Received: 12 January 2021 DOI: 10.1002/ueg2.12111 ORIGINAL ARTICLE - Accepted: 31 March 2021 Early diarrhoea under sorafenib as a marker to consider the early migration to second‐line drugs Álvaro Díaz‐González1 | Víctor Sapena1 | Loreto Boix1 | Ferrán Torres2 | 1 1 1 Marco Sanduzzi‐Zamparelli | Leonardo G. Da Fonseca | Neus LLarch | 1 1 1 Gemma Iserte | Cassia Guedes | Sergio Muñoz‐Martínez | Anna Darnell3 | Ernest Belmonte3 | Jordi Rimola3 | Alejandro Forner1 | Carmen Ayuso3 | Jordi Bruix1 | María Reig1 1 Barcelona Clinic Liver Cancer (BCLC) Group. Liver Unit, Hospital Clínic de Barcelona. Abstract IDIBAPS. CIBERehd. University of Barcelona, Background: Despite atezolizumab and bevacizumab (A + B) is currently the first‐ Barcelona, Spain 2 line treatment for hepatocellular carcinoma (HCC) patients, some patients will Medical Statistics Core Facility, IDIBAPS. Hospital Clínic de Barcelona. Biostatistics Unit, not be adequate for this combination. In the setting of sorafenib some adverse Faculty of Medicine, Universitat Autònoma de events have been proposed as prognostic factors. Barcelona, Barcelona, Spain 3 Barcelona Clinic Liver Cancer (BCLC) Group. Objective: To characterize the early diarrhoea development as prognostic factor in Radiology Department, Hospital Clínic de 344 HCC patients. Barcelona. IDIBAPS. CIBERehd. University of Barcelona, Barcelona, Spain Methods: The development of early diarrhoea in sorafenib treatment defined as patients who developed diarrhoea and needed dose modification within the first Correspondence 60 days of treatment (e‐diarrhoea) and 3‐grouping variables were analysed: Patients Maria Reig and Jordi Bruix, Barcelona Clinic Liver Cancer (BCLC) Group. Liver Unit, with e‐diarrhoea, patients who developed diarrhoea after the first 60 days of treat- Hospital Clínic of Barcelona. IDIBAPS. ment (L‐diarrhoea) and patients that never developed diarrhoea (never diarrhoea). University of Barcelona. Barcelona, Spain. Centro de Investigación Biomédica en Red de Results: The median overall survival in sorafenib treated patients was significantly Enfermedades Hepáticas y Digestivas different across groups (6.8 months for e‐diarrhoea, 26.7 months for L‐diarrhoea (CIBERehd), Spain. C/Villarroel, 170. 08036 Barcelona, Spain. and 13.3 months for never‐diarrhoea). The emergence of e‐diarrhoea was associ- Email: MREIG1@clinic.cat and jbruix@clinic. ated with poor outcomes (hazard ratio [HR] 1.84 [95%CI 1.15–2.95]), while there cat was no increased/decreased risk of dismal evolution in patients with L‐diarrhoea Funding information (HR 0.66 [95%CI 0.42–1.03]). World Cancer Research Fund, Grant/Award Conclusion: The emergence of e‐diarrhoea in HCC patients treated with sorafenib is Number: 16‐0026; Asociación Mexicana de Gastroenterología, Grant/Award Number: an early predictor of dismal evolution under this therapy. Thus, prompt identification Beca para Perfeccionamiento en of these non‐responders may be useful for an early switch to second‐line therapies. Gastroenterología; Societat Catalana de Digestologia, Grant/Award Numbers: Ajuts per a la iniciació a la recerca 2017, Ajuts per a KEYWORDS la iniciació a la recerca 2019; Instituto de Salud diarrhoea, hepatocellular carcinoma, resistance, sorafenib, survival, tyrosine kinase inhibitor Carlos III, Grant/Award Numbers: CM15/ Álvaro Díaz‐González and Víctor Sapena contributed equally. - This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. © 2021 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology. United European Gastroenterol J. 2021;9:655–661. wileyonlinelibrary.com/journal/ueg2 655 656 - UNITED EUROPEAN GASTROENTEROLOGY JOURNAL 00050, FI19/00222, PI13/01229, PI15/00145, PI18/00542, PI18/00768, PI18/0358; Key