PHILADELPHIA—Immunotherapy has been lauded as a game changer for cancer patients, but these therapies can result in toxicities. As use of these treatments continues to grow, gastroenterologists are likely to see more gastrointestinal, hepatic and pancreatic complications in patients undergoing adjuvant and neoadjuvant cancer therapies.

“As gastroenterologists and hepatologists, it’s essential that we identify and evaluate patients with suspected immune-related toxicities, work them up and start their treatment quickly,” said Shilpa Grover, MD, MPH, the director of the onco-gastroenterology program at Brigham and Women’s Hospital, in Boston, during a presentation at ACG 2024.

The three different classes of immune checkpoint inhibitors (ICIs) are all monoclonal antibodies that target two key pathways, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death-1/programmed death ligand-1 (PD-1/PD-L1), allowing activated T cells to target cancer cells, Dr. Grover said.

“But used this way, immunotherapy can also cause a variety of immune-related adverse events [irAEs].” By some estimates, she said, up to 90% of patients have one or more irAEs, with common sites including the skin, GI tract, lungs and endocrine glands. The incidence of colitis and hepatitis varies based on the class of immunotherapy and is highest when these treatments are used in combination.

ICI colitis may occur as early as five weeks into treatment, but it can occur as late as two years after completion of treatment, Dr. Grover said. “So when you see a patient with a history of cancer and diarrhea, it’s important to know what cancer regimen they were treated with.”

ICI Colitis

Patients with ICI colitis usually present with frequent watery stools. They can have urgency, incontinence and mild abdominal pain, Dr. Grover said, adding that severe abdominal pain warrants considering an alternate diagnosis or the presence of a complication.

“The patients with delayed diagnoses are those with an atypical presentation, such as those with constipation or tenesmus due to inflammation isolated to the rectum,” she added.

Ruling out infectious causes of diarrhea is an essential part of the workup in all patients and should not be overlooked. Abdominal imaging may show bowel wall thickening, fat stranding, mucosal hyperenhancement and fluid in the colon, as well as mesenteric vessel engorgement. “But these features are not specific to ICI colitis,” she explained. Just as imaging is not very specific, it’s also not very sensitive. She noted that the main reason to order CT is to rule out other complications.

Flexible sigmoidoscopy or colonoscopy is indicated in patients with persistent grade 2 diarrhea, any grade 3 or 4 diarrhea, steroid-refractory colitis, significant abdominal pain, or hematochezia. Endoscopic appearance is not specific and imaging can appear completely normal, Dr. Grover said.

When a patient’s symptoms warrant flexible sigmoidoscopy, it’s important that they get an upper endoscopy to check for ICI enteritis. “It can be isolated,” she said, and patients can have “ulceration in the duodenum, even with a normal ileum.”

Patients also may present with ICI gastritis. “In retrospective data from our own study, only 30% of patients had isolated ICI gastritis. Most of them had it with enteritis or colitis,” she said. “Patients with isolated ICI gastritis can be managed with steroids alone. Biologics are usually needed only in patients with concomitant enteritis and colitis.”

As with any patients with diarrhea, management depends on the severity of symptoms, and hospitalization should be considered for those with severe ICI colitis. “Patients frequently need high-dose corticosteroids, often IV fluids. We use antidiarrheals sparingly, if at all,” Dr. Grover said.

She advised early evaluation for contraindications to anti–tumor necrosis factor medications and other biologics. Although most patients will improve, one-third will have persistent or progressive disease. “Patients who improve can be converted to low-dose prednisone with a slow taper,” she said. “Those with persistent/progressive disease will need a biologic.”

On the topic of steroids versus biologics, Shrinivas Bishu, MD, a clinical assistant professor of internal medicine at the University of Michigan Health, in Northville, noted that some patients would benefit from the use of biologics sooner, but oncologists usually see cancer patients before gastroenterologists do, and oncologists’ treatment of choice is often steroids.

“That’s why by the time they see a GI doctor, they may be refractory to steroids or steroid dependent. I think if we saw these patients earlier, we’d probably go to biologics sooner,” Dr. Bishu said. “It’s very different from biologics in inflammatory bowel disease patients, because once the condition is controlled, it’s controlled. This is not a lifelong therapy for the patient.”

ICI Pancreatitis And Hepatitis

The incidence of ICI-related pancreatic injury is relatively low, occurring in 1% to 2% of patients, Dr. Grover said. ICI therapy is the largest single cause of elevated lipase, but in two-thirds of these cases, ICIs are not the cause. “So it’s important to rule out other etiologies,” she added.

Many patients have no symptoms beyond lipase elevations, but it is important to assess for pancreatitis with abdominal imaging, as ICI pancreatitis is treated with IV fluids and steroids. “We don’t yet have convincing evidence that steroids improve outcomes, but [they] continue to be recommended at the present time,” Dr. Grover said.

ICI hepatitis occurs in 10% to 12% of patients treated with anti-CTLA-4 and anti-PD-1/PD-L1 agents, with most of these patients asymptomatic aside from an elevation in their transaminases. “We usually do ultrasound with doppler to rule out a clot,” Dr. Grover said. “Additional imaging has a role in patients with cholestatic liver disease or in patients with a high risk of hepatic metastasis.”

Patients with grade 1 liver enzyme elevation can continue ICI therapy with monitoring, but checkpoint inhibitors should be held in patients with higher elevations. “These patients often need steroids as a front, and the dose increases with the level of toxicity. Our role here is to escalate therapy when patients don’t respond,” Dr. Grover said.

Unlike patients with ICI colitis, patients with hepatic toxicities may not respond to biologics, Dr. Bishu said. “The toxicities for hepatitis are a bit different from ICI colitis, which is definitely responsive to biologics.”

—Monica J. Smith


Dr. Grover reported no relevant financial disclosures.

This article is from the May 2025 print issue.