Abstract
Purpose
Anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies are effective in treating RAS wild-type metastatic colorectal cancer (mCRC). However, their administration induces skin toxicity, markedly reducing patients’ quality of life. This study is aimed at identifying the risk factors associated with anti-EGFR monoclonal antibody-induced skin toxicities.
Methods
Patients with mCRC (n = 116) who received anti-EGFR monoclonal antibody treatment were retrospectively evaluated. Primary endpoint was evaluation of the risk factors for grade ≥ 2 overall skin toxicities during all the treatment periods. Furthermore, factors associated with each grade ≥ 2 skin symptoms were assessed.
Results
Incidence of total grade ≥ 2 skin toxicity symptoms was 61.2%, and those of grade ≥ 2 rash, dry skin, fissures, and paronychia were 34.5%, 25.9%, 20.7%, and 25.0%, respectively. Multivariate logistic regression analyses revealed that liver metastasis was an independent risk factor for overall grade ≥ 2 skin toxicities (adjusted odds ratio [OR], 2.88; 95% confidence interval [CI], 1.22–6.78; P = 0.02) and prophylactic administration of antibiotics as a preventive factor (OR 0.10; 95%CI 0.01–0.91; P = 0.04). For grade ≥ 2 rash, prophylactic use of systemic antibiotics and topical steroid ointment was a preventive factor (OR 0.37; 95%CI 0.16–0.89; P = 0.03). Moreover, liver metastasis (OR 8.37; 95%CI 1.98–35.47; P = 0.004) and prophylactic administration of antibiotics (OR 0.15; 95%CI 0.03–0.76; P = 0.02) were significantly associated with grade ≥ 2 paronychia.
Conclusion
Liver metastasis was suggested to be a risk factor for the incidence of overall grade ≥ 2 skin toxicities; moreover, preemptive systemic antibiotic administration drastically decreased this risk during all periods of anti-EGFR treatment for mCRC.
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Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
References
Kafatos G, Dube S, Burdon P, Demonty G, Flinois A, Leclerc M et al (2020) Management of EGFR inhibitor-induced skin toxicity and factors impacting patients’ adherence to skin toxicity treatment: health care provider and patient surveys in European Oncology Centers. Clin Colorectal Cancer 19:100–108
Oda K, Matsuoka Y, Funahashi A, Kitano H (2005) A comprehensive pathway map of epidermal growth factor receptor signaling. Mol Syst Biol 1(2005):0010
Abubaker J, Bavi P, Al-Haqawi W, Sultana M, Al-Harbi S, Al-Sanea N et al (2009) Prognostic significance of alterations in KRAS isoforms KRAS-4A/4B and KRAS mutations in colorectal carcinoma. J Pathol 219:435–445
Watanabe T, Yoshino T, Uetake H, Yamazaki K, Ishiguro M, Kurokawa T et al (2013) KRAS mutational status in Japanese patients with colorectal cancer: results from a nationwide, multicenter, cross-sectional study. Jpn J Clin Oncol 43:706–712
Allegra CJ, Rumble RB, Hamilton SR, Mangu PB, Roach N, Hantel A et al (2016) Extended RAS gene mutation testing in metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy: American Society of Clinical Oncology provisional clinical opinion update 2015. J Clin Oncol 34:179–185
Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A et al (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337–345
Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ et al (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626–1634
Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A et al (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408–1417
Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE et al (2014) FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol 15:1065–1075
Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M 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 28:4697–4705
Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y 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 28:4706–4713
Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP et al (2008) EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 26:2311–2319
Petrelli F, Ardito R, Ghidini A, Zaniboni A, Ghidini M, Barni S (2018) Different toxicity of cetuximab and panitumumab in metastatic colorectal cancer treatment: a systematic review and meta-analysis. Oncology 94:191–199
Jatoi A, Green EM, Rowland KM, Sargent DJ, Alberts SR (2009) Clinical predictors of severe cetuximab-induced rash: observations from 933 patients enrolled in north central cancer treatment group study N0147. Oncology 77:120–123
Raimondi A, Fucà G, Leone AG, Lonardi S, Antoniotti C, Smiroldo V et al (2021) Impact of age and gender on the efficacy and safety of upfront therapy with panitumumab plus FOLFOX followed by panitumumab-based maintenance: a pre-specified subgroup analysis of the Valentino study. ESMO Open 6:100246
Graziano F, Ruzzo A, Loupakis F, Canestrari E, Santini D, Catalano V et al (2008) Pharmacogenetic profiling for cetuximab plus irinotecan therapy in patients with refractory advanced colorectal cancer. J Clin Oncol 26:1427–1434
Vallböhmer D, Zhang W, Gordon M, Yang DY, Yun J, Press OA et al (2005) Molecular determinants of cetuximab efficacy. J Clin Oncol 23:3536–3544
Takahashi N, Yamada Y, Furuta K, Nagashima K, Kubo A, Sasaki Y et al (2015) Association between serum ligands and the skin toxicity of anti-epidermal growth factor receptor antibody in metastatic colorectal cancer. Cancer Sci 106:604–610
Takahashi N, Yamada Y, Furuta K, Honma Y, Iwasa S, Takashima A et al (2014) Serum levels of hepatocyte growth factor and epiregulin are associated with the prognosis on anti-EGFR antibody treatment in KRAS wild-type metastatic colorectal cancer. Br J Cancer 110:2716–2727
Kubo A, Hashimoto H, Takahashi N, Yamada Y (2016) Biomarkers of skin toxicity induced by anti-epidermal growth factor receptor antibody treatment in colorectal cancer. World J Gastroenterol 22:887–894
Lacouture ME, Mitchell EP, Piperdi B, Pillai MV, Shearer H, Iannotti N et al (2010) Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol 28:1351–1357
Kobayashi Y, Komatsu Y, Yuki S, Fukushima H, Sasaki T, Iwanaga I et al (2015) Randomized controlled trial on the skin toxicity of panitumumab in Japanese patients with metastatic colorectal cancer: HGCSG1001 study; J-STEPP. Future Oncol 11:617–627
Aogi K, Takeuchi H, Saeki T, Aiba K, Tamura K, Iino K et al (2021) Optimizing antiemetic treatment for chemotherapy-induced nausea and vomiting in Japan: update summary of the 2015 Japan Society of Clinical Oncology Clinical Practice Guidelines for Antiemesis. Int J Clin Oncol 26:1–17
Lacouture ME, Anadkat MJ, Bensadoun RJ, Bryce J, Chan A, Epstein JB et al (2011) Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer 19:1079–1095
Annunziata MC, De Stefano A, Fabbrocini G, Leo S, Marchetti P, Romano MC et al (2019) Current recommendations and novel strategies for the management of skin toxicities related to anti-EGFR therapies in patients with metastatic colorectal cancer. Clin Drug Investig 39:825–834
Hofheinz RD, Deplanque G, Komatsu Y, Kobayashi Y, Ocvirk J, Racca P et al (2016) Recommendations for the prophylactic management of skin reactions induced by epidermal growth factor receptor inhibitors in patients with solid tumors. Oncologist 21:1483–1491
Melosky B, Anderson H, Burkes RL, Chu Q, Hao D, Ho V et al (2016) Pan Canadian rash trial: a randomized phase iii trial evaluating the impact of a prophylactic skin treatment regimen on epidermal growth factor receptor-tyrosine kinase inhibitor-induced skin toxicities in patients with metastatic lung cancer. J Clin Oncol 34:810–815
Arrieta O, Vega-González MT, López-Macías D, Martínez-Hernández JN, Bacon-Fonseca L, Macedo-Pérez EO et al (2015) Randomized, open-label trial evaluating the preventive effect of tetracycline on afatinib induced-skin toxicities in non-small cell lung cancer patients. Lung Cancer 88:282–288
