618129
research-article2015
TAG0010.1177/1756283X15618129Therapeutic Advances in GastroenterologyA Granito, S Marinelli
Therapeutic Advances in Gastroenterology
Review
Prognostic significance of adverse events in patients with hepatocellular carcinoma treated with sorafenib
Ther Adv Gastroenterol 1–10 DOI: 10.1177/ 1756283X15618129 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Alessandro Granito, Sara Marinelli, Giulia Negrini, Saverio Menetti, Francesca Benevento and Luigi Bolondi
Abstract: Sorafenib is the standard treatment for patients with hepatocellular carcinoma (HCC) with advanced stage disease. Although its effectiveness has been demonstrated by randomized clinical trials and confirmed by field practice studies, reliable markers predicting therapeutic response have not yet been identified. Like other tyrosine kinase inhibitors, treatment with sorafenib is burdened by the development of adverse effects, the most frequent being cutaneous toxicity, diarrhoea, arterial hypertension and fatigue. In recent years, several studies have analysed the correlation between off-target effects and sorafenib efficacy in patients with HCC. In this review, an overview of the studies assessing the prognostic significance of sorafenib-related adverse events is provided.
Keywords: hepatocellular carcinoma, sorafenib, adverse events, prognostic significance, survival
Introduction Sorafenib (Nexavar; Bayer HealthCare Pharmaceuticals, Montville, NJ, USA), an orally active multitargeted tyrosine kinase inhibitor (TKI), currently sets the standard of treatment for patients with hepatocellular carcinoma (HCC) with preserved liver function [Child–Pugh (CP) A class] and advanced stage [Barcelona Clinic Liver Cancer (BCLC-C)] [Bruix and Sherman, 2005].
The development of treatment-related toxicity is of primary importance because it worsens patient quality of life and is often the cause of dose reduction or treatment discontinuation.
The clinically significant antitumoural activity demonstrated by two international, randomized, controlled phase III trials can, however, be hampered by the rise of adverse events (AEs) occurring in up to 80% of patients [Llovet et al. 2008; Cheng et al. 2009].
On the one hand, these observations have emphasized the need to improve the prevention and management of AEs in order to achieve the maximum therapeutic benefit and, on the other hand, they have stimulated studies to look at the correlation between AE development and treatment outcome [Vincenzi et al. 2010; Song et al. 2011; Otsuka et al. 2012; Bettinger et al. 2012; Shomura et al. 2014].
The most common sorafenib-related AEs are diarrhoea, fatigue, anorexia, hypertension (HTN) and dermatological toxicities, mainly hand–foot skin reaction (HFSR) and rash/desquamation, as reported by the randomized controlled trials and confirmed by several real-life studies [Iavarone et al. 2011; Lencioni et al. 2013; Cho et al. 2013; Di Marco et al. 2013].
Moreover, the need for additional drugs to manage AEs can also alter patient compliance with the targeted therapy. All this can, in turn, be a potential cause of treatment failure.
Correspondence to: Alessandro Granito, MD Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy alessandro.granito@ unibo.it Sara Marinelli, MD, PhD Giulia Negrini, MD Saverio Menetti, MD Francesca Benevento, Biologist Luigi Bolondi, MD Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
In fact, based on the concept that the occurrence of AEs may be related to the sorafenib mechanism of action and would be due to the inhibition of one or more drug targets, such as the vascular endothelial growth factor receptor family
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Therapeutic Advances in Gastroenterology (VEGFR1, 2, 3), platelet-derived growth factor receptor family (PDGFR-β), stem-cell growth factor receptor (c-KIT), Fms-like tyrosine kinase 3 (FLT-3), the receptor encoded by the ret protooncogene (RET) and Raf serine/threonine kinase activity in normal organs, several studies have tried to assess whether the off-target effects of sorafenib predict antitumoural efficacy [Zhao et al. 2012; Kamba and McDonald, 2007; Song et al. 2011; Koschny et al. 2013; Wu et al. 2008]. Thus, the potential advantage of such a predictive significance would lie in the ability to highlight the efficacy of sorafenib at an early stage, thus not discouraging treatment maintenance in patients experiencing drug-related AEs. In this review, a summary of the sorafenib toxicity profile and the recent data found in the literature regarding the potential role of AEs as surrogate markers for treatment efficacy is presented. Safety profile Randomized controlled studies Two randomized controlled trials, the Sorafenib HCC Assessment Randomized Protocol (SHARP) and the Asia-Pacific trials demonstrated a similar safety profile. In particular, both registered a high rate of AEs which were generally well tolerated