Overall survival and objective response in advanced unresectable hepatocellular carcinoma: A subanalysis of the REFLECT study.

BACKGROUND & AIMS: Validated surrogate endpoints for overall survival (OS) are important for expediting the clinical study and drug-development processes. Herein, we aimed to validate objective response as an independent predictor of OS in individuals with unresectable hepatocellular carcinoma (HCC) receiving systemic anti-angiogenic therapy. METHODS: We investigated the association between objective response (investigator-assessed mRECIST, independent radiologic review [IRR] mRECIST and RECIST v1.1) and OS in REFLECT, a phase III study of lenvatinib vs. sorafenib. We conducted landmark analyses (Simon-Makuch) of OS by objective response at 2, 4, and 6 months after randomization. RESULTS: Median OS was 21.6 months (95% CI 18.6-24.5) for responders (investigator-assessed mRECIST) vs. 11.9 months (95% CI 10.7-12.8) for non-responders (hazard ratio [HR] 0.61; 95% CI 0.49-0.76; p <0.001). Objective response by IRR per mRECIST and RECIST v1.1 supported the association with OS (HR 0.61; 95% CI 0.51-0.72; p <0.001 and HR 0.50; 95% CI 0.39-0.65; p <0.001, respectively). OS was significantly prolonged for responders vs. non-responders (investigator-assessed mRECIST) at the 2-month (HR 0.61; 95% CI 0.49-0.76; p <0.001), 4-month (HR 0.63; 95% CI 0.51-0.80; p <0.001), and 6-month (HR 0.68; 95% CI 0.54-0.86; p <0.001) landmarks. Results were similar when assessed by IRR, with both mRECIST and RECIST v1.1. An exploratory multivariate Cox regression analysis identified objective response by investigator-assessed mRECIST (HR 0.55; 95% CI 0.44-0.68; p <0.0001) and IRR-assessed RECIST v1.1 (HR 0.49; 95% CI, 0.38-0.64; p <0.0001) as independent predictors of OS in individuals with unresectable HCC. CONCLUSIONS: Objective response was an independent predictor of OS in individuals with unresectable HCC in REFLECT; additional studies are needed to confirm surrogacy. Participants achieving a complete or partial response by mRECIST or RECIST v1.1 had significantly longer survival vs. those with stable/progressive/non-evaluable disease. GOV NUMBER: NCT01761266. IMPACT AND IMPLICATIONS: This analysis of data taken from a completed clinical trial (REFLECT) looked for any link between objective response and overall survival time in individuals with unresectable HCC receiving anti-angiogenic treatments. Significantly longer median overall survival was found for responders (21.6 months) vs. non-responders (11.9 months). Overall survival was also significantly longer for responders vs. non-responders (based on objective response status at 2, 4, and 6 months) in the landmark analysis. Our results indicate that objective response is an independent predictor of overall survival in this setting, confirming its validity as a rapid marker of efficacy that can be applied in phase II trials; however, further validation is required to determine is validity for other systemic treatments (e.g. immunotherapies), or as a surrogate of overall survival.

The concomitant use of proton pump inhibitors and BRAF/MEK inhibitors in metastatic melanoma.

BACKGROUND: Proton-pump inhibitors (PPIs) are commonly used by patients with cancer, although they could reduce the absorption of oral anticancer targeted therapies. The US Food and Drug Administration states that the effect of PPIs on the efficacy of dabrafenib use by patients with metastatic melanoma is unknown. As a precautionary measure, the European Society for Medical Oncology recommends avoiding PPIs for patients receiving dabrafenib. OBJECTIVES: To determine the effect of the concomitant use of PPIs and BRAF/MEK inhibitors in patients with metastatic melanoma. METHODS: Patients with advanced melanoma receiving BRAF/MEK inhibitors as first-line treatments between 2015 and 2017 in France were selected using the French National Health Insurance database. We compared time-to-treatment discontinuation (TTD) and overall survival (OS) according to concomitant PPI exposure. We balanced the baseline characteristics of patients exposed and nonexposed to PPIs using an overlap weighting method based on a propensity score. RESULTS: The metastatic melanoma cohort comprised 1028 patients receiving BRAF/MEK inhibitors, including 361 (35.1%) patients using PPIs. PPI users had more comorbidities and a more severe metastatic disease. After having equally distributed metastatic sites and comorbidities across patients exposed and nonexposed to PPIs, concomitant PPI use was not associated with shorter TTD [weighted hazard ratio (wHR) 1.03, 95% confidence interval (CI) 0.86-1.24] or OS (wHR 1.11, 95% CI 0.88-1.39). Consistent results were observed when restricting the population to patients receiving dabrafenib, or when narrowing exposure to PPIs with stronger inhibition of cytochromes. CONCLUSIONS: In a population-based cohort of patients with advanced melanoma, the concomitant use of PPIs and BRAF/MEK inhibitors was not associated with worse outcome.

