Abstract
Development of immunotherapy agents has changed the cancer treatment paradigm with better outcomes and lesser side effects. Yet, there are adverse events associated with them. Owing to the increased stimulation of the immune system, the normal homeostatic mechanisms protecting the body from its own immune response can become disrupted, leading to a variety of side effects termed immune-related adverse effects (irAEs). irAEs can have significant associated morbidity and in many cases lead to discontinuation of therapies with unpredictable impact on the course of patients' disease. Few key articles laying out guidelines for the management of irAEs provide general treatment algorithms for the majority of the common irAEs. Nurses should have knowledge of the mechanism and adverse events associated with such therapies. Oncology nurses have a crucial role in identification of irAEs. irAEs may involve multiple systems, and thus, it is necessary to identify and manage these adverse events according to the case these at soon as possible.
Keywords: Immune-related adverse effects (irAEs), Oncology nurses, Immunotherapy, Immune checkpoints inhibitors, Cancer
Introduction
Incidence and mortality related to malignant neoplasms are increasing in developed and developing world. Decades of research and advancement in medical field and treatment modalities such as radiation therapy, chemotherapy, targeted therapy, and immunotherapy have successfully helped in managing the cancer cases and improved survival outcome.1,2 However, side effects and adverse events related to such therapies are always a matter of concern as it is important for patients’ compliance and for better quality of life.1, 2, 3 Development of immunotherapy agents has changed the cancer treatment paradigm with better outcomes and lesser side effects. Immune-targeted therapies have been a major breakthrough in cancer treatment over recent decades.4
Immune checkpoint inhibitors (ICPis) are an example of an immune-targeted therapy which works by stimulating the supressed immune system to attack tumor cells itself. Examples of ICPis include anticytotoxic T lymphocyte antigen 4 (CTLA-4), anti–programmed cell death 1 (PD-1), and anti–programmed cell death ligand 1 (PD-L1) antibodies.5 Owing to the increased stimulation of the immune system, the normal homeostatic mechanisms protecting the body from its own immune response can become disrupted, leading to a variety of side effects termed immune-related adverse effects (irAEs).5
Table 1 describes irAEs in relation to the affected organ or system of the human body.6 irAEs can have significant associated morbidity and in many cases lead to discontinuation of therapies with an unpredictable impact on the course of patients' disease.6 Severe irAEs lead to more frequent and prolonged hospital stays, requiring the input of multidisciplinary team (MDT) management, leading to increased health care costs.7
Table 1.
Common immune-related adverse effects.
| Affected organ or system of the human body | Immune-related adverse effects |
|---|---|
| Skin | Bullous dermatosis |
| Skin rash/inflammatory dermatitis | |
| Severe skin reactions | |
| Gastrointestinal | Colitis |
| Hepatitis | |
| Lung | Pneumonitis |
| Endocrine | Diabetes |
| Hyperthyroidism (primary) | |
| Hypophysitis | |
| Primary adrenal insufficiency | |
| Musculoskeletal | Inflammatory arthritis |
| Myositis | |
| Polymyalgia rheumatica | |
| Renal | Nephritis |
| Nervous System | Myasthenia gravis |
| Guillain–Barré syndrome | |
| Peripheral neuropathy | |
| Autonomic neuropathy | |
| Aseptic meningitis | |
| Encephalitis | |
| Transverse myelitis | |
| Hematological | Autoimmune hemolytic anemia |
| Acquired thrombotic thrombocytopenic purpura | |
| Uremic hemolytic syndrome | |
| Aplastic anemia | |
| Lymphopenia | |
| Immune thrombocytopenia | |
| Acquired hemophilia | |
| Cardiovascular | Myocarditis |
| Pericarditis | |
| Arrhythmias, heart failure associated with ventricular failure | |
| Vasculitis | |
| Venous thromboembolism | |
| Ocular | Uveitis/iritis |
| Episcleritis | |
| Blepharitis |
Current management
The key articles laying out guidelines for the management of irAEs are those published by the European Society of Medical Oncology (ESMO),8 the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group,9 and the National Comprehensive Cancer Network (NCCN) (National Comprehensive Cancer Network, 2018). These guidelines provide general treatment algorithms for the majority of the common irAEs, detailing the immunosuppressive drugs and duration of treatment based on their severity.5 However, these are not evidence-based approaches, instead being algorithms, suggestions, and recommendations by panels of experts.6,9,10 Table 2 describes different IrAEs and the recommended management along with the degree of toxicity.6,12
Table 2.
