Symptom Management of Chemotherapy-Induced Diarrhea: A Multidisciplinary Approach

At a symposium held in conjunction with the Twenty-Seventh Annual Congress of the Oncology Nursing Society, four leaders in oncology, nutrition, and pharmacy reviewed the current data on the management of chemotherapy-induced diarrhea. Topics included nursing assessment and management, nutritional strategies, and data on agents used to treat this life- threatening side effect.

This program was supported by an unrestricted educational grant from Novartis Pharmaceuticals Corporation.

Speakers

Chemotherapy-Induced Diarrhea: A Nurse’s Guide to Understanding the Disease  

A large percentage of patients undergoing treatment for colorectal cancer experience the side effect of diarrhea. Indeed, 56% of these patients may require alterations, such as reduced dosing, delayed administration, or discontinuation, of their cancer therapy (Arbuckle et al 2000). “Thorough assessment and management of potential chemotherapy-induced diarrhea are essential to ensure optimal quality of life and, in fact, to prevent the disruption of potentially life-saving cancer treatments,” said Carol S. Viele, RN, MS, Program Chair, Clinical Nurse Specialist, University of California, San Francisco, San Francisco, California.

Chemotherapy-Induced Diarrhea
Diarrhea may occur as the result of excessive fluid secretions, thus increasing transit time, or by impaired absorption, thereby causing liquid stool, loss of electrolytes, and increased intestinal motility. Of the four mechanisms of diarrhea, secretory diarrhea (increased intestinal secretion) is the one most often associated with chemotherapy. Chemotherapy agents commonly associated with diarrhea include 5-fluorouracil (5-FU) combinations with leucovorin, interferonalfa, doxorubicin, and mitomycin, as well as others, such as capecitabine, irinotecan, topotecan, cisplatin, and cytarabine. Indeed, chemotherapy-induced diarrhea (CID) occurs in 31% to 87% of patients receiving chemotherapy overall, 31% to 66% receiving 5-FU, 43% receiving cisplatin, and 74% to 87% receiving irinotecan (Rutledge & Engelking 1998). “Chemotherapy-induced diarrhea can be severe, not only causing impairment in quality of life, but also a negative impact on the outcome of cancer therapy,” Ms. Viele noted. According to Ms. Viele, to reduce associated morbidity and mortality and enhance patient comfort, oncology nurses need to be vigilant in providing thorough assessment and proactive management in patients who are undergoing chemotherapy for colorectal cancer.

Strategies for Assessment and Management
“In providing the initial and ongoing assessment of patients undergoing chemotherapy for colorectal cancer, oncology nurses need to be proactive in asking about normal and altered bowel habits,” Ms. Viele explained. Assessment should include a patient history, physical examination, and laboratory analyses. The patient history should include information on primary diagnosis, disease site, disease stage, comorbid conditions, and any prior therapy or concurrent medications. Patients should be asked about usual and altered bowel habits; the onset, frequency, and duration of any diarrhea; change in diet or weight; and recent travel history. The physical examination should include evaluation of vital signs, hydration status, abdominal status, and perianal or peristomal skin integrity. The laboratory analyses should include a complete blood count, evaluation of electrolyte abnormalities and hydration, stool analyses, and, in some cases, endoscopic biopsy.

In managing CID, oncology nurses must first seek to identify patients who are at high risk to minimize the risk for this potentially life-threatening effect where possible. Treatment of CID entails the use of targeted pharmacotherapy and adjunctive supportive care (dietary modification, bowel rest, fluid and electrolyte replacement, skin care), and delay or discontinuation of the causative agent. “Patients and caregivers also need to be educated about which symptoms require immediate attention [Table 1], and how to monitor and document symptoms effectively,” Ms. Viele said.

“Ultimately, preventing and treating chemotherapy-induced diarrhea effectively will help to reduce morbidity, mortality, and hospitalizations and enhance comfort, convenience, and quality of life for persons undergoing therapy for colorectal and other cancers,” the speaker concluded.

