Before the positive results recently obtained with multitarget tyrosine kinase inhibitor sorafenib,there was no standard systemic treatment for patients with advanced hepatocellular carcinoma(HCC).Sex hormones recepto...Before the positive results recently obtained with multitarget tyrosine kinase inhibitor sorafenib,there was no standard systemic treatment for patients with advanced hepatocellular carcinoma(HCC).Sex hormones receptors are expressed in a significant proportion of HCC samples.Following preclinical and epidemiological studies supporting a relationship between sex hormones and HCC tumorigenesis,several randomized controlled trials (RCTs)tested the efficacy of the anti-estrogen tamoxifen as systemic treatment.Largest among these trials showed no survival advantage from the administration of tamoxifen,and the recent Cochrane systematic review produced a completely negative result.This questions the relevance of estrogen receptor-mediated pathways in HCC.However,a possible explanation for these disappointing results is the lack of proper patients selection according to sex hormones receptors expression,but unfortunately the interaction between this expression and efficacy of tamoxifen has not been studied adequately.It has been also proposed that negative results might be explained if tamoxifen acts in HCC via an estrogen receptor-independent pathway,that requires higher doses than those usually administered, but an Asian RCT conducted to assess dose-response effect was completely negative.Interesting,preliminaryresults have been obtained when hormonal treatment (tamoxifen or megestrol)has been selected according to the presence of wild-type or variant estrogen receptors respectively,but no large RCTs are available to support this strategy.Negative results have been obtained also with anti-androgen therapy.In conclusion,there is no robust evidence to consider HCC a hormone-responsive tumor.Hormonal treatments should not be part of the current management of HCC.展开更多
Aim:Only patients with good liver function{[Child-Pugh(CP)]A class}were eligible for trials testing sorafenib as first-line treatment of hepatocellular carcinoma(HCC);nevertheless,the drug was authorized without restr...Aim:Only patients with good liver function{[Child-Pugh(CP)]A class}were eligible for trials testing sorafenib as first-line treatment of hepatocellular carcinoma(HCC);nevertheless,the drug was authorized without restrictions based on liver function.Therefore,we planned to test sorafenib efficacy and safety in patients with HCC and deteriorated liver function(CP-B).Methods:This was an open-label,multicenter,randomized phase 3 trial.Patients with HCC,no previous systemic therapy,and CP-B score 7-9 were assigned 1:1 to best supportive care alone(control arm)or with standard dose sorafenib(experimental arm).Overall survival(OS)was the primary endpoint.To detect a 0.70 HR of death,with 80%power,and two-tailedαerror 0.05,234 events were required.The study closed prematurely because of slow accrual.Descriptive analyses are reported.Results:From 2012 to 2017,13 Italian centers randomized 35 patients.In total,28 deaths were recorded,12 without and 16 with sorafenib;median OS was 4.9(95%CI:1.2-5.6)and 3.5 months(95%CI:1.3-5.3),respectively.At least one severe adverse event was reported in 2/15(13.3%)without and 9/17(52.9%)patients with sorafenib.Conclusions:This trial failed its planned enrolment goal,showing the difficulty in performing clinical trials with drugs already registered with a label broader than what available evidence supports.展开更多
文摘Before the positive results recently obtained with multitarget tyrosine kinase inhibitor sorafenib,there was no standard systemic treatment for patients with advanced hepatocellular carcinoma(HCC).Sex hormones receptors are expressed in a significant proportion of HCC samples.Following preclinical and epidemiological studies supporting a relationship between sex hormones and HCC tumorigenesis,several randomized controlled trials (RCTs)tested the efficacy of the anti-estrogen tamoxifen as systemic treatment.Largest among these trials showed no survival advantage from the administration of tamoxifen,and the recent Cochrane systematic review produced a completely negative result.This questions the relevance of estrogen receptor-mediated pathways in HCC.However,a possible explanation for these disappointing results is the lack of proper patients selection according to sex hormones receptors expression,but unfortunately the interaction between this expression and efficacy of tamoxifen has not been studied adequately.It has been also proposed that negative results might be explained if tamoxifen acts in HCC via an estrogen receptor-independent pathway,that requires higher doses than those usually administered, but an Asian RCT conducted to assess dose-response effect was completely negative.Interesting,preliminaryresults have been obtained when hormonal treatment (tamoxifen or megestrol)has been selected according to the presence of wild-type or variant estrogen receptors respectively,but no large RCTs are available to support this strategy.Negative results have been obtained also with anti-androgen therapy.In conclusion,there is no robust evidence to consider HCC a hormone-responsive tumor.Hormonal treatments should not be part of the current management of HCC.
基金supported by the Italian Drug Agency(AIFA)in May 2011(code FARM84SA2X)for trial coordination activities.
文摘Aim:Only patients with good liver function{[Child-Pugh(CP)]A class}were eligible for trials testing sorafenib as first-line treatment of hepatocellular carcinoma(HCC);nevertheless,the drug was authorized without restrictions based on liver function.Therefore,we planned to test sorafenib efficacy and safety in patients with HCC and deteriorated liver function(CP-B).Methods:This was an open-label,multicenter,randomized phase 3 trial.Patients with HCC,no previous systemic therapy,and CP-B score 7-9 were assigned 1:1 to best supportive care alone(control arm)or with standard dose sorafenib(experimental arm).Overall survival(OS)was the primary endpoint.To detect a 0.70 HR of death,with 80%power,and two-tailedαerror 0.05,234 events were required.The study closed prematurely because of slow accrual.Descriptive analyses are reported.Results:From 2012 to 2017,13 Italian centers randomized 35 patients.In total,28 deaths were recorded,12 without and 16 with sorafenib;median OS was 4.9(95%CI:1.2-5.6)and 3.5 months(95%CI:1.3-5.3),respectively.At least one severe adverse event was reported in 2/15(13.3%)without and 9/17(52.9%)patients with sorafenib.Conclusions:This trial failed its planned enrolment goal,showing the difficulty in performing clinical trials with drugs already registered with a label broader than what available evidence supports.
