Systemic Therapies in Hepatocellular Carcinoma
Systemic Therapies in Hepatocellular Carcinoma
There are seven trials that studied sorafenib alone, including a total of 1072 patients, divided in two Phase I trials, three Phase II trials and two Phase III randomized, placebo-controlled, clinical trials. All the trials showed a disease control rate (DCR) range from 26 to 82%. Five of the trials supplied short-term data about OS and TTP, respectively, with an interval ranging from 5 to 15.6 months for OS and from 3 to 5.5 months for TTP. Major adverse events (AEs; grade 3 or 4), such as hand–foot syndrome (HFS), diarrhea and fatigue, were described in all trials but with a wide variation in frequency. HFS ranged from 3 to 27%, diarrhea from 0 to 82% and fatigue from 0 to 91%.
The two highest quality reports (multicenter, Phase III, double-blind, placebo-controlled trials; we randomly assigned patients with advanced HCC who had not received previous systemic treatment to these trials) were the SHARP and the Asia–Pacific trials, which recruited patients with Child's A cirrhosis (95 and 97%, respectively), even if HBV infection frequency was much lower in the Asia–Pacific trial (71 vs 19%). These were the data provided by the SHARP trial in terms of OS and TTP: OS and TTP values were 10.7 and 5.5 months in the sorafenib group, and 7.9 and 2.8 months in the placebo group, respectively, with p < 0.05 in both groups.
The data provided by the Asia–Pacific trial were 6.5 vs 4.2 months for OS and 2.8 vs 1.4 months for TTP, respectively, for the sorafenib group versus the placebo group.
Considering the six studies that provided data about Child–Pugh score, they have shown that the majority of patients had Child's A cirrhosis. Child's B cirrhosis ranged from 3 to 52%, and only one study had included Child's C cirrhosis with two patients. HFS is more frequent in patients with Child's B cirrhosis, with an incidence of 27% in the seven trials. At the same time, in the Phase II trial by Abou-Alfa et al., there was a relatively low frequency of HFS (5%) among a population in which 28% had Child's B cirrhosis.
Thus, it seems that HBV infection could adversely affect the response to sorafenib. In fact, in the Hong Kong trial, most patients with HBV infection (90%) also had the lowest OS (5 months) and DCR (26%).
The Japanese trial, instead, studied mostly HCV patients (74%), demonstrating the longest OS (15.6 months) and the highest DCR (82%). Three (43%) of the seven studies on sorafenib alone showed an OS equal to 10 months. In the six trials that provided data about the TTP, none reported a TTP >6 months. Three of them reported a DCR >60%.
The seven studies show that treatment with sorafenib alone produces statistically significant but modest results clinically, and demonstrates improvements in OS, TTP and DCR in patient populations including men less than 70 years of age with advanced stage HCC and Chid's A cirrhosis. Insufficient data are still available on the effects of sorafenib in women, older patients (>70 years) and late stage cirrhotic patients. Sorafenib treatment alone seems to have more efficacy in HCV-infected patients than in HBV-infected patients. Moreover, sorafenib's side effects are frequent, mostly in advanced cirrhosis patients.
In a study by Di Costanzo et al., a single center's experience in treating 116 patients with advanced HCC with sorafenib was reported on. The study evaluated the response of HCC to and safety of sorafenib. The efficacy of sorafenib was evaluated considering the time to radiographical progression, DCR, OS and survival by grade of radiological response. The TTP was measured every 3 months with the modified RECIST (mRECIST) for HCC. With regards to the appearance of AEs, patients were monitored every month using the common toxicity criteria version 3.0. The 3-month overall DCR was 71%: stable disease was observed in 37%, PR in 31% and complete response in 2–5% of patients. The 3-month radiological response is in relation to OS. In the study the authors emphasize that it is very important to evaluate tumor response after 3 months of therapy. In fact the therapeutic response correlates with the prediction of survival. The OS rate at 12 months increased from 10% in complete responder patients to 100% in patients with disease progression. In both the SHARP trial and Asia–Pacific study, 71 and 54% of patients achieved stable disease, while only 2 and 3.3% achieved a PR, respectively, and no patients with a complete response were observed. The authors explain that the difference is due to the different criteria used to establish the response (RECIST was conventional in the SHARP and Asia–Pacific trials, whereas mRECIST was used in the authors studies) and early termination of the study may have underestimated the SHARP response assessment. These facts can also explain the most significant radiological TTP in this study compared with the SHARP study (12 vs 5.5 months). The AEs were moderate (grade 1 or 2), and symptom treatment and dose adjustments were usually enough to manage AEs.
Xie et al. demonstrated that sorafenib treatment is significant from the statistical point of view, but clinically only modest improvements in OS, TTP and DCR have been demonstrated. HCV patients seem to respond better. Moreover, sorafenib used in advanced cirrhosis and in combination with fluorouracil drugs is accompanied by a higher frequency of HFS. It is still not clear if sorafenib treatment alone is less effective than sorafenib used in combination with other drugs.
