How should I manage my patient with cancer who is experiencing diarrhea while on immunotherapy?

WHEN TO SUSPECT COLITIS IS RELATED TO IMMUNOTHERAPY

Immune checkpoint inhibitors such as anti-PD-1, anti–programmed cell death ligand 1 (PD-L1), anti-CTLA-4, and anti–lymphocyte-activation gene 3 antibodies manipulate the immune system to create an antitumor immune response. These agents are widely used to treat solid tumors. With the beneficial effects of these drugs come a spectrum of immune-related adverse events, a unique class of cancer treatment toxicity that can present as inflammation in any organ system. Diarrhea and colitis are among the most common immune-related adverse events. In patients treated with combination CTLA-4 and PD-L1 antibodies (ipilimumab and nivolumab), about 44% reported diarrhea and 16% had colitis.¹ Of those treated with PD-L1 antibodies, 11% reported diarrhea and 1% reported colitis.

Immune-mediated diarrhea and colitis should be considered in any patient being treated with immune checkpoint inhibitors who presents with diarrhea or abdominal pain. The median time to the manifestation of these adverse events is 6 weeks,² but they can occur as early as the first week or as late as 6 months after the first dose.³ Evidence suggests that early detection and appropriate treatment improve outcomes and timelines to resuming antitumor therapy.⁴

ASSESSING THE SEVERITY OF DIARRHEA AND COLITIS

The severity of the presentation will determine the management of diarrhea or colitis. Severity ranges from grade 1 diarrhea or colitis, which is mild, with fewer than 4 bowel movements above baseline daily and no pain, to grade 4, with life-threatening complications and severe pain. While the Common Terminology Criteria for Adverse Events (Table 1)⁵ are commonly used to grade severity, endoscopic findings are a more reliable predictor of management decisions, including the resumption of immune checkpoint inhibitor therapy, as they correlate more closely with treatment outcomes than symptoms alone.⁶

WHAT IS THE WORKUP FOR SUSPECTED DIARRHEA AND COLITIS FROM IMMUNOTHERAPY?

Standard workup for patients with suspected immune-mediated diarrhea or colitis includes the following laboratory tests⁷:

• Complete blood cell count

• Comprehensive metabolic panel

• Thyroid-stimulating hormone, and

• Testing for infectious causes, including Clostridioides difficile and other standard pathogens.

Note that infection should be excluded before steroids or biologics are started in immunocompromised patients with cancer who are being treated with immunotherapy.

In atypical cases, or if there is incongruence between response to immune-mediated diarrhea or colitis therapy and symptoms persist or recur, exocrine pancreatic insufficiency should be considered as a potential complication of immunotherapy, and stool elastase and spot fat should be checked along with celiac serology.⁸ In patients with grade 1 diarrhea or colitis who do not improve after several days or in patients with grade 2 to 4 diarrhea or colitis, testing for stool lactoferrin is recommended, as elevation indicates mucosal inflammation and supports early endoscopy and treatment, and fecal calprotectin should be checked to follow disease activity.²

Inflammation in the left colon is present in about 95% of patients with immune-mediated colitis, and endoscopic evaluation with flexible sigmoidoscopy will detect the majority of cases.⁹ Colonoscopy is useful because severe findings (ulcers ≥ 1 cm in size, ≥ 2 mm deep, with extensive colonic involvement), as classified by the Immune-Mediated Colitis Endoscopic Score, predict an earlier need for aggressive therapy.¹⁰ Biopsy with histologic evaluation is recommended even when the endoscopic evaluation is normal because microscopic findings can guide diagnosis and management.¹¹

Cross-sectional imaging is used in patients with a severe presentation to detect complications of intestinal inflammation, such as perforation; it will also provide support for the diagnosis.⁸ In a retrospective review of patients with cancer who underwent endoscopy with gastric biopsy while on immune checkpoint inhibitors, immune checkpoint inhibitor gastritis was identified in 33%, and 70% of these patients had concurrent immune checkpoint inhibitor enteritis or colitis.¹²

HOW SHOULD WE MANAGE DIARRHEA OR COLITIS?

Grade 2 or higher

In patients with diarrhea or colitis grade 2 (moderate) or higher, steroids (oral prednisone or intravenous methylprednisolone at 1 to 2 mg/kg/day) should be started and immune checkpoint inhibitors should be held.^1,8 In patients who respond to steroids and have symptom improvement to grade 1 or less, the dose should be tapered over 4 to 6 weeks. Early consultation with gastroenterology for endoscopic evaluation should be considered to identify endoscopic and histologic risk factors for early selective immunosuppressive therapy, especially if patients have anemia or low albumin on laboratory testing, do not respond to corticosteroids within 2 to 3 days, or have persistent biomarker elevations (fecal lactoferrin and calprotectin) but have improvement in symptoms.¹⁰

When there is high suspicion for complications (also defined as grades 3 to 4 colitis), such as toxic megacolon or perforation, abdominal or pelvic contrast-enhanced computed tomography can be done as an alternate noninvasive diagnostic modality.^1,2

If the patient does not respond to oral steroids within 3 days or exhibits clinical signs of toxicity, such as inability to maintain hydration, significant pain, or anemia, admission for intravenous steroids or initiation of infliximab should be considered.⁸ Current guidelines suggest an induction regimen of 3 doses at weeks 0, 2, and 6, with subsequent dosing tailored to clinical response. If there is no clinical improvement after the second dose of infliximab, switching to an alternative steroid-sparing agent such as vedolizumab may be appropriate, and prompt oncology and gastroenterology consultation should be obtained.

