ONS Role in New Guideline for irAE Management

The Oncology Nursing Society (ONS) recently collaborated with the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) to create a guideline for best-practices management of immune-related adverse events (irAEs) in patients treated with checkpoint inhibitors-anti–programmed death 1 (PD-1) antibodies, and anti–programmed death ligand 1 (PD-L1) antibodies. These immunotherapies are now approved for a range of different solid tumors and hematologic malignancies. These drugs have side effects that are distinct from those that can accompany treatment with oral targeted agents and those that can accompany chemotherapy. This guideline is published in the Journal of Clinical Oncology. Today we are speaking to one of the authors of this guideline, Kelly Brassil, PhD, RN. Dr. Brassil is the director of nursing programs at the University of Texas MD Anderson Cancer Center, in Houston.

-Interviewed by Anna Azvolinsky

Cancer Network: First, what was the process by which you and your coauthors developed this guideline to mitigate adverse events related to cancer checkpoint inhibitor antibodies? What is the guideline based on?

Kelly Brassil: Thank you for having me. The ASCO/NCCN guidelines represent the work of an inter-professional panel of physicians, nurses, and patient advocates who gathered to provide their expert feedback on their observations of toxicities and their management, specifically related to checkpoint inhibitors. The guidelines were based on a systematic review of the literature related to the occurrence and management of immunotoxicities. Given that this is really an evolving field, many of the recommendations were ultimately based on expert opinions that were achieved through panel consensus. While there is robust literature from investigative trials on these agents, there are fewer articles that speak to evidence-based management of their toxicities.

So, the panel members were broken up into groups that focused on specific system-based toxicities. They made recommendations based on evidence in the literature as well as their expert opinions and experiences, and then they made recommendations on toxicity management by system. The guidelines were then brought together into a merged document for review by the entire panel of experts. And there were several iterations that went back and forth between the authors and editors, after which they were opened for public feedback. So this allowed for individuals outside of the panel, who had clinical practice expertise and other knowledge, to provide feedback, recommendations, and queries on the content that was provided.

This information was then given to the panel for additional responses to be made before final revisions were put into place by the lead author. And that was the process, which was very organic [and] based as much on existing evidence from research, and science, and the literature, and the clinical experience of the individuals who provide this type of care every day.

Cancer Network: Did you see something specific in your own care of cancer patients who receive checkpoint inhibitors that warranted such a guideline?

Kelly Brassil: In my current role as a director of nursing research and innovation, I have been involved in clinical trials with checkpoint inhibitors and as part of the IRB review and in the support of nurses providing clinical care to these patients. What is so exciting is that the immunotherapeutic approaches are continually emerging in the context of both research studies and clinical care.

When we think about the checkpoint inhibitors, the ones that come to mind most readily are nivolumab and pembrolizumab, and they are increasingly becoming standard of care for an expanding diversity of indications. As research continues to evaluate and establish new indications, including disease types to which these agents can be applied, as well as the combination of agents with other cancer drugs, we really have a need to identify the toxicities unique to these agents alone or in combination. And these toxicities are being observed both in clinical trials and in standard of care management of patients.

To understand the importance of the guidelines, it is fundamental to understand how immunotherapy works, and how it is unique from chemotherapy or radiation or the traditional targeted therapies we use in cancer care. To put it simply, whereas chemotherapy and radiation are used to kill malignant cells both specifically and nonspecifically-and can often cause toxicities to healthy tissues in the surrounding areas, immunotherapeutic agents target specific markers within the immune system to either initiate or suppress an immune response, ideally resulting in regression of malignant cells.

What we are seeing in the clinical setting are unique toxicities as well as some that are similar to those observed with other cancer treatment modalities, but some of that are unique to immunotherapeutic agents that involve inflammatory responses that are immune-mediated. But, regardless of their manifestation, the underlying mechanisms by which these toxicities emerge are unique to the immunotherapies, and in the case of these guidelines, it’s specifically the checkpoint inhibitors that we are discussing. And so we need to take a different approach to their management and are compelled here at our institution, but also nationally and internationally, to [develop] consensus guidelines that can help us as clinicians to better manage these toxicities as they emerge and support our colleagues in community-based settings to do the same.

Cancer Network: What are some of the distinct toxicities that are immune-related and distinct from those that are seen when patients receive chemotherapy or oral targeted drugs? Could you provide some examples?

Kelly Brassil: Absolutely. Immunotherapy targets and often exponentiates an existing immune response that is innate to our bodies. The toxicity profile includes unique presentations, as well as toxicities similar to chemotherapy, but [these are] caused by different underlying pathophysiologic mechanisms. Inflammatory response is really the hallmark of immunotherapeutic toxicity and can affect all organ systems. Some of the inflammatory-driven toxicities that we highlighted in the guidelines include: hypophysitis, which is an inflammation of the pituitary gland; pneumonitis, which is inflammation of the lung; and colitis, which is inflammation of the colon.

