Immune-related adverse events (irAEs) are unintended consequences of immunotherapies used in cancer treatment. Side effects can range from mild to very serious, and health care providers cannot yet predict who will suffer more side effects than others. Serious side effects can cause patients to interrupt or discontinue treatment, so managing them is a critical piece of treatment continuation. In the case of colitis induced by ipilimumab, patients may be retreated with immunotherapy under certain conditions.
What is colitis?
Colitis is an inflammation of the gastrointestinal lining. It is among the most common side effects observed in patients receiving immunotherapy or immune checkpoint inhibitors, especially CTLA-4 inhibitors, such as ipilumimab (Yervoy). In fact, 30-45% of patients receiving CTLA-4 inhibitors will experience some level of colitis. Patients with inflammatory bowel disease have an increased risk for developing colitis. Colitis is cited as a frequent reason for treatment interruption and discontinuation.
Inflammation in the gastrointestinal lining can cause bloating, cramping, diarrhea, and pain in the abdomen. Excessive watery diarrhea is a symptom of colitis (albeit not definitive, due to multiple other causes of diarrhea) that can indicate when a patient might be developing colitis. Moderate watery diarrhea, increasing to more than five loose bowel movements per day, usually arises five to ten weeks after immunotherapy begins, or after the second to third dose of immunotherapy.
What are the risks of colitis?
Although colitis can be a serious and potentially life-threatening complication, most patients will not have colitis that develops into a more serious condition requiring immediate intervention. Less than 11% of patients treated with single-agent ipilimumab or combination regimens containing ipilimumab will develop severe colitis. Infrequent but possible complications arising from serious colitis include bowel perforation, dehydration, hospitalization, sepsis, and shock. Mortality from gastrointestinal adverse events associated with response to ipilimumab is rare.
What are symptoms of a patient presenting with colitis?
The health care team may observe any of the symptoms listed below. Immune-related diarrhea is likely to impact most patients. However, diarrhea related to immunotherapy-associated colitis can also present in combination with upper gastrointestinal toxicity, enteritis, gastroenteritis, and gastritis.
Mild to moderate symptoms: Abdominal pain, an increase of 4-6 stools per day, and blood or mucus in stool
Serious symptoms: An increase of 7 or more stools per day, decreased appetite, fever, rapid change in gastrointestinal function, severe cramping and persistent abdominal pain
Emergency symptoms: Shock, distress, and abnormal or unstable blood pressure
Why does colitis occur?
Immunotherapy is designed to supercharge the immune system. Unfortunately, the gastrointestinal tract can become susceptible to an immune system-provoked injury as an unintended consequence. Although immunotherapy is created with targeted properties aimed at the tumor’s environment, sometimes it non-specifically activates too much of the immune system throughout the body.
Nearly every organ system in the body is at risk for an unprovoked injury by ipilimumab. However, immunotherapy, particularly immune-checkpoint inhibitors in combination with ipilimumab, works so well in many patients that the risk of side effects is deemed worthwhile to achieve the possible results. Prompt and thorough communication about side effects by patients with their medical team allows for appropriate clinical support, and these two together allow immunotherapy to be used safely and successfully in many patients.
What can a clinician do for colitis?
Rapid identification and treatment can reduce the risk of progression from mild colitis. One of the first steps is to exclude infectious causes of diarrhea before treating ipilimumab-induced colitis. For patients treated with ipilimumab, colitis may rapidly progress within a period of days.
Practice guidelines recommend immunosuppression, usually with moderate to high doses of systemic corticosteroids. However, high-dose corticosteroid use is associated with other complications, such as tumor growth or an increase of infection. Prompt management of colitis can avoid drug interruption or discontinuation and allow a patient to remain on therapy.
Once a definitive diagnosis is made, supportive hydration, along with drugs such as loperamide, diphenoxylate/atropine, or a slow steroid taper may be given. Usually, the administration of high-dose systemic glucocorticoids in doses of 0.5-2 mg/kg prednisone equivalent daily is effective. Severe colitis may require intravenous steroids, such as budesonide, infliximab, or vedolizumab.
Where can I find more information on your website?
Aim with Immunotherapy’s ipilimumab – HCP toolkit; PAP; CSP for colitis
Aim with Immunotherapy’s ipi/nivo – HCP toolkit; PAP
References:
Dougan M, Wang Y, Rubio-Tapia A et al. AGA Clinical Practice Update on Diagnosis and Management of Immune Checkpoint Inhibitor Colitis and Hepatitis: Expert Review. Gastroenterology. 2021;160(4):1384-1393. doi: 10.1053/j.gastro.2020.08.063.
Frey C and Etminan M. Adverse Events of PD-1, PD-L1, CTLA-4, and LAG-3 Immune Checkpoint Inhibitors: An Analysis of the FDA Adverse Events Database. Antibodies (Basel). 2024;13(3):59. doi: 10.3390/antib13030059.
Ho C and Samlowski W. Outcome of an Accelerated Treatment Algorithm for Patients Developing Diarrhea as a Complication of Ipilimumab-Based Cancer Immunotherapy in a Community Practice. Curr Oncol. 2024;31(6):3529-3545. doi: 10.3390/curroncol31060260.
Machado AP, Shaikh AS, Saji A et al. Outcomes of Budesonide as a Treatment Option for Immune Checkpoint Inhibitor-Related Colitis in Patients with Cancer. Cancers (Basel). 2024;16(10):1919. doi: 10.3390/cancers16101919.
Magahis PT, Corso T, Livingstone P et al. Open-capsule budesonide for the treatment of immune-related enteritis from checkpoint inhibitors. J Immunother Cancer. 2024;12(7):e009051. doi: 10.1136/jitc-2024-009051.
Oliveira C, Mainoli B, Duarte GS et al. Immune‑related serious adverse events with immune checkpoint inhibitors: Systematic review and network meta‑analysis. Eur J Clin Pharmacol. 2024;80(5):677-684. doi: 10.1007/s00228-024-03647-z.
