Prognostic Scoring Models for Patients Undergoing Sorafenib Treatment for Advanced Stage Hepatocellular Carcinoma in Real-Life Practice.

BACKGROUND: The purpose of this study was to build prognostic models capable of estimating the outcomes of individual sorafenib-treated advanced stage hepatocellular carcinoma (HCC) patients based on specific patient and tumor factors. METHODS: A parametric model for time-to-event data was used to construct scoring systems based on the intent-to-treat data set from 480 sorafenib-treated patients with advanced stage HCC: 356 for derivation and 124 for validation. Clinical parameters included in the models were based on importance variable scores generated by a random forest approach and bootstrap resampling. The model's accuracy was internally and externally assessed using the time-dependent C-index of discrimination and a Hosmer-Lemeshow type test for calibration. RESULTS: The models generated for time-to-progression and overall survival based on Child-Pugh score, serum α-fetoprotein, tumor morphology, and vascular invasion and/or extrahepatic involvement had good calibration and discrimination abilities, with C-indexes of 0.669 (3 mo progression) and 0.809 (6 mo survival), respectively. External validation results also showed that these models performed well in terms of goodness-of-fit and discrimination (C-index: 0.746 for 3 mo progression and 0.875 for 6 mo survival). Receiver operating characteristic curve analysis in the validation patients indicated that these models have better predictive power than Child-Pugh scores (C-index: 0.686 for 3 mo progression and 0.777 for 6 mo survival). CONCLUSIONS: The prognostic tools developed to quantify the potential outcomes for progression and survival expected from sorafenib treatment can serve as useful clinical aids in personalized decision making regarding treatment in advanced stage HCC patients.

Comparison of chemoembolization with and without radiation therapy and sorafenib for advanced hepatocellular carcinoma with portal vein tumor thrombosis: a propensity score analysis.

PURPOSE: To compare efficacy of transarterial chemoembolization with and without radiation therapy (RT) versus sorafenib for advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). MATERIALS AND METHODS: This single-center retrospective study involved 557 patients with HCC with PVTT who initially received chemoembolization (1997-2002; n = 295), chemoembolization and RT (2003-2008; n = 196), or sorafenib (2009-2012; n = 66) according to eligibility criteria among an initial population of 617. The three groups were divided into three pairs (chemoembolization vs chemoembolization/RT, chemoembolization vs sorafenib, and chemoembolization/RT vs sorafenib), and time to progression (TTP) and overall survival (OS) were compared by propensity-score analyses. RESULTS: The chemoembolization/RT group had longer median TTP and OS than the chemoembolization-alone and sorafenib groups (P < .001). Multivariate Cox analysis revealed that chemoembolization/RT treatment was an independent predictor of favorable TTP and OS. In the matched cohort, median TTP and OS were significantly longer in the chemoembolization/RT group than the chemoembolization-alone group (102 pairs; TTP, 8.7 mo vs 3.6 mo [P < .001]; OS, 11.4 mo vs 7.4 mo [P = .023]) or the sorafenib group (30 pairs; TTP, 5.1 mo vs 1.6 mo [P < .001]; OS, 8.2 mo vs 3.2 mo [P < .001]), in agreement with the inverse probability of treatment weighted (IPTW) outcomes. In matching analyses, the chemoembolization-alone group had longer median TTP and OS than the sorafenib group (46 pairs; TTP, 3.4 mo vs 1.8 mo [P < .001]; OS, 5.9 mo vs 4.4 mo [P = .003]). There was no significant difference in terms of OS with the IPTW approach (P = .108), but there was one in terms of TTP (P < .001). CONCLUSIONS: Within the limitation of a retrospective study, the present data indicate that transarterial chemoembolization combined with RT could be considered as an alternative to the standard sorafenib in the treatment of patients with advanced-stage HCC with PVTT.

Stereotactic body radiation therapy as an alternative treatment for small hepatocellular carcinoma.