| Common adverse reactions | Research of alternative/noninflammatory etiologies | Degree of toxicity | Recommended management of irAEs |
|---|---|---|---|
| Gastrointestinaldiarrhea/colitis | Exclude infectious etiology (Clostridium difficile) | Grade 1 (Mild) | Symptomatic treatment Consider budesonide 9 mg/day Continue immunotherapy |
| Grade 2 (Moderate) | Delay immunotherapy Methylprednisolone IV 0.5–1 mg/kg/day (or oral equivalent) Consider gastroenterology and colonoscopy consultation When improving to ≤ grade 1, reduce the dose for at least 4 weeks |
||
| Grades 3–4 (Severe) | Stop immunotherapy Methylprednisolone IV 1–2 mg/kg/day When improving to ≤ grade 1, reduce the dose for at least 4 weeks If no improvement in symptoms within 48–72 h, consider 2nd-line immunosuppression (infliximab) |
||
| Hepatitis | Evaluate for
|
Grade 1 (Mild) | Continue immunotherapy Repeat LFTs within 1 week |
| Grade 2 (Moderate) | Delay immunotherapy Repeat LFTs every 3–5 days Methylprednisolone IV 0.5–1 mg/kg/day (or oral equivalent) When improving to mild or baseline, reduce the dose of steroids for at least 4 weeks |
||
| Grades 3–4 (Severe) | Stop immunotherapy Increase the frequency of LFTs to 1–2 days Methylprednisolone IV 1–2 mg/kg/day Gastroenterology consultation If no improvement in symptoms within 48–72 h, consider 2nd-line immunosuppression (infliximab) |
||
| Pneumonitis | Evaluate for
|
Grade 1 (Mild) | Delay immunotherapy Monitor symptoms Repeat chest X-ray in 2–4 weeks |
| Grade 2 (Moderate) | Delay immunotherapy Monitor symptoms closely, consider hospitalization Reimage every 1–3 days Pneumology and infectious disease consultations, consider bronchoscopy Methylprednisolone IV 1–2 mg/kg/day (or oral equivalent) When symptoms improve, reduce the dose of steroids for at least 4 weeks |
||
| Grades 3–4 (Severe) | Stop immunotherapy Methylprednisolone IV 2–4 mg/kg/day, discontinue steroids for a period of at least 6 weeks If no improvement in symptoms within 48–72 h, consider 2nd-line immunosuppression (infliximab, mycophenolate mofetil, IVIG) |
||
| Dermatological adverse reactions | Exclude noninflammatory causes (allergic reaction to other drugs, photosensitivity, etc.) | Grade 1 (Mild) | Continue immunotherapy Supportive therapy emollients, low-potency topical steroids, antihistamines |
| Grade 2 (Moderate) | Continue immunotherapy Topical steroids of moderate-high potency If persistent, despite optimized topical treatment, consider methylprednisolone 0.5–1 mg/kg/day (or oral equivalent) If it improves slightly or resolves, reduce the dose of steroids for at least 4 weeks Consider dermatological evaluation and skin biopsy |
||
| Grades 3–4 (Severe) | Delay immunotherapy Methylprednisolone IV 1–2 mg/kg/day (or oral equivalent) If it improves to mild or resolves, reduce the dose of steroids for at least 4 weeks. Consider skin biopsy |
||
| Endocrinopathies | Exclude noninflammatory etiology of symptoms | Grade 1 (Mild) | Continue immunotherapy If TSH is abnormal, add free T4 and T3 Consider morning cortisol and ACTH |
| Grade 2 (Moderate) | TSH, free T4, morning cortisol and ACTH Consider pituitary MRI Methylprednisolone IV 1–2 mg/kg/day (or oral equivalent) If it improves, reduce the dose of steroids for at least 4 weeks Hormone replacement therapy if indicated Endocrinology consultation |
||
| Grades 3–4 (Severe) | Delay or discontinue immunotherapy If adrenal crisis is suspected, exclude infection/sepsis, BP support Stress doses of mineralocorticosteroid |
ACTH, adrenocorticotrophin; COPD, chronic obstructive pulmonary disease; GI, gastrointestinal; IVIG, intravenous immunoglobulin; IV, intravenous; MRI, magnetic resonance image; BP, blood pressure; T3, triiodothyronine; T4, thyroxine; LFTs, liver function tests; TSH, thyroid-stimulating hormone; irAEs, immune-related adverse effects.
