Immune checkpoint inhibitor-induced colitis: A comprehensive review

Table 1 Percentage ranges of all grade immune-related common adverse events by checkpoint inhibitor class

Class of immune checkpoint inhibitors	Approved agents	Rash	Diarrhea	Colitis	Elevated ALT	Hypothyroidism	Hypophysitis
Anti CTLA-4	Ipilimumab, Tremelimumab	12%-68%	31%-49%	7%-11.6%	3%-9%	4%-4.2%	4%-6%
Anti PD-1	Nivolumab, Pembrolizumab	11.7%-24%	2.9%-11.5%	1.3%-2.9%	1.8%-7.1%	3.4%-8.5%	0.25%
Anti PD-L1	Atezolizumab, Durvalumab, Avelumab	7.4%	11.6%-23%	0.7%-19.7%	0.9%-4.0%	5.0%-9.6%	0.2%

CTLA-4: Cytotoxic T-lymphocyte-associated antigen 4; PD-1: Programmed cell death protein 1; PD-L1: Programmed death-ligand 1; ALT: Alanine aminotransferase.

Table 2 Grading the severity of immune checkpoint inhibitor-induced colitis and diarrhea based on Common Terminology Criteria for Adverse Events grade

	Colitis	Diarrhea
Grade 1	Asymptomatic	Increase of < 4 stools/d over baseline
Grade 2	Abdominal pain, mucus, blood in stool	Increase of 4-6 stools/d
Grade 3	Severe pain, fever, peritoneal signs	Increase of ≥ 7 stools/d
Grade 4	Life-threatening consequences such as perforation, ischemia, necrosis, bleeding, toxic megacolon	Life-threatening consequences such as hemodynamic collapse
Grade 5	Death	Death

Adapted from the Cancer Therapy Evaluation Program, National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 Program, Common Terminology Criteria for Adverse Events v5.0.

https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf.

Table 3 Management of immune checkpoint inhibitor-induced colitis and diarrhea based on Common Terminology Criteria for Adverse Events grade, as summarized by the Society for Immunotherapy of Cancer, American Society of Clinical Oncology, and European Society of Medical Oncology

