Doxycycline as a preventive treatment of skin toxicity in patients with metastatic colorectal cancer treated with an anti-EGFR and chemotherapy: interim analysis to evaluate skin toxicities

Abstract

Introduction: Anti-EGFR therapies are associated with the development of skin toxicities. These adverse events impact quality of life (QoL), increase patient risk for additional infections and lead to inconsistent anti-EGFR therapy administration. Clinical evidence has suggested that sub-antimicrobial doses of doxycycline may have the potential to treat inflammatory lesions of acne and, at the same time, may avoid the development of antibiotic resistance related to the use of higher doses. However, the efficacy of doses below 100 mg/day of doxycycline in the prevention of skin toxicity in patients treated with EGFR-targeted therapies has never been studied. The study objective was to assess the efficacy and safety of doxycycline in the prevention of skin toxicity in patients with metastatic colorectal cancer (mCRC) treated with FOLFOX or FOLFIRI +anti-EGFR, and to assess patient QoL. Methods: This was a phase II, single-arm, multicentre clinical trial. Eligible patients were≥18 years, ECOG≤2, with adequate liver, kidney and bone marrow functions, wild type RAS mCRC, and a treatment plan based on FOLFOX or FOLFIRI + anti-EGFR as first-line treatment of mCRC. In the first stage, 10 patients entered the study at a dose of doxycycline 50 mg/day for 6 weeks beginning one day before the administration of the first anti-EGFR dose and an interim analysis was performed once 10 patients finished the 6 weeks of treatment. If more than three patients demonstrated ≥grade 2 skin toxicities, the dose of doxycycline would be increased to 100 mg/day for the next 30 patients to be recruited. Skin toxicity severity was graded according to NCI-CTCAE v4.03 and QoL was evaluated using the Dermatology Life Quality Index (DLQI) (at screening and at week 7). A sample size of 40 patients was calculated to produce a 95% CI of 15-45% for the incidence of ≥ grade 2 skin toxicities during the 6-week skin treatment period (assuming anticipated drop-outs of 10%). Results: Ten patients, median age 57.5 years, 60% men, 70%/30% ECOG 0/1, were included in this interim analysis. Rectum (50%) and descending colon (30%) were the more frequent tumor locations and 60% of patients had liver metastases. Most patients (70%) received FOLFOX as chemotherapy treatment, 30% received FOL-FIRI and all patients received panitumumab as anti-EGFR therapy. All patients completed 6 weeks of treatment with doxycycline 50 mg/day. Six patients developed grade 2 skin toxicities: 3 with dermatitis acneiform, 1 with dermatitis acneiform and paronychia, 1 with dermatitis acneiform and dry skin, and 1 with rash. Median time to grade 2 skin toxicity was 22.5 days (range: 16-82). There were no toxicities related to doxycycline. Conclusion: Doxycycline 50 mg/day for 6 weeks does not seem to prevent the dermatological toxicity caused by EGFR-targeted therapies in patients with mCRC. The dose of doxycycline will be increased to 100 mg/day for the next 30 patients to be recruited. .