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Cancer therapy-induced inflammation of oral and gastrointestinal mucosae affects patients nonuniformly. Preventive strategies are limited; no biomarker exists for pretreatment identification of patients likely to be severely affected. Animal models are preferred for studying molecular responses in mucosae during chemotherapy, but translation into clinical practice is difficult. We performed a systematic review to retrieve articles that described molecular changes in human mucosae during cancer therapy.We searched MEDLINE and Ovid Embase searches for studies reported in the English language literature from January 1990 to November 2016 and studies referenced in selected articles, which analyzed mucosae from patients at risk of developing mucositis during cancer therapy. Two authors extracted data according to predefined data fields, including study quality indicators.We identified 17 human studies on chemotherapy (n = 9) and radiotherapy (n = 8), but no studies on targeted therapy. Studies were heterogeneous with regard to patient cohorts, analysis methods, cancer treatments, biopsy timings, and correlations to clinical mucositis. Consequently, a meta-analysis was not feasible.Few human studies described the molecular responses of the normal mucosa to cancer therapy. Studies were heterogeneous and had sparse correlations to clinical mucositis. We proposed a model for acquiring data on treatment- and disease-specific phenotypes and transcriptomes for predictive or preventive initiatives.