Skin toxicity with anti-EGFR monoclonal antibody in cancer patients: a meta-analysis of 65 randomized controlled trials
We performed a meta-analysis to fully investigate the skin toxicities of anti-EGFR monoclonal antibody (EGFR-MoAbs) in cancer patients. The relevant studies of the randomized controlled trials (RCTs) in cancer patients treated with EGFR-MoAbs were retrieved and the systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published till November 2017. The relevant RCTs in cancer patients treated with EGFR-MoAbs were retrieved and the systematic evaluation was conducted. 65 RCTs and 25994 patients were included. The current meta-analysis suggests that the use of EGFR-MoAbs significantly increases the risk of developing all-grade and high-grade skin toxicity, such as rash, hand–foot syndrome, dry skin and oral mucositis. Rash was the most common skin toxicity. Patients receiving nimotuzumab were associated with the least risk of skin toxicity. The risk of high-grade skin toxicity tended to be higher in the study in which the EGFR-MoAbs treatment duration was longer. The available data suggested that the use of EGFR-MoAbs significantly increases the risk of developing skin toxicity. Physicians should be aware of skin toxicity and should monitor cancer patients when receiving EGFR-MoAbs.
KeywordsEGFR-MoAbs Cancer Skin toxicity Systematic review Meta-analysis
This study was funded by the Fundamental Research Funds for the Central Universities, Southwest Minzu University, 2018NQN50.
Compliance with ethical standards
Conflict of interest
Author Jing Li declares that she has no conflict of interest. Author Hengxiu Yan declares that she has no conflict of interest.
This article does not contain any studies with human participants or animals performed by any of the authors.
- 8.Van Cutsem E, Köhne CH, Láng I et al (2011) 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 29(15):2011–2019CrossRefPubMedGoogle Scholar
- 11.Berlin JD, Feng Y, Catalano P et al (2017) An intergroup randomized phase II study of bevacizumab or cetuximab in combination with gemcitabine and in combination with chemoradiation in patients with resected pancreatic carcinoma: a trial of the ECOG-ACRIN cancer research group (E2204). Oncology. https://doi.org/10.1159/000480295 Google Scholar
- 18.Govindan R, Bogart J, Stinchcombe T et al (2011) Randomized phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small-cell lung cancer: cancer and Leukemia Group B trial 30407. J Clin Oncol 29(23):3120–3125CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Lorenzen S, Schuster T, Porschen R et al (2009) Cetuximab plus cisplatin–5-fluorouracil versus cisplatin–5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol 20(10):1667–1673CrossRefPubMedGoogle Scholar
- 20.Bradley JD, Paulus R, Komaki R et al (2015) Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 16(2):187–199CrossRefPubMedPubMedCentralGoogle Scholar
- 25.Dewdney A, Cunningham D, Tabernero J et al (2012) 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 30(14):1620–1627CrossRefPubMedGoogle Scholar
- 26.Philip PA, Benedetti J, Corless CL et al (2010) Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol 28(22):3605–3610CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Tol J, Koopman M, Rodenburg CJ et al (2008) A randomised phase III study on capecitabine, oxaliplatin and bevacizumab with or without cetuximab in first-line advanced colorectal cancer, the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). An interim analysis of toxicity. Ann Oncol 19(4):734–738CrossRefPubMedGoogle Scholar
- 34.Fleming MT, Sonpavde G, Kolodziej M et al (2012) Association of rash with outcomes in a randomized phase II trial evaluating cetuximab in combination with mitoxantrone plus prednisone after docetaxel for metastatic castration-resistant prostate cancer. Clin Genitourin Cancer 10(1):6–14CrossRefPubMedGoogle Scholar
- 40.Van den Heuvel MM, Uyterlinde W, Vincent AD et al (2014) Additional weekly Cetuximab to concurrent chemoradiotherapy in locally advanced non-small cell lung carcinoma: efficacy and safety outcomes of a randomized, multi-center phase II study investigating. Radiother Oncol 110(1):126–131CrossRefPubMedGoogle Scholar
- 43.Tveit KM, Guren T, Glimelius B et al (2012) 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 30(15):1755–1762CrossRefPubMedGoogle Scholar
- 44.Baselga J, Gómez P, Greil R et al (2013) Randomized phase II study of the anti-epidermal growth factor receptor monoclonal antibody cetuximab with cisplatin versus cisplatin alone in patients with metastatic triple-negative breast cancer. J Clin Oncol 31(20):2586–2592CrossRefPubMedPubMedCentralGoogle Scholar
- 47.Heinemann V, von Weikersthal LF, Decker T et al (2014) Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 15(10):1065–1075CrossRefPubMedGoogle Scholar
- 51.Douillard JY, Siena S, Cassidy J et al (2010) 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 28(31):4697–4705CrossRefPubMedGoogle Scholar
- 52.Giralt J, Trigo J, Nuyts S et al (2015) Panitumumab plus radiotherapy versus chemoradiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-2): a randomised, controlled, open-label phase 2 trial. Lancet Oncol 16(2):221–232CrossRefPubMedGoogle Scholar
- 54.Hecht JR, Cohn A, Dakhil S et al (2015) SPIRITT: a randomized, multicenter, phase 2 study of panitumumab plus FOLFIRI and bevacizumab plus FOLFIRI as second-line treatment in patients with unresectable wild-type KRAS metastatic colorectal cancer. Clin Colorectal Cancer 14(2):72–80CrossRefPubMedGoogle Scholar
- 57.Okines AF, Ashley SE, Cunningham D et al (2010) Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for advanced esophagogastric cancer: dose-finding study for the prospective multicenter, randomized, phase II/III REAL-3 trial. J Clin Oncol 28(25):3945–3950CrossRefPubMedGoogle Scholar
- 58.Peeters M, Price TJ, Cervantes A et al (2010) 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 28(31):4706–4713CrossRefPubMedGoogle Scholar
- 59.Schuette W, Behringer D, Stoehlmacher J et al (2015) CHAMP: a phase II study of panitumumab with pemetrexed and cisplatin versus pemetrexed and cisplatin in the treatment of patients with advanced-stage primary nonsquamous non-small-cell lung cancer with particular regard to the KRAS status. Clin Lung Cancer 16(6):447–456CrossRefPubMedGoogle Scholar
- 60.Schwartzberg LS, Rivera F, Karthaus M et al (2014) PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS Exon 2 metastatic colorectal cancer. J Clin Oncol 32(21):2240–2247CrossRefPubMedGoogle Scholar
- 61.Seymour MT, Brown SR, Middleton G et al (2013) Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol 14(8):749–759CrossRefPubMedPubMedCentralGoogle Scholar
- 64.Vermorken JB, Stöhlmacher-Williams J, Davidenko I et al (2013) Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial. Lancet Oncol 14(8):697–710CrossRefPubMedGoogle Scholar
- 65.Waddell T, Chau I, Cunningham D et al (2013) Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol 14(6):481–489CrossRefPubMedPubMedCentralGoogle Scholar
- 69.Schultheis B, Reuter D, Ebert MP et al (2017) Gemcitabine combined with the monoclonal antibody nimotuzumab is an active first-line regimen in KRAS wildtype patients with locally advanced or metastatic pancreatic cancer: a multicenter, randomized phase IIb study. Ann Oncol 28(10):2429–2435CrossRefPubMedGoogle Scholar