Sorafenib for non-selected patient population with advanced hepatocellular carcinoma: efficacy and safety data according to liver function

Objective

Sorafenib is the standard treatment of patients with advanced hepatocellular carcinoma, regardless of the liver functional reserve. We present a single institutional series of Child–Pugh A and Child–Pugh B patients treated with sorafenib with the aim to establish the efficacy and safety of sorafenib in patients of daily clinical conditions and to compare these results between Child–Pugh A and Child–Pugh B patients.

Materials and methods

A total of 51 patients were treated with sorafenib 400 mg/12 h until disease progression or unacceptable toxicity.

Results

The median progression-free survival and overall survival for the overall population were 3.5 and 8.2 months, respectively, with a 1-year survival rate of 27 %. Overall survival was significantly longer for patients Child–Pugh A compared with those with Child–Pugh B liver function (8.7 vs. 4.7 months, respectively). The most common adverse events were fatigue (62.7 %), diarrhea (58 %), hypertension (31.3 %), and hand–foot syndrome (31.3 %), and in most cases grade 1 or 2 according to the NCI-CTC 3.0. Grade 4 liver-related events occurred mainly in Child–Pugh B patients with decompensated cirrhosis at the time of sorafenib initiation (54.5 % of that group).

Discussion

The benefit of sorafenib in Child–Pugh B patients, if exist, may be limited by frequent liver-related events, especially in decompensated patients, and then, toxicity and impact in quality of life should be carefully monitored.     

The use of single‐agent sorafenib in the treatment of advanced hepatocellular carcinoma patients with underlying Child‐Pugh B liver cirrhosis

BACKGROUND:

This study explored the efficacy, tolerability, and survival benefits of using sorafenib in patients with Child‐Pugh class B (CPB) cirrhosis.

METHODS:

Patients with advanced hepatocellular carcinoma who were treated with sorafenib at Queen Mary Hospital, Hong Kong, China, were analyzed retrospectively. Treatment outcomes were analyzed according to their respective Child‐Pugh status. Patients with CPB disease were further divided into CPB7 (those with a score of 7) and CPB8‐9 (a score of 8 or 9) subgroups.

RESULTS:

The baseline demographic parameters were comparable between 108 patients with Child‐Pugh class A (CPA) disease and 64 CPB patients. Both clinical benefit rate (21.3% vs 32.4% vs 14.8%; P = .23) and progression‐free survival (median: 3.2 months vs 3.2 months vs 2.3 months; P = .26) were similar among CPA, CPB7, and CPB8‐9 groups, respectively. The overall survival was different among these groups (P = .002) and showed a trend toward worse outcome in CPB patients: the median was 6.1, 5.4, and 2.7 months among CPA, CPB7, and CPB8‐9 patients, respectively. The commonest grade 3/4 adverse events were hand‐foot syndrome (13.5%), diarrhea (9.9%), and rash (7.0%). Grade 3/4 leukopenia, thrombocytopenia, and anemia occurred in 2.9%, 5.3%, and 8.8% of the patients, respectively. Overall, the 3 groups of patients experienced similar incidence of most of these adverse events. Nonetheless, CPB patients experienced more anemia (P = .01), gastrointestinal bleeding (P = .02), and hepatic encephalopathy (P = .02).

CONCLUSIONS:

CPA and CPB patients tolerated sorafenib similarly and derived similar clinical and progression‐free survival benefit. Among CPB patients, most benefits were observed in patients with a score of 7. Nevertheless, CPB patients were more susceptible to developing cirrhotic complications, and thus more vigilant surveillance is needed. Cancer 2012. © 2012 American Cancer Society.     

Phase 1‐2 trial of PTK787/ZK222584 combined with intravenous doxorubicin for treatment of patients with advanced hepatocellular carcinoma

BACKGROUND:

This phase 1‐2 trial assessed the efficacy and tolerability of an oral angiogenesis inhibitor—PTK787/ZK222584 (PTK)—in combination with intravenous doxorubicin for the treatment of advanced hepatocellular carcinoma (HCC) patients.

METHODS:

In phase 1, advanced HCC patients received PTK at escalating doses together with doxorubicin 60 mg/m² given as an intravenous bolus every 3 weeks to establish the maximum tolerated dose (MTD). Subsequently, in phase 2, all patients received the same regimen with oral PTK at the MTD dose every 3 weeks for a maximum of 6 cycles.