Summary Fundación Científica Asociación Española Established knowledge on this subject Contra el Cáncer, Grant/Award Numbers: CLJUN18016DIAZ, PI044031 � Diarrhoea is a frequent adverse event of sorafenib and its emergence has been associated to better outcomes. What are the significant and/or new findings of this study? � Early diarrhoea (e‐diarrhoea) in hepatocellular carcinoma patients treated with sorafenib is an early predictor of dismal evolution. � Diarrhoea under sorafenib should not be taken as a predictive parameter of lack of benefit. � E‐diarrhoea could be used as clinical biomarker for switching to second‐line therapies. INTRODUCTION polymorphism, it could also reflect a suboptimal treatment regime leading to early treatment failure.15 The combination of atezolizumab with bevacizumab has surpassed the benefits of sorafenib,1 and lenvatinib has already been shown to be non‐inferior to sorafenib.2 At the same time, regorafenib,3 cabo- MATERIALS AND METHODS zantinib4 and ramucirumab5 have provided survival benefit upon progression or intolerance to sorafenib, in the case of cabozantinib4 Patients and ramucirumab.5 Indeed, cabozantinib has also been proven effective in third‐line treatment options. Furthermore, in the United This is a retrospective analysis of a prospective database of all pa- States, the Food and Drug Administration (FDA) has granted accel- tients treated with sorafenib in our unit from 2008 to 2019 (whole 6 erated approval or breakthrough designation to agents (nivolumab, cohort). pembrolizumab,7 combination of lenvatinib with pembrolizumab8 and The following inclusion/exclusion criteria were used in our unit of durvalumab with tremelimumab9) which have shown persuasive to start sorafenib: (1) Hepatocellular carcinoma (HCC) diagnosed results despite an absence of positive phase 3 Trials. The availability according to EASL guidelines; (2) adequate liver function (albumin of several options will prime the individualization of the treatment >2.8 g/dl; total bilirubin <3 mg/dl; and alanine and aspartate ami- selection according to the profile of the patients so that survival notransferases <5 times the upper limit of the normal range), and benefits are maximized and potential adverse events (AEs) leading to Child‐Pugh score 6–7 points; (3) performance status (PS) 0–1; (4) treatment intolerance and interruption minimized. In this sense, controlled arterial hypertension and stable peripheral vascular dis- despite the superiority of the atezolizumab plus bevacizumab com- ease; (5) adequate haematologic profile (haemoglobin >8.5 g/dl; and bination, some patients will not be adequate for this combination (i.e., prothrombin time >50%); and (6) adequate renal function (serum large oesophageal varices, prior transplantation and renal failure) and creatinine <1.5 times the upper limit of the normal range). Exclusion sorafenib and lenvatinib will still be used in a relevant proportion of criteria: (1) myocardial infarction in the past year or active ischaemic patients as first‐line or as a default second‐line treatment, which will heart disease; (2) acute variceal bleeding in the last month; (3) severe likely move the options into later lines. In such instance, emergence peripheral arterial disease; (4) cardiac arrhythmia under treatment of specific evolutionary events associated to better or worse with drugs other than beta‐blockers or digoxin; (5) uncontrolled as- outcome will influence the physician's ability to identify treatment cites; (6) encephalopathy; and (7) unfeasibility to fulfil the follow‐up failure/dismal outcome and try to provide therapeutic benefit by schedule. The institutional review board approved the study (and switching to a