Impact of psoas muscle index assessed by a simple measurement method on tolerability and duration of continued treatment with sorafenib in hepatocellular carcinoma patients.

BACKGROUND: In this study, we investigated the impact of simple measurement of psoas muscle index (PMI) on the tolerability of sorafenib treatment of switch from sorafenib to regorafenib. METHOD: This retrospective study enrolled 109 patients with Child-Pugh A hepatocellular carcinoma (HCC) treated with sorafenib. Pretreatment PMI was calculated by measuring and multiplying the greatest anterior/posterior and transverse diameters of the psoas muscles on axial computed tomography images at the L3 vertebral level, and normalizing the sum of bilateral psoas muscle areas by the square of the height in meters. We, then, statistically analyzed the association between PMI and adverse events (AEs) to treatment, tolerability of sorafenib, time to treatment failure (TTF), and prognosis in patients stratified according to PMI. RESULT: Patients were divided into high PMI (n = 41) and low PMI (n = 68) groups based on the cutoff PMI values (men: 7.04 cm2/m2; women: 4.40 cm2/m2) determined by receiver operating characteristic curve analysis to determine sorafenib tolerability. Frequencies of all types of severe AEs were higher in the low PMI group (50.0%) than in the high PMI group (29.3%; P = 0.045). The high PMI group (51.2%) had greater tolerance to sorafenib than the low PMI group (25.0%; P = 0.007). Moreover, in multivariable analysis, PMI was associated with sorafenib tolerability (odds ratio 0.26; P = 0.008) and was a prognostic factor affecting TTF (hazard ratio 1.77; P = 0.021). CONCLUSION: PMI might be a predictive marker of tolerance to treatment and TTF in HCC patients receiving sorafenib treatment.

Randomized, phase II trial of sequential hepatic arterial infusion chemotherapy and sorafenib versus sorafenib alone as initial therapy for advanced hepatocellular carcinoma: SCOOP-2 trial.

BACKGROUND: The efficacy of hepatic arterial infusion chemotherapy (HAIC) for advanced hepatocellular carcinoma (HCC) remains unclear. We conducted a multi-center randomized phase II study comparing a sequential HAIC-sorafenib regimen versus sorafenib alone as an initial therapy for HCC. METHODS: Patients were randomly assigned (ratio, 1:1) to receive sequential HAIC with cisplatin followed by sorafenib (HAIC group, n = 35) or sorafenib alone (sorafenib group, n = 33) as an initial therapy. The primary endpoint was the one-year survival rate. Secondary endpoint included overall survival (OS), the 2-year survival rate, the time-to-progression (TTP), the objective response rate (ORR), the disease control rate (DCR), and safety. RESULTS: For the primary endpoint, the one-year survival rates were 46% in the HAIC group and 58% in the sorafenib group. The median OS period was 10.0 months (95% CI, 7.0-18.8) in the HAIC group and 15.2 months (95% CI, 8.2-19.7) in the sorafenib group (hazard ratio [HR], 1.08; 95% CI, 0.63 to 1.86, P = 0.78). The median TTP, ORR and DCR in the HAIC group were 2.8 months (95% CI, 1.7-5.5), 14.3, and 45.7%, respectively, while those in the sorafenib group were 3.9 months (95% CI, 2.3-6.8), 9.1, and 45.5%, respectively. No unexpected adverse events related to HAIC or sorafenib were observed in either group. CONCLUSIONS: Sequential HAIC with cisplatin and sorafenib does not improve the survival benefit, compared with sorafenib alone, when used as an initial therapy for advanced HCC. However, this study was underpowered in regard to its primary and secondary endpoints, so the results should be interpreted with caution. TRIAL REGISTRATION: UMIN ID 000006147 , registration data: August 11, 2011.

A phase 1b study of transforming growth factor-beta receptor I inhibitor galunisertib in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma.

Background Galunisertib inhibits type I transforming growth factor-beta receptor serine/threonine kinase. The primary objective of this study was to evaluate the safety and tolerability of galunisertib in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma. Patients and methods This open-label, dose-escalation, multicenter, nonrandomized phase 1b study consisted of two dose levels of galunisertib, 160 or 300 mg/day, in combination with sorafenib 800 mg/day. Galunisertib 80 mg or 150 mg was administered orally twice daily for 14 days followed by 14 days of rest plus sorafenib 400 mg administered orally twice daily for 28 days. The dose-limiting toxicity evaluation was 28 days after the first dose. Safety measures, pharmacokinetics, and antitumor activity were assessed. Results Fourteen patients, 7 at each galunisertib dose, were enrolled and treated. Three dose-limiting toxicities were reported for 2 patients. The most common treatment-emergent adverse events (TEAEs) were hypophosphatemia (14 patients [100%]), palmar-plantar erythrodysesthesia syndrome (12 patients [85.7%]), and decreased platelet count (10 patients [71.4%]). The most common grade ≥ 3 TEAEs were hypophosphatemia (10 patients [71.4%]) and palmar-plantar erythrodysesthesia syndrome (7 patients [50.0%]). No grade 5 TEAEs were reported. The pharmacokinetic profile of galunisertib in combination with sorafenib was similar to that previously reported for galunisertib. Eleven patients had a best overall response of stable disease, and 1 patient achieved a partial response by hepatocellular carcinoma-specific modified RECIST. Conclusions These data are consistent with the known safety profile for galunisertib and sorafenib and confirm tolerability of the recommended dose of galunisertib (150 mg twice daily for 14 days) in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma.