RESULTS:

Nine patients were recruited in phase 1, with the MTD established as 750 mg daily. Overall, 27 patients received the regimen with PTK at 750 mg daily. The median age was 52 years (range, 23‐73 years), and 63 percent of patients were chronic hepatitis B carriers. Notably, the majority of patients had Child‐Pugh B cirrhosis. The overall response rate was 26.0%, with all the responding patients having partial response. Another 20% of patients achieved stable disease for at least 12 weeks. The median progression‐free survival was 5.4 months (range, 0.27‐23.6 months), and overall survival was 7.3 months (range, 0.8‐23.6 months). The commonest grade 3 or 4 nonhematological toxicities were mucositis (11%) and alopecia (7%), respectively. Grade 3 or 4 neutropenia was observed in 7 (26%) patients; 2 had neutropenic sepsis.

CONCLUSIONS:

The combination of PTK with intravenous doxorubicin shows encouraging activity in treating advanced HCC patients. Cancer 2010. © 2010 American Cancer Society.     

Phase 2 trial of linifanib (ABT‐869) in patients with unresectable or metastatic hepatocellular carcinoma

BACKGROUND:

The efficacy and safety of linifanib (ABT‐869), a selective inhibitor of vascular endothelial growth factor and platelet‐derived growth factor receptor tyrosine kinases, were assessed in this phase 2, single‐arm, open‐label, multicenter trial.

METHODS:

Eligible patients had unresectable or metastatic hepatocellular carcinoma and had received ≤ 1 prior systemic therapy. Patients received oral linifanib at a fasting dose of 0.25 mg/kg,. The primary endpoint was the progression‐free rate at 16 weeks. Tumor response was assessed every 8 weeks. Secondary endpoints included the time to disease progression, overall survival, and objective response rate. Safety was also assessed.

RESULTS:

Of the 44 patients enrolled, the majority were Asian (89%), had received no prior systemic therapy (82%), had Child‐Pugh class A hepatic function (86%), and had hepatitis B virus infection (61%). The estimated progression‐free rate at 16 weeks was 31.8% (34.2% for patients with Child‐Pugh class A hepatic function), the estimated objective response rate was 9.1% (10.5% for patients with Child‐Pugh class A hepatic function), the median time to disease progression was 3.7 months (3.7 months for patients with Child‐Pugh class A hepatic function), and the median overall survival was 9.7 months (10.4 months for patients with Child‐Pugh class A hepatic function). The most common linifanib‐related adverse events were diarrhea (55%) and fatigue (52%). The most common linifanib‐related grade 3/4 adverse events were hypertension (25%) and fatigue (14%). Serum levels of biomarkers cancer antigen (CA) 125, cytokeratin fragment (CYFRA)21.1, and protein induced by vitamin K absence or antagonist II (PIVKA) demonstrated potential as prognostic indicators of patient response or outcome.

CONCLUSIONS:

Single‐agent linifanib was found to be clinically active in patients with advanced hepatocellular carcinoma, with an acceptable safety profile. Cancer 2013. © 2012 American Cancer Society.     

Accelerated treatment using intensity‐modulated radiation therapy plus concurrent capecitabine for unresectable hepatocellular carcinoma

BACKGROUND:

Patients with unresectable hepatocellular carcinoma (HCC) have limited treatment options. In this study, the authors investigated the feasibility, toxicity, and efficacy associated with intensity‐modulated radiation therapy (IMRT) and concurrent, chronomodulated capecitabine in the treatment of unresectable HCC.

METHODS:

Twenty patients underwent treatment planning for HCC confined to the liver with helical tomotherapy‐based IMRT. Fifty‐five percent of patients had Child‐Pugh Class A disease, and 45% of patients had Class B disease. Ninety‐five percent of patients were prescribed 50 gray (Gy) of radiotherapy to the planning target volume delivered in 20 fractions with concurrent, chronomodulated capecitabine. Transcatheter arterial chemoembolization preceded radiotherapy in 11 patients, and 9 patients received IMRT alone because of portal vein thrombosis, esophageal varices, or tumor size.

RESULTS:

The mean greatest tumor dimension was 9 cm (range, 1.3‐17.4 cm), the mean dose to normal liver was 22.6 Gy (range, 10‐29.2 Gy), and the average volume of liver that received >30 Gy (V30) was 27.2% (range, 12%‐43%). Eighteen patients (90%) completed the prescribed treatment of 50 Gy. There was no increase from baseline in acute or late toxicity greater than 2 grades. Partial response or disease stability was achieved at 3 months to 6 months after treatment in 15 of 16 patients (94%). The median survival (±standard deviation) for patients who had Child‐Pugh Class A and B disease was 22.5 ± 5.1 months and 8 ± 3.3 months, respectively.

