GI toxicity from cancer immunotherapy is well described for anti-CTLA4 Abs. It is less well described for anti-PD-1 and anti-PDL-1 Abs as well as for combined anti-CTLA4 and anti-PD-1 Abs. Gastrointestinal toxicity of anti-CTLA4 antibodies
 Incidence
Diarrhoea occurs in 27%–54% of cancer patients treated with anti-CTLA4 Abs. In most series, approximately one-third of patients have diarrhoea, while the frequency of colitis ranges from 8% to 22%. GI toxicity is one of the most frequent and is the most severe (grade 3 or higher) of irAEs associated with anti-CTLA4. It is usually the first irAE leading to anti-CTLA4 discontinuatio. Colon perforation occurred in 1%–1.5% of melanoma patients receiving ipilimumab ; it may reach 6.6% of patients with renal cell carcinoma and 1.1% of patients die of complications related to ipilimumab-induced enterocolitis

In a recent series, non-steroidal anti-inflammatory drug (NSAID) use was associated with an increased risk of anti-CTLA4-induced enterocolitis, Very few data are available on the risk of immune-related colitis in patients with Crohn’s disease (CD) and ulcerative colitis (UC). Two out of six patients with CD or UC had ipilimumab-induced colitis or a relapse of UC or CD

 Diagnosis
Onset of GI symptoms may occur at any time during 1-10 infusions of anti-CTLA4 , Enterocolitis may even occur several months after the last dose of ipilimumab . The half-life of ipilimumab is 2 weeks; however, the biological effect may persist long after drug clearance.

The most common symptom of anti-CTLA4-induced enterocolitis is diarrhoea.In a recent series, 92% of patients with anti-CTLA4-induced enterocolitis had diarrhoea. Other presenting symptoms are abdominal pain, hematochezia, weight loss, fever and vomiting Mouth ulcers, anal lesions (fistulas, abscesses, fissures) and extra-intestinal manifestations (such as arthralgia, endocrine disorders, skin disorders, hepatitis, nephritis, pericarditis and pancreatitis) may be associated with anti-CTLA4-induced enterocolitis .

The main biological abnormalities observed in patients with anti-CTLA4-induced enterocolitis are anaemia, increased serum C-reactive protein and low serum albumin levels. Faecal level of calprotectin has been found to be elevated in patients with ipilimumab-induced enterocolitis in one study but failed to correlate with GI toxicity in another series . Abs against the enteric flora and antineutrophil cytoplasmic Abs are found in the serum of a minority of patients with ipilimumab-induced enterocolitis.

The main differential diagnoses of anti-CTLA4 enterocolitis are GI infections and tumour-related symptoms. Stool analyses for bacterial enteropathogens and Clostridium difficile toxin should be carried out in every patient with significant diarrhoea treated with anti-CTLA4. In addition, GI metastases are not uncommon in patients with disseminated melanoma and are not unknown in lung cancer; these should, therefore, be eliminated. Anti-CTLA4-induced enterocolitis should be confirmed by flexible sigmoidoscopy or colonoscopy with biopsies. Endoscopic lesions of anti-CTLA4 colitis are erythema/loss of vascular pattern, erosions and ulcerations. The sigmoid colon and the rectum are involved in most cases; therefore, a flexible sigmoidoscopy is generally sufficient to make the diagnosis of anti-CTLA4-induced enterocolitis. However, endoscopic lesions of the colon are often extensive and may extend proximal to the sigmoid colon in two thirds of cases. Patchy discontinuous endoscopic lesions are observed in half of the patients. The histological picture generally differs from that observed in inflammatory bowel disease (IBD). In most cases, it is that of an acute colitis (infiltration with neutrophils, eosinophils), either diffuse or focal with patchy crypt abscesses. In some cases, features of chronic IBD such as granulomas, basal plasmocytosis and crypt abnormalities (atrophy, distortion, branching, budding) have been reported

Upper GI symptoms (dysphagia and epigastric pain) and endoscopic lesions (oesophageal ulcerations, gastritis, duodenitis) have been reported. About half of the patients with anti-CTLA4-induced enterocolitis have chronic, mild, patchy inflammation of the stomach and the duodenum (crypt distortion, focal and heterogeneous villus shortening, increased eosinophils and mononuclear inflammatory cells in the lamina propria).

Risk Assessment
Assessment of severity relies upon the National Cancer Institute’s CTCAE, version 4. Severe diarrhoea refers to grade 3 or 4 diarrhoea but also to patients with grade 1 or 2 diarrhoea with dehydration, fever, tachycardia or haematochezia. Flexible sigmoidoscopy or colonoscopy is recommended in patients with severe diarrhoea or persistent grade 2 diarrhoea.

Gastrointestinal toxicity of combined anti-CTLA4 and anti-PD-1 antibodies
Diarrhoea and colitis, including severe forms, occur earlier & are more frequent with combined anti-CTLA4 and anti-PD-1 agents than with either ipilimumab. Other GI toxicities may also occur, including pancreatitis and small bowel enteritis, which may be visible on CT scan. These rare toxicities require discontinuation of ICPi treatment and initiation of immunosuppression treatment. There is a need for a more detailed description of GI irAEs associated with combined anti-CTLA4 anti-PD-1 Abs.

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Managing editor

Catherine

Toxicology: Open Access