Best Practice & Research Clinical Gastroenterology 28 (2014) 921e935
Contents lists available at ScienceDirect
Best Practice & Research Clinical Gastroenterology
13
Systemic treatment Maria Reig, MD a, b, 1, Alessia Gazzola, MD a, 1, Roberto Di Donato, MD a, 1, Jordi Bruix, MD a, b, * a
Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic Barcelona, IDIBAPS, University of Barcelona, Spain b ticas y Digestivas (CIBERehd), Spain n Biom Centro de Investigacio edica en Red de Enfermedades Hepa
a b s t r a c t Keywords: Hepatocellular carcinoma Systemic treatment Patients selection Management Tumour response RECIST
In the last years the management of patients with liver cancer has been improved. The BCLC staging/treatment strategy identifies the optimal candidates for each treatment option and sorafenib is the only effective systemic treatment. Others (sunitinib, brivanib, linifanib, everolimus, ramucirumab) have failed in terms of safety/ survival benefit. Some patients at intermediate/early stage, may be considered for systemic therapy when options of higher priority may have failed or not be feasible. The 800 mg/day is the recommended starting dose. Close follow-up and easy access for the patients so that they can report any adverse event and implement dose adjustments is the key point in the management of them. Development of early dermatologic adverse events has been correlated with better outcome and the pattern of radiologic progression characterizes better the prognosis/outcome of these patients. Treatment beyond progression may be considered if there is no option for a second line research trial. © 2014 Elsevier Ltd. All rights reserved.
Introduction Treatment of hepatocellular carcinoma (HCC) should aim to improve the survival of the patients with a proper balance between risks and benefits. The BCLC staging and treatment strategy [1,2](Fig. 1) serves this aim as it incorporates the effective options that are now fully accepted according to proper * Corresponding author. BCLC group, Liver Unit, Hospital Clínic, C/Villarroel 170, Floor 4 Stair 11, 08036 Barcelona, Spain. Tel.: þ34 93 227 9803; fax: þ34 93 227 5792. E-mail addresses: [email protected] (M. Reig), [email protected] (A. Gazzola), [email protected] (R. Di Donato), [email protected] (J. Bruix). 1 Tel.: þ34 93 227 9803; fax: þ34 93 227 5792.
http://dx.doi.org/10.1016/j.bpg.2014.08.003 1521-6918/© 2014 Elsevier Ltd. All rights reserved.
922
M. Reig et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 921e935
data and identifies the optimal candidates for each options. The survival benefit offered by a given option should have been demonstrated through robust investigations. The optimal method is through phase 3 randomised trials that compare any proposed intervention versus the standard of care if this exists, or versus no treatment if such established approach is not available [3]. Interestingly, such high quality evidence is not available for options that aim to provide complete removal of the malignant disease (surgical resection, ablation and liver transplantation) and the evidence is based on cohort analysis with major validation by independent groups [4]. For intermediate BCLC B stage there is adequate evidence through randomized trials and metanalysis to have transarterial chemoembolization as first option [5e7]. Until the development of sorafenib no systemic approach had shown to improve survival, and now this agent constitutes the first line intervention for patients with advanced BCLC C stage HCC and for patients with earlier stages that cannot receive the treatment that would correspond to such stage. The BCLC staging and treatments strategy [1,2] links initial staging for prognosis estimation with the first line option to be considered. It has been reviewed in extense elsewhere [1,2,8] and in this chapter we will review the current approach for systemic treatment and the still unmet needs in this field.
Fig. 1. BCLC staging and treatment strategy [modified from Forner et al (Lancet 2012; 379:1245e55)]. The figure represents the first approach to the evaluation of the patients with expected prognosis and initial treatment option to be considered. As shown, the upper part of the scheme defines prognosis according to the relevant clinical and tumour related parameters. Bottom part depicts the decision process to select a treatment option for first consideration. As in all recommendations, final treatment indication should take into account a detailed evaluation of additional characteristics (age, comorbidties) of the patients that imply a personalized decision making. * Note that Child-Pugh classification is not sensitive to accurately identify those patients with advanced liver failure that would deserve liver transplant consideration. Some patients fitting in Child-Pugh B, and even A, may present a poor prognosis because of clinical events not captured by such system, ie: spontaneous bacterial peritonitis, recurrent variceal bleeding, refractory ascites with or without hepatorenal syndrome, recurrent encephalopathy, severe malnutrition. ** Patients with end stage cirrhosis due to heavily impaired liver function (Child-Pugh C or earlier stages with predictors of poor prognosis, high MELD score) should be considered for liver transplantation. Among them, HCC may become a contraindication if exceeding the enlistment criteria.