Whereas symptom management–based intervention is often utilized for chemo-induced toxicities (so, how do we mitigate nausea, vomiting, diarrhea), the primary management in the presence of immune-mediated toxicities is really the use of corticosteroids to reduce the inflammatory response. A hallmark of this treatment modality are immune-mediated inflammatory responses, which can occur throughout the tissues of the body. Other ones that I didn’t mention yet include transaminitis, pancreatitis, pneumonitis, encephalitis, and myocarditis. Some of these are rare, and some can be potentially fatal to patients. They are really defined as immune-related adverse events, or irAEs, and they result from T-cell activation [causing an] autoimmune-related inflammation in healthy tissue.

It’s important to distinguish between these irAEs, such as colitis, and something like chemotherapy-induced diarrhea. So, you might see diarrhea both in a chemotherapy-treated patient and one treated with a checkpoint inhibitor; however the pathways that are causing these side effects are unique and as such they need to be managed differently. If you have a patient who was on chemotherapy and experiencing diarrhea, and the cause was due to the chemotherapy, you might hold or pause or reduce the chemotherapy dose and introduce an antidiarrheal [such as] loperamide. Well, in the checkpoint inhibitor guideline, loperamide might still be used, but methylprednisolone becomes a more significant player in managing this inflammatory-based response that is [triggering] diarrhea in the immunotherapy patient.

While other presentations are less common, such as pneumonitis (an inflammation of the lung tissue), they can lead to death. So it’s really critical that we are fully attentive to these manifestations. Endocrine abnormalities, particularly hypothyroidism, are also observed and require careful monitoring of thyroid stimulating hormones and other lab values. We are seeing diverse types of toxicities that are manifesting; they are immune-mediated and inflammatory, and require a unique approach for their management.

Cancer Network: What words of wisdom do you have for other oncology nurses when caring for these patients, besides studying this guideline?

Kelly Brassil: It is so important for nurses from all specialty areas, including but certainly not limited to oncology, to familiarize themselves with the various types of immunotherapeutic agents, and specifically to understand that immunotherapies, their mechanisms of action, and associated adverse events are distinct from other types of cancer treatments. Specifically, it’s important to understand the mechanisms of action of immunotherapies and the associated adverse events.

Especially, how these are distinct from other cancer treatment toxicities is so important, [since] nurses are often the primary educators of their patients. It’s really fundamental that we understand these immune-mediated toxicities associated with checkpoint inhibitors so that we can provide evidence-based assessment of these patients for early signs of the toxicities as well as highlighting recommended interventions for their management. The guidelines inform nurses’ knowledge about [immune-mediated] toxicities, so they can provide evidence-based education to use for patients and caregivers about what to expect when undergoing immunotherapeutic treatment, as well as how to self-monitor for signs and symptoms of toxicities following treatment and potentially into survivorship.

The content here is more than just ‘good to know’; it really highlights critical and potentially life-saving information that nurses should be aware of. Also, familiarizing yourself with new, expanded indications for these existing agents is critical to be current and contemporary, which can be a challenge. Nurses in all settings, not only in the larger academic medical centers where clinical trials may have taken place, should be aware of these agents. This includes our colleagues in ambulatory and community-based settings, including in primary care and emergency contexts, where patients who have undergone these therapies and may present with both acute toxicities as well as late effects. As such, awareness of immunotherapies and their potential toxicities is important for many nurses, not only those working in an oncology setting. We hope these guidelines will serve as a guidepost for nurses to educate themselves and their patients about these toxicities and their management, [so they can] continue to provide safe and effective care to individuals receiving immunotherapeutic treatment.

Cancer Network: Are there other resources for oncology nurses who would like more information and education about how best to monitor patients and address patients’ immune-related adverse events? What is your advice?

Kelly Brassil: Immunotherapy resources are continually emerging as these agents continue to evolve and gain FDA approval. Of course, for oncology nurses, The Oncology Nursing Society is a go-to resource. [ONS offers] several current resources to inform nurses about different types of immunotherapies, their indications, and potential toxicities. These include educational videos, numerous articles on diverse immunotherapy topics in both the Clinical Journal of Oncology Nursing and Oncology Nursing Forum, and online courses that can help nurses hone their skills. There are great 5-minute video refreshers for quick updates.

The ASCO-NCCN guidelines include a patient immunotherapy pocket-card that patients can carry with them and present in different treatment settings, developed by ONS. That information is important for nurses because they can relay that to patients who may need it in a nononcology care setting. In addition, the Society for Immunotherapy of Cancer has developed immunotherapy guidelines by cancer type. The Foundation for Accreditation of Cellular Therapies provides robust information on immune effector cell therapies, also referred to as CAR-T [chimeric antigen receptor T cell] therapies.

We are in a unique period of rapid evolution in cancer treatments, with immunotherapies frequently being approved for new indications, combinations, doses, or administrations. It is both an exciting time in the history of cancer treatment, but also one in which it can be difficult to keep up with the evolving treatment options and indications. I strongly encourage nurses across practice settings to seek out evidence-based information from national and professional organizations, which can help to demystify immunotherapy and identify key elements to the care of individuals receiving them. It’s an exciting time to be an oncology nurse, and I encourage nurses-not just oncology nurses-to seek out [such] evidence-based information from national and professional organizations.