–11750 (2014). https://doi.org/10.1007/s13277-014-2227-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-014-2227-z

Keywords

Search

Navigation