Treatment-induced diarrhoea is an increased frequency, and decreased consistency, of bowel motions, or ostomy output as a result of medical treatment. It may be associated with abdominal pains and/or cramping, and the patient’s faeces may also contain blood and mucus. Diarrhoea can be a side effect of chemotherapy, radiotherapy and targeted therapies and can be intensified when treatment modalities are combined. Treatment-induced diarrhoea can have a significant, negative effect on a patient’s quality of life causing discomfort and limiting daily activities. It is often progressive and requires prompt and effective management. In severe cases, if left untreated, it can become life threatening.
Chemotherapy induced diarrhoea is one of the dose limiting toxicities of chemotherapy. It may be severe enough to require a dose reduction, a delay or discontinuation of chemotherapy. It can lead to malnutrition, weight loss, electrolyte imbalance, renal insufficiency and hospital admission, and impacts negatively on quality of life. If not properly treated, it can be life threatening, especially in a patient who is also neutropenic. Some agents, in particular fluorouracil, irinotecan and ipilimumab, can cause life threatening diarrhoea that requires urgent treatment.
Radiation induced diarrhoea is a common side effect of patients undergoing radiotherapy to the abdomen and/or pelvis. Modern radiotherapy treatment techniques have reduced the incidence of severe episodes causing treatment delays however this may still occur and should be monitored closely by clinicians.
Targeted therapy induced diarrhoea can occur in many patients and may result in dose delays, reductions and/ or treatment cessation.
Chemotherapy induced diarrhoea is primarily a secretory diarrhoea.r It is thought to be multifactorial with several pathophysiological changes combining to result in diarrhoea. These changes can include damage to the intestinal mucosa, alteration in the gut microflora, altered fluid absorption and transport in the colon, damage to the crypt cells of the colon and alterations in gut motility.r
Radiation induced diarrhoea results from a variety of different pathophysiological mechanisms including malabsorption of bile salts and lactose, imbalances in local bacteria flora and changes in the intestinal patterns of motility.r The mechanism of radiation induced diarrhoea involves acute radiation damage to the epithelial crypt cells of the gastrointestinal tract which results in cell death, inflammation and ulceration of the intestinal mucosa. This mucosa is then exposed to bile salts and is vulnerable to infection. Atrophy and fibrosis are long term consequences of this radiation damage, which leads to decreased absorption of water and electrolytes.
Targeted therapy induced diarrhoea is usually secretory (most anti EGFR agents), due to direct ischemic mucosal damage (sorafenib) or is immune related (ipilimumab).r
Chemotherapy induced diarrhoea: The frequency of chemotherapy induced diarrhoea is related to the drug, dose and treatment schedule. The incidence of diarrhoea during cancer treatment has been reported to be as high as 50 to 80 % of treated patients;rr this incidence is particularly high during treatment for colorectal cancer. Regimens containing modulated fluorouracil (increased incidence when co-administered with leucovorin), single agent irinotecan, and the combination of both, result in up to 47 % of patients experiencing grade 3 to 5 diarrhoea.r
Radiation induced diarrhoea: Incidence rates of greater than or equal to grade 3 have been reported in:r
- 18 to 20 % of patients receiving conventional radiotherapy alone
- 23 to 25 % of patients receiving combination chemoradiation
With pelvic radiotherapy only, studies show a very high incidence (up to 70%) of patients experiencing diarrhoea of any grade with approximately 20% experiencing grade 3 or 4 symptoms.r Chronic post treatment diarrhoea has been reported to occur in 26-49% of patients receiving pelvic radiotherapy.r
Targeted therapy induced diarrhoea: For tyrosine kinase inhibitors (TKI, e.g. imatinib, gefitinib, erlotinib) diarrhoea is the second most common side effect after rash, affecting up to 5-60% of patients, with up to 28% experiencing grade 3 or higher. The mechanism of TKI induced diarrhoea is not fully understood9. The number of patients who experience diarrhoea with VEGF inhibitors (e.g. pazopanib, sorafenib, sunitinib, afatinib) can be as high as 66% which can be dose limiting. Small-molecule monoclonal antibodies e.g. ipilimumab are associated with immune related adverse reactions which can be severe or life-threatening. The incidence of grade 3 or 4 diarrhoea is 5%. This can be associated with perforation and death.r Cetuximab and panitumumab have been associated with up to 30% of grade 3-4 diarrhoea.r
Chemotherapy induced diarrhoea usually occurs 24 to 96 hours after commencement of the chemotherapy agent. However, some agents can cause diarrhoea at other times.
Irinotecan induced diarrhoea can be classified as either early or late onset.
Early onset diarrhoea (cholinergic syndrome):
- can occur during or shortly after commencing the irinotecan infusion, or within 24 hours of administration of the drug
- is characterised by diarrhoea, rhinitis, hypersalivation, miosis, lacrimation, diaphoresis, flushing and abdominal cramping
- is usually transient and infrequently severe
- is more likely to occur at higher doses and is associated with the onset of peak irinotecan plasma levels. Infusing irinotecan over less than 90 minutes may increase the likelihood of cholinergic syndrome
Late onset diarrhoea:
- can be life threatening and requires immediate treatment
- occurs 24 hours or more after administration. Median time to onset of late diarrhoea in trials was 11 days for weekly schedule and 5 days for the 3 weekly schedule
- possibly related to abnormal ion transport in the injured intestinal mucosa preventing the re-absorption of water and electrolytes.
Access the irinotecan induced diarrhoea management algorithm.
Radiation Induced Diarrhoea can be either acute or late:
- the onset of acute symptoms usually occurs in the second to third week of treatment with conventional fractionation, and the incidence tends to increase over the course of treatment
- acute symptoms usually occur between 10 to 30 Gyr
- the small intestine is sensitive to late effects and is a dose limiting structure in the treatment of the abdomen and pelvis
- late symptoms of radiation induced diarrhoea can occur from 8 to 12 months post radiotherapy, as a result of vascular insufficiency due to damaged cells in blood vessels and connective tissue in bowel wall.
Risk factors for treatment induced diarrhoea include, but are not limited to:
- patients aged over 65 yrs
- female patients (radiotherapy treatment fields are generally larger)
- low performance status (WHO/ECOG of 2 or more)
- psychosocial issues, including stress/anxiety
- malignancy proximal to, or including the bowel
- recent surgical intervention
- previous history of colon related co-morbid conditions, i.e. chronic intestinal dysmotility (CID), Crohn’s disease, irritable bowel syndrome
- genetic disorders, i.e. Gilberts syndrome, dihydropyrimidine dehydrogenase (DPD) deficiency
- biliary obstruction
- haemopoietic progenitor cell transplant, as this includes high dose chemotherapy +/- total body irradiation (TBI)
- radiotherapy to the pelvis and/or abdomen