Clinicians face significant challenges in determining the optimal number of infliximab doses needed to manage colitis as an immune-related adverse event while maintaining the antitumor efficacy of immune checkpoint inhibitors. Emerging evidence highlights the potential benefits of early administration of infliximab or vedolizumab, which is associated with more favorable immunotherapy-related colitis outcomes, including reduced hospitalizations, lower incidence of steroid taper failures, shorter steroid courses, and shorter duration of symptoms compared with delayed treatment.¹³ In patients who require infliximab or vedolizumab, a more rapid (2 to 4 weeks) steroid taper may be used to minimize infectious complications.⁸

In patients who do not respond to therapy with infliximab and vedolizumab, use of fecal microbiota transplant or other inflammatory bowel disease therapies like the Janus kinase inhibitor tofacitinib and interleukin-12– and interleukin-23–blocking antibody ustekinumab has been reported.^2,8

An approach to diagnosing and treating immune-mediated colitis is presented in Figure 1.^8,10

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Figure 1

Diagnosing and treating immune-mediated diarrhea and colitis.

^aTest for ova and parasites; do molecular testing for Giardia, Cryptosporidium, Entamoeba histolytica, microsporidia, or Cyclospora or Isospora in appropriate context.

^bDietary modifications may include a lactose-free, low-fiber diet like BRAT (bananas, rice, applesauce, toast) until diarrhea subsides.

^cHigh-risk findings on colonoscopy include ulcers ≥ 1 cm large and ≥ 2 mm deep and extensive colonic involvement.¹⁰

^dTesting for hepatitis A, B, and C; human immunodeficiency virus; and tuberculosis (T-Spot or QuantiFeron TB Gold) is recommended. Do not delay administering infliximab or vedolizmab while waiting for test results.

^eStarting infliximab within 10 days of symptom onset is associated with more favorable outcomes in immune-mediated colitis.

^fIf immune-mediated diarrhea or colitis improves with infliximab therapy, consider maintenance infliximab or vedolizumab with a gastroenterology consultation, and consider resuming ICI therapy based on multidisciplinary discussion.

^gConsider permanently stopping anti–cytotoxic T-lymphocyte–associated protein 4 agents in grade 3 or higher.

Based on information from reference 8.

WHEN DO WE RESTART THERAPY?

The decision to resume immune checkpoint inhibitors is nuanced and depends on patient-specific factors, including the severity of diarrhea or colitis and steroid responsiveness, tumor type, and treatment intent (ie, adjuvant vs unresectable). An oncologist should assess the response to cancer treatment and the expected benefit from continued immune checkpoint inhibitors and weigh the risks and benefits of resuming therapy. Close multidisciplinary collaboration between oncology and gastroenterology is essential.

In patients who develop high-grade colitis while on ipilimumab and nivolumab and in whom the risk-benefit ratio of resuming immune checkpoint inhibitors is believed to be favorable, stopping ipilimumab and resuming single-agent PD-1 is preferred.⁹ For grade 1 diarrhea or colitis, immune checkpoint inhibitors can be resumed after symptoms resolve. For higher-grade diarrhea or colitis, immune checkpoint inhibitors may be resumed when symptoms are improved to grade 1 or less and the patient has completed a steroid taper.

HOW SHOULD WE MANAGE RECURRENCE OF IMMUNE-MEDIATED COLITIS?

The recurrence of colitis poses a significant challenge. The recurrence rate of immune-mediated adverse events when rechallenging with immunotherapy is approximately 28% to 30%.^14,15 The risk of recurrent colitis varies by immune checkpoint inhibitor regimen. Risk factors associated with recurrence include initial treatment with anti-PD-L1 antibodies, rechallenge with anti-CTLA-4 antibodies, higher grade of colitis, requirement for immunosuppressive therapy during the initial colitis episode, and prolonged duration of the initial colitis.^1,15

If symptoms recur after corticosteroids are tapered, clinicians should use an evaluation and treatment approach similar to what they used in managing the initial episode. However, if steroids alone were used at the first event, starting biologic therapy should be strongly considered.¹⁶

There currently is no strategy for prophylactic prevention of recurrent immune-mediated diarrhea or colitis, although vedolizumab is suggested in some cases where there is persistent endoscopic or histologic evidence of inflammation and resumption of immune checkpoint inhibitor therapy is necessary.⁹ This requires a multidisciplinary approach and careful patient monitoring.

THE BOTTOM LINE

Early identification and management of immune-mediated diarrhea or colitis improves outcomes.¹³ Once diagnosed, appropriate therapy with steroids and early use of biologics in steroid-refractory colitis can minimize complications and may facilitate resumption of immune checkpoint inhibitor therapy.

DISCLOSURES

Dr. Philpott has disclosed teaching and speaking for Abbvie Pharmaceuticals. Dr. Boyce Kennedy has disclosed serving as a research primary investigator for EpicentRx, Ideaya Biosciences, and Regeneron. The other authors report no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.