M. Reig et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 921e935
923
Systemic treatment Conventional chemotherapy has never been proven to improve survival. Several agents alone or in combination, administered intravenously or selectively into the hepatic artery have never proven their benefit. In some areas the intrarterial injection of chemotherapy is based in its emulsion in lipiodol. This aims to enhance tumour cells exposure to the drug while reducing systemic adverse events. Unfortunately, the emulsion in lipiodol is not stable and the advantages of such administration are not established. A recent trial suggested that folfox-4 regime was effective as it compared positively with doxorubicin administration [9]. However, the primary endpoint of the study (survival) was not met and hence, there is no scientific strength to support this view. Agents such as antiestrogens [10], antiandrogens [11], vitamin D derivatives [12] or interferon [13] have also failed to offer benefit. This negative situation primed the research of novel agents that would target molecular mechanisms driving proliferation, angiogenesis or apoptosis. The list of agents that have been raised during the recent years is quite extense but only a minority have reached advanced phase 2 leading to phase 3 (Table 1). Among them, the only one that has been successful to improve the survival of the patients is sorafenib [14,15]. Sorafenib This agent is a multikinase inhibitor that inhibits tumour-cell proliferation and tumour angiogenesis and increases the rate of apoptosis in a wide range of tumour models. It acts by inhibiting the serineethreonine kinases Raf-1 and B-Raf and the receptor tyrosine kinase activity of vascular endothelial growth factor receptors (VEGFRs) one, two, and three and platelet-derived growth [16]. In a single arm phase 2 trial [17] it was shown that the drug had an adequate safety profile, but it did not induce a significant rate of treatment responses according to the conventional oncology RECIST criteria [18]. As a consequence the study was classified as negative and the further development of the drug was controversial. In that sense, it was realised that the tumour progression rate and the survival of the treated patients were encouraging if compared with the available data derived from prior prospective investigations [5e7,10e12]. In addition, in some patients treatment was associated to significant tumour necrosis indicating a certain activity. Because of these data, it was decided to run a phase 3 trial of sorafenib vs best supportive care in a large Western population [14]. At the same time, a similar trial was launched in Asian-Pacific population [15]. Both investigations obtained positive results and of the same magnitude. Overall survival in the Western trial was improved from 7.9 months in the placebo arm to 10.7 months in the sorafenib arm. This represented a HR of 0.69 reflecting a 30% increase in the likelihood to be alive during follow-up. The survival in the Eastern trials was lower due to the recruitment of patients at a more advanced stage. Patients in the placebo arm had a median survival of 4.2 months while this was 6.5 in the control arm. The magnitude of improvement was the same as in the Western trial confirming that the drug was active in all populations. Subgroup analysis showed that the benefits of the drug were no affected by gender, aetiologies of underlying disease, degree of liver function impairment or tumour burden [19,20]. The search of biomarkers to identify patients with significantly higher benefit or those not benefitting of treatment did not offer meaningful results [21]. Thus, sorafenib is now the established first line option for HCC patients being considered for systemic therapy [4,22,23]. The results of the pivotal sorafenib trials confirmed the phase 2 findings of improvement in survival in the absence of significant tumour burden reduction [14,17]. Sorafenib showed a higher disease control rate and significantly delayed tumour progression and this is translated into survival improvement without significant impairment of the quality of life. Indeed sorafenib was safe and treatment related adverse events were manageable. The most frequent were hand food skin reaction, asthenia, diarrhoea and arterial hypertension [14,15,24,25]. Interestingly, the incidence of AE is higher in Asian patient [15], and recent studies have shown that the emergence of drug related adverse events correlates with better outcome [24,26,27]. The design of the sorafenib trials introduced several novelties that are relevant [14]. The target population was selected to have a well preserved liver function (Child-Pugh A) so that the competing risk of death due to liver function impairment because of underlying liver cirrhosis was minimised. Thus, the potential to capture the benefits of sorafenib was facilitated. Patient stratification was done
924
First line Drug in study
Author
Year
Randomized drugs
n
DCR (%)
p Value
TTP (mo)
p Value
OS (mo)
p Value
Sorafenib
Llovet et al. Cheng et al. Zhu et al.