BACKGROUND: Even with early stage hepatocellular carcinoma (HCC), patients are often ineligible for surgical resection, transplantation, or local ablation due to advanced cirrhosis, donor shortage, or difficult location. Stereotactic body radiation therapy (SBRT) has been established as a standard treatment option for patients with stage I lung cancer, who are not eligible for surgery, and may be a promising alternative treatment for patients with small HCC who are not eligible for curative treatment. MATERIALS AND METHODS: A registry database of 93 patients who were treated with SBRT for HCC between 2007 and 2009 was analyzed. A dose of 10-20 Gy per fraction was given over 3-4 consecutive days, resulting in a total dose of 30-60 Gy. The tumor response was determined using dynamic computed tomography or magnetic resonance imaging, which was performed 3 months after completion of SBRT. RESULTS: The median follow-up period was 25.6 months. Median size of tumors was 2 cm (range: 1-6 cm). Overall patients' survival rates at 1 and 3 years were 86.0% and 53.8%, respectively. Complete and partial tumor response were achieved in 15.5% and 45.7% of patients, respectively. Local recurrence-free survival rate was 92.1% at 3 years. Most local failures were found in patients with HCCs > 3 cm, and local control rate at 3 years was 76.3% in patients with HCC > 3 cm, 93.3% in patients with tumors between 2.1-3 cm, and 100% in patients with tumors ≤ 2 cm, respectively. Out-of-field intrahepatic recurrence-free survival rates at 1 and 3 years were 51.9% and 32.4%, respectively. Grade ≥ 3 hepatic toxicity was observed in 6 (6.5%). CONCLUSIONS: SBRT was effective in local control of small HCC. SBRT may be a promising alternative treatment for patients with small HCC which is unsuitable for other curative therapy.

Sorafenib alone versus sorafenib combined with transarterial chemoembolization for advanced-stage hepatocellular carcinoma: results of propensity score analyses.

PURPOSE: To compare the time to progression (TTP) and overall survival (OS) in patients with advanced-stage hepatocellular carcinoma (HCC) who are undergoing sorafenib treatment combined with transarterial chemoembolization (TACE) versus sorafenib monotherapy. MATERIALS AND METHODS: The retrospective analysis of the data was approved by the institutional review board, and the requirement to obtain informed consent was waived. Of 355 patients with advanced-stage HCC (Barcelona Clinic Liver Cancer stage C) who were undergoing sorafenib therapy for at least 5 weeks between April 2007 and July 2011, 164 (46.2%) underwent repeat TACE (or chemolipiodolization if indicated) along with sorafenib therapy (combined group); the remaining 191 patients (53.8%) received sorafenib alone (monotherapy group). The median patient age was 53 years (range, 22-84 years). The median age was 53 years (range, 26-84 years) for men and 56 years (range, 22-75 years) for women. Propensity score-based methods were used to minimize bias when evaluating TTP on the basis of modified Response Evaluation Criteria in Solid Tumors and OS. Statistical analysis was performed with the Kaplan-Meier method by using the log-rank test and Cox regression models. RESULTS: In the combined and monotherapy groups, respectively, 64.6% and 49.2% of patients had vascular invasion, 87.8% and 91.1% had extrahepatic metastasis, and 54.3% and 47.1% had both. During follow-up (median duration, 5.5 months), the median TTP and OS in the combined group were longer than those in the monotherapy group (TTP: 2.5 months vs 2.1 months, respectively, P = .008; OS: 8.9 months vs 5.9 months, P = .009). At univariate and subsequent multivariate analyses, additional TACE was an independent predictor of favorable TTP and OS (adjusted hazard ratio: 0.74 and 0.57, respectively; P < .05 for both), consistent with the outcomes of inverse probability of treatment weighting. In the propensity score-matched cohort (96 pairs), the median TTP in the combined group was significantly longer than that in the monotherapy group (2.7 months vs 2.1 months, respectively; P = .011), but median OS was not (9.1 months vs 6.7 months, P = .21). CONCLUSION: In this retrospective study, TACE plus sorafenib was superior to sorafenib alone with respect to TTP in patients with advanced-stage HCC, although it may or may not improve OS. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13130150/-/DC1.

Predisposing factors of hepatocellular carcinoma recurrence following complete remission in response to transarterial chemoembolization.

