Definition
Diarrhoea is frequently reported among patients treated with fluoropyrimidine chemotherapy (5-fluorouracil or capecitabine), with or without additional agents such as oxaliplatin or irinotecan. Severe enteropathy is characterised by grade 3 or higher diarrhoear and bowel wall injury (BWI, small or large) requiring hospitalisation for the management of severe diarrhoea or dehydration, and radiological or endoscopic evidence of bowel thickening or ulceration.r
Incidence/prevalence
The incidence of grade 3 and 4 diarrhoea is between 10-47%, depending on the fluoropyrimidine and addition of combination agent.r A study by Kuebler et al published the results of 1857 patients treated with weekly bolus fluorouracil and leucovorin (FL; "Roswell Park Regimen") or the same regimen plus oxaliplatin (FLOX). There were 5 deaths related to enteropathy.r
Frequency and severity of diarrhoea with frequently used combinations of fluoropyrimidine agentsr
©Ann Onc 2018
Bowel wall injury (BWI)
79 patients (4.3%) developed bowel wall injury of either small or large bowel. These adverse events were more common in FLOX 64% (51 patients) than FL 35.4% (28 patients) (p<0.01). 71% of patients resumed treatment with fluorouracil after recovery.r
Enteric sepsis (ES)
Enteric sepsis characterised by grade 3 or greater diarrhoea and grade 4 neutropenia with or without proven bacteraemia occurred in 22 patients treated with FLOX and 8 patients treated with FL (p=0.01).r
Onset/duration
The highest frequency of onset for fluoropyrimidine induced diarrhoea is within the first 5 days of exposure. In Kuebler et al study, severe gastrointestinal toxicity which required hospitalisation usually occurred during the third or fourth week on the first cycle and was managed by fluids, antidiarrhoeals and antibiotics.r
Risk factors
Several studies have looked at factors associated with increased risk of diarrhoea and severe enteropathy. Factors include:rrr
- age over 60 years
- female patients (both with bolus regimens and with combination therapy)
- unresected primary tumour
- prior bowel resection (shortened total bowel length)
- dihydropyrimidine dehydrogenase deficiency (including DPYD variant carriers)
- onset during warmer months (higher risk of associated dehydration)