Immune-related adverse effects in palliative care clinic
The rapid progress of immune checkpoint inhibitors (ICIs) in oncology has revolutionized cancer treatment. ICIs modulate T cell activity to promote detection and destruction of cancer cells. They are now widely used in many settings and disease types. However, ICIs come with a range of toxicities known as immune-related adverse events (irAEs). Unlike traditional chemotherapy side effects, irAEs stem from an overactivation of the immune system and can affect nearly any organ (1). Even mild irAEs can greatly impact quality of life and lead to severe or life-threatening complications.
Palliative care clinicians see an increasing number of patients with cancer who have received treatment with an ICI. They should be equipped to recognize and understand irAEs. There is a growing interest in palliative care representation on multidisciplinary teams built at cancer centers to address immunotoxicity (2). However, education on irAEs for palliative care teams has not kept pace with the increased use of ICIs. In this letter, we provide a broad overview of the role of palliative care clinicians in the care of patients with cancer treated with ICI. The palliative care team is uniquely positioned to enhance patient-centered care and improve outcomes for patients navigating both cancer and ICI treatment-related complications. The palliative care clinician can be expected to detect symptoms of mild irAEs, participate in symptom-directed management of irAEs, and engage in serious illness conversations surrounding severe irAEs.
Palliative care clinicians should be prepared to recognize the breadth and variety of irAE presentations. irAEs can be difficult to distinguish from cancer-related symptoms or comorbid conditions, underlining the need for palliative care providers to receive education on this topic. They may be the first team members to detect subtle symptoms of irAEs. Qualitative interviews show that patients on immunotherapy underreport side effects to their primary oncologists for a variety of reasons (3). Dedicated palliative care visits offer an opportunity for a thorough review of systems to identify mild irAE symptoms. Identification of early irAEs can prevent potential progression to more serious side effects. While low grade toxicities may not be life-threatening, they can significantly impact quality of life and lead to complications if left unaddressed.
The onset, affected organ system, and severity of irAEs are variable and often difficult to predict (1). Because ICIs harness the immune system, side effects mimic autoimmune conditions and can impact any part of the body. Patients on ICI therapy can experience side effects at any time during treatment. Some patients may develop side effects immediately after the first cycle, while others may not see any side effects for months or years. Therefore, it is prudent to ask about symptoms that could signal irAEs at every encounter. A thorough review of systems is necessary to screen for subtle irAEs for all patients on an ICI. Table 1 offers suggestions for targeted questions in history to be used during outpatient palliative care visits for patients on ICI therapy.
Table 1
| Symptoms | irAE | Sample targeted history questions |
|---|---|---|
| Fatigue | Hypophysitis, thyroiditis | “Walk me through a normal day for you. What did a normal day look like before you started your most recent cancer treatment? What does a normal day look like now?” |
| Rash, pruritus | Dermatitis | “Tell me about any changes you’ve noticed on your skin. Has your skin been more dry, itchy, or red?” |
| Vision changes | Episcleritis, uveitis | “Have you noticed any changes to your vision? Do you have any discomfort in your eyes?” |
| Chest pain, orthopnea | Myocarditis, pericarditis | “Have you experienced any chest pain or awareness of your heartbeat? Have you noticed that you have difficulty breathing when lying flat?” |
| Dyspnea | Pneumonitis | “Have you felt short of breath with walking? What about when you are resting?” |
| Reflux, globus sensation, abdominal pain | Esophagitis, gastritis | “Do you feel any discomfort in your chest or your throat after eating?” |
| Diarrhea | Colitis | “How many bowel movements are you having each day? What do they look like?” |
| Joint pain | Arthralgia | “Are you noticing any change in the activities you can do comfortably with your hands?” |
| Muscle aches | Myalgias, polymyalgia rheumatica | “Are you noticing any pain in your muscles with activities that you used to do comfortably?” |
| Numbness, tingling | Neuropathy | “Some people who are treated with the same medication as you feel numbness, tingling or pain in their fingers or toes. Does that ever happen to you?” |
| Weakness | Myasthenia gravis, Guillain-Barré syndrome, demyelinating disease | “Have you experienced any new weakness, either overall or of a particular muscle? Have you noticed any difficulty with swallowing? Have you had any pain in your lower back or thighs?” |
irAE, immune-related adverse event.
Palliative care clinicians may participate in symptom management related to irAEs while the patient is undergoing appropriate workup and definitive management. Any side effects should be discussed directly with the treating oncologist. The hallmarks of irAE management are steroids and anti-inflammatory biologics, such as infliximab. These are typically managed by the oncology team. Severe irAEs require prompt communication with the relevant subspecialist to prevent rapid progression, hospitalization, or death. It is paramount to discuss with the treating oncologist before starting steroids in a patient on ICI therapy, since steroids may affect treatment efficacy or clinical trial eligibility.
Non-steroidal symptom management strategies may be best implemented by the palliative care clinician, who has specialized training as well as dedicated visits to focus on symptoms. There are many available resources to guide the treatment of irAEs. The major cancer-related professional societies have published guidelines for irAE management, including American Society of Clinical Oncology (ASCO) (4), European Society for Medical Oncology (ESMO) (5), Multinational Association of Supportive Care in Cancer (MASCC) (6), National Comprehensive Cancer Network (NCCN) (7), and Society for Immunotherapy of Cancer (SITC) (8). The Alliance for Support and Prevention of Immune-Related Adverse Events (ASPiRE) also offers a monthly newsletter and focused webinars covering high yield topics in irAE management (9). Resources targeted specifically to palliative care audiences are more limited but include FastFacts (10) and recent presentations at the American Academy of Hospice and Palliative Medicine (AAHPM) Annual Assembly (11).
Palliative care clinicians can use their advanced training in communication skills to promote quality of life and facilitate goal-concordant care for patients living with irAEs. This process entails open and honest communication with the patient about side effects and multidisciplinary communication with the treatment team about management. The palliative care clinician is positioned to facilitate bidirectional communication between the patient and the care team: (I) to amplify the patient’s voice in coordination with the multidisciplinary team to ensure irAEs are identified and treated promptly, and (II) to offer a patient-centered lens for conveying complex and life-altering information about irAE severity and management. Palliative care clinicians should be empowered to communicate with appropriate specialists. They also play a vital role in supporting patients experiencing high grade irAEs. Serious illness conversations surrounding severe irAEs include topics of informed consent, iatrogenic illness, high-stakes interventions, treatment discontinuation, and threat to life. Palliative care visits offer a forum to discuss and better understand a patient’s treatment values and priorities, which can inform a decision to continue or discontinue ICI.
As ICIs become the standard of care in many cancers, irAEs present new challenges for both patients and clinicians. Palliative care teams can provide valuable support by assessing and managing symptoms, facilitating interdisciplinary communication, and helping patients navigate uncertainty related to complex side effects and evolving treatment decisions. Integrating palliative care into the management of patients receiving ICIs can contribute to more coordinated, patient-centered care and should become the standard of care in all cancer centers.
Acknowledgments
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Footnote
Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Palliative Medicine. The article has undergone external peer review.
Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-25-112/prf
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-25-112/coif). M.T. reports support from the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery. She reports consulting fees from Genentech. She received honoraria from BioAscend and travel support from BioAscend. She has served on advisory boards or data safety monitoring boards for Novartis and AstraZeneca and for Genentech. She holds a leadership role in the American Society of Clinical Oncology. She also reports stock or stock options in Atara and Poseida Therapeutics. The other authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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