Diarrhea in patients with cancer is a well-known phenomenon with clear guidelines for prevention and management. However, it remains a condition with poorly explored consequences and a lack of sufficient and fast-acting treatments.
In a webinar presented by members of the Multinational Association of Supportive Care in Cancer (MASCC), Florian Scotté, MD, PhD, and Paolo Bossi, MD, discussed the importance of provider awareness of severe diarrhea in their patients and promoted an understanding of treatment options and current evidence-based management approaches.1
Florian Scotté, MD, PhD
Paolo Bossi, MD
According to Dr. Bossi, Associate Professor of Medical Oncology at the University of Brescia in Italy, effectively treating diarrhea in patients with cancer requires a robust and holistic assessment of patients, both at presentation and during their treatment journey. “It’s not just a matter of evaluating one single symptom; we need to assess the overall symptoms the patient is experiencing,” he said. “And I always stress that we need to identify specific [individuals]—in particular, the nurses—who can best discuss these issues with our patients. That practice should be embedded in the oncologic clinic.”
Cancer Treatments and Diarrhea
Diarrhea in patients with cancer is extremely common, with 20% to 70% of patients who undergo radiotherapy and between 50% and 80% of those on chemotherapy suffering from diarrhea. Among patients treated with chemotherapy, about 30% of those cases are severe.2
For patients receiving pelvic or abdominal radiotherapy, symptoms typically begin soon after the start of treatment, presenting around the second week and peaking between the fourth and fifth weeks, whereas delayed symptoms can be seen months to years later.3 In patients receiving chemotherapy, multifactorial causes contribute to diarrhea, but incidence largely depends on the type of treatment received: The highest incidence is in patients treated for colorectal cancer and in those who have cancers treated with fluoropyrimidine and irinotecan.4
“These patients can receive treatment for a long time,” noted Dr. Scotté, Head of the Interdisciplinary Department for the Organization of Patient Pathways at Gustave Roussy, Villejuif, France. “They can have acute diarrhea but also clinical disorders. So, it’s important to keep that in mind to provide the best supportive care for all our patients.”
It’s not just a matter of evaluating one single symptom; we need to assess the overall symptoms that the patient is experiencing.— Paolo Bossi, MD
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The incidence of diarrhea is increasing with new targeted therapies, with all-grade diarrhea affecting more than 90% of patients on either afatinib or neratinib, and 40% of neratinib-treated patients experiencing grade 3 or 4 diarrhea.5 Dr. Scotté pointed out that providers should be aware of long-term diarrhea (in patients on drugs such as sacituzumab govitecan-hziy),6 vs acute diarrhea (with targeted therapies such as neratinib).
“These revolutionary targeted treatments can significantly increase response rate but can also impact symptoms like diarrhea, particularly when combined with immunotherapies,” added Dr. Bossi.
Diarrhea usually appears in week 5 of checkpoint inhibitor treatment and resolves by week 10. The combination of anti–CTLA-4 and anti–PD-1 therapies also increases the incidence of all-grade diarrhea in these patients. According to Dr. Scotté, supportive care efforts for diarrhea during this time should focus on prevention, anticipation, detection, treatment, and monitoring.7
Clinical practice guidelines outline clear treatment pathways for the management of immune-related gastrointestinal toxicities. According to Dr. Bossi, baseline assessment should include —at a minimum—full blood cell count, biochemical examination, stool microscopy, and culture for drug-resistant organisms. “We have to define all the possible causes of superimposed diarrhea,” he said. For outpatients, consider abdominal x-ray, exclude steatorrhea, be prepared to book sigmoidoscopy/colonoscopy, and always contact the patient every 72 hours for follow-up, he added.
Assessing Diarrhea
Diarrhea is assessed in clinical practice with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, which grades severity based on the number of stools per day over baseline, in addition to the level of interference with activities of daily living at grade 3 and an indication for urgent intervention at grade 4.8
Although the physician point of view measured by the CTCAE is critical to assessing and treating diarrhea, the patient point of view is just as important.9 “We know from the research that patients might upgrade their assessment of symptom severity, whereas physicians might downgrade their assessment,” said Dr. Scotté. “It’s important to be aware of how patients perceive the severity of their symptoms, specifically diarrhea.”
Self-reporting of diarrhea is measured by the PRO-CTCAE, a patient-reported outcome (PRO) measurement system developed to evaluate symptomatic toxicity. According to Dr. Scotté, using the PRO-CTCAE specifically for remote monitoring is crucial in recognizing and treating severe diarrhea.
A newer method for assessing the daily impact of diarrhea is to measure the peak of symptoms with the CTCAE or PRO-CTCAE and use the area under the curve of toxicities (AUCtox) to identify symptoms that significantly impact quality of life.10 This method can better detect the impact of all toxicities, allowing for a more patient-oriented evaluation of drug safety.