Phase I/II study of first-line combination therapy with sorafenib plus resminostat, an oral HDAC inhibitor, versus sorafenib monotherapy for advanced hepatocellular carcinoma in east Asian patients.

PURPOSE: Resminostat is an oral inhibitor of class I, IIB, and IV histone deacetylases. This phase I/II study compared the safety and efficacy of resminostat plus sorafenib versus sorafenib monotherapy as first-line therapy for advanced hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: In phase I, resminostat (400 mg or 600 mg/day on days 1 to 5 every 14 days) was administered with sorafenib (800 mg/day for 14 days) to determine the recommended dose for phase II. In phase II, patients were randomized (1:1) to sorafenib monotherapy or resminostat plus sorafenib. The primary endpoint was time-to-progression (TTP). RESULTS: Nine patients (3: 400 mg, 6: 600 mg) were enrolled in phase I, and the recommended dose of resminostat was determined to be 400 mg/day. Then 170 patients were enrolled in phase II. Median TTP/overall survival (OS) were 2.8/14.1 months with monotherapy versus 2.8/11.8 months with combination therapy (Hazard Ratio [HR]: 0.984, p = 0.925/HR: 1.046, p = 0.824). The overall incidence of adverse events was similar in both groups (98.8% versus 100.0%). However, thrombocytopenia ≥ Grade 3 was significantly more frequent in the combination therapy group (34.5% versus 2.4%, p < 0.001). Subgroup analysis revealed that median TTP/OS was 1.5/6.9 months for monotherapy versus 2.8/13.1 months for combination therapy (HR: 0.795, p = 0.392/HR: 0.567, p = 0.065) among patients with a normal-to-high baseline platelet count (≥ 150 × 103/mm3). CONCLUSIONS: In patients with advanced HCC, first-line therapy with resminostat at the recommended dose plus sorafenib showed no significant efficacy advantage over sorafenib monotherapy.

Modified response evaluation criteria in solid tumors is superior to response evaluation criteria in solid tumors for assessment of responses to sorafenib in patients with advanced hepatocellular carcinoma.

BACKGROUND: Modified response evaluation criteria in solid tumors (mRECIST) and RECIST are used to assess the effect of treatment with targeted agents for hepatocellular carcinoma (HCC). The aim of this study was to determine which set of criteria is superior in patients with advanced HCC treated with sorafenib. METHODS: A multicenter retrospective study to assess the tumor response and patient prognosis of 191 patients with HCC who had been treated with sorafenib from May 2009 through December 2011. We analyzed tumor responses as shown by contrast-enhanced computed tomography scan images according to RECIST 1.1 and mRECIST and compared the findings. RESULTS: The median duration of follow-up was 9.7 months and median overall survival was 10.8 months. Twenty-five patients (13.1 %) were assessed as responders by mRECIST and 15 (7.8 %) by RECIST 1.1. There was a significant difference in overall survival (OS) between responders and non-responders according to mRECIST (P = 0.0117), but no significant difference in OS between responders and non-responders according to RECIST 1.1 (P = 0.0722). Sixteen patients (8.4 %) had no measurable enhanced target lesions that could be assessed as required by mRECIST; however, these patients could be assessed by RECIST 1.1. According to RECIST 1.1, eight of them had stable disease (SD) and eight had progressive disease (PD). There was a significant difference in OS between these SD and PD patients (P = 0.0312). CONCLUSIONS: Patients treated with sorafenib for HCC should be evaluated by mRECIST; RECIST 1.1 is preferable only for assessment of patients with lesions that are non-measurable according to mRESIST.

Hepatocellular carcinoma: concomitant sorafenib promotes necrosis after radiofrequency ablation--propensity score matching analysis.

