ESMO guidelines for management of Diarrhea in adult cancer patients

The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for diarrhea in adult cancer patients is a comprehensive assessment of diarrhea in an oncological setting. The guidelines consider the risk of this symptom associated with several cancer-related therapies, comprising chemotherapy, targeted agents, immunotherapy, surgery, and radiation.

A specific focus is dedicated to other causes of diarrhea in cancer patients; the clinical patterns of neutropaenic and non-neutropaenic enterocolitis as a potential acute life-threatening complication are also provided. The peculiarities of diarrhea in elderly cancer patients are described, indicating how to deal with this frailer population.

The guidelines published in the Annals of Oncology, also evaluate the importance of an accurate grading of diarrhea symptoms; use of patient-reported outcomes (PROs) CTCAE system allows a clearer pattern of symptoms to be collected.

KEY RECOMMENDATIONS:

General principles of management

• Patients with grade 1 or 2 diarrhea with no other complicating signs or symptoms may be managed conservatively with oral hydration and loperamide.


• Patients with mild to moderate diarrhea complicated by moderate to severe cramping, nausea, and vomiting, diminished performance status, fever, sepsis, neutropenia, bleeding or dehydration, and patients with severe diarrhea should be hospitalized and evaluated further, monitored closely and intensively treated. These patients should be evaluated by a multidisciplinary team including the expertise of gastroenterologists.

Management of neutropaenic enterocolitis

• The initial treatment of neutropaenic enterocolitis is medical, with the administration of broad-spectrum antibiotics, G-CSFs, nasogastric decompression, i.v. fluids, bowel rest and serial abdominal examinations.


• The administered antibiotics should cover enteric gram-negative organisms, gram-positive organisms and anaerobes.


• Reasonable initial choices include monotherapy with piperacillin-tazobactam or imipenem-cilastatin or combination therapy with cefepime or ceftazidime along with metronidazole. In cases which do not respond to antibacterial agents, amphotericin should be considered, because fungemia is common.


• Blood transfusions may be necessary because the diarrhea is often bloody.


• Anticholinergic, antidiarrhoeal and opioid agents should be avoided since they may aggravate ileus.


• Indications for surgery include: (i) persistent gastrointestinal bleeding after correction of thrombocytopenia and coagulopathy; (ii) evidence of free intraperitoneal perforation; (iii) abscess formation; (iv) clinical deterioration despite aggressive supportive measures; (v) to rule out other intraabdominal processes such as bowel obstruction or acute appendicitis through radiological examinations.


• Failure to remove the necrotic focus in these severely immunocompromised patients is often fatal . Primary anastomosis is not generally recommended in such severely immunocompromised patients because of the increased incidence of anastomotic leak.

Treatment approaches

• ORT is generally appropriate for mild diarrhea. ORSs, including standard WHO ORSs or commercial ORSs may be more appropriate in patients with more severe diarrhoeal disease.


• Rapid fluid resuscitation is not necessary for patients with mild to moderate hypovolaemia. The rate of fluid administration must be greater than the rate of continued fluid losses, which is equal to the urine output plus estimated insensible losses (usually 30–50 mL/h) plus gastrointestinal losses.


• If the patient has tachycardia and is potentially septic, an initial fluid bolus of 20 mL/kg should be given.


• Fluid replacement is continued at a rapid rate until the clinical signs of hypovolaemia improve.


• Fluid balance should aim for an adequate central venous pressure and urine output > 0.5 mL/kg/h. Patients who develop oliguric acute kidney injury (< 0.5 mL/kg/h) despite adequate volume resuscitation, as judged by central venous pressure, are at risk of developing pulmonary edema and the advice of intensive-care experts or nephrologists must be urgently sought.


• Loperamide can be started at an initial dose of 4 mg followed by 2 mg every 2–4 h or after every unformed stool. The maximum daily dose of loperamide is 16 mg.


• Other opioids, such as tincture of opium, morphine or codeine can be used.