second option among those known to be effective. A HCB/2017/1016). known example of an AE linked to better outcome is the develop- ment of dermatologic AEs,10–12 but in the case of other AEs such as diarrhoea, the association with distinct survival is not well Treatment and follow up 10,13,14 established. In this study, we evaluated, through time‐dependent statistical Sorafenib was initiated at full dose (800 mg/day) and adjusted ac- analysis, the association of the development of diarrhoea and the cording to the manufacturer's recommendations in most of the pa- timing of its onset with patient survival in order to determine tients included in the cohort. Specific details about dose initiation are whether such an AE may help to predict prognosis while on treat- described in Table S1. Clinical and biochemical assessments took ment. In this sense, in a prior study in a subgroup of this cohort, we place every 4 weeks. Imaging assessment (RECIST 1.1 plus BCLC observed that those patients who presented diarrhoea early during amendments) took place at 4 weeks and every 8 weeks there- follow‐up had lower systemic levels of sorafenib and its metabolite. after.16,17 Patients ineligible for regorafenib were enrolled in second‐ While such findings could be linked to a specific MRP2*3972 line clinical trials when appropriate (Table S2). DÍAZ‐GONZÁLEZ ET AL. - 657 Adverse events mellitus). None of the patients with e‐diarrhoea or L‐diarrhoea were treated with laxatives prior or at the moment of diarrhoea We recorded all AEs of grade ≥ II occurring between treatment emergence. initiation and 30 days after the last dose. AEs were classified ac- cording to the Common Terminology Criteria for Adverse Events version 4.03.18 Adverse events Baseline characteristics of patients stratified by the time of Statistical analysis appearance of diarrhoea as defined above are summarized in Ta- ble 2. Median time to first diarrhoea onset was 84 days (IQR 26– Quantitative variables were expressed as median and interquartile 158). Twenty‐two patients (6.4%) developed e‐diarrhoea and 30 range (IQR 25th–75th percentiles). Categorical variables were (8.4%) L‐diarrhoea. Finally, 292 patients never presented diarrhoea described as absolute frequencies and percentages (%). Time to event during follow‐up. Only two patients who developed e‐diarrhoea variables were described with the Kaplan–Meier method, reporting and eight patients who presented L‐diarrhoea had DAE60 median and confidence intervals (95% CI), and the observed survival (Table S1). functions was compared with the log‐rank test. Univariate and multivariate time‐dependent survival Cox models were used to estimate the hazard ratios (HR) and their 95% CI. For Diarrhoea as a predictor of OS the multivariate models, we included the clinically relevant variables: baseline BCLC status, baseline ECOG‐PS and DAE60 as time‐ We found no differences between patients who developed dependent covariables. Two principal categorical time‐dependent e‐diarrhoea or L‐diarrhoea according to baseline characteristics or variables were analysed, the first was the development of early initial dose of sorafenib. However, the rate of discontinuation in the diarrhoea (Yes/No) defined as patients who developed diarrhoea and first 60 days was higher in the e‐diarrhoea group, and as expected, needed dose modification within the first 60 days of treatment (e‐ the OS was longer in the L‐diarrhoea group of patients. Evolutionary diarrhoea). The second was a three‐grouping variable: Patients with events are summarized in Table S1. e‐diarrhoea, patients who developed diarrhoea after the first 60 days The multivariate analysis consistently identified baseline ECOG‐ of treatment (L‐diarrhoea) and the third group included the patients PS and BCLC stage as well as the emergence of early dermatologic that never developed diarrhoea (never diarrhoea). For all these an- AE60 (DAE60) as independent predictors of OS, while Child‐Pugh did alyses, only grade ≥ II AEs were considered. not have independent predictive power in this study. The figures for the visualization of the risk between the groups of OS was significantly different according to the presence of the time‐dependent variables were created using the survival func- e‐diarrhoea, L‐diarrhoea and never diarrhoea (p < 0.0001). Median tion, estimated with the survival Cox models. OS was 6.8 months (95%CI 3.3–11.2), 26.7 months (95%CI 17.5– The level of significance was set at the two‐sided 5% level, and all 37.9) and 13.3 months (95%CI 11.7–14.7), respectively. To avoid the calculations were performed with SAS 9.4 software (SAS Institute). flaw due to the fact that late diarrhoea always includes long‐term survivors we performed a time‐dependent cox regression analysis. This model identified that the development of e‐diarrhoea was RESULTS associated with worse outcome as compared against those who never developed diarrhoea, with HR values of 1.84 (95%CI 1.15– Patients 2.95) and against those who presented L‐diarrhoea, with HR 0.66 (95%CI 0.42–1.03). Predicted survival function is represented in From January 2008 to August 2019, 344 patients were treated with Figure 1 and multivariate analysis in Table 3. sorafenib in our Unit. At the time of database lock (August 2019), the median follow‐up was 12.3 months (IQR 5.7–22.5), the median treatment time 5.6 months (IQR 2–12.8) and overall survival (OS) Diarrhoea and radiological progression 13.6 months (95%CI 12–15.1) and 52 patients presented grade ≥ II diarrhoea. Fourteen out of the 22 patients who presented e‐diarrhoea did not present radiological progression of the tumour at the time of diar- rhoea emergence. The pattern of progression of those eight patients Baseline characteristics who presented radiological progression was growth of preexisting intrahepatic lesions (IHG), growth of preexisting extrahepatic lesions Table 1 summarizes the baseline characteristics of the 344 patients (EHG), new intrahepatic lesions (NIH) and new extrahepatic lesions included in the whole cohort (83.7% Child‐Pugh A, 54.1% BCLC‐C, (NEH), with two patients for each pattern. The median OS of patients 90.1% ECOG‐PS 0, 41.9% arterial hypertension, and 28.2% diabetes who had radiological progression at the time of developing diarrhoea 658 - UNITED EUROPEAN GASTROENTEROLOGY JOURNAL TABLE 1 Baseline characteristics of the whole cohort Characteristics n Patients, n 344 Gender (male/Female), n (%) 296 (86)/48 (14) Age (Years), median [IQR] 63.8 [55.9–71.1] Aetiology HCV 135 (39.2) Alcohol 83 (24.1) HCV + alcohol 42 (12.2) HBV 22 (6.4) Cryptogenic 7 (2) No cirrhosis 10 (2.9) Others 45 (13.2) Child‐pugh (A/B/No cirrhosis), n (%) 288 (83.7)/46 (13.4)/10 (2.9) BCLC (A/B/C), n (%) 2 (0.6)/156 (45.3)/186 (54.1) Diabetes mellitus (yes), n (%) 97 (28.2) Arterial hypertension (yes), n (%) 144 (41.9) Vascular invasion (yes), n (%) 120 (34.9) Extrahepatic spread (yes), n (%) 89 (25.9) ECOG‐performance status (0/1/2), n (%) 310 (90.1)/33 (9.6)/1 (0.3) Haemoglobin (g/L), median [IQR] 13.5 [12.1–14.8] 9 Leukocytes (count 10 ), median [IQR] 5.3 [4.1–6.7] 9 Platelets (count 10 ), median [IQR] 131 [87–186] AST (UI/L), median [IQR] 64 [40–104] ALT (IU/L), median [IQR] 54 [33–95] Alkaline phosphatase (IU/L), median [IQR] 232 [155–348] GGT (IU/L), median [IQR] 143 [82–274] Total bilirubin (mg/dl), median [IQR] 1 [0.7–1.6] Conjugated bilirubin (mg/dl), median [IQR] 0.5 [0.3–0.8] Albumin (g/L), median [IQR] 39 [35–43] Prothrombin time (%), median [IQR] 81 [68–91] Alpha‐fetoprotein (ng/dl), median [IQR] 27 [8–391] Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BCLC, Barcelona Clinic Liver Cancer; GGT, gamma‐glutamyl transferase; HBV, hepatitis B virus; HCV, hepatitis C virus; IQR, interquartile range; IU, International Units. was 3.7 months (IC95% 2.7–9.3), while the median OS of those who stress that the prognostic value involves the development of such an developed diarrhoea without radiological progression was event early during follow‐up, while the registration of diarrhoea at any 8.1 months (IC95% 3.3–17.2). time point during the clinical evolution of the patients is surely flawed. Patients who survive longer and thus enjoy the maximal benefits of sorafenib, have longer time exposure under treatment and, by default, DISCUSSION this is closely related with higher rate of AEs. Prior studies13,14,19 suggested a better survival in patients who developed diarrhoea According to the results of our study, the development of early diar- among other toxicities, but no control for the time of appearance was rhoea after starting sorafenib is associated to reduced survival if done in those investigations and this potential flaw is shared by most compared to patients who do not develop such AE. It is important to studies in the oncology realm. Time‐dependent assessment of the AEs DÍAZ‐GONZÁLEZ ET AL. - 659 TABLE 2 Baseline characteristics of patients attending to diarrhoea presentation E‐diarrhoea L‐diarrhoea Never diarrhoea p‐value Patients, n 22 30 292 Male/Female (n, %) 22 (100)/0 (0) 28 (93.3)/2 (6.7) 246 (84.3)/46 (15.7) 0.0528 Age (median, IQR) 61.9 [57.8–70.8] 62.6 [57.4–67.9] 64.1 [55.8–71.4] 0.8892 Aetiology, n (%) 0.8309 HCV 7 (31.8) 11 (36.7) 117 (40.1) Alcohol 7 (31.8) 9 (30) 67 (22.9) HCV + alcohol 4 (18.2) 5 (16.7) 33 (11.3) HBV 3 (13.6) 1 (3.3) 18 (6.2) Cryptogenic 0 2 (6.7) 5 (1.7) No cirrhosis 0 0 10 (3.4) Others 1 (4.5) 2 (6.7) 42 (14.4) Child‐Pugh (A/B/No cirrhosis) 18 (81.6)/4 (18.2)/0 (0) 27 (90)/3 (10)/0 (0) 243 (83.2)/39 (13.4)/10 (3.4) 0.6691 BCLC (A/B/C) 0 (0)/10 (45.4)/12 (55.6) 0 (0)/15 (50)/15 (50) 2 (0.7)/131 (44.9)/159 (54.4) 0.9004 Diabetes mellitus, n 8 (36.4) 9 (30) 80 (27.4) 0.6272 Arterial Hypertension, n 9 (40.9) 8 (26.7) 127 (43.4) 0.2057 Vascular invasion, n 10 (45.4) 9 (30) 101 (34.5) 0.5011 Extrahepatic spread, n 5 (22.7) 8 (26.7) 76 (26) >0.999 ECOG‐performance status (0/1/2) 18 (81.8)/4 (18.2)/0 (0) 29 (96.7)/1 (3.3)/0 (0) 261 (89.4)/30 (10.3)/1 (0.3) 0.6021 Haemoglobin in g/L, median (IQR) 12.9 (11.8–14.4) 13.5 (12.4–14.8) 13.5 (12.1–14.85) 0.2762 9 Leukocytes in 10 , median (IQR) 4.43 [3.4 to 6] 5.6 [3.5 to 6.8] 5.3 [4.1 to 6.7] 0.2287 9 Platelets in 10 , median (IQR) 107 [86 to 181] 132.5 [89 to 205] 134.5 [87 to 186] 0.8036 AST in UI/L, median (IQR) 66.5 (37–143) 69.5 (33–97) 64 (41–101) 0.6560 ALT in IU/L, median (IQR) 50.5 (31–96) 64.5 (26–102) 54 (34–95) 0.9278 Alkaline phosphatase in IU/L, median (IQR) 232 (182–311) 198.5 (99–320) 232 (158–356) 0.3839 GGT in IU/L, median (IQR) 189 (123–289) 129 (67–248) 142 (82–269) 0.2939 Total bilirubin in mg/dl, median (IQR) 1.25 (0.9–1.9) 1.2 (0.7–1.6) 1 (0.7–1.6) 0.2035 Conjugated bilirubin in mg/dl, median (IQR) 0.5 (0.4–0.9) 0.6 (0.3–0.8) 0.5 (0.3–0.8) 0.5225 Albumin in g/L, median (IQR) 36.5 (34–40) 39.5 (37–44) 39 (35.5–42.5) 0.0960 Prothrombin time in %, median (IQR) 80.05 (68–89) 80 (66–91) 81.5 (69–91) 0.6978 Alpha‐fetoprotein in ng/dl (median, IQR) 26 (6–3052) 43 (6–402) 26 (8–366) 0.9954 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BCLC, Barcelona Clinic Liver Cancer; e‐diarrhoea, early diarrhoea, in the first 60 days; GGT, gamma‐glutamyl transferase; HBV, hepatitis B virus; HCV, hepatitis