COMMENTARY

Managing Side Effects of Immunotherapy: Diarrhea/Colitis

Asim Amin, MD, PhD

December 23, 2015

Editorial Collaboration

Medscape &

Modulation of the immune checkpoint inhibitors cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death-1 (PD-1) has been shown to have impressive clinical activity.[1,2,3,4,5,6,7] Ipilimumab, pembrolizumab, nivolumab, and the combination of ipilimumab and nivolumab have been approved by the US Food and Drug Administration (FDA) for treatment of advanced melanoma[1,2,3,5,6,8]; pembrolizumab and nivolumab have been approved for treatment of advanced non-small cell lung cancer,[4,7] and additional indications are expected in other areas. It is critical for the oncology community to recognize that these immunotherapy agents elicit toxicities that may mimic some of the adverse effects observed with cytotoxic chemotherapy, yet the underlying mechanisms and management of these adverse effects are significantly different.

Guidelines for management of immune-related adverse events (irAEs) have been developed and published.[9,10,11] We have developed algorithms at our institution that are published online to be used within our system that closely follow the published guidelines and provide more specific details for the treating physicians.[12]

These are based on the following general principles:

  1. irAEs can present insidiously—comprehensive education of patients receiving immunotherapy regarding potential toxicities will allow them to recognize and report them.

  2. If recognized early, irAEs can be reversed successfully in almost all cases.

  3. Delay in intervention can result in significant morbidity and even mortality.

  4. Judicious use of immune suppression is the cornerstone of management.

  5. Appropriate antibiotic prophylaxis should be considered for patients on long-term immune suppression to prevent opportunistic infections.

Immune-mediated gastrointestinal toxicity in the form of diarrhea and colitis is one of the most common and potentially serious events caused by immunotherapy.[9,10,11,12] Management of diarrhea and colitis is presented to illustrate our institutional approach.

We have used the Common Terminology Criteria for Adverse Events (CTCAE)[13] to risk stratify the severity of symptoms; intervention is based on the severity.[12]

Grade 1: Less than 4 stools per day over baseline, requires stool studies to be obtained including Clostridium difficile, ova and parasites, and lactoferrin.

Additional labs should include a complete blood count with differential, comprehensive metabolic panel, and magnesium and phosphorus levels. We do not support reflex use of antidiarrheals (eg, loperamide, diphenoxylate/atropine), given that these agents may mask higher-grade toxicity. Emphasis regarding adequate hydration and altering oral intake to a bland diet is reinforced, and patients are asked to call in and keep the clinic updated up to three times a week. Immunotherapy is continued—no steroids are indicated.[12]

Grade 2: 4-6 stools per day over baseline; abdominal discomfort or blood/mucus in stool.

The initial laboratory investigations are the same as for grade 1. Immunotherapy is withheld until resolution to grade 0/1. We prefer not to use reflex steroids in this situation. If symptoms persist for more than 7 days, then flexible sigmoidoscopy is considered prior to committing the patient to systemic steroids. Additional investigation may be warranted with imaging.[12]

Grade 3 or 4: Greater than 7 stools per day over baseline; peritoneal signs and fever warrant admission to the hospital for intravenous hydration and further evaluation.

Initial laboratory investigations as above are obtained. If the patient is clinically stable, then consideration is given to gastroenterology consultation and flexible sigmoidoscopy (if possible within 24 hours) without reflex initiation of high-dose steroids until Clostridium difficile results are available. If a patient is symptomatic with peritoneal signs and fever, then steroids are initiated urgently; our preference is methylprednisolone 125 mg intravenously for 3 days.

Once symptoms improve, then oral prednisone is initiated at 1-2 mg/kg to be tapered over at least 4 weeks with appropriate antibiotic prophylaxis. If patients do not respond to 7 days of high-dose steroids, then consideration is given to treatment with infliximab 5 mg/kg in addition to continued steroids. In extremely severe cases, patients may require complete bowel rest with institution of total parental nutrition. Imaging may be warranted based on symptoms. Immunotherapy is permanently discontinued.[12]

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