CONCLUSIONS:

In this initial experience with accelerated IMRT plus capecitabine for patients who had large HCC lesions, the results demonstrated acceptable toxicity with promising local control. The relatively low acute and late toxicity observed with this program suggested that dose intensification can be incorporated into the treatment regimen if needed. Cancer 2009. © 2009 American Cancer Society.     

Role of hepatic resection in patients with intermediate‐stage hepatocellular carcinoma: A multicenter study from Japan

Transarterial chemoembolization (TACE) is recommended for patients with intermediate‐stage (Barcelona Clinic Liver Cancer criteria B [BCLC‐B]) hepatocellular carcinoma (HCC). However, patients with BCLC‐B HCC can differ in background factors related to hepatic function, as well as tumor size and number. In the present study, we clarified the role of hepatic resection in patients with BCLC‐B HCC. A total of 489 BCLC‐B HCC patients with Child–Pugh class A disease initially treated with hepatic resection or TACE were included. After propensity score matching (n = 264), hepatic resection (hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.35–0.91) was independently associated with survival in the multivariate analysis. We then divided patients into two groups based on the results of statistical analysis. There were 170 patients treated with resection and 319 with TACE. Child–Pugh score and number of tumors (cut‐off, three tumors) were independently associated with type of HCC treatment in the multivariate analysis. We then divided patients in Group A (Child–Pugh score of 5 and ≤3 tumors; n = 186) and Group B (Child–Pugh score of 6 or ≥4 tumors; n = 303). In Group A, cumulative survival was significantly higher in the hepatic resection group than in the TACE group (P = 0.014). In Cox proportional hazards models, hepatic resection (HR, 0.38; 95% CI, 0.23–0.64) was independently associated with survival in Group A patients. In Group B, treatment status was not associated with overall survival. Hepatic resection should be considered in patients with a Child–Pugh score of 5 and ≤3 tumors, despite having BCLC‐B HCC.     

Bevacizumab in combination with oxaliplatin and doxorubicin or liposomal doxorubicin for hepatocellular cancer: a case series

Aims: Despite the emergence of sorafenib as the standard treatment for patients with advanced hepatocellular cancer (HCC), therapy remains sub‐optimal and toxic. Methods: We report on five patients with advanced HCC treated with bevacizumab, oxaliplatin and doxorubicin or liposomal doxorubicin. Results: Of the five patients, four had cirrhosis; two patients had Child‐Pugh A cirrhosis, while one each had Child‐Pugh B and C cirrhosis. Grade 3/4 toxicity was uncommon. Four patients had a decrease of ≥50% in alpha‐fetoprotein levels following therapy and one patient each had a radiographic complete response and stable disease. Conclusion: These data add to the growing phase II data that bevacizumab‐containing regimens are active in advanced HCC patients. Further evaluation of regimens containing bevacizumab with oxaliplatin and/or doxorubicin may be warranted.     

CF102 for the Treatment of Hepatocellular Carcinoma: A Phase I/II,Open‐Label,Dose‐Escalation Study

Background.

The A₃ adenosine receptor (A₃AR) is overexpressed in the tumor and in the peripheral blood mononuclear cells of patients with hepatocellular carcinoma (HCC). The orally active drug candidate CF102, an A₃AR agonist, induces apoptosis of HCC cells via deregulation of the Wnt signaling pathway. In this open label phase I/II trial, the safety and clinical effects of CF102 were assessed in patients with advanced unresectable HCC.

Methods.

The primary objectives of this trial were to examine the safety and pharmacokinetic (PK) behavior of CF102 given orally (1, 5, and 25 mg BID) in 28-day cycles. Evaluation of anti-tumor effects and the utilization of A₃AR as a biological predictive marker of response to CF102 were the secondary objectives.

Results.

Eighteen patients received CF102—six at each dose level. No serious drug-related adverse events or dose-limiting toxicities were observed. CF102 demonstrated good oral bioavailability and linear PK behavior. Median overall survival in the study population, 67% of whom had received prior sorafenib, was 7.8 months, and for Child Pugh B patients (28%) it was 8.1 months. Stable disease by RECIST was observed in four patients for at least 4 months. CF102 maintained liver function over a 6-month period. A correlation between receptor overexpression levels at baseline and patients'' overall survival was found. One of the patients who presented with skin nodules that were biopsy-proven to be HCC metastases prior to the trial showed complete metastasis regression during three months of treatment with CF102.