C virus; IQR, interquartile range; IU, International Units; L‐ diarrhoea: late diarrhoea, after the first 60 days. of any drug is missing in the conventional evaluation of toxicity and and the presence of cancer‐related symptoms at treatment initiation. tolerance usually applied in all oncology trials. Diarrhoea under sorafenib should not be taken as a predictive In our study the incidence of diarrhoea during the first week of parameter of lack of benefit. The reported association with outcome sorafenib administration was low (1.2%), while the number increased may be due to any non‐identified parameter linked to poor patient at 60 days (6.4%) if we consider the whole time lapse the patients prognosis irrespective of the fact that sorafenib would increase life have been under treatment. expectancy according to the known reduction of the risk of death The most relevant message of our study is that those patients along time. who develop early diarrhoea present a poorer prognosis even if we The mechanism for diarrhoea may very likely not be the same in control for baseline tumour stage, concomitant tumour progression, all patients and several factors could be involved including patient 660 - UNITED EUROPEAN GASTROENTEROLOGY JOURNAL In summary, we identified early diarrhoea within the first 60 days of sorafenib treatment as a predictor of worse outcomes. Identifi- cation of the predictors for developing diarrhoea would allow to select the optimal therapy in a proportion of patients diagnosed with HCC while avoiding an intervention that may not provide a signifi- cant real‐world survival benefit. A C K NO W L ED G E M E N T S Álvaro Díaz‐González was supported by the following grants: Insti- tuto de Salud Carlos III (CM15/00050), Societat Catalana de Diges- tologia Ajuts per a la iniciació a la recerca 2017, and Asociación Española Contra el Cáncer Ayuda Clínico Junior 2018 (CLJUN18016DIAZ). Marco Sanduzzi‐Zamparelli was supported by ‘Ajuts per a la iniciació a la recerca 2019 from Societat Catalana de Digestologia (SCD)’ and FI19/00222 from Instituto de Salud Carlos III. Sergio Muñoz‐Martinez was supported by ‘Beca para Perfeccio- namiento en Gastroenterología en el Extranjero’ from Asociación F I G U R E 1 Predicted survival function. Patients presenting Mexicana de Gastroenterología. Alejandro Forner received grant early diarrhoea are at higher risk of death support from Instituto de Salud Carlos III (PI13/01229 and PI18/ 00542). Jordi Bruix received grant support from Instituto de Salud T A B L E 3 Survival prediction in the cohort using multivariate time‐dependent cox model Carlos III (PI18/00768), AECC (PI044031), and WCR (AICR) 16‐ 0026. María Reig received grant support from Instituto de Salud HR HR CI95% p‐value Carlos III (PI15/00145 and PI18/0358). Performance status 1.88 1.27–2.80 <0.01 Child‐Pugh 1.21 0.85–1.73 0.3 C O N F L I CT OF I N T ER ES T Álvaro Díaz‐González: Speaker fees from Bayer and Intercept. BCLC stage 1.44 1.11–1.86 <0.01 Meeting expenses from BTG, Bayer, Intercept and GILEAD. Víctor DAE60 0.62 0.47–0.82 <0.001 Sapena: Travel funding from Bayer. Loreto Boix: Travel funding from E‐diarrhoeaa 1.84 1.15–2.95 0.01 Bayer. Neus Llarch: Travel funding and consultancy for Bayer and a consultancy for AstraZeneca. Gemma Iserte: None. Marco Sanduzzi‐ L‐diarrhoea 0.66 0.42–1.03 0.07 Zamparelli: Speaker fees and travel funding from Bayer. Travel grant Abbreviations: BCLC. Barcelona Clinic Liver Cancer; DAE60, early dermatologic adverse events in the first 60 days; e‐diarrhoea, early from BTG and Eisai. Sergio Muñoz‐Martínez: Speaker fees and travel diarrhoea, in the first 60 days; L‐diarrhoea, late diarrhoea, after the first funding from Bayer. Alejandro