Oxaliplatin and 5-Fluorouracil in Advanced Well-Differentiated Digestive Neuroendocrine Tumors: A Multicenter National Retrospective Study from the French Group of Endocrine Tumors.

INTRODUCTION: Oxaliplatin-based regimens have shown promising antitumor activity in digestive neuroendocrine tumors (NETs); however, the available data are limited. Our aim was to assess the efficacy of FOLFOX (association of 5-fluorouracil with oxaliplatin) in a large series of patients with advanced digestive NETs. METHODS: All patients with advanced digestive well-differentiated NETs treated with at least 3 cycles of FOLFOX between January 2004 and December 2018 in 12 centers from the French Group of Endocrine Tumors were included. Tumor response rate according to Response Evaluation Criteria in Solid Tumors version 1.1 criteria, progression free survival (PFS), and overall survival, as well as prognostic factors, were analyzed retrospectively. RESULTS: One hundred fifty-five patients were included. Primary tumor locations were pancreas (n = 89), small intestine (n = 40), unknown with no evidence for lung primary (n = 13), stomach (n = 7), and rectum (n = 6). Median Ki-67 was 10%, and 65% of the tumors were grade 2. The partial response rate was 30% for pancreatic NETs, 12.5% for small intestine NETs, 38.5% for unknown primary NETs, 14% for gastric NETs, and 17% for rectal NETs. Significant prognostic factors for poor PFS after FOLFOX were progressive disease at the beginning of treatment (hazard ratio [HR] = 1.83, p = 0.007), hepatic involvement superior to 50% (HR = 2.67, p = 0.0001), and rectal primary tumor location (HR = 2.6, p = 0.0036). Among pancreatic NETs, insulinomas had a better median PFS (22 months) than other pancreatic NETs (9 months, p = 0.026) and showed a high rate (8/9) of serum glucose normalization. CONCLUSIONS: FOLFOX shows a promising antitumor activity in advanced digestive NETs. Rapid symptomatic response is observed in metastatic insulinomas.

Ramucirumab in elderly patients with hepatocellular carcinoma and elevated alpha-fetoprotein after sorafenib in REACH and REACH-2.

BACKGROUND & AIMS: Limited data on treatment of elderly patients with hepatocellular carcinoma (HCC) increase the unmet need. REACH and REACH-2 were global phase III studies of ramucirumab in patients with HCC after prior sorafenib, where patients with alpha-fetoprotein (AFP) ≥400 ng/mL showed an overall ssurvival (OS) benefit for ramucirumab. These post-hoc analyses examined efficacy and safety of ramucirumab in patients with HCC and baseline AFP ≥ 400 ng/mL by three prespecified age subgroups (<65, ≥65 to <75 and ≥75 years). METHODS: Individual patient data were pooled from REACH (baseline AFP ≥400 ng/mL) and REACH-2. Kaplan-Meier and Cox proportional hazards regression methods (stratified by study) assessed OS, progression-free survival (PFS), time to progression (TTP) and patient-reported outcomes (Functional Hepatobiliary System Index-8 [FHSI-8] score). RESULTS: A total of 542 patients (<65 years: n = 302; ≥65 to <75 years: n = 160; ≥75 years: n = 80) showed similar baseline characteristics between ramucirumab and placebo. Older subgroups had higher hepatitis C and steatohepatitis incidences, and lower AFP levels, than the <65 years subgroup. Ramucirumab prolonged OS in patients <65 years (hazard ratio [HR], 0.753; 95% CI 0.581-0.975), ≥65 to <75 years (0.602; 0.419-0.866) and ≥75 years (0.709; 0.420-1.199), PFS and TTP irrespective of age. Ramucirumab showed similar overall safety profiles across subgroups, with a consistent median relative dose intensity ≥97.8%. A trend towards a delay in symptom deterioration in FHSI-8 with ramucirumab was observed in all subgroups. CONCLUSIONS: In this post-hoc analysis, ramucirumab showed a survival benefit across age subgroups with a tolerable safety profile, supporting its use in advanced HCC with elevated AFP, irrespective of age, including ≥75 years.

Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations have poor prognosis. We aimed to establish the efficacy of ramucirumab in patients with advanced hepatocellular carcinoma and α-fetoprotein concentrations of 400 ng/mL or higher. METHODS: REACH-2 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 92 hospitals, clinics, and medical centres in 20 countries. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed hepatocellular carcinoma, or diagnosed cirrhosis and hepatocellular carcinoma, Barcelona Clinic Liver Cancer stage B or C disease, Child-Pugh class A liver disease, Eastern Cooperative Oncology Group (ECOG) performance statuses of 0 or 1, α-fetoprotein concentrations of 400 ng/mL or greater, and had previously received first-line sorafenib. Participants were randomly assigned (2:1) via an interactive web response system with a computer-generated random sequence to 8 mg/kg intravenous ramucirumab every 2 weeks or placebo. All patients received best supportive care. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportion of patients achieving an objective response, time to radiographic progression, safety, time to deterioration in scores on the Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index 8 (FHSI-8), and time to deterioration in ECOG performance status. We also pooled individual patient data from REACH-2 with data from REACH (NCT01140347) for patients with α-fetoprotein concentrations of 400 ng/mL or greater. Efficacy analyses were by intention to treat, whereas safety analyses were done in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02435433. FINDINGS: Between July 26, 2015, and Aug 30, 2017, 292 patients were randomly assigned, 197 to the ramucirumab group and 95 to the placebo group. At a median follow-up of 7·6 months (IQR 4·0-12·5), median overall survival (8·5 months [95% CI 7·0-10·6] vs 7·3 months [5·4-9·1]; hazard ratio [HR] 0·710 [95% CI 0·531-0·949]; p=0·0199) and progression-free survival (2·8 months [2·8-4·1] vs 1·6 months [1·5-2·7]; 0·452 [0·339-0·603]; p<0·0001) were significantly improved in the ramucirumab group compared with the placebo group. The proportion of patients with an objective response did not differ significantly between groups (nine [5%] of 197 vs one [1%] of 95; p=0·1697). Median time to deterioration in FHSI-8 total scores (3·7 months [95% CI 2·8-4·4] vs 2·8 months [1·6-2·9]; HR 0·799 [95% CI 0·545-1·171]; p=0·238) and ECOG performance statuses (HR 1·082 [95% CI 0·639-1·832]; p=0·77) did not differ between groups. Grade 3 or worse treatment-emergent adverse events that occurred in at least 5% of patients in either group were hypertension (25 [13%] in the ramucirumab group vs five [5%] in the placebo group), hyponatraemia (11 [6%] vs 0) and increased aspartate aminotransferase (six [3%] vs five [5%]). Serious adverse events of any grade and cause occurred in 68 (35%) patients in the ramucirumab group and 28 (29%) patients in the placebo group. Three patients in the ramucirumab group died from treatment-emergent adverse events that were judged to be related to study treatment (one had acute kidney injury, one had hepatorenal syndrome, and one had renal failure). INTERPRETATION: REACH-2 met its primary endpoint, showing improved overall survival for ramucirumab compared with placebo in patients with hepatocellular carcinoma and α-fetoprotein concentrations of at least 400 ng/mL who had previously received sorafenib. Ramucirumab was well tolerated, with a manageable safety profile. To our knowledge, REACH-2 is the first positive phase 3 trial done in a biomarker-selected patient population with hepatocellular carcinoma. FUNDING: Eli Lilly.

