Preliminary results of the Phase 1 Lip-Re I clinical trial: biodistribution and dosimetry assessments in hepatocellular carcinoma patients treated with 188Re-SSS Lipiodol radioembolization.

PURPOSE: This study sought to provide preliminary results on the biodistribution and dosimetry following intra-arterial liver injection of 188Re-SSS Lipiodol on hepatocellular carcinoma patients included in the Phase I Lip-Re 1 study. METHODS: Results of the first six patients included are reported. Analysis of the 188Re-SSS Lipiodol biodistribution was based on planar scintigraphic and tomoscintigraphic (SPECT) studies performed at 1, 6, 24, 48, and 72 h post-administration. Quantification in blood, urine, and stool samples was performed. Determination of the tumour to non-tumour uptake ratio (T/NT) was calculated. Absorbed doses to target organs and tumours were evaluated using the MIRD formalism. RESULTS: The mean injected activity of 188Re-SSS Lipiodol was 1645 ± 361 MBq. Uptakes were seen in the liver (tumour and healthy liver) and the lungs only. All these uptakes were stable over time. A mean 1.4 ± 0.7% of 188Re-SSS Lipiodol administered was detected in serum samples at 6 h, declining rapidly thereafter. On average, 1.5 ± 1.6% of administered activity was eliminated in urine and feces over 72 h. Overall, 90.7 ± 1.6% of detected activity on SPECT studies was found in the liver (74.9 ± 1.8% in tumours and 19.1 ± 1.7% in the healthy liver) and 9.3 ± 1.6% in the lungs (5.7 ± 1.1% in right and 3.7 ± 0.5% in left lungs). Mean doses absorbed were 7.9 ± 3.7Gy to the whole liver, 42.7 ± 34.0Gy to the tumours, 10.2 ± 3.7Gy to the healthy liver, and 1.5 ± 1.2Gy to the lungs. Four patients had stable disease on CT scans at 2 months. The first patient with rapidly progressive disease died at 1 month, most probably of massive tumour progression. Due to this early death and using a conservative approach, the trial independent evaluation committee decided to consider this event as a treatment-related toxicity. CONCLUSION: 188Re-SSS Lipiodol has a favorable biodistribution profile concerning radioembolization, with the highest in-vivo stability among all radiolabeled Lipiodol compounds reported to date. These preliminary results must be further confirmed while completing this Phase I Lip Re1 study.

Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: Additional analyses from the phase III RESORCE trial.

BACKGROUND & AIMS: The RESORCE trial showed that regorafenib improves overall survival (OS) in patients with hepatocellular carcinoma progressing during sorafenib treatment (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.50-0.78; p <0.0001). This exploratory analysis describes outcomes of sequential treatment with sorafenib followed by regorafenib. METHODS: In RESORCE, 573 patients were randomized 2:1 to regorafenib 160 mg/day or placebo for 3 weeks on/1 week off. Efficacy and safety were evaluated by last sorafenib dose. The time from the start of sorafenib to death was assessed. Time to progression (TTP) in RESORCE was analyzed by TTP during prior sorafenib treatment. RESULTS: HRs (regorafenib/placebo) for OS by last sorafenib dose were similar (0.67 for 800 mg/day; 0.68 for <800 mg/day). Rates of grade 3, 4, and 5 adverse events with regorafenib by last sorafenib dose (800 mg/day vs. <800 mg/day) were 52%, 11%, and 15% vs. 60%, 10%, and 12%, respectively. Median times (95% CI) from the start of sorafenib to death were 26.0 months (22.6-28.1) for regorafenib and 19.2 months (16.3-22.8) for placebo. Median time from the start of sorafenib to progression on sorafenib was 7.2 months for the regorafenib arm and 7.1 months for the placebo arm. An analysis of TTP in RESORCE in subgroups defined by TTP during prior sorafenib in quartiles (Q) showed HRs (regorafenib/placebo; 95% CI) of 0.66 (0.45-0.96; Q1); 0.26 (0.17-0.40; Q2); 0.40 (0.27-0.60; Q3); and 0.54 (0.36-0.81; Q4). CONCLUSIONS: These exploratory analyses show that regorafenib conferred a clinical benefit regardless of the last sorafenib dose or TTP on prior sorafenib. Rates of adverse events were generally similar regardless of the last sorafenib dose. LAY SUMMARY: This analysis examined characteristics and outcomes of patients with hepatocellular carcinoma who were treated with regorafenib after they had disease progression during sorafenib treatment. Regorafenib provided clinical benefit to patients regardless of the pace of their disease progression during prior sorafenib treatment and regardless of their last sorafenib dose. The sequence of sorafenib followed by regorafenib for hepatocellular carcinoma may extend survival beyond what has been previously reported. ClinicalTrials.gov NCT01774344.

Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: There are no systemic treatments for patients with hepatocellular carcinoma (HCC) whose disease progresses during sorafenib treatment. We aimed to assess the efficacy and safety of regorafenib in patients with HCC who have progressed during sorafenib treatment. METHODS: In this randomised, double-blind, parallel-group, phase 3 trial done at 152 sites in 21 countries, adults with HCC who tolerated sorafenib (≥400 mg/day for ≥20 of last 28 days of treatment), progressed on sorafenib, and had Child-Pugh A liver function were enrolled. Participants were randomly assigned (2:1) by a computer-generated randomisation list and interactive voice response system and stratified by geographical region, Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic disease, and α-fetoprotein level to best supportive care plus oral regorafenib 160 mg or placebo once daily during weeks 1-3 of each 4-week cycle. Investigators, patients, and the funder were masked to treatment assignment. The primary endpoint was overall survival (defined as time from randomisation to death due to any cause) and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01774344. FINDINGS: Between May 14, 2013, and Dec 31, 2015, 843 patients were screened, of whom 573 were enrolled and randomised (379 to regorafenib and 194 to placebo; population for efficacy analyses), and 567 initiated treatment (374 received regorafenib and 193 received placebo; population for safety analyses). Regorafenib improved overall survival with a hazard ratio of 0·63 (95% CI 0·50-0·79; one-sided p<0·0001); median survival was 10·6 months (95% CI 9·1-12·1) for regorafenib versus 7·8 months (6·3-8·8) for placebo. Adverse events were reported in all regorafenib recipients (374 [100%] of 374) and 179 (93%) of 193 placebo recipients. The most common clinically relevant grade 3 or 4 treatment-emergent events were hypertension (57 patients [15%] in the regorafenib group vs nine patients [5%] in the placebo group), hand-foot skin reaction (47 patients [13%] vs one [1%]), fatigue (34 patients [9%] vs nine patients [5%]), and diarrhoea (12 patients [3%] vs no patients). Of the 88 deaths (grade 5 adverse events) reported during the study (50 patients [13%] assigned to regorafenib and 38 [20%] assigned to placebo), seven (2%) were considered by the investigator to be related to study drug in the regorafenib group and two (1%) in the placebo group, including two patients (1%) with hepatic failure in the placebo group. INTERPRETATION: Regorafenib is the only systemic treatment shown to provide survival benefit in HCC patients progressing on sorafenib treatment. Future trials should explore combinations of regorafenib with other systemic agents and third-line treatments for patients who fail or who do not tolerate the sequence of sorafenib and regorafenib. FUNDING: Bayer.

Selective internal radiation therapy compared with sorafenib for hepatocellular carcinoma with portal vein thrombosis.

PURPOSE: Tumoural portal vein thrombosis (PVT) is a major prognostic factor in hepatocellular carcinoma (HCC). The efficacy of sorafenib, the only treatment approved at an advanced stage, is limited. Based on previous data, selective internal radiation therapy (SIRT), or (90)Y radioembolization, seems an interesting option. We aimed to compare both treatments in this population. METHODS: We retrospectively compared patients treated in two centres for HCC with tumoural PVT. We compared overall survival (OS) between patients treated with SIRT and patients treated with sorafenib. Analyses were performed before and after 1:1 matching with a propensity score for controlling indication bias, using a Cox proportional hazards model. RESULTS: A total of 151 patients were analysed, 34 patients treated with SIRT and 117 patients treated with sorafenib only. In the whole population, SIRT was associated with a higher median OS as compared with sorafenib: 18.8 vs 6.5 months (log-rank p < 0.001). There was an imbalance of baseline characteristics between patients treated by SIRT and sorafenib, which justified patient matching with use of a propensity score: 24 patients treated with SIRT could be matched with 24 patients treated with sorafenib. OS was estimated with a median of 26.2 vs 8.7 months in patients treated with SIRT vs sorafenib, respectively (log-rank p = 0.054). Before and after patient matching, the adjusted hazard ratio related to treatment by SIRT was estimated at 0.62 [95 % confidence interval (CI) 0.39-0.97] (p = 0.037) and 0.40 (95 % CI 0.19-0.82) (p = 0.013), respectively. CONCLUSION: SIRT seems more effective than sorafenib in patients presenting with HCC and tumoural PVT. This hypothesis is being tested in prospective randomized trials.

Gemcitabine and Oxaliplatin, but Not Sorafenib or Paclitaxel, Have a Synergistic Effect with Yttrium-90 in Reducing Hepatocellular Carcinoma and Cholangiocarcinoma Cell Line Viability.