Oral or intravenous (IV) corticosteroids are the mainstay of current irAE treatment, depending on the grade of the toxicity. Most of the irAEs can be managed with early detection and the use of high-dose steroids, which are then stepped down over 2–4 weeks as the patients’ symptoms improve. Before resuming ICPi therapy, the severity should have reduced to grade 1 at least, or resolved entirely. Other immunosuppressive medications are indicated in more severe or refractory cases.11,12
Future developments
Autoimmune disease
In the past, patients with autoimmune diseases or their associated symptoms have been excluded from clinical trials involving ICPis beause of a higher risk of developing irAEs; however, retrospective studies have suggested that they can be relatively safe and tolerable in these circumstances,13 with research suggesting that active autoimmune disease can be controlled in patients with anti-PD1 antibodies with concomitant use of immunosuppression.5 There is a need to further research into the efficacy of using ICPi treatments for patients with autoimmune conditions.
Personalized surveillance strategies
Another suggested future development would be the identification of biomarkers which could be used to monitor for the development of specific irAEs, allowing for earlier identification and treatment of these events, as well as the safety of ICPi administration.14 The proposed method would involve continuous observations of nonspecific biological markers (such as creatinine kinase, liver enzymes, inflammatory markers, isolated autoantibodies).5 Morgado et al. proposed a method for surveillance of irAEs which is shown in Box 1.15
Box 1. Proposed surveillance strategy for immune-related adverse events (irAEs).6.
General pretreatment assessments
|
Workup for suspicion of specific irAEs and/or autoimmune diseases
|
All patients
|
Alt-text: Box 1
Optimizing the choice of the immunosuppressive agent
Current treatment of irAEs relies heavily on the use of steroids. However, long-term steroid use can be associated with a variety of adverse effects that can affect multiple system, such as gastritis, hypertension, insomnia, hyperglycaemia, and increased risk of opportunistic infections.16 There has been growing interest in the use of steroid-sparing immune-modulating agents in the management of irAEs.4 For example, tocilizumab (interleukin-6 receptor monoclonal antibody) has been used in the management of patients with immunotherapy-related pneumonitis and arthritis.17,18 They have been shown to be both effective and important in treating irAEs that are not steroid sensitive (failing to resolve withing six to 12 weeks of adequate corticosteroid treatment) and are used once other potential causes have been excluded.19 Considering the promise of using this class of drugs in the management of refractory irAEs, further prospective studies are needed to evaluate the dosing and effectiveness of such treatments.4
Improving clinical characterization
The current Common Terminology Criteria for Adverse Events (CTCAE) can be difficult to apply and do not allow for accurate reporting of severity and effect of some irAEs (such as systemic/rheumatic irAEs).9 It has therefore been suggested that adding more terms into the CTCAE would be beneficial and allow for a standardized capture of all irAEs, and there is a taskforce currently in place which is developing a module to include more irAEs.4
Education
Patient education is key for early recognition and effective management of irAEs.20 They should be informed of the presentation of some of the most common of these side effects and given hotline numbers to call if they are developing symptoms. It is also important to educate members of the MDTs caring for these patients on the irAEs and their management, avoiding delays in treatment.10,13 This extends to education of General Practitioners (GP) and emergency department practitioners who may be the first to see these patients presenting with irAEs from immune checkpoint inhibitor (ICI) treatment. Prompts such as medical alert cards or electronic alerts on patients notes may be needed to prompt practitioners who are not experienced in oncology to consider irAEs as a differential diagnosis in these patients.12,21
Further our understanding of mechanism of irAEs
The exact pathophysiology by which the adverse events are related to the immune system is unknown, although it is thought to be related to the role of ICPis in immune homeostasis.22 Translational studies have shown that the T-cell, antibody, and cytokine responses may be involved. Studies are needed to understand the mechanisms of irAEs to allow for development of more precise treatments of irAEs.22
Role of oncology nurses in managing irAEs
Oncology nurses have a crucial role in identification of irAEs of therapeutic agents such as ipilimumab. Nurses have an important role in communications related to identification of irAE signs and symptoms to the patients and caregivers and advised to make a call, in case of any adverse events. It should be noted that these adverse events may happen even within 2 years of treatment.23,24 Nurses should have knowledge of the mechanism and adverse events associated with such therapies.25 irAEs may involve multiple systems, and thus, it is necessary to identify and manage these adverse events according to the case as soon as possible.24,26
The Clatterbridge Cancer Centre formulated guidelines for nurses to manage irAEs. With a dedicated nursing team for irAEs, it categorized the adverse events or toxicity into four grades, that is, mild (grade 1) to severe or life-threatening (grade 4) with specific management of each type of graded events. They adopted widely used color coding, that is, red, amber, green (RAG), to make these guidelines easy to implement.26 Updated version of these guidelines is available online (www.clatterbridgecc.nhs.uk).