Yamada M, Iihara H, Fujii H, Ishihara M, Matsuhashi N, Takahashi T et al (2015) Prophylactic effect of oral minocycline in combination with topical steroid and skin care against panitumumab-induced acneiform rash in metastatic colorectal cancer patients. Anticancer Res 35:6175–6181
Nakata K, Komori T, Saso K, Ota H, Kagawa Y, Morita S et al (2021) Pre-emptive oral clarithromycin reduces the skin toxicity of panitumumab treatment for metastatic colorectal cancer. Int J Colorectal Dis 36:2621–2627
Zuckerman JM, Qamar F, Bono BR (2011) Review of macrolides (azithromycin, clarithromycin), ketolids (telithromycin) and glycylcyclines (tigecycline). Med Clin North Am 95(4):761–791
Potthoff K, Hofheinz R, Hassel JC, Volkenandt M, Lordick F, Hartmann JT et al (2011) Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a German expert opinion. Ann Oncol 22:524–535
Ueda T, Shimada E, Urakawa T (1994) Serum levels of cytokines in patients with colorectal cancer: possible involvement of interleukin-6 and interleukin-8 in hematogenous metastasis. J Gastroenterol 29:423–429
Suenaga M, Mashima T, Kawata N, Wakatsuki T, Dan S, Seimiya H et al (2021) Serum IL-8 level as a candidate prognostic marker of response to anti-angiogenic therapy for metastatic colorectal cancer. Int J Colorectal Dis 36:131–139
Hamilton TD, Leugner D, Kopciuk K, Dixon E, Sutherland FR, Bathe OF (2014) Identification of prognostic inflammatory factors in colorectal liver metastases. BMC Cancer 14:542
Larsen CG, Anderson AO, Oppenheim JJ, Matsushima K (1989) Production of interleukin-8 by human dermal fibroblasts and keratinocytes in response to interleukin-1 or tumour necrosis factor. Immunology 68:31–36
Hoffmann TK, Schirlau K, Sonkoly E, Brandau S, Lang S, Pivarcsi A et al (2009) A novel mechanism for anti-EGFR antibody action involves chemokine-mediated leukocyte infiltration. Int J Cancer 124:2589–2596
Bangsgaard N, Houtkamp M, Schuurhuis DH, Parren PW, Baadsgaard O, Niessen HW et al (2012) Neutralization of IL-8 prevents the induction of dermatologic adverse events associated with the inhibition of epidermal growth factor receptor. PLoS One 7:e39706
Reenstra WR, Yaar M, Gilchrest BA (1996) Aging affects epidermal growth factor receptor phosphorylation and traffic kinetics. Exp Cell Res 227:252–255
Migliaccio A, Castoria G, Di Domenico M, Ciociola A, Lombardi M, De Falco A et al (2006) Crosstalk between EGFR and extranuclear steroid receptors. Ann N Y Acad Sci 1089:194–200
Du R, Yang H, Zhou H, Ma L, Getu MA, Chen C et al (2022) The relationship between medication literacy and skin adverse reactions in non-small-cell lung cancer patients undergoing targeted EGFR-TKI therapy. BMC Cancer 22:491
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Participated in research design: YS, KU, and YK.
Conducted experiments: YS.
Performed data analysis: YS.
Drafting of the manuscript: YS.
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All procedures performed in this study involving human participants were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. For this type of study, the need for formal consent was waived by the Ethical Review Board for Life Science and Medical Research at Hokkaido University Hospital.
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YS, KU, YT, and MS have no conflicts of interest. YK reports receiving grants and personal fees from Ono, TAIHO, CHUGAI, Eli Lilly, Yakult, Bristol-Myers, Merck, Takeda, Novartis, Bayer, and Daiichi-Sankyo and grants from Iqvia outside the submitted work.
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Saito, Y., Uchiyama, K., Takekuma, Y. et al. Risk factor analysis for anti-epidermal growth factor receptor monoclonal antibody–induced skin toxicities in real-world metastatic colorectal cancer treatment. Support Care Cancer 31, 504 (2023). https://doi.org/10.1007/s00520-023-07973-3
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DOI: https://doi.org/10.1007/s00520-023-07973-3