• The usual starting dose for octreotide is 100–150 μg s.c./i.v. tid. The dose can be titrated up to 500 µg s.c./i.v. tid or 25–50 µg/h by continual i.v. infusion.


• Uridine triacetate (dose of 10 g orally every 6 h for 20 doses) is indicated for the management of early-onset, severe or life-threatening toxicity including diarrhea within 96 h following the end of 5-FU or capecitabine administration.


• Oral budesonide may be suggested for treatment of ChT-induced diarrhea that was refractory to loperamide. Prophylactic use of budesonide is not recommended.


• In the case of bile salt malabsorption, bile acid sequestrants (e.g. cholestyramine, colestipol, colesevelam) may be an active adjuvant therapy.


• Immunotherapy-induced diarrhea:
  
  
  
  • Grade 1: symptomatic treatment with oral rehydration and antidiarrhoeal treatment, racecadotril or loperamide.
  
  
  • Grade 2: budesonide 9 mg once a day can be added to the symptomatic treatment, if no bloody diarrhoea; oral corticosteroids (0.5–1 mg/kg/ day prednisone equivalent) are recommended in the case of diffuse ulceration or bleeding, or persistent symptoms after 3 days with symptomatic treatments ± budesonid.
  
  
  • Grade 3 and 4: 1–2 mg/kg/day prednisone equivalent, with i.v. injections first. Loperamide and opioids should be avoided. If symptoms persist for > 3–5 days, infliximab 5 mg/kg once every 2 weeks until a resolution is recommended. Vedolizumab could be an efficient and safe alternative to infliximab.
  
  
  
  

Role of diet

• Spices and beverages such as coffee and alcohol should be avoided and reduction of insoluble fiber intake may also be useful.


• In patients presenting with diarrhea during ChT, avoidance of milk and dairy products (apart from yogurt and firm cheeses) may be a reasonable strategy to reduce the intensity and duration of symptoms.

Prevention and treatment of acute RT-induced diarrhea

Technical RT measures:

• RT techniques (e.g. IMRT)


• Physical measures (belly board device, bladder distension and surgical approach to displace small bowel volume)

Nutritional status and prophylactic agent

• Dietary counseling (e.g. reduction of fatty food, lactose-free diet in case of lactose intolerance, avoidance of drinks with caffeine or alcohol and of tobacco).


• High-fiber diet


• Oral supplements (e.g. administration of colesevelam for patients with bile salt malabsorption).


• Probiotics (Lactobacillus, Bifidobacterium, and cocci). Need for further safety analysis in immunocompromised patients.

Treatment

• Caloric and fluid intakes


• Loperamide (4 mg as an initial dose, followed by 2 mg every 4 h, or after each unformed stool; daily total dose should not exceed 16 mg


• Octreotide in patients not responsive to loperamide and with severe toxicity (100 μg three times daily)


• Anticholinergic antispasmodic agent to alleviate bowel cramping

Treatment of chronic RT-induced diarrhea

• Referral to expert dietician after the completion of a 7-day dietary diary.


• Lifestyle advice (e.g. smoking cessation)


• Consider referral for psychological support


• Highly caloric nutritional supplements containing iron, folic acid, vitamin B12, vitamin D, magnesium, calcium, trace elements and fat-soluble vitamins


• Colesevelam is better tolerated than colestyramine for bile salt malabsorption treatment


• Broad-spectrum antimicrobial therapy (often empirical) requiring in some cases prolonged and cyclical courses


• Antidiarrhoeal agents (e.g. loperamide)


• Pelvic floor and toileting exercises if evidence of radiation proctopathy and increased frequency of defecation.

Diarrhea in cancer patients is a symptom with high impact on QoL and social functioning. The clinical approach should follow the correct identification of pathogenesis of this symptom. Prevention of associated complications is one of the pillars of the therapeutic strategy. In the future, identification of patients at higher risk of developing diarrhea following specific treatments will allow for selection of personalized programmes to reduce the severity and duration of this symptom.

For further information click on the link: https://doi.org/10.1093/annonc/mdy145