Table 1. Symptoms Requiring Immediate Attention

• Fever
• Excessive thirst
• Dizziness
• Palpitations
• Rectal spasm
• Abdominal cramps
• Watery stool
• Bloody stool
• Refractory diarrhea

Management of Chemotherapy-Induced Diarrhea: Nutritional Support and Diet Alterations

“For patients preparing to undergo chemotherapy for gastrointestinal cancer, strategies to determine and maintain appropriate nutrition guidelines can be instrumental in minimizing the risk of chemotherapy-induced diarrhea,” according to Jean Marie Stern, MS, RD, CD, Nutrition Education Coordinator, Seattle Cancer Care Alliance, Seattle, Washington. In addition to ensuring that all foods are properly stored and prepared (Table 1), several nutrition-related factors are important to consider when counseling a patient with cancer.

Nutritional Considerations and Goals
First, the patient’s ethnicity-related preferences and tolerances must be considered, as must his or her current diet practice, the caregiver’s ability to help with grocery shopping and food preparation, cost, and available kitchen utilities. The nutrition goals during cancer treatment include maintaining weight and muscle mass (high calorie, high protein intake), replacing electrolytes, and maintaining vitamin and mineral requirements. “To accomplish nutrition goals during therapy, a patient should eat small frequent meals; eat complex rather than simple carbohydrate foods; eat foods containing soluble fibers; eat protein-rich foods; drink adequate fluids, especially calorie-containing beverages between meals; eat slowly; and follow ASCN and other nutrition guidelines, as appropriate, to minimize the risk of diarrhea,” Ms. Stern advised.

Nutritional Guidelines to Minimize Diarrhea
“In providing nutritional assessment and counseling in patients who are undergoing chemotherapy, it is imperative to consider the needs of each individual person,” Ms. Stern said. Indeed, following the 1998 ASCN guidelines and taking a few other simple nutritional steps can help to minimize the risk for chemotherapy-induced diarrhea.

To Avoid
First, patients who are lactose intolerant should avoid milk and dairy products or select low-lactose choices, such as LactAid® milk, live culture yogurt, aged cheese, soy milk, and liquid supplement drinks. “Lactaid tablets, however, are often ineffective in the case of chemotherapy-induced diarrhea,” Ms. Stern explained. Other substances to avoid include spices and herbal supplements that stimulate discomfort and diarrhea; alcohol, which damages the gastrointestinal mucosa and increases gastrointestinal motility; and caffeine, which is also a gastric irritant and gastrointestinal stimulant. High-sorbitol juices, such as prune, pear, sweet cherry, peach, and apple juices, should be avoided. However, diluted cranberry juice and half-strength Kool-Aid is generally well tolerated. High-insoluble fiber foods (raw fruits and vegetables, whole grains, nuts and legumes, popcorn), gas-causing foods (carbonated beverages, cruciferous and other vegetables, legumes and nuts, chewing gum), and high-fat foods should be avoided. Foods containing sugar alcohols (such as maltitol, xylitol, sorbitol, mannitol) should be avoided. “In addition,” said Ms. Stern, “patients who need pancreatic enzyme replacement should be educated on when and how to use this medication.”

To Consider
In choosing foods and liquids to reduce the risk of diarrhea, patients should consider low-osmolality drinks, such as Gatorade, Pedialyte, and broth. Try foods containing soluble fibers such as oatmeal, barley, applesauce, potatoes, bananas, and psyllium. In addition, green bananas contain amylase-resistant starch, which is digested in the colon, stimulating water and salt absorption. Electrolyte replacement (Table 2) must include replenishment of sodium, potassium, zinc, and magnesium. “Unfortunately, oral magnesium supplements and food sources of magnesium tend to promote diarrhea; therefore, intravenous infusion may be necessary,” Ms. Stern explained. Finally, adequate fluid intake—30 to 35 mL/kg—is essential, and should consist of drinks that are high in calories, isosmotic, low in sorbitol, and served at room temperature. Ms. Stern noted that use of glutamine may help diminish diarrhea, and is currently under study.

In closing, Ms. Stern emphasized that baseline and ongoing assessment of gastrointestinal and nutritional status in all patients undergoing chemotherapy, including those with an ostomy, is of vital importance in providing effective nutritional strategies to minimize the risk of treatment-related diarrhea.

