One way that cancer has been able to evade the immune system is through overexpression of immune checkpoint proteins (immune inhibitory pathway), which allow cancer cells to be considered “self” instead of foreign and block T-cell action. Immune checkpoint proteins cytotoxic T-lymphocyte–associated 4 (CTLA-4) and programmed cell death protein (PD-1) are receptors that are expressed on the surface of cytotoxic T cells. Immune checkpoint inhibitors prevent those receptors from binding to their natural ligands, disrupting the immune inhibitory pathway. See Table 1 for a list of approved agents and indications.
Managing Adverse Events
Toxicities from checkpoint inhibitors are quite different from chemotherapy, affect multiple body systems, and have the potential to be fatal if not recognized promptly and properly managed. As their use increases, oncology advanced practice RNs (APRNs) to be knowledgeable about the agents and how to manage toxicities.
Prior to initiating treatment with a checkpoint inhibitor, a thorough history and physical exam, medication review, and social history must be taken. Special attention to and documentation of any history of autoimmune disease, infectious disease, and endocrine disorders is required. Other comorbidities must be considered as well. Patients with pre-existing conditions like pulmonary disease or renal dysfunction must be monitored carefully for risks of immune-mediated pneumonitis and nephritis. Patients with diabetes must be observed for elevations in blood glucose if corticosteroids are given to manage certain toxicities. Patients with colitis, diverticulitis, or other bowel disorders might be at higher risk for gastrointestinal toxicities. Patients with multiple allergies may be at higher risk for infusion reactions, including anaphylaxis.
In general, APRNs must maintain a high level of suspicion for new treatment-related toxicities. For grade 1 toxicities, patients should be closely monitored and may continue treatment (with possible exceptions of some neurologic, hematologic, and cardiac toxicities). Most grade 2 toxicities require temporary dose delays that can be resumed when toxicities decline to grade 1 or resolve; corticosteroids may be administered. Grade 3 toxicities require temporary treatment delay and initiation of high-dose steroids that should be tapered over at least four to six weeks. Most likely, treatment should be permanently discontinued for grade 4 toxicities, with the possible exception of endocrinopathies controlled by hormone replacement.
Specific toxicities of checkpoint inhibitor therapy are noted in Figure 1. Management guidelines (see Figure 2) should be consulted and followed. The most common adverse event reported for checkpoint inhibitor therapy is fatigue, yet fatigue is only mentioned in the guidelines as it occurs with other specific toxicities such as hypophysitis or hypothyroidism. No specific areas in the guidelines address management of fatigue.
At this point, the literature contains more toxicity management algorithms than routine assessment and monitoring once therapy is initiated. However, patients on multiple immunotherapies and combination therapies should be monitored more closely. Specific drug prescribing information will also drive monitoring requirements such as testing. The frequency of monitoring depends on the toxicity, grade, and patient status. Immune responses can be sustained over a long period of time and have the potential to deepen over time as some cytotoxic T cells mature into memory T cells; essentially the immune system is trained to respond in a more effective manner.
Pseudoprogression can occur, and although it is uncommon (less than 10% of patients), it should be considered when evaluating response to immunotherapy. However, when determining whether pseudoprogression exists, other factors have to be taken into consideration, such as patient physical symptoms of progression or response or circulating tumor DNA.
An immune-related modification of the RECIST criteria was developed (irRECIST) and is more appropriate for determining response to checkpoint inhibitor therapy. The modifications were based on published data on radiology practice and clinical trial experience and include use of unidimensional measurements, which have less variability than other measurements. Waiting up to 12 weeks after initiating therapy to confirm disease progression accounts for the possibility of pseudoprogression or “tumor flare” and allows for clinically insignificant progressive disease (small new lesions in the setting of other responsive disease).
Checkpoint inhibition represents an exciting new opportunity in cancer treatment. Understanding the mechanism of action of these agents is critical to oncology APRNs’ success in determining therapy efficacy and toxicity management.