Elsevier Global Medical News. 2009 Oct 26, C Helwick
CHICAGO (EGMN) - The incidence of the oldest side effect of anticancer treatment - diarrhea - is rising in parallel with the use of targeted agents, and clinicians need to manage this proactively in order to keep patients on treatment, according to Dr. Joanna M. Brell of the Division of Cancer Prevention at the National Cancer Institute.
"Diarrhea occurs in about 80% of chemotherapy patients, and about 30% is grade 3/4 toxicity. It is common, it is associated with newer targeted therapies, it is additive with combination treatment, and patients are receiving treatment for longer periods. We'd better be good at managing it," she told attendees at the annual Chicago Supportive Oncology Conference.
Diarrhea is a class effect of many older drugs and of the small-molecule agents that are approved in treating at least 10 malignancies, with many more compounds in the pipeline. (See box.) The fact that more targeted agents will be used in maintenance therapy means that more patients will experience diarrhea for longer periods of time, Dr. Brell warned.
Diarrhea (informally defined as bowel movements of any type that are bothersome to the patient) occurs in cancer patients for many reasons. It is the presenting symptom of many tumors (for example, colorectal, pancreatic, and neuroendocrine). It can result from surgical treatment, such as gastrectomy and pancreaticoduoenectomy, as well as from radiotherapy. Infections such as febrile neutropenia and Clostridium difficile, graft-versus-host disease, and supportive medications can produce diarrhea. Anxiety can also cause diarrhea, as can some comorbid conditions.
The physical consequences include dehydration, electrolyte imbalance, acute renal failure, renal insufficiency, weight loss, malnutrition, and risk of infection. It causes generalized malaise, diminishes activities of daily living, enhances treatment noncompliance, and reduces quality of life. Importantly, an abnormal GI tract may affect absorption of oral chemotherapy, and dose reductions of anticancer drugs or discontinuations of treatment are sometimes required.
"Treatment delays have uncertain effects on the tumor, and this is distressing to the patient, who wants full treatment," she said.
Why Diarrhea Occurs With Targeted Agents
The mechanisms by which diarrhea occurs with targeted agents were recently described (Nat. Clin. Pract. Oncol. 2008;5:268-78). They vary according to the class of agent, but among them are secretory processes caused by inhibition of epidermal growth factor receptor (EGFR) effects on chloride secretion, direct damage of intestinal mucosa, microflora alteration, malabsorption, alteration of Cajal cells, and autonomic nerve dysfunction.
With the EGFR inhibitor erlotinib (Tarceva), the incidence - but not the severity - of diarrhea is dose related. Its occurrence is associated with EGFR gene mutations, particularly the G/G CYP3A5 genotype that controls EGFR expression. Erlotinib promotes chloride secretion in colonic luminal cells, leading to secretory diarrhea.
Sorafenib (Nexavar), a multitargeted vascular inhibitor, causes diarrhea in 30%-43% of patients. This is thought to be related to small-vessel ischemia or ischemic colitis with mucosal changes, and to direct damage to mucosal cells.
"Remember that sorafenib is approved for hepatocellular carcinoma, and patients may have abnormal liver function tests, changed metabolic function, and lactulose use at baseline," Dr. Brell advised.
With bortezomib (Velcade), an NF-kappaB inhibitor, diarrhea can have a relatively quick onset (with associated postural hypotension, syncope, or near-syncope) and can be dose limiting. Changes are thought to be related to autonomic nerve dysfunction.
Flavopiridol, which inhibits multiple cyclin-dependent kinases, enhances the efficacy of other chemotherapies. Poor metabolism of flavopiridol leads to increased levels of the drug, which potentially injure mucosal cells directly. Cholestyramine can bind to flavopiridol and therefore protect against diarrhea, but how this may affect anticancer treatment is unknown, Dr. Brell said.
Management of Diarrhea Associated With Targeted Agents
There is little to no evidence to guide the management of diarrhea that is specifically associated with targeted therapies, said Dr. Brell. Unlike conventional chemotherapy, the goal with these agents is not to increase response, and they are not dosed according to body surface area. The actual effective dose of the drugs, therefore, is generally unknown.
Given these considerations, the major management strategy with these agents is dose delay, she said. Brief dose interruptions are usually adequate, and the dose can usually be maintained in spite of the toxicity, "which we don't do with [5-fluorouracil] or irinotecan," she noted. Dose reductions are done, if required, to maintain quality of life. Cholestyramine can be tried for diarrhea that is associated with sorafenib, sunitinib (Sutent), and flavopiridol.
The usual management strategies also apply, added Dr. Brell. Clinicians should monitor stool output closely; stop supportive medications for constipation; use oral loperamide (Imodium) up to 16 mg/day, or diphenoxylate plus atropine (Lomotil) 5 mg two to four times per day; give intravenous fluids; rule out C. difficile; prescribe empiric antibiotics; and give octreotide (Sandostatin LAR Depot) 100 mcg three times daily, or at higher doses).
Clinicians should check for the use of medications that might increase diarrhea, such as CYP3A4 inhibitors that can affect drug metabolism such that levels of the anticancer therapy are increased and therefore toxicity is enhanced.
For prophylaxis, data are even more limited. Dr. Brell suggested trying cholestyramine prior to dosing sorafenib and sunitinib, giving octreotide LAR monthly, and giving octreotide and loperamide prior to chemoradiation to the pelvis.
The meeting was sponsored by Elsevier Oncology, a sister company to this news organization.
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