Gastrointestinal Toxicity in Oncology: Evolutionary Science

ABSTRACT Proper practice of Medical Oncology requires an understanding of the science of regimen-related toxicity (RRT); and as treatment regimens evolve, so too does that science. Mouth ulcers, pain, diarrhea and constipation are among the common side effects of chemotherapy and hinder our ability to give adequate, perhaps curative, doses. As we increase our understanding of toxicity mechanism, so we slowly improve its prevention and treatment. However, this must not come at the cost of tumour-response, thus requiring understanding of the interaction between mechanism of action and of toxicity. Animal models have become increasingly sophisticated, and are used to screen for interventions that reduce toxicity without affecting tumour response. The introduction of the targeted anti-cancer (TAT) agents has further complicated the picture, with GI toxicity being a major, and not always predicted effect. The mechanism of toxicity is often the same as the mechanism of action, making successful management difficult. Each new class of TAT has a new mechanism, epidemiology and presentation of toxicity, so we constantly need to update our understanding of the science. A mouth ulcer caused by methotrexate is not the same as one caused by an mTOR inhibitor. There has been a corresponding evolution in the doctor-patient relationship surrounding toxicity, as we have moved from the paternalistic relationship to a partnership, with Patient Reported Outcomes (PROs) increasingly important. Clinicians will usually rate a given toxicity less severely than will the patient; the message being that we need to listen to the patient. Risk prediction is receiving more attention, with Oncologists now talking about response prediction and risk prediction as two sides of the same coin, aiming to offer treatment to non-toxic responders, treatment with toxicity interventions to toxic responders, and completely avoid ineffective treatment for non-responders. We have moved from the simplistic risk prediction of age, sex, comorbidity and drugs, to complex gene and SNP analysis using modern bioinformatics. However, given the common lag between drug development and successful toxicity interventions, toxicity specialists should be involved earlier in drug development. The science will continue to evolve as long as cancer treatment evolves. Disclosure D. Keefe: Prof Keefe works with many companies in the development of agents in the field of GI toxicity. These include: Helsinn, Entera Health, Pfizer, GSK and Merck.