Manage Immunotherapy-Related Diarrhea and Colitis
Although immunotherapy has a unique set of toxicities compared to traditional chemotherapy, in general, grade 3 or 4 toxicities are rare—with the exception of grade 3 diarrhea and colitis. The mechanisms by which immune-related diarrhea and colitis occur are not clear. However, T-cell activation leads to high levels of CD4 T-helper cell cytokines and cytolytic CD8 T-cell tissue infiltration. Some research suggests that depleting regulatory T cells also induces autoimmunity (https://doi.org/10.12998/wjcc.v7.i4.405).
Additionally, blocking CTLA-4 disables its protection against autoimmunity, resulting in immune system inflammatory response against certain organs and tissues. Colitis secondary to ipilimumab is similar to that of graft-versus-host disease and is a current area of research (https://doi.org/10.12998/wjcc.v7.i4.405).
Diagnosis
Infectious causes should be ruled out, especially in patients who have blood in the stools or fever. Evaluate stool for bacteria pathogens (https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf), Clostridium difficile, ova and parasites, viral pathogens, and lactoferrin and calprotectin. Immune-related toxicity and infection may coexist (https://doi.org/10.12998/wjcc.v7.i4.405), and blood in the stools may also indicate a gastrointestinal bleed from peptic ulcer disease or malignancy.
Immune-mediated colitis and inflammatory bowel disease appear similar on endoscopy; however, immune-mediated colitis has more neutrophilic inflammation without chronic inflammation (https://doi.org/10.4253/vjge.v10.i12.392). Normal mucosal appearance does not rule out enterocolitis, so biopsies should be obtained. If a differentiation proves difficult, immune-mediated colitis is much more likely if patients exhibit concomitant immune-related adverse events (https://doi.org/10.12998/wjcc.v7.i4.405) (e.g., hepatitis, hypophysitis).
Abdominal and pelvic computed tomography with contrast could be considered (https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf), especially in patients with fever and severe abdominal tenderness, distention, and rigidity (https://doi.org/10.12998/wjcc.v7.i4.405). Bowel perforations have been reported rarely (less than 1%) with the use of certain immunotherapies, but they can be fatal (https://doi.org/10.4253/vjge.v10.i12.392).
Management
Guidelines for managing immunotherapy-related toxicities are listed in the sidebar. Mild (grade 1) diarrhea and colitis can usually be managed with loperamide or diphenoxylate and atropine. Patients should be observed closely with follow-up visits or phone calls (https://doi.org/10.1200/JCO.2017.77.6385) within 24–48 hours and instructed to follow a bland diet (https://doi.org/10.1093/annonc/mdx225), avoiding high fiber and lactose, with adequate hydration (https://doi.org/10.1186/s40425-017-0300-z). Oncology practitioners will decide on a case-by-case basis whether to hold immunotherapy with grade 1 toxicity (https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf).
Moderate (grade 2) or severe (grade 3) toxicity requires holding immunotherapy, and symptom management should begin immediately while infectious causes are ruled out (https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf). Use of corticosteroids to treat immune-related toxicity has not been shown to reduce the drug’s antitumor effects. If grade 2 diarrhea persists more than two to three days after holding the treatment, prescribe prednisone or methylprednisolone 1 mg/kg per day.
With steroids, early intervention (https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf) is key. Treatment should continue until symptoms improve to grade 1 or less, then taper for four to eight weeks (https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf). If patients do not respond in two to three days, increase the dose to 2 mg/kg per day and consider adding infliximab. NCCN did not define (https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf) the duration of therapy, but recommendations range from a single 5 mg/kg dose to one dose every two weeks until symptoms resolve (https://doi.org/10.12998/wjcc.v7.i4.405). Repeating endoscopy may be helpful.
Severe colitis and diarrhea (grade 3–4) may require inpatient supportive care, and immunotherapy may be permanently discontinued for grade 4 symptoms. For severe toxicity (https://doi.org/10.1186/s40425-017-0300-z), consider IV methylprednisolone at 2 mg/kg per day; convert to prednisone when symptoms reduce to grade 2 (https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf). Add infliximab up to 10 mg/kg if patients do not respond within three to five days (https://doi.org/10.1200/JCO.2017.77.6385). If patients are infliximab-refractory, consider IV vedolizumab at 300 mg (https://doi.org/10.1186/s40425-018-0461-4).
About one third to two thirds of patients are steroid refractory and will benefit from infliximab (https://doi.org/10.12998/wjcc.v7.i4.405). Endoscopic evaluation may help determine (https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf) need for infliximab and calprotectin testing can be considered to monitor treatment response (https://doi.org/10.1200/JCO.2017.77.6385). Other suppressants such as tacrolimis could be considered (https://doi.org/10.1093/annonc/mdx225).
Resuming immunotherapy is not recommended for grade 4 toxicity but it is for grade 3 or less once corticosteroid treatment is tapered to less than 10 mg per day and patients are symptom free. With concomitant anti-CTLA-4 and anti-PD-1 therapy, continuation of the anti-PD-1 therapy alone is recommended (https://doi.org/10.1186/s40425-017-0300-z). Immunotherapy dose reductions are not recommended.
Interestingly and encouragingly, some evidence suggests that increased immune-related toxicities, including diarrhea, may be an independent predictor of improved survival (https://doi.org/10.12998/wjcc.v7.i4.405).
ONS’s immunotherapy patient wallet card can help identify patients receiving treatments that may cause diarrhea and colitis if they present to other healthcare professionals. Learn more atons.org/toolkits/immunotherapy-patient-wallet-card-1.