2008 2009 2012
Sorafenib vs. Placebo Sorafenib þ erlotinib vs. sorafenib
299/303 150/76 362/358
43 vs.32 35.3 vs.15.8 43.9 vs.52.5
0.002 0.0019 NS
5.5 vs. 2.8 2.8 vs. 1.4 3.2 vs. 4
Contents lists available at ScienceDirect
Best Practice & Research Clinical Gastroenterology
13
Systemic treatment Maria Reig, MD a, b, 1, Alessia Gazzola, MD a, 1, Roberto Di Donato, MD a, 1, Jordi Bruix, MD a, b, * a
Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic Barcelona, IDIBAPS, University of Barcelona, Spain b ticas y Digestivas (CIBERehd), Spain n Biom Centro de Investigacio edica en Red de Enfermedades Hepa
a b s t r a c t Keywords: Hepatocellular carcinoma Systemic treatment Patients selection Management Tumour response RECIST
In the last years the management of patients with liver cancer has been improved. The BCLC staging/treatment strategy identifies the optimal candidates for each treatment option and sorafenib is the only effective systemic treatment. Others (sunitinib, brivanib, linifanib, everolimus, ramucirumab) have failed in terms of safety/ survival benefit. Some patients at intermediate/early stage, may be considered for systemic therapy when options of higher priority may have failed or not be feasible. The 800 mg/day is the recommended starting dose. Close follow-up and easy access for the patients so that they can report any adverse event and implement dose adjustments is the key point in the management of them. Development of early dermatologic adverse events has been correlated with better outcome and the pattern of radiologic progression characterizes better the prognosis/outcome of these patients. Treatment beyond progression may be considered if there is no option for a second line research trial. © 2014 Elsevier Ltd. All rights reserved.
Introduction Treatment of hepatocellular carcinoma (HCC) should aim to improve the survival of the patients with a proper balance between risks and benefits. The BCLC staging and treatment strategy [1,2](Fig. 1) serves this aim as it incorporates the effective options that are now fully accepted according to proper * Corresponding author. BCLC group, Liver Unit, Hospital Clínic, C/Villarroel 170, Floor 4 Stair 11, 08036 Barcelona, Spain. Tel.: þ34 93 227 9803; fax: þ34 93 227 5792. E-mail addresses: [email protected] (M. Reig), [email protected] (A. Gazzola), [email protected] (R. Di Donato), [email protected] (J. Bruix). 1 Tel.: þ34 93 227 9803; fax: þ34 93 227 5792.
http://dx.doi.org/10.1016/j.bpg.2014.08.003 1521-6918/© 2014 Elsevier Ltd. All rights reserved.
922
M. Reig et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 921e935
data and identifies the optimal candidates for each options. The survival benefit offered by a given option should have been demonstrated through robust investigations. The optimal method is through phase 3 randomised trials that compare any proposed intervention versus the standard of care if this exists, or versus no treatment if such established approach is not available [3]. Interestingly, such high quality evidence is not available for options that aim to provide complete removal of the malignant disease (surgical resection, ablation and liver transplantation) and the evidence is based on cohort analysis with major validation by independent groups [4]. For intermediate BCLC B stage there is adequate evidence through randomized trials and metanalysis to have transarterial chemoembolization as first option [5e7]. Until the development of sorafenib no systemic approach had shown to improve survival, and now this agent constitutes the first line intervention for patients with advanced BCLC C stage HCC and for patients with earlier stages that cannot receive the treatment that would correspond to such stage. The BCLC staging and treatments strategy [1,2] links initial staging for prognosis estimation with the first line option to be considered. It has been reviewed in extense elsewhere [1,2,8] and in this chapter we will review the current approach for systemic treatment and the still unmet needs in this field.
Fig. 1. BCLC staging and treatment strategy [modified from Forner et al (Lancet 2012; 379:1245e55)]. The figure represents the first approach to the evaluation of the patients with expected prognosis and initial treatment option to be considered. As shown, the upper part of the scheme defines prognosis according to the relevant clinical and tumour related parameters. Bottom part depicts the decision process to select a treatment option for first consideration. As in all recommendations, final treatment indication should take into account a detailed evaluation of additional characteristics (age, comorbidties) of the patients that imply a personalized decision making. * Note that Child-Pugh classification is not sensitive to accurately identify those patients with advanced liver failure that would deserve liver transplant consideration. Some patients fitting in Child-Pugh B, and even A, may present a poor prognosis because of clinical events not captured by such system, ie: spontaneous bacterial peritonitis, recurrent variceal bleeding, refractory ascites with or without hepatorenal syndrome, recurrent encephalopathy, severe malnutrition. ** Patients with end stage cirrhosis due to heavily impaired liver function (Child-Pugh C or earlier stages with predictors of poor prognosis, high MELD score) should be considered for liver transplantation. Among them, HCC may become a contraindication if exceeding the enlistment criteria.