The American Society of Clinical Oncology recommends educating the patients as an initial step in managing irAEs. Use of wallet card can be arranged to identify the patients who are receiving immunotherapy. Nurses should be familiar in identifying any adverse signs or symptoms, benign or advance stage, and triage accordingly.27
The Oncology Nursing Society collaborated with the National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology to formulate guidelines to manage irAEs. These guidelines include information related to adverse events and education to patients and caregivers during therapies and afterward.25
Conclusions
ICIs are clearly an important development in the treatment of cancer. Despite this, irAEs requiring specialist MDT management can occur as a result of treatment. Many of these are reversible through the use of high-dose corticosteroids. Patient and practitioner education is vital however to ensure early detection and therefore management of these events. However, further research is needed to create internationally accepted evidence-based guidance on management of irAEs.
Further research is also needed to understand the pathophysiology of these events to improve both management and allow for the use of personalized surveillance strategies, adjusted to monitor for biochemical markers of developing irAEs.
Funding
Nil.
Declaration of competing interest
None declared.
References
- 1.Devlin E.J., Denson L.A., Whitford H.S. Cancer treatment side effects: a meta-analysis of the relationship between response expectancies and experience. J Pain Symptom Manag. 2017;54:245–258.e2. doi: 10.1016/j.jpainsymman.2017.03.017. [DOI] [PubMed] [Google Scholar]
- 2.Shankar A., Roy S., Malik A., Julka P.K., Rath G.K. Prevention of chemotherapy-induced nausea and vomiting in cancer patients. APJCP. 2015;16:6207–6213. doi: 10.7314/apjcp.2015.16.15.6207. [DOI] [PubMed] [Google Scholar]
- 3.Shankar A., Roy S., Bhandari M., Rath G.K., Biswas A.S., Kanodia R., et al. Current trends in management of oral mucositis in cancer treatment. APJCP. 2017;18:2019–2026. doi: 10.22034/APJCP.2017.18.8.2019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Naing A., Hajjar J., Gulley J.L., Atkins M.B., Ciliberto G., Meric-Bernstam F., et al. Strategies for improving the management of immune-related adverse events. J Immunother Cancer. 2020;8 doi: 10.1136/jitc-2020-001754. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Martins F., Sofiya L., Sykiotis G.P., Lamine F., Maillard M., Fraga M., et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol. 2019;16:563–580. doi: 10.1038/s41571-019-0218-0. [DOI] [PubMed] [Google Scholar]
- 6.Brahmer J.R., Lacchetti C., Schneider B.J., Atkins M.B., Brassil K.J., Caterino J.M., et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American society of clinical oncology clinical practice guideline. J Clin Oncol. 2018;36:1714–1768. doi: 10.1200/JCO.2017.77.6385. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Balaji A., Zhang J., Wills B., Marrone K.A., Elmariah H., Yarchoan M., et al. Immune-related adverse events requiring hospitalization: spectrum of toxicity, treatment, and outcomes. J Oncology Practice. 2019;15:e825–e834. doi: 10.1200/JOP.18.00703. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Haanen J., Carbonnel F., Robert C., Kerr K.M., Peters S., Larkin J., et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28:iv119–i142. doi: 10.1093/annonc/mdx225. [DOI] [PubMed] [Google Scholar]
- 9.Puzanov I., Diab A., Abdallah K., Bingham C.O., 3rd, Brogdon C., Dadu R., et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the society for immunotherapy of cancer (SITC) toxicity management working Group. J Immunother Cancer. 2017;5:95. doi: 10.1186/s40425-017-0300-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Barquín-García A., Molina-Cerrillo J., Garrido P., Garcia-Palos D., Carrato A., Alonso-Gordoa T. New oncologic emergencies: what is there to know about inmunotherapy and its potential side effects? Eur J Intern Med. 2019;66:1–8. doi: 10.1016/j.ejim.2019.05.020. [DOI] [PubMed] [Google Scholar]
