Immune checkpoint inhibitor–related gastrointestinal adverse events
Management
Evaluation and management of GI irAEs are guided by severity, based on the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grading classification (Table 1).10
A thorough history of GI and systemic symptoms should be obtained and compared to baseline bowel habits. Patients with mild symptoms should undergo studies to assess alternate etiologies for their symptoms. Bacterial stool cultures and testing for C. difficile should be performed. Erythrocyte sedimentation rate, C-reactive protein, fecal lactoferrin, and calprotectin can help assess the degree of intestinal inflammation and can be used to risk-stratify or assess treatment response. CT scans can assess for colitis and associated complications, including abdominal abscess, toxic megacolon, and bowel perforation.
Patients unresponsive to initial treatment for grade I irAE, with hematochezia, or with at least grade 2 diarrhea, should undergo GI consultation and endoscopic evaluation. Flexible sigmoidoscopy is the test of choice, as 95% of patients will have left-sided colonic inflammation.11 Patients with at least grade 3 diarrhea should be hospitalized for treatment. In cases of failed methylprednisolone and when infliximab is ineffective or contraindicated, vedolizumab is suggested, although evidence is limited.12
Patients responsive to systemic corticosteroids (complete resolution or improvement to grade 1) can continue a tapered regimen over 4-6 weeks. There is conflicting evidence on the effect that corticosteroids have on ICI-related antitumor response rates. While some studies report no change in antitumor response rates or survival, others report reduced overall survival.13 Regardless, given its unfavorable side-effect profile, steroids should be used only for short periods of time.
PD-1 and PD-L1 antibodies can be restarted after symptoms have resolved or improved to grade 1, having finished the corticosteroid taper. CTLA-4 antibodies should be discontinued permanently in the setting of grade 3 toxicity. All ICIs should be discontinued permanently in grade 4 toxicity.
A grading system also exists for ICI-associated hepatitis (Table 2) and AP (Table 3). Patients with elevated aminotransferases greater than 2x upper limit of normal (ULN) should have alternative etiologies excluded. A thorough medication reconciliation, including over-the-counter and nonpharmaceutical supplements, should be performed. All potentially-hepatotoxic drugs and substances (including alcohol) should be discontinued. Viral hepatitis serology (A,B,C), Epstein-Barr virus, and cytomegalovirus also should be performed. Additional tests, including prothrombin time and albumin, can help assess for liver synthetic dysfunction. Abdominal ultrasound or CT can assist in excluding biliary obstruction or metastatic disease. Magnetic resonance cholangiopancreatography (MRCP) can be considered for further evaluation of biliary obstruction in patients with hyperbilirubinemia and normal ultrasound.14
Table 2 reviews the grading system and management of ICI-associated hepatitis. Patients with grade 3 and above should be hospitalized for treatment. As with the management of colitis, patients responding to corticosteroids should be tapered off over 4-6 weeks. In steroid-refractory cases or if there is no improvement after 3 days, mycophenolate mofetil is used. Other immunomodulators such as azathioprine and tacrolimus also can be considered, although evidence is limited.15 ICI-associated cholangitis presenting with elevated bilirubin and alkaline phosphatase is approached similarly to ICI-associated hepatitis. Abnormal findings of biliary obstruction or sclerosing cholangitis should be further evaluated with endoscopic retrograde cholangiopancreatography.
Mild asymptomatic elevation in lipase and amylase <3x ULN can be managed with observation and ICIs can be safely continued. Symptomatic patients should have a diagnostic workup for other etiologies. As with hepatitis, a thorough history including alcohol intake and a medication reconciliation should be performed. In the absence of other etiologies, grade 2 ICI-associated AP is managed by holding immunotherapy, administering steroids, and managing AP with fluid resuscitation and analgesia.