M. Reig et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 921e935
923
Systemic treatment Conventional chemotherapy has never been proven to improve survival. Several agents alone or in combination, administered intravenously or selectively into the hepatic artery have never proven their benefit. In some areas the intrarterial injection of chemotherapy is based in its emulsion in lipiodol. This aims to enhance tumour cells exposure to the drug while reducing systemic adverse events. Unfortunately, the emulsion in lipiodol is not stable and the advantages of such administration are not established. A recent trial suggested that folfox-4 regime was effective as it compared positively with doxorubicin administration [9]. However, the primary endpoint of the study (survival) was not met and hence, there is no scientific strength to support this view. Agents such as antiestrogens [10], antiandrogens [11], vitamin D derivatives [12] or interferon [13] have also failed to offer benefit. This negative situation primed the research of novel agents that would target molecular mechanisms driving proliferation, angiogenesis or apoptosis. The list of agents that have been raised during the recent years is quite extense but only a minority have reached advanced phase 2 leading to phase 3 (Table 1). Among them, the only one that has been successful to improve the survival of the patients is sorafenib [14,15]. Sorafenib This agent is a multikinase inhibitor that inhibits tumour-cell proliferation and tumour angiogenesis and increases the rate of apoptosis in a wide range of tumour models. It acts by inhibiting the serineethreonine kinases Raf-1 and B-Raf and the receptor tyrosine kinase activity of vascular endothelial growth factor receptors (VEGFRs) one, two, and three and platelet-derived growth [16]. In a single arm phase 2 trial [17] it was shown that the drug had an adequate safety profile, but it did not induce a significant rate of treatment responses according to the conventional oncology RECIST criteria [18]. As a consequence the study was classified as negative and the further development of the drug was controversial. In that sense, it was realised that the tumour progression rate and the survival of the treated patients were encouraging if compared with the available data derived from prior prospective investigations [5e7,10e12]. In addition, in some patients treatment was associated to significant tumour necrosis indicating a certain activity. Because of these data, it was decided to run a phase 3 trial of sorafenib vs best supportive care in a large Western population [14]. At the same time, a similar trial was launched in Asian-Pacific population [15]. Both investigations obtained positive results and of the same magnitude. Overall survival in the Western trial was improved from 7.9 months in the placebo arm to 10.7 months in the sorafenib arm. This represented a HR of 0.69 reflecting a 30% increase in the likelihood to be alive during follow-up. The survival in the Eastern trials was lower due to the recruitment of patients at a more advanced stage. Patients in the placebo arm had a median survival of 4.2 months while this was 6.5 in the control arm. The magnitude of improvement was the same as in the Western trial confirming that the drug was active in all populations. Subgroup analysis showed that the benefits of the drug were no affected by gender, aetiologies of underlying disease, degree of liver function impairment or tumour burden [19,20]. The search of biomarkers to identify patients with significantly higher benefit or those not benefitting of treatment did not offer meaningful results [21]. Thus, sorafenib is now the established first line option for HCC patients being considered for systemic therapy [4,22,23]. The results of the pivotal sorafenib trials confirmed the phase 2 findings of improvement in survival in the absence of significant tumour burden reduction [14,17]. Sorafenib showed a higher disease control rate and significantly delayed tumour progression and this is translated into survival improvement without significant impairment of the quality of life. Indeed sorafenib was safe and treatment related adverse events were manageable. The most frequent were hand food skin reaction, asthenia, diarrhoea and arterial hypertension [14,15,24,25]. Interestingly, the incidence of AE is higher in Asian patient [15], and recent studies have shown that the emergence of drug related adverse events correlates with better outcome [24,26,27]. The design of the sorafenib trials introduced several novelties that are relevant [14]. The target population was selected to have a well preserved liver function (Child-Pugh A) so that the competing risk of death due to liver function impairment because of underlying liver cirrhosis was minimised. Thus, the potential to capture the benefits of sorafenib was facilitated. Patient stratification was done
924
First line Drug in study
Author
Year
Randomized drugs
n
DCR (%)
p Value
TTP (mo)
p Value
OS (mo)
p Value
Sorafenib
Llovet et al. Cheng et al. Zhu et al.
2008 2009 2012
Sorafenib vs. Placebo Sorafenib þ erlotinib vs. sorafenib
299/303 150/76 362/358
43 vs.32 35.3 vs.15.8 43.9 vs.52.5
0.002 0.0019 NS
5.5 vs. 2.8 2.8 vs. 1.4 3.2 vs. 4