Synergy between yttrium-90 (90Y) and antineoplastic drugs was investigated. Viability of HepaRG (hepatocellular carcinoma) and HuCCT1 (cholangiocarcinoma) cells was studied through a tetrazolium dye reduction assay. A combination index (CI) was calculated, with CI < 1 denoting synergy and CI > 1 denoting antagonism. In HepaRG cells, gemcitabine showed synergy with 90Y (CI = 0.70 [95% confidence interval = 0.65-0.75]), whereas oxaliplatin (CI = 1.15 [1.08-1.21]), paclitaxel (CI = 1.26 [1.15-1.37]), and sorafenib (CI = 1.77 [1.65-1.89]) showed antagonism. In HuCCT1 cells, gemcitabine (CI = 0.54 [0.50-0.58]) and oxaliplatin (CI = 0.86 [0.82-0.90]) showed synergy with 90Y, whereas paclitaxel (CI = 1.18 [1.09-1.27]) and sorafenib (CI = 1.21 [1.12-1.30]) showed antagonism. These results suggest that gemcitabine and oxaliplatin should be tested in combination with 90Y radioembolization for treatment of liver cancer.

In vitro demonstration of synergy/additivity between (188)rhenium and sorafenib on hepatoma lines: preliminary results.

BACKGROUND: Hepatocellular carcinoma is generally diagnosed at advanced stages, for which only palliative treatments are possible by intra-arterial route or by targeted therapies. Among these treatments, metabolic radiotherapy using (90)-yttrium or (188)Re and sorafenib are two options adopted in monotherapy. MATERIALS AND METHODS: We address the question of a possible synergy arising from the combination of these two treatments. Two primary malignant hepatoma cell lines, N1S1 (murine HCC) and HepG2 (human hepatoblastoma) were treated in media containing increasing concentrations of sorafenib with/without (188)Re to assess the cellular toxicities of each treatment alone and in combination. The combination index method was used to look for synergy or additivity. RESULTS: A synergistic advantage of a treatment combining (188)Re and sorafenib is shown in vitro on hepatoma cell lines. CONCLUSION: This combined approach is promising and now needs to be confirmed by more complex in vitro models integrating the tumoral stroma, as well as by in vivo studies.

Comparison of tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST in patients treated with sorafenib for hepatocellular carcinoma.

BACKGROUND: A significant improvement in overall survival (OS) was demonstrated in patients with advanced hepatocellular carcinoma (HCC) who received sorafenib (Sor) in the Sorafenib HCC Assessment Randomized Protocol (SHARP) study, in contrast to a response rate (RR) of 2% assessed according to Response Evaluation Criteria in Solid Tumors (RECIST). Modified RECIST (mRECIST) were developed to assess the response in patients with HCC, based on measurement of viable tumor with arterial enhancement on a computed tomography (CT) scan. In the current study, mRECIST were evaluated and were compared with RECIST in patients who received Sor for advanced HCC. METHODS: The authors retrospectively analyzed 53 patients who received Sor for advanced HCC. Patients must to have undergone a 4-phase CT scan before treatment and repeatedly thereafter. CT scans were analyzed using RECIST 1.1 and mRECIST. RESULTS: The rates of objective response (OR), stable disease (SD), and progressive disease (PD) were 2%, 79%, and 19%, respectively, according to RECIST and 23%, 57%, and 21%, respectively, according to mRECIST (P < .001). Patients who achieved an OR according to mRECIST had a longer OS than nonresponding patients with SD or PD (median OS, 18 months and 8 months, respectively; P = .013). In the 42 patients who achieved SD according to RECIST, OS differed depending on tumor response according to mRECIST, with a median OS of 17 months, 10 months, and 4 months for patients who achieved an OR (n = 11), SD (n = 29), and PD (n = 2), respectively (P = .016). CONCLUSIONS: The current series validated mRECIST in patients who received Sor for advanced HCC. The majority of patients who had SD according to RECIST had a different prognosis according to mRECIST. The results indicated that, for patients with HCC, mRECIST should be used for the standard assessment of treatment efficacy, particularly in patients who are receiving antiangiogenic drugs.

Impressive efficacy of sorafenib in a patient with an hepatocellular carcinoma and a portal vein thrombosis associated with a metastatic ENT cancer.

Sorafenib, a new antiangiogenic and antiproliferative agent, is currently used for hepatocellular and renal cell carcinoma. We report here the case of a patient with two cancers, a locally advanced cancer of the piriform sinus and a hepatocellular carcinoma, who was given sorafenib. Tumor response of both cancers might suggest that sorafenib could be effective against head and neck cancer.

Clubbing and hypertrophic osteoarthropathy in two patients taking long-term bevacizumab for metastatic colorectal cancer.

INTRODUCTION: The authors report two cases of young patients who developed clubbing and hypertrophic osteoarthropathy in one case or lung diffusion disorder in the second, after a long-term use of bevacizumab plus chemotherapy in a palliative setting of metastatic colorectal cancer. DISCUSSION: We propose that patients on long-term bevacizumab be examined for clubbing and undergo respiratory function tests and that this would be studied prospectively before beginning trials in evaluating this monoclonal antibody given for 2 years in an adjuvant setting.