BACKGROUND AND AIM: The aim of our study was to determine the predictors of recurrences in hepatocellular carcinoma (HCC) patients who had achieved complete remission (CR) by transarterial chemoembolization (TACE). METHODS: A total of 220 consecutive HCC patients who had achieved CR by TACE were followed for a median 72 months. CR was defined as complete lipiodol uptake based on the results of lipiodol-computed tomography 4 weeks after TACE and no additional tumor staining on the follow-up angiography. Recurrence patterns were classified as local recurrence and secondary tumor, respectively, in relation to the location of recurrence; early and late recurrence were classified in relation to recurrence time. RESULTS: Recurrence of HCC was observed in 169 patients (77 %), of whom 91 (54 %) had local recurrences, 61 (36 %) had secondary tumor, and 17 (10 %) had both. There were 45 (27 %) early and 124 (73 %) late recurrences. Local recurrence developed more frequently in patients with early recurrence than in those with late recurrence (62 vs. 51 %, respectively), while secondary tumor was detected more commonly in patients with late recurrence than in those with early recurrence (39 vs. 29 %, respectively; P < 0.001). In multivariate analyses, multinodularity [hazard ratio (HR) 2.351, P = 0.023] and a persistently high serum alpha-fetoprotein level following CR (HR 3.173, P < 0.001) were significant predictors of early recurrence. Older age (≥ 60 years; HR 1.531, P = 0.043), advanced Child-Pugh class (HR 1.983, P = 0.002), and the association with cirrhosis (HR 1.756, P = 0.028) were predictors of late recurrence following CR. CONCLUSIONS: Early recurrences following CR by TACE may be due mainly to undetectable remaining tumors, whereas late recurrences may be caused by newly appearing tumors in patients with a background of advanced cirrhotic liver.

Optimal measurement modality and method for evaluation of responses to transarterial chemoembolization of hepatocellular carcinoma based on enhancement criteria.

PURPOSE: To determine the usefulness of enhancement by iodized oil deposits on computed tomography (CT) following transarterial chemoembolization for hepatocellular carcinoma (HCC), and to compare the reliability of such CT imaging with that of magnetic resonance (MR) imaging. MATERIALS AND METHODS: Fifty-one patients for whom resected or explanted livers containing chemoembolized HCC lesions of at least 1 cm were available. Imaging responses were determined based on modified Response Evaluation Criteria In Solid Tumors (mRECIST) and European Association for the Study of the Liver (EASL) criteria for 59 target tumors on CT and MR scans before surgery. CT-based evaluation was performed per mRECIST and EASL criteria, considering iodized oil retention as indicating necrosis and, alternatively, as enhancing viable tissue ("mRECIST-Lipiodol" and "EASL-Lipiodol"). Pathologic necrosis was graded as 100%, 50%-99%, or less than 50%. RESULTS: Goodman-Kruskal γ-values for radiologic-pathologic correlation were greater than 0.95 for mRECIST and EASL criteria on CT or MR imaging. However, mRECIST-Lipiodol and EASL-Lipiodol measurements showed weaker correlation with pathologic findings, with γ-values of 0.797 and 0.846, respectively. With respect to intermethod agreement, weighted γ-values for mRECIST by CT and MR, and for EASL criteria by CT and MR, both exceeded 0.80, whereas mRECIST-Lipiodol and EASL-Lipiodol showed only moderate levels of agreement with mRECIST/EASL criteria by CT or MR imaging, with γ-values of 0.522-0.631. CONCLUSIONS: Response estimation based on measurement of iodized oil deposits as necrosis on CT when applying enhancement criteria after chemoembolization for HCC correlated well with actual pathologic class, and agreed with MR-based evaluation.

Sorafenib dose escalation in the treatment of advanced hepatocellular carcinoma.