Studies on Treatment With Sorafenib Alone
There are seven trials that studied sorafenib alone, including a total of 1072 patients, divided in two Phase I trials, three Phase II trials and two Phase III randomized, placebo-controlled, clinical trials. All the trials showed a disease control rate (DCR) range from 26 to 82%. Five of the trials supplied short-term data about OS and TTP, respectively, with an interval ranging from 5 to 15.6 months for OS and from 3 to 5.5 months for TTP. Major adverse events (AEs; grade 3 or 4), such as hand–foot syndrome (HFS), diarrhea and fatigue, were described in all trials but with a wide variation in frequency. HFS ranged from 3 to 27%, diarrhea from 0 to 82% and fatigue from 0 to 91%.
The two highest quality reports (multicenter, Phase III, double-blind, placebo-controlled trials; we randomly assigned patients with advanced HCC who had not received previous systemic treatment to these trials) were the SHARP and the Asia–Pacific trials, which recruited patients with Child's A cirrhosis (95 and 97%, respectively), even if HBV infection frequency was much lower in the Asia–Pacific trial (71 vs 19%). These were the data provided by the SHARP trial in terms of OS and TTP: OS and TTP values were 10.7 and 5.5 months in the sorafenib group, and 7.9 and 2.8 months in the placebo group, respectively, with p < 0.05 in both groups.
The data provided by the Asia–Pacific trial were 6.5 vs 4.2 months for OS and 2.8 vs 1.4 months for TTP, respectively, for the sorafenib group versus the placebo group.
Considering the six studies that provided data about Child–Pugh score, they have shown that the majority of patients had Child's A cirrhosis. Child's B cirrhosis ranged from 3 to 52%, and only one study had included Child's C cirrhosis with two patients. HFS is more frequent in patients with Child's B cirrhosis, with an incidence of 27% in the seven trials. At the same time, in the Phase II trial by Abou-Alfa et al., there was a relatively low frequency of HFS (5%) among a population in which 28% had Child's B cirrhosis.
Thus, it seems that HBV infection could adversely affect the response to sorafenib. In fact, in the Hong Kong trial, most patients with HBV infection (90%) also had the lowest OS (5 months) and DCR (26%).
The Japanese trial, instead, studied mostly HCV patients (74%), demonstrating the longest OS (15.6 months) and the highest DCR (82%). Three (43%) of the seven studies on sorafenib alone showed an OS equal to 10 months. In the six trials that provided data about the TTP, none reported a TTP >6 months. Three of them reported a DCR >60%.
The seven studies show that treatment with sorafenib alone produces statistically significant but modest results clinically, and demonstrates improvements in OS, TTP and DCR in patient populations including men less than 70 years of age with advanced stage HCC and Chid's A cirrhosis. Insufficient data are still available on the effects of sorafenib in women, older patients (>70 years) and late stage cirrhotic patients. Sorafenib treatment alone seems to have more efficacy in HCV-infected patients than in HBV-infected patients. Moreover, sorafenib's side effects are frequent, mostly in advanced cirrhosis patients.
In a study by Di Costanzo et al., a single center's experience in treating 116 patients with advanced HCC with sorafenib was reported on. The study evaluated the response of HCC to and safety of sorafenib. The efficacy of sorafenib was evaluated considering the time to radiographical progression, DCR, OS and survival by grade of radiological response. The TTP was measured every 3 months with the modified RECIST (mRECIST) for HCC. With regards to the appearance of AEs, patients were monitored every month using the common toxicity criteria version 3.0. The 3-month overall DCR was 71%: stable disease was observed in 37%, PR in 31% and complete response in 2–5% of patients. The 3-month radiological response is in relation to OS. In the study the authors emphasize that it is very important to evaluate tumor response after 3 months of therapy. In fact the therapeutic response correlates with the prediction of survival. The OS rate at 12 months increased from 10% in complete responder patients to 100% in patients with disease progression. In both the SHARP trial and Asia–Pacific study, 71 and 54% of patients achieved stable disease, while only 2 and 3.3% achieved a PR, respectively, and no patients with a complete response were observed. The authors explain that the difference is due to the different criteria used to establish the response (RECIST was conventional in the SHARP and Asia–Pacific trials, whereas mRECIST was used in the authors studies) and early termination of the study may have underestimated the SHARP response assessment. These facts can also explain the most significant radiological TTP in this study compared with the SHARP study (12 vs 5.5 months). The AEs were moderate (grade 1 or 2), and symptom treatment and dose adjustments were usually enough to manage AEs.
Xie et al. demonstrated that sorafenib treatment is significant from the statistical point of view, but clinically only modest improvements in OS, TTP and DCR have been demonstrated. HCV patients seem to respond better. Moreover, sorafenib used in advanced cirrhosis and in combination with fluorouracil drugs is accompanied by a higher frequency of HFS. It is still not clear if sorafenib treatment alone is less effective than sorafenib used in combination with other drugs.
