Table 2.

Management of GI irAEs in Patients Treated With ICPis

2.0 GI Toxicities
2.1 Colitis
Definition: A disorder characterized by inflammation of the colon
Diagnostic work-up
G2
Work-up of blood (CBC, comprehensive metabolic panel, TSH, ESR, CRP), stool (culture, Clostridium difficile, parasite, CMV or other viral etiology, ova and parasite) should be performed
Consider testing for lactoferrin (for patient stratification to determine who needs more urgent endoscopy) and calprotectin (to follow up on disease activity)
Screening laboratories (HIV, hepatitisAand B, and blood quantiferon forTB) to prepare patients to start infliximab should be routinelydone in patients at high risk for those infections and appropriately selected patients based on infectious disease expert's evaluation
Imaging (eg, CT scan ofabdomen and pelvis and GIendoscopywith biopsy) should be considered as there is evidence showing thatthe presence of ulceration in the colon can predict a corticosteroid-refractory course, which may require early infliximab
Consider repeating endoscopy for patients who do not respond to immunosuppressive agents; repeating endoscopy for disease monitoring can be considered when clinically indicated and when planning to resume therapy
G3–4
All the work-up listed for G2 (blood, stool, imaging, and scope with biopsy) should be completed immediately
Consider repeating endoscopy for patients who do not respond to immunosuppressive agents; repeating endoscopy for disease monitoring should only be considered when clinically indicated and when planning to resume ICPi
Grading (based on CTCAE for diarrhea, as most often used clinically)	Management
All patients	Counsel all patients to be aware of and inform their health care provider immediately if they experience:  Abdominal pain, nausea, cramping, blood or mucus in stool or changes in bowel habits  Fever, abdominal distention, obstipation, constipation  For G2 or higher, consider permanently discontinuing CTLA-4 agents and may restart PD-1, PD- L1 agents if patient can recover to G1 or less; concurrent immunosuppressant maintenance therapy should be considered only if clinically indicated in individual cases
G1: Increaseoffewerthan fourstools perdayover baseline; mild increase in ostomy output compared with baseline	Continue ICPi; alternatively, ICPi may be held temporarilyand resumed iftoxicitydoes notexceed G1  Monitor for dehydration and recommend dietary changes  Facilitate expedited phone contact with patient/caregiver  May obtain gastroenterology consult for prolonged G1 cases
G2: Increase offour to six stools perday over baseline; moderate increase in ostomy output compared with baseline	Should hold ICPi temporarily until patient’s symptoms recover to G1; can consider permanently discontinuing CTLA-4 agents and may restart PD-1, PD-L1 agents if patientcan recovertoG1 or less  Concurrent immunosuppressant maintenance therapy (< 10 mg prednisone equivalent dose) may be offered only if clinically indicated in individual cases  Mayalso include supportive care with medications such as Imodium if infection has been ruled out  Should consult with gastroenterology for G2 or higher  Administer corticosteroids, unless diarrhea is transient, starting with initial dose of 1 mg/kg/day prednisone or equivalent  When symptoms improve to G1 or less, taper corticosteroids over at least 4–6 weeks before resuming treatment, although resuming treatment while on low-dose corticosteroid may also be an option after an evaluation of the risks and benefits  >EGD/colonoscopy, endoscopy evaluation should be highly recommended for cases grade ≥ 2 to stratify patients for early treatment with infliximab based on the endoscopic findings and to determine the safety of resuming PD-1, PD-L1 therapy  Stool inflammatory markers can be considered (lactoferrin and calprotectin) in cases of G2 or higher to differentiate functional v inflammatory diarrhea, and use calprotectin to monitor treatment response if provider prefers  Repeat colonoscopy is optional for cases of G2 or higher for disease activity monitoring to achieve complete remission, especially if there is a plan to resume ICPi
G3: Increase of seven or more stools per day over baseline, incontinence, hospitalization indicated, severe increase in ostomy output compared with baseline, limiting self-care ADL	Should consider permanently discontinuing CTLA-4 agents and may restart PD-1, PD-L1 agents if patient can recover to G1 or less.  Administer corticosteroids (initial dose of 1–2 mg/kg/d prednisone or equivalent)  Consider hospitalization or outpatient facility for patients with dehydration or electrolyte imbalance  If symptoms persist ≥ 3–5 days or recur after improvement, consider administering IV corticosteroid or noncorticosteroid (eg, infliximab)  Consider colonoscopy in cases where patients have been on immunosuppression and may be at risk for opportunistic infections as an independent cause for diarrhea (ie, CMV colitis) and for those who are anti-TNF or corticosteroid refractory
G4: Life-threatening consequences; urgent intervention indicated	Permanently discontinue treatment  Should admit patientwhen clinically indicated; patients managed as outpatients should bevery closely monitored  Administer 1–2 mg/kg/d methylprednisolone or equivalent until symptoms improve to G1, and then start taper over 4–6 weeks  Consider early infliximab 5–10 mg/kg if symptoms refractory to corticosteroid within 2–3 days Consider lowerGI endoscopy if symptoms are refractory despite treatment or there is concern of new infections
Additional considerations