OBJECTIVE: Although sorafenib has shown survival benefits in patients with hepatocellular carcinoma (HCC), many patients require discontinuation or dose reduction due to adverse events (AEs). We applied a dose escalation scheme to increase patient compliance and avoid AEs. METHODS: Of 267 HCC patients treated with first-line sorafenib, 25 at increased risk of AEs, including those with advanced liver cirrhosis, a history of liver transplantation, or cytopenia, received the dose escalation scheme. They started on a reduced dose of sorafenib which increased to the standard dosage according to tolerance in each patient. We analyzed the efficacy and safety of the dose escalation scheme. RESULTS: Patients with risk factors showed a lower disease control rate, shorter survival, and more frequently grade 3/4 AEs. Among patients presenting risk factors, the dose scheme did not affect the efficacy of sorafenib or survival, but reduced the incidence of grade 3/4 AEs. Rates of sorafenib discontinuation and dose reduction related to AEs were also lower in the dose escalation group. Dose escalation to the standard dose of sorafenib was achieved in 16 of the 25 patients in the dose escalation group (64.0%). After 2 weeks, the dose intensity of sorafenib did not differ between the two dose schemes. CONCLUSIONS: The sorafenib dose escalation scheme may increase patient compliance and tolerance to prolonged treatment, thus enhancing the efficacy of sorafenib in patients at high risk of AEs or with poor tolerance. Further prospective analyses are needed to determine the usefulness of the dose escalation scheme.

Radiotherapy plus transarterial chemoembolization for hepatocellular carcinoma invading the portal vein: long-term patient outcomes.

PURPOSE: We have evaluated the clinical outcomes of patients after transarterial chemoembolization (TACE) and 3-dimensional conformal radiotherapy for hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). METHODS AND MATERIALS: A registry database of 412 patients treated with TACE and three-dimensional conformal radiotherapy for HCC with PVTT between August 2002 and August 2008 were analyzed retrospectively. The radiotherapy volume included the PVTT, with a 2- to 3-cm margin to cover adjacent HCC. Intrahepatic primary HCC was managed by TACE before or after radiotherapy. RESULTS: Median patient age was 52 years old, and 88.1% of patients were male. Main or bilateral PVTT was observed in 200 (48.5%) patients. Median radiation dose was 40 Gy (range, 21-60 Gy) delivered in 2- to 5-Gy fractions. We found that 3.6% of patients achieved a complete response and that 24.3% of patients achieved a partial response. The response and progression-free rates of PVTT were 39.6% and 85.6%, respectively. Median patient survival was 10.6 months, and the 1- and 2-year survival rates were 42.5% and 22.8%, respectively. Significant independent variables associated with overall survival included advanced tumor stage, alpha-fetoprotein level, degree of PVTT, and response to radiotherapy. Forty-one patients (10.0%) showed grade 3-4 hepatic toxicity during or 3 months after completion of radiotherapy. Grades 2-3 gastroduodenal complications were observed in 15 patients (3.6%). CONCLUSIONS: Radiotherapy is a safe and effective treatment for PVTT in patients with HCC. These results suggested that the combination of TACE and radiotherapy is a treatment option for relieving and/or stabilizing PVTT in patients with advanced HCC.

Sorafenib for hepatocellular carcinoma according to Child-Pugh class of liver function.

PURPOSE: We compared the efficacy and safety of sorafenib in patients with Child-Pugh (CP) class B and CP class A. METHODS: Clinical data from 267 patients with HCC who had been treated with sorafenib were reviewed. Patients were grouped according to CP score (5-6, 7, and 8-9), and their tumor response, tolerance, and survival were assessed. RESULTS: Median patient age was 55 years, and 87.6% were men. Gender, HCC etiology, and extrahepatic metastasis did not differ according to CP score. Of the 225 evaluable patients, 4 achieved partial response and 121 achieved stable disease, making the disease control rate 46.8%. DCR was higher in patients with CP A than CP B score, but did not differ between those with CP scores of 7 and 8-9. The incidence rates of grade 3/4 toxicities did not differ according to CP score. Many patients with CP score 8-9 (26.3%) had to stop sorafenib due to cirrhosis-related complications. At a median follow-up of 15.6 months, the median time to progression and overall survival of all patients were 2.6 and 7.9 months, respectively. OS was greater in patients with CP score 5-6 than in patients with CP scores of 7 or 8-9. CONCLUSIONS: Sorafenib efficacy and survival outcomes were worse in patients with CP B function. Patients with a CP score of 7 had the same incidence of adverse events and cirrhosis-related complications as those with CP A liver function, suggesting that the former can be included in clinical trials of new agents.