A Constellation of Symptoms
Dr. Bossi noted that the severity of diarrhea is not the only factor to consider in its management; the duration can be just as detrimental to quality of life. “The incidence of grade 3 or 4 diarrhea with chemotherapy can be quite high, particularly with some schedules,” he said. “But a lower-grade diarrhea that lasts several weeks may impact a patient more than just 3 or 4 days of a higher-grade diarrhea,” he said.
We don’t have a lot of data right now, but in the future, diarrhea prophylaxis will be a very important topic to discuss.— Florian Scotté, MD, PhD
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And it’s not just the diarrhea that affects patients: An entire constellation of other symptoms is associated with this distressing side effect, including dry mouth, difficulty swallowing, nausea, vomiting, changes in appetite, and abdominal cramps, Dr. Bossi added.11
He emphasized the importance of identifying other treatable causes of diarrhea before chemotherapy (eg, thyroid dysfunction, vitamin B12 deficiency), as well as during and after chemotherapy, such as small intestinal bacterial overgrowth, unsuspected urinary tract infection, and bile acid malabsorption.12
“Before chemotherapy, one in five patients has other treatable but missed comorbidities that may impact upon this symptom,” noted Dr. Bossi. “These conditions can cause—but also worsen—diarrhea.”
Management of Severe Diarrhea
According to Dr. Scotté, all patients with diarrhea should receive supportive care, including hydration, electrolyte replacement, and dietary counseling.13 In terms of pharmacotherapy, loperamide—followed by morphine and codeine—are the most widely used treatments. The 2018 European Society for Medical Oncology (ESMO) Clinical Practice Guidelines advise loperamide for first-line use and other opioids—such as opium, tincture of morphine, or codeine—as recommendations for the second line. However, loperamide is less effective in severe cases of diarrhea and has been associated with reports of cardiac events in patients taking high doses.2
Newer drugs have been efficacious in helping patients avoid or alleviate diarrhea. These agents include opioid tinctures, mesalamine, and cholestyramine for patients on immune checkpoint inhibitors,14 as well as steroids. For glucocorticoid-refractory cases with CTCAE grade 2 or higher diarrhea or colitis, biologics such as infliximab or vedolizumab should be used at an early point.15
Depending on the type of targeted treatment used (and whether or not it is combined with immunotherapy), exact management recommendations will vary but should employ some combination of antidiarrheal treatment (eg, loperamide, opioid tincture), dose reductions/interruptions (paying attention to the impact on anticancer treatment efficacy), antidiarrheal prophylaxis (only for patients on neratinib), patient education, and/or supportive care. According to Dr. Bossi, it is possible that innovative approaches to treating immunotherapy-induced diarrhea might also benefit patients with similar symptoms caused by targeted treatments. For instance, therapeutic manipulation of gut microbiota through fecal microbiota transplantation has demonstrated efficacy for both types, even if there are several questions to be clarified before its use may be implemented.
Dr. Bossi pointed out some “gray zones” in the treatment of diarrhea, noting that some of the drugs commonly used for routine treatment are not actually in the guidelines. Preferred resuscitation strategies (eg, oral rehydration, intravenous sugar solutions) may also deviate from the guidelines in actual clinical practice.16
He added that the threshold between uncomplicated and complicated diarrhea may be difficult to distinguish, since it not only depends on the grade of diarrhea, but also the patient presenting with it (ie, elderly, frail patients often suffer more from the consequences of diarrhea). “So, please consider the patient in front of you to better evaluate the risk of complications,” he said.
Dr. Scotté emphasized the importance of more research into diarrhea prophylaxis and a push toward clinical trials, as prophylaxis is not currently included in the MASCC guidelines. “We don’t have a lot of data right now, but in the future, diarrhea prophylaxis will be a very important topic to discuss,” he said. “MASCC is very involved in clinical trials, with affiliate societies all over the world.”
Dr. Bossi concluded by pointing out some unanswered questions about immunotherapy-induced diarrhea that are not yet addressed in the guidelines, regarding treating patients with inflammatory bowel disease, re-starting immunotherapy after an episode of immune-related diarrhea or colitis, and early introduction of selective immunosuppressive therapy. He maintains that the data are sorely lacking in regard to both targeted agent– and immunotherapy-induced diarrhea, and more research into tailored approaches to treatment is needed.
DISCLOSURE: This webinar was made possible by an educational grant from Pharmanovia. Dr. Scotté has served as a consultant, advisor, or speaker for Helsinn, Sanofi, MSD, Prostrakan, Leo Pharma, Janssen, Hospira, Boehringer, Amgen, Pierre Fabre Oncologie, Vifor Pharma, Pfizer, BMS, Arrow, Viatris, Sanofi, and Pharmanovia; and is a member of MASCC, ESMO, ASCO, and AFSOS. Dr. Bossi has served on an advisory board for Merck, Sanofi-Regeneron, Merck Sharp & Dohme, Sun Pharma, Angelini, Nestlè, and Elevar.
REFERENCES
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