and rarely led to treatment discontinuation [Llovet et al. 2008; Cheng et al. 2009]. In the SHARP trial, the overall incidence of treatment-related AEs was 80% in the sorafenib group and 52% in the placebo group, with serious AEs in 52% and 54% of the treated and the placebo groups, respectively. However, grade 3 treatmentrelated AEs were more common in the sorafenib group and included diarrhoea (8%), HFSR (8%), HTN (2%) and abdominal pain (2%). The rate of patients who discontinued treatment due to toxicity was 38% in the sorafenib patients versus 37% in the placebo patients. AE-related dose reductions occurred in 26% of the sorafenib group versus 7% of the placebo group, and were due to diarrhoea (8%), HFSR (5%) and skin toxicities (3%) [Llovet et al. 2008]. In the Asia-Pacific trial, the overall incidence of treatment-related AEs was 81.9% in the sorafenib group compared with 38.7% in the
placebo group, and the most frequent grade 3/4 drug-related AEs in the sorafenib group were HFSR (10.7%), diarrhoea (6.0%) and fatigue (3.4%). The rate of patients who discontinued treatment for toxicity was 19.5% and 13.3% in the sorafenib and the placebo arms, respectively. Dose reductions owing to AEs occurred in 30.9% of the sorafenib group and in 2.7% of the placebo group, mostly related to the development of HFSR (11.4%) and diarrhoea (7.4%) [Cheng et al. 2009]. A more detailed safety profile of the two studies is shown in Table 1. Field practice studies Whereas patients enrolled in clinical trials do not represent the real-life scenario, observational postmarketing studies can provide data regarding drug safety and efficacy in larger cohorts of patients who present comorbidities and are not selected according to the very restrictive enrolment criteria of phase III studies. The SOFIA (Sorafenib Italian Assessment) study was a multicentre, observational, noninterventional study conducted in Italy and aimed at evaluating safety and efficacy of sorafenib in clinical practice. A total of 296 patients with HCC (88% CP A) with advanced (BCLC-C, 75%) or intermediate (BCLC-B, 25%) stage disease were enrolled. The median treatment duration was 4.2 months [95% confidence level (CI) 3.4–5] in the 260 CP A patients and 2 months (95% CI 0.2–3.8) in the 36 CP B patients [Iavarone et al. 2011]. Sorafenib was permanently discontinued in 44% of patients due to disease progression: in 40% due to AEs, mainly fatigue (6%), and in 16% for liver function deterioration. The overall incidence of AEs was 91%, 45% of which were grade 3/4 and included fatigue (25%), HFSR (9%), arterial HTN (7%), weight loss (6%), diarrhoea (6%) and bleeding (5%). Treatment was down dosed in 54% of patients due to AEs and liver function deterioration in 83% and 17%, respectively. The most frequent AEs leading to dose reduction were fatigue (39%), HFSR (18%) and diarrhoea (14%).
2 http://tag.sagepub.com
Downloaded from tag.sagepub.com at UNIV CALIFORNIA SAN DIEGO on December 27, 2015
A Granito, S Marinelli et al. Table 1. Safety profiles of sorafenib in patients with HCC from the SHARP and Asia-Pacific trials. SHARP trial
Asia-Pacific trial
Sorafenib (n = 297)
Placebo (n = 302)
Sorafenib (n = 149)
Placebo (n = 75)
Any grade
Any grade
Any grade
Any grade
Drug-related AEs (%) Overall incidence Fatigue Alopecia HFSR Rash/ desquamation Diarrhoea Nausea Vomiting Hypertension Voice changes Bleeding Hypophosphatemia Thrombocytopenia Liver dysfunction Dose reduction (%) Overall incidence Diarrhoea HFSR Rash/ desquamation Discontinuation (%) Overall incidence Bleeding, upper GI Ascites Fatigue Liver dysfunction
Grade 3/4
Grade 3/4
Grade 3/4
Grade 3/4
80 22 14 21 16 39 11 5 5 6 7
research-article2015
TAG0010.1177/1756283X15618129Therapeutic Advances in GastroenterologyA Granito, S Marinelli
Therapeutic Advances in Gastroenterology
Review
Prognostic significance of adverse events in patients with hepatocellular carcinoma treated with sorafenib
Ther Adv Gastroenterol 1–10 DOI: 10.1177/ 1756283X15618129 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Alessandro Granito, Sara Marinelli, Giulia Negrini, Saverio Menetti, Francesca Benevento and Luigi Bolondi
Abstract: Sorafenib is the standard treatment for patients with hepatocellular carcinoma (HCC) with advanced stage disease. Although its effectiveness has been demonstrated by randomized clinical trials and confirmed by field practice studies, reliable markers predicting therapeutic response have not yet been identified. Like other tyrosine kinase inhibitors, treatment with sorafenib is burdened by the development of adverse effects, the most frequent being cutaneous toxicity, diarrhoea, arterial hypertension and fatigue. In recent years, several studies have analysed the correlation between off-target effects and sorafenib efficacy in patients with HCC. In this review, an overview of the studies assessing the prognostic significance of sorafenib-related adverse events is provided.
