Treatable causes of diarrhoea in patients on tyrosine kinase inhibitors for metastatic renal cell carcinoma
Authors: S.V. Lightowlers, B. Greef, T. Eisen, A. Matakidou, K. Fife, E.A. Cameron
Journal: Annals of Oncology (2018)

The antiangiogenic tyrosine kinase inhibitors (TKIs) sunitinib, pazopanib, axitinib and cabozantinib have transformed management and lengthened survival of patients with metastatic renal cell carcinoma [1.Rao A. Wiggins C. Lauer R. Survival outcomes for advanced kidney cancer patients in the era of targeted therapies.Ann Transl Med. 2018; 6: 165.Crossref PubMed Google Scholar]: 12% now survive more than 5 years [1.Rao A. Wiggins C. Lauer R. Survival outcomes for advanced kidney cancer patients in the era of targeted therapies.Ann Transl Med. 2018; 6: 165.Crossref PubMed Google Scholar]. TKIs are taken long-term, until disease progression or intolerable toxicity [1.Rao A. Wiggins C. Lauer R. Survival outcomes for advanced kidney cancer patients in the era of targeted therapies.Ann Transl Med. 2018; 6: 165.Crossref PubMed Google Scholar], so even low grade adverse effects may detract from quality of life. Diarrhoea is a common TKI-related toxicity; reported rates of all grades are 55%–65%. However, the causative mechanism is unclear. Over 2 years, 27 patients from our unit were referred to gastroenterology for TKI-associated diarrhoea; referrals were at clinician discretion considering multiple factors including grade and nature of diarrhoea, associated symptoms and quality of life effects. Twenty-four (89%) had a time course of symptoms corresponding to TKI treatment: onset within 3 months of initiation (10 patients), worsening with dose increases (4 patients) and/or improvement on treatment breaks (13 patients). Twenty (74%) were diagnosed as having a secondary cause for diarrhoea. Eight patients had evidence of pancreatic exocrine insufficiency (low faecal elastase levels, or a borderline result with compatible history and response to enzyme replacement). Four responded to pancreatic enzyme replacement, enabling one to reduce the frequency of missed TKI doses. Pancreatic insufficiency has been reported in a series of patients taking the TKI sorafenib [2.Mir O. Coriat R. Boudou-Rouquette P. et al.Sorafenib-induced diarrhoea and hypophosphatemia: mechanisms and therapeutic implications.Ann Oncol. 2012; 23: 280-281Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar]. Two patients were diagnosed with small bowel bacterial overgrowth on hydrogen breath testing; in both, symptoms improved following appropriate antibiotics. Ten patients had selenium homocholic acid taurine (SeHCAT) scan results suggestive of bile acid malabsorption. Nine of these responded symptomatically to treatment with either bile acid sequestrants (cholestyramine/colesevelam) or dietary modification, in one case permitting a TKI dose increase. Expert opinion suggests that both bile acid malabsorption and bacterial overgrowth may cause chemotherapy-associated diarrhoea [3.Andreyev J. Ross P. Donnellan C. et al.Guidance on the management of diarrhoea during cancer chemotherapy.Lancet Oncol. 2014; 15: e447-e460Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar], although no published data are currently available. This is the first report of either of these entities associated with TKI treatment. In the absence of pathology, 95% of bile acids secreted are reabsorbed in the ileum; the remainder enter the colon. Excess colonic bile acids cause diarrhoea by stimulating water, electrolyte and mucus secretion, altering motility and neuronal function [4.Pattni S. Walters J. Recent advances in the understanding of bile acid malabsorption.Br Med Bull. 2009; 92: 79-93Crossref PubMed Scopus (86) Google Scholar]. This may be secondary to other pathologies, or be idiopathic. Recent evidence suggests that idiopathic bile acid diarrhoea may in fact relate to impaired inhibition of bile acid synthesis [4.Pattni S. Walters J. Recent advances in the understanding of bile acid malabsorption.Br Med Bull. 2009; 92: 79-93Crossref PubMed Scopus (86) Google Scholar], due to defective fibroblast growth factor receptor 4 (FGFR4) signalling [5.Pattni S.S. Brydon W.G. Dew T. et al.Fibroblast growth factor 19 in patients with bile acid diarrhoea: a prospective comparison of FGF19 serum assay and SeHCAT retention.Aliment Pharmacol Ther. 2013; 38: 967-976Crossref PubMed Scopus (82) Google Scholar]. Kinase databases reveal that sunitinib, pazopanib and axitinib have activity against FGFR4 [6.Anastassiadis T. Deacon S. Devarajan K. et al.Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity.Nat Biotechnol. 2011; 29: 1039-1045Crossref PubMed Scopus (657) Google Scholar, 7.Uitdehaag J. de Roos J. van Doornmalen A. et al.Comparison of the cancer gene targeting and biochemical selectivities of all targeted kinase inhibitors approved for clinical use.PLoS One. 2014; 9: e92146.Crossref PubMed Scopus (75) Google Scholar]; effects on this pathway are a plausible mechanism of bile acid diarrhoea in this setting. Management of toxicities during long-term TKI treatment is important both in maintaining treatment intensity and duration, and in preserving patient wellbeing. The advent of combination TKI-immune checkpoint inhibitor therapy will make distinction between causes of diarrhoea crucial [8.Samaan M. Polychronis P. Papa S. et al.Gastrointestinal toxicity of immune checkpoint inhibitors: from mechanisms to management.Nat Rev Gastroenterol Hepatol. 2018; 15: 222-234Crossref PubMed Scopus (58) Google Scholar]. We suggest a systematic approach to the management of TKI-associated diarrhoea, as per UK guidelines [9.Andreyev J. Davidson S. Gillespie C. et al.Practice guidelines on the management of acute and chronic gastrointestinal problems arising as a result of treatment for cancer.Gut. 2012; 61: 179-192Crossref PubMed Scopus (182) Google Scholar]. In particular those with severe symptoms and/or steatorrhoea may have unrecognised bile acid diarrhoea, bacterial overgrowth or pancreatic insufficiency, and referral to the emerging specialty of oncogastroenterology [10.Grover S. Lim R. Blumberg R. Syngal S. Oncogastroenterology.J Clin Oncol. 2016; 34: 1154-1155Crossref PubMed Scopus (8) Google Scholar] is recommended. Seventy-four percent of patients referred from our clinic to specialist gastroenterology services were found to have secondary causes of diarrhoea; these conditions are potentially amenable to treatment. Translational studies aimed at elucidating mechanisms of bile acid diarrhoea in patients taking TKIs, and indeed other anticancer medications, may improve treatment still further in future. None declared.