The use of vedolizumab may be considered in patients refractory to infliximab and/or contraindicated to TNF-α blocker. The decision should be made on an individual basis from gastroenterology and oncology evaluation. This is based on case series showing promising results13–15
Patients with hepatitis and irAE colitis are rare, and management should include permanently discontinuing ICPi and offering other immunosuppressant agents that work systemically for both conditions
Currently, enteritis alone as the cause of diarrhea is uncommon and requires small bowel biopsy as the evaluation tool. It may be managed similar as colitis, including corticosteroid and/or infliximab, etc
2.2 Hepatitis
Definition: A disorder characterized by a viral pathologic process involving the liver parenchyma
Diagnostic work-up
Monitor patient for abnormal liver blood tests: AST, ALT, and bilirubin prior to each infusion and/or weekly if G1 liver function test elevations. No treatment is recommended for G1 liver function test abnormality
For G2 or higher:
Work-up for other causes of elevated liver enzymes should be tested, viral hepatitis, alcohol history, iron study, thromboembolic event, liver ultrasound, crosssectional imaging for potential liver metastasis from primary malignancy. If suspicion for primary autoimmune hepatitis is high, can consider ANAs, antismooth muscle antibodies, antineutrophil cytoplasmic antibodies. If patients with elevated alkaline phosphatase alone, γ-glutamyl transferase should be tested. For isolated elevation of transaminases, consider checking CK for other etiologies
Grading	Management
All patients	Counsel all patients to be aware of and inform their health care provider immediately if they experience:  Yellowing of skin or whites of the eyes  Severe nausea or vomiting  Pain on the right side of the abdomen  Drowsiness  Dark urine (tea colored)  Bleeding or bruising more easily than normal  Feeling less hungry than usual
G1: Asymptomatic (AST or ALT > ULN to 3.0 × ULN and/or total bilirubin > ULN to 1.5 × ULN)	Continue ICPi with close monitoring; consider alternate etiologies  Monitor laboratories one to two times weekly  Manage with supportive care for symptom control
G2: Asymptomatic (AST or ALT > 3.0 to ≤ 5 × ULN and/or total bilirubin > 1.5 to ≤ 3 × ULN)	Hold ICPi temporarily and resume if recover to G1 or less on prednisone ≤ 10 mg/d  For grade 2 hepatic toxicity with symptoms, may administer corticosteroid 0.5–1 mg/kg/d prednisone or equivalent if the abnormal elevation persists with significant clinical symptoms in 3–5 days  Increase frequency of monitoring to every 3 days  Infliximab might not be the most appropriate treatment option in the situation of immune-mediated hepatitis given the potential risk of idiosyncratic liver failure (Note: No clear evidence shows the liver toxicity from infliximab from other studies)  In follow-up, may resume ICPi treatment followed by taper only when symptoms improve to G1 or less and corticosteroid ≤ 10 mg/d; taper over at least 1 month  Patients should be advised to stop unnecessary medications and any known hepatotoxic drugs
G3: Symptomatic liver dysfunction, fibrosis by biopsy, compensated cirrhosis, reactivation of chronic hepatitis (AST or ALT 5–20 × ULN and/or total bilirubin 3–10 × ULN)	Permanently discontinue ICPi  Immediately start corticosteroid 1–2 mg/kg methylprednisolone or equivalent  If corticosteroid refractory or no improvement after 3 days, consider mycophenolate mofetil or azathioprine (if using azathioprine should test for thiopurine methyltransferase deficiency)  Laboratories at daily or every other day; consider inpatient monitoring for patients with AST/ALT > 8 × ULN and/or elevated TB 3 × ULN Increase frequency of monitoring to every 1–2 days  Infliximab might not be the most appropriate treatment option in the situation of immune-mediated hepatitis given the potential risk of liver failure (Note: No clear evidence shows that the liver toxicity from infliximab from other studies); alternatives include non–TNF-α agents as systemic immunosuppressants  If no improvement is achieved with corticosteroids or for patients on combination therapy with a novel agent, with standard chemotherapy, or with targeted therapy, refer to hepatologist for further pathologic evaluation of hepatitis  Corticosteroid taper can be attempted around 4–6 weeks; re-escalate if needed; optimal duration unclear
G4: Decompensated liverfunction (eg, ascites, coagulopathy, encephalopathy, coma; AST orALT > 20 × ULN and/or total bilirubin > 10 × ULN)	Permanently discontinue ICPi  Administer 2 mg/kg/d methylprednisolone equivalents  If corticosteroid refractory or no improvement after 3 days, consider mycophenolate mofetil  Monitor laboratories daily; consider inpatient monitoring  Avoid the use of infliximab in the situation of immune-mediated hepatitis  Hepatology consult if no improvement was achieved with corticosteroid  Corticosteroid taper can be attempted around 4–6 weeks when symptoms improve to G1 or less; re-escalate if needed; optimal duration unclear  Consider transfer to tertiary care facility if necessary
All recommendations are expert consensus based, with benefits outweighing harms, and strength of recommendations is moderate.

Abbreviations: ADL, activities of daily living; ANA, antinuclearantibody; CK, creatine kinase; CMV, cytomegalovirus; CRP, C-reactive protein; CT, computed tomography; CTCAE, Common Terminology Criteria for Adverse Events; CTLA-4, cytotoxicT-cell lymphocyte-4; EGD, esophagogastroduodenoscopy; ESR, erythrocyte sedimentation rate; G, grade; ICPi, immune checkpoint inhibitor; irAE, immune-related adverse event; IV, intravenous; PD-1; programmed death 1; PD-L1, programmed death ligand 1; TB, tuberculosis; TNF, tumor necrosis factor; TSH, thyroid-stimulating hormone; ULN, upper limit of normal.