PURPOSE: To retrospectively compare radiofrequency ablation (RFA) combined with the multikinase inhibitor sorafenib (hereafter, sorafenib-RFA) and RFA alone in the treatment of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. Between January 2007 and December 2011, 16 patients (mean age, 72.8 years; age range 52-84 years; 10 men, six women) with HCC tumors less than 3 cm in diameter were included in the sorafenib-RFA group, and 136 patients (mean age, 72.1 years; age range, 51-86 years; 92 men, 44 women) with HCC tumors less than 3 cm in diameter were included in the RFA alone (control) group. Mean diameters of the greatest long-axis dimensions of HCC were 22.8 mm ± 4.6 (standard deviation) in the sorafenib-RFA group and 18.1 mm ± 4.4 in the control group. RFA was performed immediately after the 7-day administration of sorafenib. Propensity score matching analysis was used to adjust for potential biases. RESULTS: Fifteen of the 16 patients in the sorafenib-RFA group and 30 of the 136 patients in the control group were selected during propensity score matching. No significant differences between the sorafenib-RFA group (n = 15) and the control group (n = 30) were observed with regard to age, sex, etiology, Child-Pugh class, tumor size, puncture number, needle size, location at the liver margin, or location adjacent to a main vessel. The respective mean diameters of the greatest long- and short-axis dimensions of the RFA-induced ablated area were 46.3 mm ± 10.3 and 33.0 mm ± 6.9 in the sorafenib-RFA group and 32.9 mm ± 7.6 and 25.6 mm ± 5.7 in the control group; both of these dimensions were significantly larger in the sorafenib-RFA group (both P < .001). CONCLUSION: Sorafenib-RFA may be superior to standard RFA alone in the treatment of HCC tumors smaller than 3 cm in diameter.

[Influence of body surface area on efficacy and safety of sorafenib in advanced hepatocellular carcinoma].

UNLABELLED: Some clinical studies confirmed the efficacy and safety of sorafenib in advanced hepatocellular carcinoma(HCC), for which the standard initial dose is 400 mg twice daily. However, it is unclear whether this dosage is tolerable for patients with a low body surface area(BSA). We retrospectively analyzed the difference in efficacy and safety of sorafenib between patients with low BSA and high BSA. METHOD: From July 2009 to June 2010, 64 patients with Child-Pugh grade A cirrhosis receiving sorafenib at 4 institutions were enrolled, and divided into two groups(BSA<1. 6m2 and ≥1. 6m2). RESULTS: In BSA<1. 6m2 and BSA≥1. 6m2 groups, grade 3-4 adverse events were observed in 64. 3% and 55. 3% of patients, respectively, and subsequent discontinuation was 38. 5% and 24. 2%, respectively indicating poor compliance in the former group. The disease control rate was 33. 3% and 37. 8%, the median time-to-radiological progression(TTRP)was 2. 1 months and 3. 6 months(p=0. 003), and median survival time was 6. 6 months and 11. 2 months in low BSA and high BSA groups(p=0. 10), respectively. Multi-variate analysis showed that poor prognostic factors for TTRP were ECOG performance status of ≥1 and BSA<1. 6m2. CONCLUSION: Standard dosage seems intolerable for patients with low BSA, and results in poor prognosis.

Inflammation-based prognostic score for hepatocellular carcinoma patients on sorafenib treatment.

BACKGROUND: No reliable prognostic predictor is known for patients undergoing sorafenib treatment for advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS: In 81 patients receiving sorafenib treatment for advanced HCC, we evaluated the prognostic significance of an inflammation-based prognostic score, the Glasgow prognostic score [evidenced by an elevated C-reactive protein level (>1.0 mg/dl) and hypoalbuminemia (<3.5 g/dl)] and compared it with Child-Pugh grade, Barcelona Clinic Liver Cancer staging system, Japan Integrated Staging (JIS) score, and the performance status by Cox-proportional analysis. RESULTS: Median overall survival after sorafenib administration was 11.3 months. On multivariate analysis, Glasgow prognostic score (0 vs. 1 and 2; p<0.001), JIS score (1 and 2 vs. 3 and 4; p=0.001), and performance status (0 vs. 1; p=0.001) were found to be independently associated with survival. CONCLUSION: The Glasgow prognostic score has significant prognostic value in patients undergoing sorafenib treatment for advanced HCC.

Radiofrequency ablation of the liver: extended effect of transcatheter arterial embolization with iodized oil and gelatin sponge on histopathologic changes during follow-up in a pig model.

