Cancer therapy-induced intestinal injury: Mechanisms, clinical manifestations, and management strategies

Table 1 Incidence of intestinal injury (especially diarrhoea) caused by different kinds of cancer treatments

Treatment type	Drug examples		Incidence of intestinal injury (especially diarrhea)	Ref.
Chemotherapy	Platinum-based agents	Cisplatin	< 1%	[8]
		Carboplatin	6%-10%
		Oxaliplatin	41%-56%
	Fluoropyrimidine	5-fluorouracil	13%-50%	[74]
		Capecitabine	30%-40%
	Irinotecan	Irinotecan (UGT1A1*1/*1)	Up to 87% experience delayed diarrhea; 40% severe	[17]
		Irinotecan (UGT1A1*28/*28)	A two-fold increase of risk of severe diarrhea
	Taxanes	Cabazitaxel	19%-47%	[75]
		Docetaxel	20%-40%
		Paclitaxel	17%-55%
Targeted therapy	EGFR-TKIs	Gefitinib	26%-52%, 1%-5%, grade 3-4	[76]
		Erlotinib	18%-57%, 3%-6%, grade 3-4	[77,78]
		Afatinib	87%-95%, 14%-22%, grade 3-4
		Cetuximab	13%-28%, 4%-28%, grade 3-4
	HER2-TKIs	Lapatinib	47%-75%, 3%-14%, grade 3-4	[79]
		Trastuzumab	2%-63%, 2%-6%, grade 3-4
		Pertuzumab	10%-67%, 5%-8%, grade 3-4
	VEGFR-TKIs	Bevacizumab	16%-20%, 2%-7%, grade 3-4	[58,80]
		Aflibercept	58%-69%, 13%-19%, grade 3-4	[81]
	Multi-target TKIs	Imatinib	20%-26%	[82]
		Sunitinib	44%-55%
		Sorafenib	43%-55%
Immunotherapy	PD-1/PD-L1 inhibitors	Nivolumab	8%-17%	[83,84]
		Pembrolizumab	2%-42%
		Atezolizumab	9%-11%
		Durvalumab	6%-50%
	CTLA-4 inhibitors	Ipilimumab	Diarrhea 27%-54%, colitis 8% to 22%, colon perforation 1%-1.5%	[70]
	LAG-3, TIM-3, and TIGIT	Relatlimab
Surgical treatment		N/A	30%-38%	[46]
Radiotherapy	Radiation	N/A	17%-60%	[69]

EGFR: Epidermal growth factor receptor; TKI: Tyrosine kinase inhibitor; VEGFR: Vascular endothelial growth factor receptor; HER2: Human epidermal growth factor receptor 2; PD-1: Programmed cell death protein 1; PD-L1: Programmed cell death ligand 1; CTLA-4: Cytotoxic T lymphocyte-associated protein 4; LAG-3: Lymphocyte activation gene 3; TIM-3: T-cell immunoglobulin and mucin-domain containing-3; TIGIT: T-cell immunoreceptor with Ig and ITIM domains.

Table 2 Therapeutic drugs/measures for intestinal injury caused by different kinds of cancer treatments

Treatment category	Drugs/measures	Mechanism	Clinical evidence level	Ref.
Symptomatic treatment	Loperamide, octreotide	Relieves symptoms by regulating intestinal activity and secretions	2	[67]
Immune modulation and immunotherapy	Corticosteroids, TNF-α antagonists, intravenous immunoglobulin, mycophenolate mofetil, methotrexate	Suppresses immune activation and reduces inflammation-related damage	2	[56-58]
Antioxidant and anti-inflammatory treatment	Glutathione, alpha-lipoic acid, TNF-α inhibitors, interleukin-6 inhibitors	Reduces oxidative stress and inflammation to protect intestinal cells	2-3	[4,60,61,68]
Stem cell and gut microbiota modulation	Glucagon-like peptide-2, probiotics, fecal microbiota transplantation, short-chain fatty acids	Enhances epithelial cell repair and restores gut microbiota balance	2-3	[62-65]
Emerging therapies	Mesenchymal stem cells, gene editing, nanoparticle drug delivery	Stimulates regeneration and promotes recovery through advanced techniques	4-5	[66]

Clinical evidence levels (1-5) in this table are assigned according to the 2011 Oxford Levels of Evidence (Centre for Evidence-Based Medicine, University of Oxford). Level 1 represents high-quality evidence derived from systematic reviews or randomized controlled trials; level 2 represents moderate-quality evidence from individual randomized controlled trials, cohort studies, or observational studies with dramatic effect; level 3 represents evidence from non-randomized controlled cohort or case-control studies; level 4 represents evidence from case series, poor-quality cohort/case-control studies, or historically controlled studies; level 5 represents expert opinion or mechanism-based reasoning. These levels reflect the reliability of clinical evidence supporting each intervention. TNF-α: Tumour necrosis factor-alpha.