Cancer is a major public health burden and one of the leading causes of human death worldwide. Globally, more than 19.3 million cases of cancer are diagnosed each year and more than 9.9 million people die as a result. Remarkable advances have been made in the fight against cancer in recent years, including early detection, diagnosis, and treatment of cancer. There was a gradual increase in the number of cancer drug approvals from 2009 (8 approvals) to 2020 (57 approvals). These newly approved drugs have greatly enriched therapeutic options and improved survival and quality of life for cancer patients. The clinical use of anticancer drugs varies depending on tumor location, age, stage of disease, metastatic status, genetic heterogeneity, etc.
Taking colorectal cancer as an example, in patients with high-risk stage II and III colorectal cancer, defined as those with poor prognostic features, adjuvant systemic chemotherapy provides an overall survival benefit. First-line regimens are generally based on various combinations of the cytotoxic drugs oxaliplatin, 5-fluorouracil (5-FU), capecitabine, and leucovorin. However, prolonged administration, lack of specificity, and disparate cytotoxic adverse effects are major limitations in its clinical applications. Between 2004 and 2006, three new monoclonal antibodies (bevacizumab, cetuximab, and panitumumab) began to be used as targeted therapies for the treatment of metastatic colorectal cancer, while they are only indicated for certain genetic types and are mainly used in combination with cytotoxic chemotherapies.
Oxaliplatin is the latest platinum-based chemotherapeutic agent and is recommended as a first-line regimen for the treatment of advanced colon and rectal cancer. Oxaliplatin exerts its anticancer effect primarily through the formation of platinum DNA sequestrants to cause cell death and inhibit DNA replication. Additionally, oxaliplatin induces immunogenic cell death by stimulating immune cells such as CD8+ T cells.
Both the efficacy and toxicity of oxaliplatin are affected by the gut microbiota. A recent study in an antibiotic-treated mouse model suggested that gut microbial metabolites, especially butyrate, enhanced the chemotherapeutic efficacy of oxaliplatin by upregulating CD8+ T-cell function, which plays a central role in tumor immunity. Furthermore, cancer patients who responded to oxaliplatin exhibited a higher abundance of serum butyrate compared with non-responders. In addition, ileal microbiota (eg, B. fragilis) were found to potentially stimulate local immune responses (eg, increased immune gene transcripts and CD45+ lymphoid cell infiltration) and enhance antitumor efficacy. of oxaliplatin-based chemotherapy.
In addition, oxaliplatin could induce a number of adverse effects, including peripheral neurotoxicity, which affects up to 90% of patients receiving chemotherapy, and could lead to treatment discontinuation. Shen et al. demonstrated that oxaliplatin-induced hyperalgesia was alleviated in GF mice and antibiotic-treated mice, compared to the control group. Furthermore, GF FMT mice restored oxaliplatin-induced hyperalgesia, demonstrating the role of the gut microbiota in the development of oxaliplatin-induced neurotoxicity. However, the mechanism linking the gut microbiota to oxaliplatin-induced hyperalgesia is unclear. Also, most of the experiments in the studies mentioned above were performed on mice, which may vary from the situation in the clinic. Therefore, clinical evaluations across a relatively large sample size of the patient cohort are necessary for validation of previous findings from mouse studies.