PURPOSE: To assess the extended effects of transcatheter arterial embolization with iodized oil and gelatin sponge on liver histopathologic changes in radiofrequency (RF)-ablated zones and the surrounding liver parenchyma in a pig model. MATERIALS AND METHODS: Eighteen consecutive pigs subjected to 36 RF applications performed immediately after segmental embolization with iodized oil and gelatin sponge to the left lobe of the liver (embolization/RF ablation) were euthanized immediately after the procedure or 1 or 4 weeks later. The right lobes were used as controls for RF applications without embolization. The ablated zones and the surrounding liver parenchyma were measured and examined histopathologically. RESULTS: The average maximum ablated zone was significantly larger in the embolization/RF ablation specimens than in the RF ablation-alone specimens at all three follow-up time points. Ten of the 12 specimens obtained immediately after embolization/RF ablation showed wide hemorrhagic areas spreading to the periphery of the liver and microscopically showed marked intralobular congestion with sinusoidal dilation. This hemorrhagic change had disappeared in all the specimens obtained 1 week after embolization/RF ablation, but 10 of the 12 specimens showed wedge-shaped areas of segmental degenerative parenchyma beginning at the ablated zone and extending to the periphery of the liver; these were microscopically revealed to be areas of coagulative necrosis, indicating hepatic infarction. The sizes of these necrotic zones had decreased at 4 weeks after embolization/RF ablation. CONCLUSIONS: RF ablation performed immediately after embolization in normal pig liver induced large ablated zones accompanied by wedge-shaped areas of segmental infarction.

Extension of radiofrequency ablation of the liver by transcatheter arterial embolization with iodized oil and gelatin sponge: results in a pig model.

PURPOSE: To determine whether transcatheter arterial embolization (TAE) with iodized oil and gelatin sponge particles can be used to expand radiofrequency (RF)-induced coagulation necrosis, the morphology and histologic characteristics of ablation lesions were evaluated in the normal pig liver after three different TAE procedures. MATERIALS AND METHODS: Ten consecutive animals with 33 ablation lesions produced with an RF ablation system were randomly assigned to one of three treatment groups and a control group: a group treated with TAE with iodized oil, a group treated with TAE with gelatin sponge, a group treated with TAE with iodized oil and gelatin sponge, and a control group in which TAE was not performed. After the completion of ablation, the lesions were excised for gross and histologic examination. RESULTS: The longest and shortest diameters of ablation lesions were greatest in the group treated with TAE with iodized oil and gelatin sponge, followed by the groups treated with TAE with gelatin sponge and TAE with iodized oil (P < .05 vs controls, respectively). The hemorrhagic rim was also widest in the group treated with TAE with iodized oil and gelatin sponge (P < .05 vs controls), and it spread toward the liver periphery like a segmental hemorrhagic area adjacent to the ablation lesion. Histochemical staining for lactate dehydrogenase, maleate dehydrogenase, and nicotinamide adenine dinucleotide diaphorase showed what appeared to be 100% cellular destruction in all the ablation lesions and their hemorrhagic rims. CONCLUSION: RF ablation combined with TAE with iodized oil and gelatin sponge induces the greatest area of coagulation necrosis accompanied by peripherally spreading segmental necrosis in normal pig liver tissue.

[Radiofrequency ablation combined with transcatheter arterial chemoembolization for hepatocellular carcinoma--CT examination during the follow-up period].

Radiofrequency ablation (RFA) combined with transcatheter arterial embolization (TAE) can increase the volume of coagulation necrosis to treat patients with hepatocellular carcinoma. Furthermore, in clinical practice, RFA combined with TAE using iodized oil and gelatin sponge often induced the sub-segmental or segmental necrosis toward the liver periphery of the ablated lesion. In this study, we compared the CT findings and histological characteristics of peripherally spreading necrosis induced by this combination therapy for 12 patients with hepatocellular carcinoma. In all cases, complete necrosis of ablated lesions and peripherally spreading necrotic areas were confirmed by CT examination. The histochemical (lactate-dehydrogenase, maleate-dehydrogenase, and NADPH-diaphorase) stained specimens, biopsies from ablated lesions and peripherally spreading necrotic areas, were absent suggesting a 100% cellular destruction. No incomplete local treatments after the therapy were obtained during the 4-26 months of follow-up periods. We conclude that RFA combined with TAE using iodized oil and gelatin sponge makes it possible to induce the segmental or sub-segmental necrosis including tumors.

Hepatocellular carcinoma: a case of extrahepatic seeding after percutaneous radiofrequency ablation using an expandable needle electrode.

A 2.5-cm diameter, exophytic seeding of hepatocellular carcinoma was detected by contrast-enhanced computed tomography in a 76-year-old man. He had previously undergone a radiofrequency ablation therapy with an expandable, ten-hook needle electrode for the treatment of a 1.5-cm hepatocellular carcinoma in liver segment VI. Ultrasound-guided fine needle biopsy revealed that this hepatocellular carcinoma was moderately differentiated, as initial tumor was. An additional radiofrequency ablation achieved complete ablation of this neoplastic mass on contrast-enhanced computed tomography scanning. Recurrences were not found for eight months after. To prevent tumor seeding, using thermocoagulation when retracting the needle electrode may be useful.