Immune checkpoint inhibitors (ICI) have shown much promise in the management of advanced malignancies in the last decade. They have become the standard of care for many cancers including but not limited to melanoma, non-small- cell lung cancer, renal cell cancer (Thompson et al. 2021). ICIs target regulators of the immune system, namely programmed cell death- 1 (PD-1), programmed cell death ligand 1(PD-L1), and cytotoxic T lymphocyte antigen − 4 (CTLA-4) and unleash restrained T cell-mediated antitumor responses (Johnson, Sullivan, & Menzies 2017). Blockade of these immune checkpoints can also lead to an augmented immune response resulting in end-organ toxicity and side-effects termed immune related adverse events (irAEs) (Lam, Lin, & Sun 2018). Diarrhea and colitis are the second most common irAEs, and the symptoms include diarrhea, abdominal pain and cramping, urgency, blood or mucus in the stool, fever, collectively termed as immune mediated diarrhea and colitis, or IMDC (Thompson et al. 2021).The clinical severity is graded by the Common Terminology of Clinical Adverse Events1 and may range from mild to life threatening complications like perforation and can result in death.
The grading of IMDC takes into account the frequency of bowel movements and symptoms in addition to the impact on quality of life. Grade 1 IMDC is classified as asymptomatic colitis or an increase of 4 bowel movements from baseline while grade 2 IMDC presents with abdominal pain and blood in the stool or 4–6 stools per day over baseline (CTCAE, version 5.0). Grade 3 IMDC is usually life-limiting and presents with greater than 7 stools a day over baseline, severe abdominal pain, and occasionally peritoneal signs. These patients are at risk for further decompensation and should be monitored closely while hospitalized. Grade 4 IMDC presents with hemodynamic instability, usually requiring urgent surgical intervention. Finally, grade 5 is death related to adverse events. Grade 1 diarrhea is managed in the outpatient setting with infectious work-up, symptomatic supportive management, fluid hydration, correcting electrolyte imbalances, and antidiarrheals (Thompson et al. 2021; Gong and Wang 2020). For grade 2 diarrhea and above, further inpatient workup is warranted along with GI consultation. Current algorithms suggest ruling out infectious or medication induced diarrhea along with supportive management, then consideration of colonoscopy for persistent grade 2 IMDC or any grade 3–4 IMDC. The presence of ulcerations on endoscopy and elevation in biomarkers such as C-reactive protein and fecal calprotectin often point to increasing severity of disease (Gong & Wang 2020). Endoscopy findings of IMDC are stratified into low risk features, moderate-risk features, and high-risk features. Low-risk features consist of normal colon appearance and histology. Moderate- risk features can either consist of normal colon appearance on endoscopy with inflammation on pathology, or small, shallow ulcers < 1 cm in size and < 2 mm in depth. High -risk features show greater or equal to 3 ulcers that are large > 1 cm in size, and deep > 2 mm in depth (Gong & Wang 2020). High risk endoscopy features consist of extensive inflammation on pathology. Management is initiated with weight based systemic corticosteroids followed by taper in conjunction with selective immunosuppression treatment (SIT) with infliximab or vedolizumab when patients do not respond to steroids (Brahmer et al. 2021; Grover et al. 2018). For refractory cases, ustekinumab (Thomas, Ma, & Wang 2021), tofacitinib (Esfahani, Hudson & Batist 2020) and fecal microbiota transplantation (Wang et al. 2020) have also been reported in smaller studies to be beneficial.
The development of severe IMDC particularly impacts cancer care due to withholding ICI therapy, in particular for patients with grades 3–4 diarrhea and colitis (Thompson et al. 2021). Due to provider inexperience or unfamiliarity with management of irAEs, cancer therapy can be prematurely or permanently discontinued prior to achieving tumor response. Poor outcomes such as cancer progression and decreased overall survival amongst patients with irAEs who have been discontinued from ICI therapy compared to patients who resume therapy have been described given toxicity associated with immune checkpoint inhibitors (Santini et al. 2018; Zou et al. 2021). Furthermore, treatment response in patients with aggressive disease is often short lived and leads to higher rates of cancer recurrence. Specialist expertise and a strategic management plan to address IMDC is imperative to determine the appropriate time and patient population to rechallenge ICI, and therefore improve outcomes and overall survival. Our group has previously demonstrated that aggressive measures including early endoscopy to provide more accurate measure of IMDC severity), early introduction of SIT (less than 10 days after diagnosis), and close surveillance for guidance of treatment duration are associated with favorable outcomes (Abu-Sbeih et al. 2018, 2019).
Early recognition and management of IMDC is best achieved by a multidisciplinary approach across specializations including nursing, emergency medicine, pharmacy, internal medicine, oncology, and gastroenterology. To date, there have not been any quality studies investigating the role of a dedicated GI service in the management of IMDC, however, multiple academic organizations and guideline committees such as JNCCN, ASCO, and SITC have emphasized the use of standard operating protocols to standardize treatment. Individual health organizations have also suggested multidisciplinary teams to facilitate early identification of irAEs across all organ systems (Londono & Reig 2020). Certain reviews have also proposed the use of a wallet card for direct communication between patients and providers about immunotherapy regimens and expected side effects to watch for (Fecher et al. 2013).
Given the complexity in GI irAE management, a practice algorithm for early and aggressive management was implemented across the institution since October 2017 to manage our institution’s unique population more effectively at a tertiary cancer center. To ease accessibility and improve the compliance of the algorithm, a comprehensive evaluation order set was created in our Electronic Health Records (EHR) which changed our practice on a large scale for our inpatient and outpatient IMDC population. In this study, we measured the impact of the changes of our practice for IMDC after implementation of the algorithm and analyzed the IMDC outcome secondary to this practice change among hospitalized patients with IMDC.