Conclusions.

CF102 is safe and well-tolerated, showing favorable PK characteristics in Child Pugh A and B HCC patients, justifying further clinical development.     

Comparative dosing and efficacy of sorafenib in hepatocellular cancer patients with varying liver dysfunction

Background

Sorafenib is the only FDA-approved systemic therapy for advanced hepatocellular carcinoma (HCC). In clinical practice, dose reductions are often required, although there are limited efficacy data related to dose modifications. Given the prevalence of HCC in South Texas, we assessed the efficacy and safety of sorafenib therapy in relation to dose and Child Pugh (CP) score.

Methods

A retrospective analysis was done of advanced HCC patients, starting sorafenib at 400 mg twice daily, or at physician discretion at 400 mg daily, with the goal of titrating to twice daily. Overall survival (OS) and progression-free survival (PFS) were assessed.

Results

Among 107 patients, median OS (mOS) was 10.2 months; median PFS (mPFS) was 5.2 months. mOS for sorafenib 400 mg/day was 6.6 vs. 800 mg/day was 12.8 months [hazard ratio (HR), 0.59; P=0.04]; mPFS was 3.5 vs. 5.9 months, respectively (HR, 0.66; P=0.07). For Child Pugh A class (CP-A) patients, mOS was 15.8 months for 400 mg/day vs. 12.8 months for 800 mg/day (HR, 1.48; P=0.35); mPFS was 9.0 vs. 5.9 months, respectively (HR, 1.23; P=0.56). For Child Pugh B class (CP-B) patients, mOS was 5.0 months for 400 mg/day vs. 11.2 months for 800 mg/day (HR, 0.33; P=0.002); mPFS was 2.1 vs. 5.6 months, respectively (HR, 0.41; P=0.006). No differences in adverse events (AEs) were observed in CP-A vs. CP-B.

Conclusions

Patients with CP-A or CP-B advanced HCC should be offered sorafenib at 400 mg twice daily with optimal management of AEs in order to improve survival.     

Phase 2 trial of bevacizumab, capecitabine, and oxaliplatin in treatment of advanced hepatocellular carcinoma

BACKGROUND:

Anti‐angiogenesis agents have shown effectiveness in treatment of hepatocellular carcinoma (HCC). It is important to investigate more effective and safe systemic treatment options for patients with advanced HCC. This phase 2 study was designed to determine the efficacy and toxicity of the combination of bevacizumab, capecitabine, and oxaliplatin in patients with advanced unresectable and untransplantable HCC.

METHODS:

Chemotherapy‐naive patients with advanced unresectable and untransplantable HCC were treated with bevacizumab 5 mg/kg and oxaliplatin 130 mg/m² on day 1 of each cycle, and capecitabine 825 mg/m² orally twice a day from days 1 to 14 of a 21‐day cycle.

RESULTS:

Forty patients were enrolled to the study, in which 40% had Child‐Pugh B disease. Forty percent had an Eastern Cooperative Oncology Group performance status (PS) of 0, 55% had PS of 1, and 5% had PS of 2. Forty percent of patients had hepatitis B virus infection. The median progression‐free survival was 6.8 months (95% CI, 3.4‐9.1 months), and the median overall survival was 9.8 months (95% CI, 5.2‐12.1 months). Eight patients (20%) achieved partial response; 23 patients had stable disease with overall 77.5% disease control rate. The combination was tolerable with limited grade 3/4 toxicity, mainly peripheral neurotoxicity and fatigue.

CONCLUSIONS:

The combination appeared effective and safe, and the results were encouraging. Further investigation should be considered. Cancer 2011. © 2011 American Cancer Society.     

The combination of transcatheter arterial chemoembolization and sorafenib is well tolerated and effective in Asian patients with hepatocellular carcinoma: Final results of the START trial