Keywords: hepatocellular carcinoma, sorafenib, adverse events, prognostic significance, survival
Introduction Sorafenib (Nexavar; Bayer HealthCare Pharmaceuticals, Montville, NJ, USA), an orally active multitargeted tyrosine kinase inhibitor (TKI), currently sets the standard of treatment for patients with hepatocellular carcinoma (HCC) with preserved liver function [Child–Pugh (CP) A class] and advanced stage [Barcelona Clinic Liver Cancer (BCLC-C)] [Bruix and Sherman, 2005].
The development of treatment-related toxicity is of primary importance because it worsens patient quality of life and is often the cause of dose reduction or treatment discontinuation.
The clinically significant antitumoural activity demonstrated by two international, randomized, controlled phase III trials can, however, be hampered by the rise of adverse events (AEs) occurring in up to 80% of patients [Llovet et al. 2008; Cheng et al. 2009].
On the one hand, these observations have emphasized the need to improve the prevention and management of AEs in order to achieve the maximum therapeutic benefit and, on the other hand, they have stimulated studies to look at the correlation between AE development and treatment outcome [Vincenzi et al. 2010; Song et al. 2011; Otsuka et al. 2012; Bettinger et al. 2012; Shomura et al. 2014].
The most common sorafenib-related AEs are diarrhoea, fatigue, anorexia, hypertension (HTN) and dermatological toxicities, mainly hand–foot skin reaction (HFSR) and rash/desquamation, as reported by the randomized controlled trials and confirmed by several real-life studies [Iavarone et al. 2011; Lencioni et al. 2013; Cho et al. 2013; Di Marco et al. 2013].
Moreover, the need for additional drugs to manage AEs can also alter patient compliance with the targeted therapy. All this can, in turn, be a potential cause of treatment failure.
Correspondence to: Alessandro Granito, MD Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy alessandro.granito@ unibo.it Sara Marinelli, MD, PhD Giulia Negrini, MD Saverio Menetti, MD Francesca Benevento, Biologist Luigi Bolondi, MD Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
In fact, based on the concept that the occurrence of AEs may be related to the sorafenib mechanism of action and would be due to the inhibition of one or more drug targets, such as the vascular endothelial growth factor receptor family
http://tag.sagepub.com 1
Downloaded from tag.sagepub.com at UNIV CALIFORNIA SAN DIEGO on December 27, 2015
Therapeutic Advances in Gastroenterology (VEGFR1, 2, 3), platelet-derived growth factor receptor family (PDGFR-β), stem-cell growth factor receptor (c-KIT), Fms-like tyrosine kinase 3 (FLT-3), the receptor encoded by the ret protooncogene (RET) and Raf serine/threonine kinase activity in normal organs, several studies have tried to assess whether the off-target effects of sorafenib predict antitumoural efficacy [Zhao et al. 2012; Kamba and McDonald, 2007; Song et al. 2011; Koschny et al. 2013; Wu et al. 2008]. Thus, the potential advantage of such a predictive significance would lie in the ability to highlight the efficacy of sorafenib at an early stage, thus not discouraging treatment maintenance in patients experiencing drug-related AEs. In this review, a summary of the sorafenib toxicity profile and the recent data found in the literature regarding the potential role of AEs as surrogate markers for treatment efficacy is presented. Safety profile Randomized controlled studies Two randomized controlled trials, the Sorafenib HCC Assessment Randomized Protocol (SHARP) and the Asia-Pacific trials demonstrated a similar safety profile. In particular, both registered a high rate of AEs which were