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.

Yttrium-90 glass microspheres radioembolization (RE) for biliary tract cancer: a large single-center experience.

PURPOSE: Radioembolization (RE) is a promising treatment option for biliary tract cancers (BTC). We report here the largest series to date using this treatment modality. METHODS: We retrospectively studied data from 64 patients treated outside prospective clinical trial at our institution. We studied baseline characteristics as potential prognostic factors. We studied dose delivered to the tumor as predictive factors of outcomes in patients not receiving concomitant chemotherapy. RESULTS: The Progression-Free Survival and Overall Survival (OS) were 7.6 months [95% Confidence Interval (CI): 4.6-10.6] and 16.4 months [95% CI: 7.8-25.0] in the whole cohort. The factors independently associated with OS in multivariable analysis were the primary localization of ICC (HR = 0.27, 95% CI: 0.11-0.68, p = 0.005) and a PS > 0 (HR = 2.21, 95% CI: 1.11-4.38, p = 0.024). During follow-up, 12 patients (19%) underwent surgery following downstaging, with a median OS of 51.9 months. In patients not treated with concomitant chemotherapy (n = 31), OS was significantly higher in patients with a dose delivered to the tumor 260Gy or higher than in patients with a dose delivered to the tumor lower than 260Gy (median 28.2 vs 11.4 months, log-rank p = 0.019). CONCLUSION: Our results confirm that RE is a promising treatment modality in BTC. A high proportion of patients could be downstaged to surgery, with promising long-term survival. Dose delivered to the tumor correlated with clinical outcomes when chemotherapy was not used concomitantly.

Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study.

BACKGROUND: Tivantinib (ARQ 197), a selective, oral MET inhibitor, improved overall survival and progression-free survival compared with placebo in a randomised phase 2 study in patients with high MET expression (MET-high) hepatocellular carcinoma previously treated with sorafenib. The aim of this phase 3 study was to confirm the results of the phase 2 trial. METHODS: We did a phase 3, randomised, double-blind, placebo-controlled study in 90 centres in Australia, the Americas, Europe, and New Zealand. Eligible patients were 18 years or older and had unresectable, histologically confirmed, hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0-1, high MET expression (MET-high; staining intensity score ≥2 in ≥50% of tumour cells), Child-Pugh A cirrhosis, and radiographically-confirmed disease progression after receiving sorafenib-containing systemic therapy. We randomly assigned patients (2:1) in block sizes of three using a computer-generated randomisation sequence to receive oral tivantinib (120 mg twice daily) or placebo (twice daily); patients were stratified by vascular invasion, extrahepatic spread, and α-fetoprotein concentrations (≤200 ng/mL or >200 ng/mL). The primary endpoint was overall survival in the intention-to-treat population. Efficacy analyses were by intention to treat and safety analyses were done in all patients who received any amount of study drug. This study is registered with ClinicalTrials.gov, number NCT01755767. FINDINGS: Between Dec 27, 2012, and Dec 10, 2015, 340 patients were randomly assigned to receive tivantinib (n=226) or placebo (n=114). At a median follow-up of 18·1 months (IQR 14·1-23·1), median overall survival was 8·4 months (95% CI 6·8-10·0) in the tivantinib group and 9·1 months (7·3-10·4) in the placebo group (hazard ratio 0·97; 95% CI 0·75-1·25; p=0·81). Grade 3 or worse treatment-emergent adverse events occurred in 125 (56%) of 225 patients in the tivantinib group and in 63 (55%) of 114 patients in the placebo group, with the most common being ascites (16 [7%] patients]), anaemia (11 [5%] patients), abdominal pain (nine [4%] patients), and neutropenia (nine [4%] patients) in the tivantinib group. 50 (22%) of 226 patients in the tivantinib group and 18 (16%) of 114 patients in the placebo group died within 30 days of the last dose of study medication, and general deterioration (eight [4%] patients) and hepatic failure (four [2%] patients) were the most common causes of death in the tivantinib group. Three (1%) of 225 patients in the tivantinib group died from a treatment-related adverse event (one sepsis, one anaemia and acute renal failure, and one acute coronary syndrome). INTERPRETATION: Tivantinib did not improve overall survival compared with placebo in patients with MET-high advanced hepatocellular carcinoma previously treated with sorafenib. Although this METIV-HCC trial was negative, the study shows the feasibility of doing integral tissue biomarker studies in patients with advanced hepatocellular carcinoma. Additional randomised studies are needed to establish whether MET inhibition could be a potential therapy for some subsets of patients with advanced hepatocellular carcinoma. FUNDING: ArQule Inc and Daiichi Sankyo (Daiichi Sankyo Group).