This phase II, investigator‐initiated, prospective single‐arm multinational study ( ClinicalTrials.gov registration NCT00990860) evaluated sorafenib in combination with doxorubicin‐based transarterial chemoembolization (TACE) in patients with intermediate‐stage, unresectable hepatocellular carcinoma (HCC). Patients with histologically or clinically diagnosed HCC received TACE with interrupted dosing of sorafenib (sorafenib discontinued for 3 days before and 4–7 days after TACE). TACE/sorafenib cycles were repeated every 6–8 weeks. Primary and secondary objectives were, respectively: to evaluate the safety and tolerability of TACE combined with sorafenib, and also their efficacy. The full analysis set comprised 192 patients (mean age 56.1 years). Most were male (87.0%), Eastern Cooperative Oncology Group (ECOG) score 0 (81.8%), Child‐Pugh A (91.8%) and Barcelona Clinic Liver Cancer (BCLC) stage B (81.5%); 81.2% had chronic hepatitis B. Combined TACE/sorafenib was well tolerated, with only 8.1% of patients discontinuing owing to adverse events (AEs). The most common grade ≥3 AEs were palmar‐plantar erythrodysesthesia syndrome (15.1%) and decreased platelet count (10.9%). Serious AEs (SAEs) occurred in 52 patients during the study; however, only four were considered related to sorafenib. A mean of 2.7 TACE cycles were administered and 52.6% of patients achieved complete response in target lesions; 16.8% achieved partial response, and 5.8% had progression of disease as their best response, evaluated by modified RECIST. Median progression‐free survival and time to progression were 384 and 415 days, respectively, and the estimated 3‐year overall survival was 86.1%. This study suggests that the combination of TACE and sorafenib is well tolerated and efficacious; the interrupted sorafenib dosing schedule may have contributed to a considerably lower AE profile than observed in other combination trials.     

Exploring the efficacy and safety of single-agent sorafenib in a cohort of Italian patients with hepatocellular carcinoma

This study investigates the effectiveness and safety of sorafenib in a heterogeneous cohort of Child–Pugh A, B and C patients with advanced hepatocellular carcinoma in a clinical-practice scenario. Adult patients with hepatocellular carcinoma and treated with sorafenib 800 mg/day were eligible for this multicentric retrospective observational study. Safety analyses were performed and the effectiveness of sorafenib was assessed in terms of time to progression (TTP) and overall survival (OS). In total, 93 patients were enrolled: 14 were Child–Pugh A, 70 were Child–Pugh B and nine were Child–Pugh C. No differences in the frequency of grade 3 adverse events among different Child–Pugh classes were reported. In the overall cohort, median OS was 12 months (95% CI: 11.7–12.8 months) and TTP was 3 months (95% CI: 2.5–3.4 months). The Child–Pugh score had a statistically significant effect on TTP: 6.6 months in Child–Pugh A, 2.8 months in Child–Pugh B and 2.0 months in Child–Pugh C patients (p = 0.012). To our knowledge, this study includes the largest cohort of Caucasian Child–Pugh B and C patients ever treated with sorafenib. Although the retrospective design of this study does not allow reaching any definite conclusion, the results could lend some preliminary support to the safety and the effectiveness of sorafenib monotherapy in patients with Child–Pugh B and Child–Pugh C liver function.     

Pro‐angiogenic TIE‐2‐expressing monocytes/TEMs as a biomarker of the effect of sorafenib in patients with advanced hepatocellular carcinoma

Sorafenib, a multi‐kinase inhibitor, inhibits tumor angiogenesis and is the first‐line systemic therapy for patients with advanced hepatocellular carcinoma (HCC). However, due to its limited effects and frequent occurrence of side effects, biomarkers are needed to predict the effects of sorafenib. We considered the possibility of using TIE‐2‐expressing monocytes (TEMs) to predict the response in sorafenib‐treated patients with advanced HCC. TEMs serve as a diagnostic marker of HCC and are related to angiogenesis. We analyzed 25 advanced HCC patients and prospectively evaluated TEMs before (Pre TEMs) and at 1 month after initial therapy (T1m TEMs). The radiologic response was evaluated by modified Response Evaluation Criteria in Solid Tumors (mRECIST). Median survival time (MST) was significantly longer in the partial response/stable disease (PR/SD) group (21.8 months) than in the PD group (8.7 months). ΔTEMs (changes of T1m TEMs compared to Pre TEMs) were significantly lower in the PR/SD group than in the PD group. MST of the ΔTEMs low group (14.2 months) was significantly longer than that of the high group (8.7 months). Univariate and multivariate Cox regression analyses showed that ΔTEMs [hazard ratio (HR) = 8.53, 95% confidence interval (CI) = 1.51–48.16, p = 0.015] and Child‐Pugh class (HR = 5.59, 95% CI = 1.06–29.63, p = 0.043) were independently associated with overall survival. Our results suggest that ΔTEMs could serve as a biomarker for predicting radiologic response and overall survival in sorafenib‐treated patients with advanced HCC.     

