Jatoi, A., Rowland, K., Sloan, J.A., Gross, H.M., Fishkin, P.A., Kahanic, S.P., . . . Loprinzi, C.L. (2008). Tetracycline to prevent epidermal growth factor receptor inhibitor-induced skin rashes: Results of a placebo-controlled trial from the North Central Cancer Treatment Group (N03CB). Cancer, 113, 847–853.

To compare the effectiveness of tetracycline 500 mg orally BID versus placebo for 28 days starting on day 1 of treatment with any epidermal growth factor receptor–inhibitor (EGFRI) agent to prevent or reduce EGFRI-induced rash in patients with cancer.

Patients were randomized to either the tetracycline arm (500 mg orally BID for 28 days) or the placebo arm.

• The study reported on a sample of 61 adult men and women with cancer.
• Thirty-one patients were randomized to the tetracycline arm, and 30 patients were randomized to the placebo arm.
• Median patient age was 71 years in the tetracycline arm and 63 years in the placebo arm.

This study was a collaborative effort of the North Central Cancer Treatment Group (including centers in Illinois, Iowa, Kansas, South Dakota, and Ohio) and the Mayo Clinic (Rochester, MN).

This was a placebo-controlled, doubled-blind trial.

Three patient-reported assessments were used.

• A brief rash incidence questionnaire
• SKINDEX-16 questionnaire relevant to rash development and its implications on patients' quality of life (this tool was previously validated)
• Questionnaire regarding patient compliance with EGFRI therapy

Those three questionnaires were completed at baseline and weekly for eight weeks after initiation of tetracycline or placebo. Oncologists performed an evaluation at the end of four weeks and eight weeks. The evaluation included a history and physical examination, an assessment of patient performance status, and an assessment of adverse events (e.g., gastrointestinal toxicity, rash development) as per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.

• At week 4, 70% of patients in the tetracycline arm (n = 16) and 76% of patients in the placebo arm (n = 22) developed a rash (p = 0.61).
• At week 8, 87% of patients in the tetracycline arm (n = 13) and 84% of patients in the placebo arm (n = 16) developed a rash (p = 0.84).
• By week 4, physician-reported grade 2 rash or rash covering more than 50% of body surface area (BSA) occurred in 17% of patients in the tetracycline arm (n = 4) and 55% of patients in the placebo arm (n = 16) (p = 0.04).
• By week 8, when 44% of the cohort had dropped out, physician-reported grade 2 rash or rash covering more than 50% of BSA occurred in 27% of patients in the tetracycline arm (n = 4) and 47% of patients in the placebo arm (n = 9) (p = 0.5).
• Of note, the worst physician reported rash (grade 3) occurred in one patient in the tetracycline arm.
• Results of the SKINDEX-16 questionnaire did not demonstrate uniform, statistically significant differences, with a few exceptions. Tetracycline exerted positive effects on quality of life in four questions (skin itching, skin burning or stinging, skin irritation, and being bothered by a persistence or recurrence of the skin condition). Tetracycline exerted a negative effect on one question (bothered about being annoyed about your skin). No statistical significance was found for the remaining 11 questions.
• Tetracycline was well tolerated with no significant difference in adverse events between study arms.

Administration of tetracycline prophylactically did not significantly affect the incidence of rash development in patients receiving EGFRI drugs. Indicators suggest administration of tetracycline prophylactically may have a favorable influence with regard to rash severity in patients receiving EGFRI drugs. In addition, the results suggested these rashes bother patients, who must contend with itching, burning, and other types of skin irritation.

• The sample size was relatively small.
• The measurement method for clinician grading of rash symptoms was not described.
• Six patients, including three patients from each study arm, stopped taking EGFRI medication within the first month because of the development of skin rash.