Clinical outcome of 251 patients with extrahepatic metastasis at initial diagnosis of hepatocellular carcinoma: does transarterial chemoembolization improve survival in these patients?

BACKGROUND AND AIMS: The therapeutic efficacy of transarterial chemoembolization (TACE) has not been evaluated in hepatocellular carcinoma (HCC) patients with extrahepatic metastasis. We investigated the efficacy of TACE with/without systemic chemotherapy (s-chemo) in these patients. METHODS: We performed a survival analysis of consecutive HCC patients with extrahepatic metastasis, diagnosed at initial presentation according to treatment modality after stratification, using the Child-Pugh classification and intrahepatic HCC T stage, retrospectively. RESULTS: Between 2005 and 2007, 251 patients were newly diagnosed with HCC involving extrahepatic metastasis at our institution. Among those, 226 were classified as Child-Pugh A-B and the other 25, Child-Pugh C. Within the Child-Pugh A-B group, repeated TACE or transarterial chemoinfusion (TACI) was performed with/without s-chemo in 171 patients. Eight of 226 received s-chemo alone, and 47, conservative management (CM) alone. The median survival time of patients treated with TACE/TACI with s-chemo, TACE/TACI alone, and CM was 10, 5, and 2.9 months in patients classified as Child-Pugh A and T3-stage HCC (TACE/TACI with s-chemo vs CM, P=0.0354; TACE/TACI alone vs CM, P=0.0553) and 7.1, 2.6, and 1.6 months in Child-Pugh B and T3-stage patients, respectively (TACE/TACI with s-chemo vs CM, P=0.0097; TACE/TACI alone vs CM, P<0.0001). Individual treatment with TACE/TACI or sorafenib showed independent prognostic significance in the multivariate analysis. CONCLUSION: Repeated TACE could show significant survival benefits in metastatic HCC patients with conserved liver function and intrahepatic HCC T3 stage. The survival data of our study could be used as a historical control for TACE monotherapy in future clinical trials evaluating combination treatments containing TACE in these patients.

Therapeutic efficacy of transcatheter arterial chemoembolization as compared with hepatic resection in hepatocellular carcinoma patients with compensated liver function in a hepatitis B virus-endemic area: a prospective cohort study.

PURPOSE: Identifying a special subgroup of hepatocellular carcinoma (HCC) patients who may benefit from transcatheter arterial chemoembolization (TACE) when compared with the standard treatment of hepatic resection (HR) warrants research in Asian countries. PATIENTS AND METHODS: From January 1993 to December 1994, 182 patients with operable HCC (Child-Pugh class A and International Union Against Cancer [UICC] stage T1-3N0M0) were enrolled. After initial TACE and lipiodol computed tomography, 91 received HR and 91, who refused the operation, received repeated sessions of TACE. After stratification according to the tumor stage (UICC and Cancer of the Liver Italian Program [CLIP]) and lipiodol retention pattern, the survival rates of the two treatment groups were compared. The median follow-up period was 83 months. RESULTS: As of December 31, 2000, 48 patients who underwent HR and 68 patients who underwent TACE had died. In a subgroup analysis according to tumor stage, the HR group survival rate was significantly higher than the TACE group in both UICC T1-2N0M0 (P =.0058) and CLIP 0 (P =.0027) subgroups. However, there was no significant difference in either UICC T3N0M0 (P =.7512) or CLIP 1-2 (P =.5366) subgroups. Even in patients with UICC T1-2N0M0 HCC, when lipiodol was compactly retained, the survival rate of the HR group was comparable to that of the TACE group (P =.0596). CONCLUSION: TACE proved to be as effective as HR in the subpopulations with UICC T3N0M0 or CLIP 1-2 HCC and adequate liver function, and even with UICC T1-2N0M0 HCC when lipiodol was compactly retained in the tumor. In such cases, the choice of treatment modality between TACE and HR may be left to the patient's preference.