Phase 2 trial of concurrent bevacizumab and transhepatic arterial chemoembolization in patients with unresectable hepatocellular carcinoma

BACKGROUND:

Vascular endothelial growth factor is up‐regulated in hepatocellular carcinoma (HCC) and is further up‐regulated after transhepatic arterial chemoembolization. The authors of this report conducted a phase 2 trial to evaluate the safety and efficacy of bevacizumab combined with chemoembolization in patients with unresectable HCC.

METHODS:

Patients who had an Eastern Cooperative Oncology Group performance of status 0 to 2, a Child‐Pugh score of A or B, and Barcelona Clinic Liver Cancer stage B or C HCC were eligible. Treatment consisted of bevacizumab every 2 weeks and chemoembolization during the third week of a 6‐week cycle for up to 3 cycles over 6 months. The primary endpoints were safety and efficacy.

RESULTS:

Twenty‐five patients received chemoembolization and bevacizumab. The most common grade 3 and 4 events after the first treatment cycle were leukocytopenia (12%), fatigue (12%), and hyponatremia (12%). Serious toxicities that had a known association with bevacizumab were observed in 4 patients. Thirty‐day mortality was 0%. The median time to tumor progression for the targeted lesions was not reached, and overall survival was 10.8 months. The objective response rate was 60% using enhancement response evaluation criteria, and the disease control rate was 100%.

CONCLUSIONS:

Concurrent treatment with bevacizumab and chemoembolization was safe in carefully selected patients and demonstrated antitumor activity in patients with unresectable HCC. These results support the further development of bevacizumab combined with chemoembolization as a treatment for unresectable HCC. Cancer 2013. © 2012 American Cancer Society.     

A phase Ib study of selumetinib (AZD6244, ARRY-142886) in combination with sorafenib in advanced hepatocellular carcinoma (HCC)

Angiogenesis and RAS/RAF/MEK/ERK pathway have been demonstrated to be relevant in hepatocellular carcinoma (HCC). Sorafenib, an oral multikinase inhibitor with activity against RAF kinase and vascular endothelial growth factor receptor-2, is approved for the treatment of advanced HCC. The therapeutic benefit however is modest. While displaying tumour growth inhibition and angiogenesis, sorafenib treatment in pre-clinical models exhibited up-regulation of pERK which may limit its anti-tumour activity. Inhibition of the MEK/ERK pathway by selumetinib enhanced the anti-tumour effect of sorafenib in pre-clinical models of HCC. In this phase I study, we investigated the maximum tolerated dose (MTD), safety and activity of combination sorafenib and selumetinib in patients with advanced HCC. The combination of selumetinib and sorafenib has manageable toxicity and showed encouraging anti-tumour activity. These findings support further evaluation in a phase II study.BackgroundTreatment with sorafenib, although associated with inhibition of tumour growth and angiogenesis in in vivo studies, leads to up-regulation of pERK. The addition of MEK inhibition could potentially abrogate this effect and potentiate anti-tumour activity. This phase I study investigated the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK) and biomarker correlates of selumetinib combined with sorafenib in patients with advanced hepatocellular carcinoma (HCC).MethodsPatients with Child–Pugh (CP) score ≤7 were treated with 400 mg twice daily of sorafenib with escalating doses of selumetinib in a 3 + 3 study design. The dose-limiting toxicity (DLT) evaluation period was 28 days. PK of selumetinib was determined. Angiogenic effect was evaluated with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).ResultsTwenty-seven patients of Asian ethnicity were enrolled. The MTD was selumetinib 75 mg daily with sorafenib 400 mg twice daily. DLT included grade 3 transaminitis, diarrhoea and fatigue. Most common treatment-related adverse events at MTD (all grades) were diarrhoea (85%), rash (59%), hypertension (44%), fatigue (30%), anorexia (22%) and hand–foot syndrome (22%). Four patients (15%) had PR and 13 (48%) had SD. PR or SD was observed for ≥6 months in seven patients. The median overall survival was 14.4 months. Selumetinib exposures in combination with sorafenib were comparable to other monotherapy studies. A reduction in permeability-surface area product noted in DCE-MRI with treatment correlated with worse survival outcomes.ConclusionThe MTD of selumetinib was 75 mg daily when combined with sorafenib 400 mg twice a day in CP ≤7 HCC. Acceptable adverse events and encouraging anti-tumour activity warrant further evaluation. DCE-MRI findings deserve prospective evaluation.ClinicalTrials.gov identifierNCT01029418.     