Table 1. Ensuring Food Safety

• Wash hands before handling food
• Keep raw meat and ready-to-eat foods separated
• Cook foods to proper temperature
• Refrigerate foods promptly to below 40° F
• Check expiration dates
• Avoid high-risk foods, such as sushi, street vendors, uncooked sprouts, raw eggs

Table 2. Adult Homemade Electrolyte Replacement Solution

• 1 tsp salt
• 1 tsp baking soda
• 1 tbs corn syrup
• 6 oz frozen orange juice concentrate
• 6 cups water
• 47 kcal/cup, 515 mg Na+, 164 mg K+

Source: The Cancer Survival Cookbook 1998

Choosing Optimal Interventions for Chemotherapy-Induced Diarrhea

Chemotherapy-induced diarrhea (CID) is a significant cause of morbidity in patients with gastrointestinal and other cancers, with up to 50% of affected patients experiencing grade 3/4 diarrhea. “Chemotherapy-induced diarrhea requires prompt and aggressive therapy, with use of high-dose loperamide for patients with grade 1/2 diarrhea, and octreotide in those with grade 3/4 or loperamide-refractory diarrhea being an effective treatment approach [Figure 1],” said Cindy Ippoliti, PharmD, Pharmacy Clinical Coordinator, University of Texas, MD Anderson Cancer Center, Houston, Texas.

Treatment of Chemotherapy-Induced Diarrhea
According to Dr. Ippoliti, four main agents are used in the treatment of CID. These agents include loperamide, diphenoxylate-atropine, tincture of opium, and octreotide. Loperamide acts by slowing peristolic activity of the gastrointestinal tract. This agent, administered at up to 16 mg/day, remains the standard of care for treatment of CID. Side effects are minimal and may include abdominal distention and cramping, dry mouth, and sedation.
Diphenoxylate-atropine consists of the active agent diphenoxylate, a derivative of meperidine, and atropine, which curves the tendency for drug abuse. Up to eight tablets per day may be used, and dose-limiting side effects may include dry mouth, dry mucous membranes, flushing, tachycardia, urinary retention, and accumulation of drug in the elderly and persons with renal or liver dysfunction.

Tincture of opium, like other narcotics, works to decrease peristalsis. This agent, given at .6 mL every 4 to 6 hours, is easy to administer and includes some analgesic activity. Tincture of opium is a controlled substance, and potential side effects are those of all narcotic agents.

Octreotide works by a number of mechanisms, including enhancement of gastrointestinal absorption and inhibition of secretory flow. The dosage for CID is 100 to 500 mcg subcutaneously three times daily. Intravenous delivery is also an option, and is equivalent in efficacy to subcutaneous injection. In addition, octreotide LAR may be administered at 30 mg once per month. “This agent is highly effective, and must be discontinued as soon as the diarrhea dissipates to avoid potential side effects, such as severe constipation,” Dr. Ippoliti said. In choosing an appropriate agent, clinicians need to consider efficacy, toxicity, and cost.

The Data
In one study, Casinu and colleagues (2000) treated 36 patients with grade 1 to 4 5-FU-associated diarrhea with high-dose loperamide, continued for 48 hours. The results showed an overall response rate of 69% in those with grade 1/2 diarrhea, and 54% in those with grade 3/4 diarrhea. In another recent study, Barbounis and colleagues (2001) treated 23 individuals with grade 3/4 irinotecan-induced diarrhea with high-dose loperamide. In 13 patients for whom loperamide failed, octreotide 500 mcg three times daily for 48 to 96 hours was administered. In these patients, the response rate was 92%. Similarly, Zidan and associates (2001) treated 32 patients with grade 2/3 loperamide-refractory 5-FU-induced diarrhea with octreotide 100 mcg three times daily. Octreotide doses were tapered based on patient response. These findings showed a 94% complete response rate in patients for whom loperamide had failed. Other trials by Wadler and Goumas study groups (1995, 1998) suggest that the optimally effective octreotide dose appears to be 500 mcg three times daily. In addition, studies investigating the use of octreotide prophylactically for CID are underway.

“More than one third of patients with chemotherapy-induced diarrhea are hospitalized due to dehydration. Aggressive therapy with high-dose loperamide or octreotide as appropriate [Figure 1] is essential to reducing diarrhea-related morbidity and preventing potential disruption in potentially curative cancer treatments,” Dr. Ippoliti concluded.