Grade of colitis	Society for Immunotherapy of Cancer recommendations	American Society of Clinical Oncology recommendations	European Society for Medical Oncology recommendations
Grade 1	Continue ICI; Close follow up within 24 h-48 h; If symptoms persist, routine stool and blood tests; Bland diet during period of acute diarrhea; Anti-diarrheal medication is optional but not highly recommended but only if infectious work-up is negative	May continue ICI or hold ICI temporarily and resume if toxicity does not exceed grade 1. Monitor for dehydration and recommend dietary changes; Expedited phone contact with patient/caregiver; May obtain gastroenterology consult for prolonged grade 1 cases	Continue ICI; If symptomatic, treat with oral fluids, loperamide, avoid high fiber and lactose in diet; If persists > 14 d treat with Prednisolone 0.5 mg/kg-1 mg/kg or oral budesonide 9 mg daily; Blood tests: FBC, UEC, LFTs, CRP, TFTs; Stool microscopy for ova and parasites, culture, viral PCR, C difficile toxin and cryptosporidia
Grade 2	Hold ICI; Outpatient stool and blood work; CRP, ESR, fecal calprotectin, lactoferrin, imaging and endoscopy are optional; If diarrhea only, observe for 2 d-3 d. If no improvement start prednisone 1 mg/kg per day (or equivalent dose of methylprednisolone); anti-diarrheal medication is not recommended; If diarrhea and colitis symptoms (abdominal pain ± blood in BM), start prednisone 1 mg/kg per day (or equivalent dose of methylprednisolone) immediately; If no improvement in 48 h, increase corticosteroid dose to prednisone 2 mg/kg per day (or equivalent dose of methylprednisolone); If patient improves, Taper corticosteroid over 4 wk-6 wk; Resume ICI when corticosteroid is tapered to ≤ 10 mg/d and patient remains symptom-free (grade ≤ 1); Continue anti-PD-1 or anti-PD-L1 monotherapy; If using combination anti-CTLA-4/anti-PD-1 immunotherapy, continue anti-PD-1 agent only; ICI dose reduction is not recommended; If colitis returns on resuming ICI: Grade ≤ 2: Temporarily hold ICI Grade ≥ 3: permanently discontinue ICI	Hold ICI until symptoms recover to grade 1 or less; Consider permanently discontinuing CTLA-4 agents; may restart PD-1, PD-L1 agents if recovers to grade 1 or less. Concurrent immunosuppressant maintenance therapy (< 10 mg prednisone equivalent dose) if clinically indicated in individual cases; Supportive care with loperamide if infection ruled out; Consult gastroenterology; Administer corticosteroids starting with an initial dose of 1 mg/kg per day prednisone or equivalent; When symptoms improve to grade 1 or less, taper corticosteroids over at least 4 wk to 6 wk before resuming treatment, although resuming treatment while on low-dose corticosteroid may also be an option after an evaluation of the risks and benefits; Endoscopic evaluation 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; Testing for stool inflammatory markers, lactoferrin, or calprotectin to differentiate functional versus inflammatory diarrhea. Calprotectin testing may also be offered to monitor treatment response; Repeat colonoscopy is optional and may be offered for cases of grade 2 or higher for disease activity monitoring to achieve complete remission, especially if there is a plan to resume ICI	Hold ICI; Symptomatic management as above; If persists > 3 d or worsens, treat with Prednisolone 0.5 mg/kg-1 mg/kg or oral budesonide 9 mg daily; Schedule colonoscopy but do not wait for colonoscopy to start therapy; Baseline testing as above; consider abdominal X-ray for signs of colitis; Contact patient every 72 h; If no improvement in 72 h or worsening or absorption concern, treat as grade 3 with IV steroid
Grade 3	Grade 3: withhold ICI; consider resuming ICI when corticosteroid is tapered to ≤ 10 mg/d and patient remains symptom-free (grade ≤ 1). Consider hospitalization; Grade 4: Permanently discontinue ICI and hospitalize; Blood and stool infection work-up, inflammatory markers, imaging, endoscopy and GI consult; Start intravenous prednisone 1-2 mg/kg per day (or equivalent dose of methylprednisolone) immediately; If patient improves, follow instructions for “If patient improves” for grade 2; If refractory or no improvement on IV corticosteroid, start prednisone 2 mg/kg per day (or equivalent dose of methylprednisolone) for 3 d; Consider other anti-inflammatory agents e.g., infliximab 5 mg/kg, which can be given again after two weeks if a second dose is needed. Vedolizumab may also be used	Should consider permanently discontinuing CTLA-4 agents and may restart PD-1, PD-L1 agents if patient can recover to grade 1 or less; Should administer corticosteroids (initial dose of 1 mg/kg to 2 mg/kg per day prednisone or equivalent); Should refer to hospitalization or outpatient facility for patients with dehydration or electrolyte imbalance; If symptoms persist ≥ 3 d to 5 d or recur after improvement, may administer IV corticosteroid or noncorticosteroid (e.g., infliximab); May offer colonoscopy in cases where patients have been on immunosuppression and may be at risk for opportunistic infections as an independent cause for diarrhea (i.e., CMV colitis) and for those who are anti-TNF or corticosteroid refractory.	Hold ICI; Hospitalization until infection excluded; Gastroenterology consultation; Treat with IV methylprednisolone 1 mg/kg-2 mg/kg; If no improvement or worsening in 72 h, treat with infliximab 5 mg/kg (if no perforation, sepsis, TB, hepatitis, NYHA III/IV CHF); can repeat 2 wk later; Colonoscopy prior to initiation of infliximab; May consider other immunosuppressants: MMF 500-1000 mg BID or tacrolimus; Consider CT abdomen and pelvis; Review diet (NPO, clear fluids, TPN); Early surgical consultation if bleeding, pain or distension
Grade 4	Should permanently discontinue all ICI treatment; Rest same as grade 3	Permanently discontinue all ICI treatment; Should admit patient when clinically indicated. Patients managed as outpatients should be very closely monitored; Should administer IV corticosteroid until symptoms improve to grade 1 and then start taper over 4 wk to 6 wk; May offer early infliximab 5 mg/kg to 10 mg/kg if symptoms are refractory to corticosteroid within 2 d to 3 d; May offer lower GI endoscopy if	No distinction from Grade 3; Taper steroids over 2 wk-4 wk if moderate symptoms and 4 wk-8 wk if severe

ICI: Immune checkpoint inhibitors; FBC: Full blood count; UEC: Urea, electrolytes, creatinine; LFTs: Liver function tests; CRP: C-reactive protein; TFTs: Thyroid function tests; PCR: Polymerase chain reaction; CTLA-4: Cytotoxic T-lymphocyte-associated antigen 4; PD-1: Programmed cell death protein 1; PD-L1: Programmed death-ligand 1; NYHA: New York Heart Association; CHF: Congestive heart failure.