Temsirolimus combined with sorafenib in hepatocellular carcinoma: a phase I dose-finding trial with pharmacokinetic and biomarker correlates

BackgroundBased upon preclinical evidence for improved antitumor activity in combination, this phase I study investigated the maximum-tolerated dose (MTD), safety, activity, pharmacokinetics (PK), and biomarkers of the mammalian target of rapamycin inhibitor, temsirolimus, combined with sorafenib in hepatocellular carcinoma (HCC).Patients and methodsPatients with incurable HCC and Child Pugh score ≤B7 were treated with sorafenib plus temsirolimus by 3 + 3 design. The dose-limiting toxicity (DLT) interval was 28 days. The response was assessed every two cycles. PK of temsirolimus was measured in a cohort at MTD.ResultsTwenty-five patients were enrolled. The MTD was temsirolimus 10 mg weekly plus sorafenib 200 mg twice daily. Among 18 patients at MTD, DLT included grade 3 hand–foot skin reaction (HFSR) and grade 3 thrombocytopenia. Grade 3 or 4 related adverse events at MTD included hypophosphatemia (33%), infection (22%), thrombocytopenia (17%), HFSR (11%), and fatigue (11%). With sorafenib, temsirolimus clearance was more rapid (P < 0.05). Two patients (8%) had a confirmed partial response (PR); 15 (60%) had stable disease (SD). Alpha-fetoprotein (AFP) declined ≥50% in 60% assessable patients.ConclusionThe MTD of sorafenib plus temsirolimus in HCC was lower than in other tumor types. HCC-specific phase I studies are necessary. The observed efficacy warrants further study.     

A study of circulating interleukin 10 in prognostication of unresectable hepatocellular carcinoma

BACKGROUND:

The level of circulating interleukin 10 (IL‐10) is elevated in a proportion of patients with hepatocellular carcinoma (HCC). The objective of the current study was to evaluate the prognostic significance of serum the IL‐10 level in patients with unresectable HCC.

METHODS:

Patients with unresectable HCC who provided serum at the time of diagnosis were enrolled prospectively in the study. The level of circulating IL‐10 in serum samples was determined by enzyme‐linked immunosorbent assay. The association of the IL‐10 level with overall survival was evaluated in relation to sociodemographics, liver function, hepatitis B viral load, and tumor staging.

RESULTS:

In total, 222 patients were recruited; of these, 82.4% were positive for hepatitis B virus surface antigen, and 65.8% had Barcelona Clinic Liver Cancer stage C disease. The mean log IL‐10 level was 1.1 pg/mL, and 146 patients had an IL‐10 level >1 pg/mL (high IL‐10 group). The high IL‐10 group had worse overall survival than the low IL‐10 group (5.0 months vs 14.9 months; hazard ratio, 2.192; P < .0001). The IL‐10 level was associated with worse hepatic function and with a high alanine transaminase (ALT) level. The IL‐10 level remained an independent prognostic factor (hazard ratio, 1.824; P = .0005) after adjustment for sociodemographics, tumor staging, treatment, Child‐Pugh stage, and ALT level. The IL‐10 level also subdivided patients into 2 populations with distinct survival (10.2 months vs 3.5 months; P = .0027).

CONCLUSIONS:

The serum IL‐10 level was identified as an independent prognostic factor for unresectable HCC. The current findings suggested that an elevated IL‐10 level may be related to hepatic injury caused by cirrhotic processes rather than tumor load. The authors concluded that the IL‐10 level offers additional prognostic value to the existing tumor staging systems. Cancer 2012. © 2011 American Cancer Society.     

Early alpha‐fetoprotein response predicts treatment efficacy of antiangiogenic systemic therapy in patients with advanced hepatocellular carcinoma

BACKGROUND:

Antiangiogenic therapy has become the most important treatment modality for patients with advanced hepatocellular carcinoma (HCC). In this study, the authors investigated levels of alpha‐fetoprotein (AFP) as a potential biomarker for treatment efficacy of antiangiogenic therapy.

METHODS:

Patients with advanced HCC who had been enrolled in 3 prospective phase 2 clinical trials that evaluated either sorafenib, bevacizumab, or thalidomide in combination with a potentially antiangiogenic, metronomic, oral 5‐fluoropyrimidine as first‐line systemic therapy were included. An early AFP response was defined as a decline >20% from baseline after 2 to 4 weeks of treatment. AFP response was analyzed for its association with treatment efficacy and survival outcome.