- 11.Spain L., Diem S., Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev. 2016;44:51–60. doi: 10.1016/j.ctrv.2016.02.001. [DOI] [PubMed] [Google Scholar]
- 12.Bourke J.M., O'Sullivan M., Khattak M.A. Management of adverse events related to new cancer immunotherapy (immune checkpoint inhibitors) Med J Aust. 2016;205:418–424. doi: 10.5694/mja16.00586. [DOI] [PubMed] [Google Scholar]
- 13.Nagai H., Muto M. Optimal management of immune-related adverse events resulting from treatment with immune checkpoint inhibitors: a review and update. Int J Clin Oncol. 2018;23:410–420. doi: 10.1007/s10147-018-1259-6. [DOI] [PubMed] [Google Scholar]
- 14.Martins F., Sykiotis G.P., Maillard M., Fraga M., Ribi C., Kuntzer T., et al. New therapeutic perspectives to manage refractory immune checkpoint-related toxicities. Lancet Oncol. 2019;20:e54–e64. doi: 10.1016/S1470-2045(18)30828-3. [DOI] [PubMed] [Google Scholar]
- 15.Morgado M., Plácido A., Morgado S., Roque F. Management of the adverse effects of immune checkpoint inhibitors. Vaccines (Basel) 2020;8:575. doi: 10.3390/vaccines8040575. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Wang H., Zhou J., Guo X., Li Y., Duan L., Si X., et al. Use of glucocorticoids in the management of immunotherapy-related adverse effects. Thorac Cancer. 2020;11:3047–3052. doi: 10.1111/1759-7714.13589. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Naqash A.R., Yang L.V., Sanderlin E.J., Atwell D.C., Walker P.R. Interleukin-6 as one of the potential mediators of immune-related adverse events in non-small cell lung cancer patients treated with immune checkpoint blockade: evidence from a case report. Acta Oncologica (Stockholm, Sweden) 2018;57:705–708. doi: 10.1080/0284186X.2017.1406668. [DOI] [PubMed] [Google Scholar]
- 18.Kim S.T., Tayar J., Trinh V.A., Suarez-Almazor M., Garcia S., Hwu P., et al. Successful treatment of arthritis induced by checkpoint inhibitors with tocilizumab: a case series. Ann Rheumatic Dis. 2017;76:2061–2064. doi: 10.1136/annrheumdis-2017-211560. [DOI] [PubMed] [Google Scholar]
- 19.Si X., Song P., Ni J., Di M., He C., Zhang L., et al. Management of immune checkpoint inhibitor-related adverse events: a review of case reports. Thorac Cancer. 2020;11:498–504. doi: 10.1111/1759-7714.13315. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Elder C.T., Davis E.C., Jaipal S., Wight C.E. Immune-checkpoint inhibitor toxicity during a pandemic: overcoming patient fears to provide care. A case report. J Oncol Pharm Pract. 2021;27:2035–2040. doi: 10.1177/10781552211012782. [DOI] [PubMed] [Google Scholar]
- 21.Champiat S., Lambotte O., Barreau E., Belkhir R., Berdelou A., Carbonnel F., et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol. 2016;27:559–574. doi: 10.1093/annonc/mdv623. [DOI] [PubMed] [Google Scholar]
- 22.Postow M.A., Sidlow R., Hellmann M.D. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378:158–168. doi: 10.1056/NEJMra1703481. [DOI] [PubMed] [Google Scholar]
- 23.Boutros C., Tarhini A., Routier E., Lambotte O., Ladurie F.L., Carbonnel F., et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol. 2016;13:473–486. doi: 10.1038/nrclinonc.2016.58. [DOI] [PubMed] [Google Scholar]
- 24.Rubin K.M. Managing immune-related adverse events to ipilimumab: a nurse's guide. Clin J Oncol Nurs. 2012;16:E69–E75. doi: 10.1188/12.CJON.E69-E75. [DOI] [PubMed] [Google Scholar]
- 25.Brassil K. Oncology nursing society's annual meeting | conference. CancerNetwork; 2018. ONS role in new guideline for irAE management.https://www.cancernetwork.com/view/ons-role-new-guideline-irae-management [updated May 16; cited Aug 9, 2021]. Available from: [Google Scholar]
- 26.Upton J. 2017. Creating guidelines for managing the side-effects of immunotherapy: nursing Times.https://www.nursingtimes.net/clinical-archive/cancer-clinical-archive/creating-guidelines-for-managing-the-side-effects-of-immunotherapy-27-11-2017/ [online]; [cited July 2, 2021]. Available from: [Google Scholar]
- 27.Cole S., Zibelman M., Bertino E., Yucebay F., Reynolds K. Managing immuno-oncology toxicity: top 10 innovative institutional solutions. Am Soc Clin Oncol Educ Book. 2019:96–104. doi: 10.1200/EDBK_100018. [DOI] [PubMed] [Google Scholar]