Forner: Conference fees and travel 60 days. funding from Bayer; Lecture fees from Gilead and MSD; consultancy a Reference category: Never diarrhoea. fees from Bayer, Guerbert and AstraZeneca. Jordi Bruix: Consultancy fees from Arqule, Bayer, Novartis, BMS, BTG‐ Biocompatibles, Eisai, profile at treatment initiation, direct and acute drug‐related toxicity Kowa, Terumo, Gilead, Bio‐Alliance/Onxeo, Roche, AbbVie, Merck, and toxicity at long‐term in other organs such as the pancreas.20,21 Sirtex, Ipsen, Astra‐Medimmune, Incyte, Quirem, Adaptimmune, Lilly, We reported that some patients under sorafenib developed in- Basilea, Nerviano. Research grants from Bayer and BTG. Educational testinal malabsorption and that this was due to pancreatic atrophy grants from Bayer and BTG. Lecture fees from Bayer, BTG‐ Bio- that could be compensated by pancreatic enzyme supplementation.21 compatibles, Eisai, Terumo, Sirtex, Ipsen. María Reig: Consultancy In that study, we did not identify a single conventional parameter fees from Bayer, BMS, Roche, Ipsen, AstraZeneca and Lilly. Lecture related to patients' profile, liver function or tumour burden that could fees from Roche, Bayer, BMS, Gilead, and Lilly. Research grants from be associated to an increased risk of diarrhoea. In addition, despite Bayer and Ipsen. the inconclusive results of the pharmacokinetics and pharmacoge- nomics of relationship between drug metabolization, genomic profile D A T A A V A I L A BI L I T Y S T AT E M E N T and development of AEs and improved efficacy15 it was a trend to- The data that support the findings of this study are available on wards lower systemic availability of the drug related to a poly- request from the corresponding author. The data are not publicly morphism of genes such as MRP2*3972. These allelic differences available due to privacy or ethical restrictions. were associated to a higher incidence of diarrhoea and prompted us to hypothesize that such genomic profiles would induce a reduced ORCID absorption of the drug and/or prime an impairment of the perme- Álvaro Díaz‐González https://orcid.org/0000-0003-3610-2263 ability of the intestinal wall leading to diarrhoea. Víctor Sapena https://orcid.org/0000-0003-4379-6486 DÍAZ‐GONZÁLEZ ET AL. - 661 Loreto Boix https://orcid.org/0000-0002-6015-3901 with hepatocellular carcinoma treated with sorafenib. Ann Hepatol. Ferrán Torres https://orcid.org/0000-0002-7355-7913 2017;16:263–8. 12. Díaz‐González Á, Sanduzzi‐Zamparelli M, Sapena V, Torres F, LLarch Marco Sanduzzi‐Zamparelli https://orcid.org/0000-0003-3795- N, Iserte G, et al. Systematic review with meta‐analysis: the critical 3705 role of dermatological events in patients with hepatocellular carci- Leonardo G. Da Fonseca https://orcid.org/0000-0002-0216-3618 noma treated with sorafenib. Aliment Pharmacol Ther. 2019;49: Neus LLarch https://orcid.org/0000-0003-3209-0453 482–91. 13. Bettinger D, Schultheiss M, Knüppel E, Thimme R, Blum HE, Span- Gemma Iserte https://orcid.org/0000-0003-3908-8743 genberg HC. Diarrhoea predicts a positive response to sorafenib in Sergio Muñoz‐Martínez https://orcid.org/0000-0003-0663-0575 patients with advanced hepatocellular carcinoma. Hepatology. Jordi Rimola https://orcid.org/0000-0002-1814-4198 2012;56:789–90. Alejandro Forner https://orcid.org/0000-0002-9014-4950 14. Koschny R, Gotthardt D, Koehler C, Jaeger D, Stremmel W, Ganten TM. Diarrhoea is a positive outcome predictor for sorafenib treat- Carmen Ayuso https://orcid.org/0000-0002-9606-6957 ment of advanced hepatocellular carcinoma. Oncology. 2013;84: Jordi Bruix https://orcid.org/0000-0002-9826-0753 6–13. María Reig https://orcid.org/0000-0002-5711-9534 15. 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