RESULTS:

Seventy‐two patients were included for early AFP response evaluation, and 12 of those patients (17%) were classified as early AFP responders. Early AFP responders, compared with nonresponders, had a significantly improved overall response rate (33% vs 8%; P = .037) and a significantly improved disease control rate (83% vs 35%; P = .002), which was defined as the percentage of patients who had an objective response plus stable disease for a minimum of 8 weeks. AFP responders, compared with nonresponders, also had longer median progression‐free survival (PFS) (7.5 months vs 1.9 months; P = .001) and longer median overall survival (OS) (15.3 months vs 4.1 months; P = .019). In a multivariate analysis, AFP response remained a significant independent predictor of better PFS and OS.

CONCLUSIONS:

The current results indicated that an early AFP response is a useful surrogate marker to predict treatment response and prognosis in patients with advanced HCC who receive antiangiogenic therapy. Cancer 2010. © 2010 American Cancer Society.     

Prognostic impact of pERK in advanced hepatocellular carcinoma patients treated with sorafenib

Background

Sorafenib represents the standard of care targeted therapy for patients with advanced hepatocellular carcinoma (HCC). However, biomolecules that predict a patient's response to sorafenib treatment for HCC remain largely unknown. Thus, this study was designed to investigate whether phosphorylated ERK (pERK) and members of the sorafenib target or PI3K/Akt/mTOR signaling pathway predict the efficacy of sorafenib in advanced HCC patients.

Methodology

From December 2008 to October 2011, pathological specimens from 54 advanced HCC patients received sorafenib treatment were obtained. Clinicopathological variables, treatment response, survival and time to progression (TTP) were recorded. Immunophenotypical analysis was carried out using antibodies against pERK, phosphorylated S6K (pS6K), VEGFR2 and PTEN.

Results

The median overall survival (OS) and TTP were 14.2 and 3.4 months, respectively, and the disease control rate (DCR) was 59.3%. Better Eastern Cooperative Oncology Group Performance Status (ECOG PS) (95% CI: 3.27–4.93 m vs. 1.15–2.85 m, p = 0.01), Child–Pugh class A score (95% CI: 3.47–4.53 vs. 1.14–2.06 m, p < 0.01), and higher pERK (3.34–6.66 m vs. 1.33–2.67 m, p = 0.03) and VEGFR2 (3.49–6.52 m vs. 2.15–2.73 m, p = 0.04) immunohistochemical staining score were associated with increased TTP by univariate analysis. The ECOG PS (p = 0.022), Child–Pugh class (p = 0.045) and pERK staining score (p = 0.012) were found to be associated with TTP using multivariate analysis.

Conclusion

Sorafenib treatment outcome is favorable in advanced HCC patients who received tumor resection and who have a good ECOG PS and Child–Pugh class A liver function. The pERK immunohistological staining score, ECOG PS and Child–Pugh class may be helpful in determining patients most likely to benefit from sorafenib therapy.     

Pilot prognostic model of extremely poor survival among high‐risk hepatocellular carcinoma patients

BACKGROUND:

Populations with low income, economic barriers, and cultural and/or linguistic access barriers to medical care are at risk for worse cancer‐related outcomes. Medically underserved patients with hepatocellular carcinoma (HCC) have decreased survival compared with those in the Surveillance, Epidemiology, and End Results database. Given this suboptimal outcome, the high cost of HCC treatment, and unknown risk‐to‐benefit ratios of invasive therapies, the authors sought to identify a predictive model of extremely poor overall survival (OS).

METHODS:

A retrospective review of an institutional HCC database was conducted. Payor status, race, treatment, clinicopathologic, and outcome parameters were recorded. The primary outcome was OS <1 month. A logistic regression model predictive of OS <1 month was developed using backward, stepwise elimination and bootstrapping techniques.

RESULTS:

In total, 337 patients HCC (272 men and 65 women) were identified. Only 4% of patients had Medicare coverage; whereas 96% relied on publicly funded, safety‐net health programs. OS <1 month was noted in 90 patients (26.7%). There were no differences in race or sex between patients who had an OS <1 month and those with an OS >1 month. A higher percentage of patients who had an OS <1 month had advanced stage disease and did not receive therapy for HCC. Advanced liver disease, as measured by laboratory parameters and a composite score (Child‐Pugh and Model for End‐Stage Liver Disease [MELD]), alpha fetoprotein level, creatinine level, disease stage, and lack of treatment were predictors of OS <1 month.

CONCLUSIONS:

Survival for medically underserved patients with HCC remains poor. Advanced clinical stage and liver disease appear to preclude treatment, and novel methods to identify those who may benefit from palliative care/symptom control may be indicated for patients who are predicted to have poor survival. Cancer 2012. © 2012 American Cancer Society.