Abstract
Purpose
Chemotherapy with panitumumab is expected to be well tolerated and improve survival in patients with metastatic colorectal cancer (mCRC). However, skin toxicities are its most common adverse events. The aim of this trial was to evaluate the efficacy and safety of pre-emptive antibiotic treatment with clarithromycin (CAM) to prevent panitumumab skin toxicities.
Methods
We conducted a phase lll, multicenter, open-label, randomized clinical trial on mCRC patients treated with panitumumab. Eligible patients were randomly assigned 1:1 to pre-emptive antibiotic and control groups. In the pre-emptive group, CAM administration (200 mg twice per day) continued daily through the panitumumab treatment period. The control regimen consisted of skin care only. The primary end point was the incidence of grade ≥ 2 skin toxicities during the 6-week skin treatment period.
Results
Of 156 enrolled patients, 78 received pre-emptive antibiotic treatment, and 78 received reactive treatment. The number and incidence of grade ≥ 2 skin toxicities during the 6-week skin treatment period were 16 (21.3%) and 41 (54.7%) for the pre-emptive and control groups, respectively (HR, 0.32; 95% CI, 0.17–0.56). There was almost no difference in the rate of other adverse events between the two groups, but the incidence of grade ≥ 3 diarrhea in the pre-emptive group was high, at 8% vs. 1.3% in the control group. There were no treatment-related deaths.
Conclusion
Prophylactic oral CAM together with relatively simple skin care was found to be effective in suppressing the development of grade ≥ 2 skin toxicities induced by panitumumab.
Clinical trial registration
UMIN000011485
Date of registration
Sep 1st, 2013
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Availability of data and material
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
Lacouture ME (2006) Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer. https://doi.org/10.1038/nrc1970
Agero ALC, Dusza SW, Benvenuto-Andrade C, Busam KJ, Myskowski P, Halpern AC (2006) Dermatologic side effects associated with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol. https://doi.org/10.1016/j.jaad.2005.10.010
Lynch TJ, Kim ES, Eaby B, Garey J, West DP, Lacouture ME (2007) Epidermal growth factor receptor inhibitor–associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. https://doi.org/10.1634/theoncologist.12-5-610
Chanprapaph K, Vachiramon V, Rattanakaemakorn P (2014) Epidermal growth factor receptor inhibitors: a review of cutaneous adverse events and management. Dermatol Res Pract. https://doi.org/10.1155/2014/734249
Lacouture ME et al (2011) “Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities,” Support Care Cancer 19(8):1079–1095. https://doi.org/10.1007/s00520-011-1197-6
White KJ, Roydhouse JK, Scott K (2011) “Psychosocial impact of cutaneous toxicities associated with epidermal growth factor receptor-inhibitor treatment,” Clin J Oncol Nurs 15(1). https://doi.org/10.1188/11.CJON.88-96
Naughton MJ et al (2013) “Quality of life (QOL) and toxicity among patients in CALGB 80405.,” J Clin Oncol. https://doi.org/10.1200/jco.2013.31.15_suppl.3611
Peeters M 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):4706–4713. https://doi.org/10.1200/JCO.2009.27.6055
Stintzing S et al (2013) Prognostic value of cetuximab-related skin toxicity in metastatic colorectal cancer patients and its correlation with parameters of the epidermal growth factor receptor signal transduction pathway: results from a randomized trial of the German AIO CRC Stu. Int J Cancer 132(1):236–245. https://doi.org/10.1002/ijc.27654
Duvic M (2008) EGFR inhibitor-associated acneiform folliculitis: assessment and management. Am J Clin Dermatol. https://doi.org/10.2165/00128071-200809050-00002
Boone SL, Rademaker A, Liu D, Pfeiffer C, Mauro DJ, Lacouture ME (2008) Impact and management of skin toxicity associated with anti-epidermal growth factor receptor therapy: survey results. Oncology. https://doi.org/10.1159/000112795
Lacouture ME 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(8):1351–1357. https://doi.org/10.1200/JCO.2008.21.7828
Kobayashi Y et al (2015) Randomized controlled trial on the skin toxicity of panitumumab in Japanese patients with metastatic colorectal cancer: HGCSG1001 study; J-STEPP. Futur Oncol 11(4):617–627. https://doi.org/10.2217/fon.14.251
Petrelli F et al (2016) Antibiotic prophylaxis for skin toxicity induced by antiepidermal growth factor receptor agents: a systematic review and meta-analysis. Br J Dermatol 175(6):1166–1174. https://doi.org/10.1111/bjd.14756
Yamada M 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(11):6175–6181
Van Cutsem E et al (2007) Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy- refractory metastatic colorectal cancer. J Clin Oncol 25(13):1658–1664. https://doi.org/10.1200/JCO.2006.08.1620
Douillard JY 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):4697–4705. https://doi.org/10.1200/JCO.2009.27.4860
Eng HT, Chan A (2009) Evidence-based treatment options for the management of skin toxicities associated with epidermal growth factor receptor inhibitors. Ann Pharmacother. https://doi.org/10.1345/aph.1M241
Zuckerman JM, Qamar F, Bono BR (2011) Review of macrolides (azithromycin, clarithromycin), ketolids (telithromycin) and glycylcyclines (tigecycline). Med Clin North Am. https://doi.org/10.1016/j.mcna.2011.03.012
Acknowledgements
The authors thank all the patients and their families. The authors also thank all the members of the Clinical Study Group of Osaka University (CSGO), Colorectal Group, Japan, for collection of data, and of the Supporting Center for Clinical Research and Education (SCCRE) in Osaka, Japan, for data management.
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ST designed the study. KS, MU, and CM analyzed and interpreted the data. HO, YK, SM, SN, NH, and KM collected and assembled the data. TM contributed in drafting of the article. TK dedicated for critical revision of the article for important intellectual content. YD and HE finally approved the article.
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The protocol was approved by the ethics committees at the participating sites. All patients signed informed consent before any study-related procedures were performed. The trial was carried out in accordance with the Declaration of Helsinki.
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The authors declare no competing interests.
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Nakata, K., Komori, T., Saso, K. et al. Pre-emptive oral clarithromycin reduces the skin toxicity of panitumumab treatment for metastatic colorectal cancer. Int J Colorectal Dis 36, 2621–2627 (2021). https://doi.org/10.1007/s00384-021-04002-9
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DOI: https://doi.org/10.1007/s00384-021-04002-9