Cancer-treatment–induced diarrhea (CTID) occurs in 50% to 80% of patients receiving chemotherapy and 50% of patients undergoing radiotherapy. Older patients, women, patients on an irinotecan-containing regimen, and patients treated in the adjuvant setting are at higher risk of CTID, reported Kelly Markey, PharmD, BCOP. Markey is a clinical pharmacist with the gastrointestinal tumor program at Moffitt Cancer Center in Tampa, Florida, and discussed CTID at the annual meeting of the Hematology Oncology Pharmacy Association.
"There are many different sources for diarrhea in this patient population," she said. It can be caused by surgery, nosocomial infection, treatment, graft-versus-host disease, and the patient's malignancy.
A diagnostic work-up for diarrhea requires obtaining a clinical history and a description of the stool. "Stool description is especially important, including not only the number of stools but the composition," said Markey. "Are they watery or bloody? Did they occur nocturnally?" Patients should be checked for fever and asked if they have experienced dizziness, cramping, pain, or weakness. "Sometimes fever can indicate infection or even bowel obstruction," she noted. Current medications or diet might also contribute to diarrhea.
Persistent diarrhea requires a stool work up, complete blood count, and assessment of electrolyte levels. Markey said an abdominal examination is also necessary, as is an endoscopy in some cases, to check for clostridium difficile or inflammatory bowel disease. "Nosocomial infections are most often associated with c. difficile," she said. Other culprits include salmonella, shigella, campylobacter, and Escherichia coli. For diarrhea lasting >7 days, "You need to start thinking about your protozoa."
Patients meeting National Cancer Institute criteria for grade 1/2 persistent diarrhea but without fever, dehydration, neutropenia, or blood in their stool can be seen at the office. Patients with grade 3/4 diarrhea require hospital admittance, even if they have no other symptoms. Markey said probiotics, which contain live bacteria or yeast, are a hot topic in CTID. They secrete acids that lower the Ph level in the gastrointestinal (GI) tract, which thwarts the growth of pathogenic bacteria. "They also secret toxins to these bacteria, such as hydrogen peroxide, and they inhibit the binding of these bacteria to the GI tract, " she explained. Caution is recommended when using probiotics in patients who are immunocompromised or have central venous devices. Probiotics should not be used in patients on an antifungal agent. One concern with probiotics is that they are not quality controlled by the US Food and Drug Administration. They are relatively inexpensive, however, and Markey said well-designed trials should examine how effective they are at preventing CTID.
Several anti-motility agents are used in the initial treatment of CTID. "Many times I find my patients haven't maximized use of their first-line agents, such as loperamide, and we prematurely move them to a second-line agent," said Markey. "You want to make sure you're maximizing your dosing."
For patients with persistent diarrhea, long-acting and short-acting octreotide are available. "Long-acting wouldn't be used in the refractory-treatment population, but it is being investigated as a prophylactic, particularly in the radiation-induced population," she said. One study found continuous octreotide infusion effective in patients with colorectal cancer who were receiving 5-fluorouracil. Diphenoxylate, opium tincture, budesonide, and cholestyramine resin are other options for CTID.
If c. difficile is the culprit, metronidazole or vancomycin are standard first-line options. "The problem with these agents is they can be efficacious up front, but 20% to 30% of patients are going to recur within 60 days...the majority recur within 2 weeks," said Markey. The c. difficile pathogen produces spores, and some experts believe treatment should be extended to 2 months.
Several new drugs for c. difficile are on the market. In 2010, a small study by Basu and colleagues reported that 73% of patients who were refractory to metronidazole responded to rifamycin (Xifaxan). A 2011 study by Louie and associates determined that fidaxomicin (not yet approved) was noninferior to vancomycin as initial therapy for c. difficile andit was associated with a lower rate of recurrence. Nitazoxanide (Alinia) is a new agent used against protozoa that is similar in effectiveness to vancomycin. It has the added benefit of being active against norovirus and rotavirus.
Persistent diarrhea can be a life-threatening complication of anticancer therapy, and even low-grade persistent diarrhea has a negative effect on quality of life. Persistent diarrhea requires prompt investigation, particularly when accompanied by fever. Markey said it is important to let patients with cancer know when diarrhea warrants calling their healthcare provider or seeking hospitalization.