Practical Approaches to Managing Chemotherapy-Induced Diarrhea: Lessons from Case Studies

Five-year survival rates for patients with Dukes B2 colon cancer are approximately 60% with surgery alone, and 80% with adjuvant therapy. With Dukes C colon cancer, these rates are approximately 40% and 55%, respectively. “However, diarrhea is a potentially dose-limiting adverse effect that often occurs in association with adjuvant chemotherapy for colon cancer,” Stephen H. Rosenoff, MD, FACP, Clinical Professor of Medicine, University of Virginia, Cancer Center of Western Virginia, Roanoke, Virginia. According to Dr. Rosenoff, prevention and treatment of CID are critical in ensuring that patients are able to receive potentially life-saving adjuvant therapy for colon cancer.

Case Report One: Diarrhea with Chemotherapy for Dukes C2 Colon Cancer
Dr. Rosenoff treated one patient, TG, a 61-year-old White male with Dukes C2 colon cancer. He underwent surgery, and 11 of 18 lymph nodes were found to be involved. After adjuvant therapy with a standard 5-fluorouracil (5-FU)/leucovorin regimen, TG promptly developed severe chemotherapy-induced diarrhea (CID). Stool was C difficile-negative, there was no response to high-dose loperamide, and TG was hospitalized. Chemotherapy was delayed, and eventually restarted at a reduced dose. “In addition to diphenoxylate-atropine and loperamide, TG received octreotide LAR,” Dr. Rosenoff reported. After a second hospitalization, TG underwent full-dose chemotherapy with an increased dose of octreotide LAR (30 mg). With this approach, the patient was able to undergo chemotherapy with no incidence of CID and with diminished abdominal pain, although he did have some hand-cracking symptoms. When TG had a recurrence in the liver, he underwent therapy with irinotecan and continued octreotide LAR. Surprisingly, TG experienced no diarrhea or abdominal pain with this regimen. “Use of long-acting octreotide resulted in an enhanced sense of well-being and quality of life, as well as continuation of palliative cancer therapy for TG,” Dr. Rosenoff noted.

Case Report Two: Diarrhea with Chemotherapy for Dukes B2 Colon Cancer
GL, a 64-year-old male with Dukes B2 colon cancer, underwent surgery and adjuvant therapy with 5-FU/leucovorin. He developed severe CID, even while taking diphenoxylate-atropine and loperamide, and was hospitalized. Though the leucovorin dose was subsequently reduced by 33%, GL was hospitalized again with diarrhea and abdominal pain. After a third hospitalization with CID, GL refused further adjuvant therapy. Less than 1 year later, GL suffered a recurrence, with a solitary liver lesion. At this time, the lesion was resected, but GL refused adjuvant therapy with irinotecan. A second liver lesion 1 year later was also resected, and GL decided to undergo adjuvant irinotecan therapy at this time. “GL received octreotide LAR 30 mg, and fortunately had decreased abdominal cramping, improved quality of life, and was able to complete the irinotecan regimen,” Dr. Rosenoff said.

Conclusions
Dr. Rosenoff also reported on 10 other patients with colon cancer for whom octreotide LAR prevented subsequent episodes of CID and allowed completion of chemotherapy. “Prevention is the key. Patients and caregivers need to be educated about the alarming frequency of CID and potential treatments. Once grade 1/2 diarrhea occurs, treatment should be aggressive, with diphenoxylate-atropine and loperamide [2 tablets first episode, 1 tablet subsequent episodes, up to 8 tablets/24 h]. For patients having diarrhea with irinotecan or grade 3 or higher diarrhea with 5-FU/leucovorin, patients should receive two diphenoxylate-atropine tablets, and one tablet with subsequent episodes [up to 8 tablets/24 h], as well as one tablet of loperamide four times daily. For patients who have already experienced grade 2/3 or greater diarrhea without adequate response to opioids, ocreotide LAR 30 mg every 4 weeks, along with prompt opioid therapy for breakthrough diarrhea, may be effective,” Dr. Rosenoff concluded.