The principal exceptions pertain to hypothyroidism and other endocrinopathies, which might be treated with hormone replacement therapy. indications will likely expand in the near future, as ongoing investigations evaluate the activity of existing and investigational immunotherapeutic brokers in multiple types of cancer. However, the mechanisms of action that achieve wide-ranging antitumor activity can cause a host of immune-related toxicities. Effective management of these toxicities plays a key role in reaching and maintaining maximal clinical efficacy, as discussed at JADPRO Live 2017 by Brianna Hoffner, MSN, RN, ANP-BC, AOCNP?, of the University of Colorado, and Laura J. Zitella, MS, RN, ACNP-BC, AOCN?, of Stanford Cancer Institute. PATHOPHYSIOLOGY AND GENERAL APPROACH The CTLA-4 pathway, targeted by ipilimumab, and the PD-1 pathway are associated with immune tolerance. The wide-ranging activity of immune checkpoint inhibitors results from the drugs activation of the human immune system, a generic type of antitumor activity, as opposed to induction of a disease-specific anticancer activity. Early clinical studies of immune checkpoint inhibitors often involved cancers that exhibited minimal susceptibility to conventional chemotherapy. Inhibition of the immune checkpoint pathways removes tolerance, a phenomenon often described as “releasing the brakes around the immune system. ” Removing tolerance also leads to activation of the immune system against cancer cells. “At the same time, if we activate the immune system so that you drop tolerance, sometimes normal cells, which should have tolerance to the immune system, suddenly become targets of the immune system,” said Ms. Zitella. Most adverse effects associated with immune checkpoint inhibitors are moderate or moderate, and the most common toxicities are rash and diarrhea. However, less common and potentially severe toxicities can occur (Champiat et al., 2016), and the list continues to grow as indications and clinical experience with immune checkpoint inhibitors increase (Table 1). Table 1 Open in a separate window Immune-Related Adverse Reactions Immune-related side effects do not occur immediately, but instead emerge over the course of several weeks of treatment, especially with the PD-1/PD-L1 inhibitors (4C10 weeks). CTLA-4 inhibition produces more severe side effects, which tend to occur earlier in the course of treatment. Similarly, combination therapy with a CTLA-4 inhibitor and a PD-1/PD-L1 inhibitor causes more severe side effects that appear earlier. The European Society for Medical Oncology published guidelines on screening patients for the risk of immunotherapy-associated toxicities (Champiat et al., 2016), and both the National Comprehensive Malignancy Network (NCCN) and the American Society of Clinical Oncology have released their own consensus guidelines (Brahmer et al., 2018; NCCN, 2018), said Ms. Zitella. In the absence of consensus, the management of immune-related adverse events remains empiric. For moderate or moderate (grade 1C2) side effects, supportive care is CYM 5442 HCl CYM 5442 HCl usually indicated, whereas severe side effects (grade 3C4) are usually treated with steroids. The principal exceptions pertain to hypothyroidism and other endocrinopathies, which might be treated with hormone replacement therapy. In those cases, steroids will CYM 5442 HCl be omitted. Use of steroids introduces several other considerations (NCCN, 2017). Patients who require steroids, particularly high-dose steroids, often develop gastritis, which can be prevented with a histamine receptor antagonist (H2 blocker). Many patients on steroids develop oral thrush, which can be prevented with good oral care and the use of clotrimazole troches. Finally, patients treated with prednisone at 20 mg or comparative for more than 4 weeks should receive pneumocystis prophylaxis (but doesnt have diarrhea, and it just doesnt make sense. We see Igfbp1 that here, as well. In your workup, usually CYM 5442 HCl rule out infectious causes. ” In addition to stool and blood analyses, contrast computed tomography of the stomach and pelvis can reveal any thickening of the bowel that would be characteristic of colitis. Ms. Hoffner emphasized that this occurrence of diarrhea and/or colitis with one type of immune checkpoint inhibitor does not rule out treatment with a different checkpoint inhibitor. Pneumonitis About 1% to 2% of patients treated with a PD-1/PD-L1 inhibitor or CTLA-4 inhibitor develop inflammation of.