generally well tolerated and rarely led to treatment discontinuation [Llovet et al. 2008; Cheng et al. 2009]. In the SHARP trial, the overall incidence of treatment-related AEs was 80% in the sorafenib group and 52% in the placebo group, with serious AEs in 52% and 54% of the treated and the placebo groups, respectively. However, grade 3 treatmentrelated AEs were more common in the sorafenib group and included diarrhoea (8%), HFSR (8%), HTN (2%) and abdominal pain (2%). The rate of patients who discontinued treatment due to toxicity was 38% in the sorafenib patients versus 37% in the placebo patients. AE-related dose reductions occurred in 26% of the sorafenib group versus 7% of the placebo group, and were due to diarrhoea (8%), HFSR (5%) and skin toxicities (3%) [Llovet et al. 2008]. In the Asia-Pacific trial, the overall incidence of treatment-related AEs was 81.9% in the sorafenib group compared with 38.7% in the
placebo group, and the most frequent grade 3/4 drug-related AEs in the sorafenib group were HFSR (10.7%), diarrhoea (6.0%) and fatigue (3.4%). The rate of patients who discontinued treatment for toxicity was 19.5% and 13.3% in the sorafenib and the placebo arms, respectively. Dose reductions owing to AEs occurred in 30.9% of the sorafenib group and in 2.7% of the placebo group, mostly related to the development of HFSR (11.4%) and diarrhoea (7.4%) [Cheng et al. 2009]. A more detailed safety profile of the two studies is shown in Table 1. Field practice studies Whereas patients enrolled in clinical trials do not represent the real-life scenario, observational postmarketing studies can provide data regarding drug safety and efficacy in larger cohorts of patients who present comorbidities and are not selected according to the very restrictive enrolment criteria of phase III studies. The SOFIA (Sorafenib Italian Assessment) study was a multicentre, observational, noninterventional study conducted in Italy and aimed at evaluating safety and efficacy of sorafenib in clinical practice. A total of 296 patients with HCC (88% CP A) with advanced (BCLC-C, 75%) or intermediate (BCLC-B, 25%) stage disease were enrolled. The median treatment duration was 4.2 months [95% confidence level (CI) 3.4–5] in the 260 CP A patients and 2 months (95% CI 0.2–3.8) in the 36 CP B patients [Iavarone et al. 2011]. Sorafenib was permanently discontinued in 44% of patients due to disease progression: in 40% due to AEs, mainly fatigue (6%), and in 16% for liver function deterioration. The overall incidence of AEs was 91%, 45% of which were grade 3/4 and included fatigue (25%), HFSR (9%), arterial HTN (7%), weight loss (6%), diarrhoea (6%) and bleeding (5%). Treatment was down dosed in 54% of patients due to AEs and liver function deterioration in 83% and 17%, respectively. The most frequent AEs leading to dose reduction were fatigue (39%), HFSR (18%) and diarrhoea (14%).
2 http://tag.sagepub.com
Downloaded from tag.sagepub.com at UNIV CALIFORNIA SAN DIEGO on December 27, 2015
A Granito, S Marinelli et al. Table 1. Safety profiles of sorafenib in patients with HCC from the SHARP and Asia-Pacific trials. SHARP trial
Asia-Pacific trial
Sorafenib (n = 297)
Placebo (n = 302)
Sorafenib (n = 149)
Placebo (n = 75)
Any grade
Any grade
Any grade
Any grade
Drug-related AEs (%) Overall incidence Fatigue Alopecia HFSR Rash/ desquamation Diarrhoea Nausea Vomiting Hypertension Voice changes Bleeding Hypophosphatemia Thrombocytopenia Liver dysfunction Dose reduction (%) Overall incidence Diarrhoea HFSR Rash/ desquamation Discontinuation (%) Overall incidence Bleeding, upper GI Ascites Fatigue Liver dysfunction
Grade 3/4
Grade 3/4
Grade 3/4
Grade 3/4
80 22 14 21 16 39 11 5 5 6 7
