LAUSR

Introduction Immune checkpoint inhibitors (ICPI), including monoclonal antibodies targeting CLTA-4 (e.g. ipilimumab) and PD-1 (e.g. nivolumab) have transformed the treatment landscape for cancer. However, their success is hampered by the high incidence of immune-mediated toxicity. ICPI- induced diarrhoea/colitis, resembling some aspects of IBD, occurs in up to 46% of patients and is the most common cause of ICPI discontinuation and death. Presently, treatment of ICPI-induced colitis is ad hoc, but typically involves systemic steroids, with biologics (most commonly anti-TNF) used as rescue therapy. ICPI use is anticipated to increase substantially in coming years, and expert gastroenterology input, and development of evidence-based treatment algorithms is now urgently needed. Our aim was to conduct a systematic review on the effectiveness of anti-inflammatory therapy in the management of ICPI- induced diarrhoea/colitis. Methods Relevant databases including Medline (PubMed and OVID), EMBASE, Web of Science and Cochrane were searched up to September 2017. Inclusion criteria included adult cancer patients treated with at least one dose of an ICPI, and reported outcome data following anti-inflammatory drug management of diarrhoea. Two independent reviewers assessed eligibility of studies. Results After reviewing 1838 studies, 26 met the inclusion criteria (15 original articles, 11 abstracts), of which 17 (65%) were retrospective studies. A total of 983 patients had diarrhoea and/or colitis. 16 studies reported on anti-CTLA-4 therapy (ipilimumab or tremelimumab), 4 on anti PD-1, and 6 on both (either anti-CTLA-4 or anti-PD1) or combination therapy. 558 (57%) patients were treated with corticosteroids, with clinical response reported in 333 (62%). However, reporting of the corticosteroid dose, type and regimen used was inconsistent. 297 (30%) patients with steroid refractory disease received infliximab with good response rates (86%)- although response rates were only reported for 188 patients. A single case series reported vedolizumab to be effective in the management of 6 out of 7 steroid refractory patients. Conclusions ICPI-induced diarrhoea/colitis is a significant complication of cancer immunotherapy and engagement with specialist gastroenterology services are now urgently needed to improve outcomes. Systematic review of therapeutic experience in this setting indicates that about two-thirds of patients respond to high-dose steroids, and rescue therapy with biologics captures response in most patients. Given the predicted expansion in use of ICPI in cancer, better quality clinical data are needed to inform standardised treatment protocols.