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.

Dosimetric parameters predicting contralateral liver hypertrophy after unilobar radioembolization of hepatocellular carcinoma.

PURPOSE: This study aimed at identifying prior therapy dosimetric parameters using 99mTc-labeled macro-aggregates of albumin (MAA) that are associated with contralateral hepatic hypertrophy occurring after unilobar radioembolization of hepatocellular carcinoma (HCC) performed with 90Y-loaded glass microspheres. METHODS: The dosimetry data of 73 HCC patients were collected prior to the treatment with 90Y-loaded microspheres for unilateral disease. The injected liver dose (ILD), the tumor dose (TD) and healthy injected liver dose (HILD) were calculated based on MAA quantification. Following treatment, the maximal hypertrophy (MHT) of an untreated lobe was calculated. RESULTS: Mean MHT was 35.4 ± 40.4%. When using continuous variables, the MHT was not correlated with any tested variable, i.e., injected activity, ILD, HILD or TD except with a percentage of future remnant liver (FRL) following the 90Y-microspheres injection  (r = -0.56). MHT ≥ 10% was significantly more frequent for patients with HILD ≥ 88 Gy, (52% of the cases), i.e., in 92.2% versus 65.7% for HILD < 88 Gy (p = 0.032). MHT ≥ 10% was also significantly more frequent for patients with a TD ≥ 205 Gy and a tumor volume (VT) ≥ 100 cm3 in patients with initial FRL < 50%. MHT ≥10% was seen in 83.9% for patients with either an HILD ≥ 88 Gy or a TD ≥ 205 Gy for tumors larger than 100cm3 (85% of the cases), versus only 54.5% (p = 0.0265) for patients with none of those parameters. MHT ≥10% was also associated with FRL and the Child-Pugh score. Using multivariate analysis, the Child-Pugh score (p < 0.0001), FRL (p = 0.0023) and HILD (p = 0.0029) were still significantly associated with MHT ≥10%. CONCLUSION: This study demonstrates for the first time that HILD is significantly associated with liver hypertrophy. There is also an impact of high tumor doses in large lesions in one subgroup of patients. Larger prospective studies evaluating the MAA dosimetric parameters have to be conducted to confirm these promising results.

High impact of macroaggregated albumin-based tumour dose on response and overall survival in hepatocellular carcinoma patients treated with 90 Y-loaded glass microsphere radioembolization.

BACKGROUND & AIMS: Efficacy of radioembolization is derived from radioinduced damage, whereas tumour dosimetry is not considered as yet in prospective clinical trials. OBJECTIVES: This study evaluates the impact of tumour dose (TD), based on 99m Tc macroaggregated albumin (MAA) quantification, on response and overall survival (OS). MATERIALS AND METHODS: We consecutively included 85 patients with hepatocellular carcinoma treated with 90 Y-loaded glass microspheres. TD was calculated using a quantitative analysis of the MAA SPECT/CT. Responses were assessed after 3 months using the European Association for the Study of the Liver criteria. OS was assessed using Kaplan-Meier tests. RESULTS: Response rate was 80.3% on lesion-based analysis (n=132), and 77.5% on patient-based analysis. The response rate was only 9.1% for patients with TD <205 Gy against 89.7% for those with TD ≥205 Gy (P<10-7 ). Non-portal vein thrombosis (PVT) patients exhibited a median OS of 11.75 m (95% CI: 3-30.7 m) for TD <205 Gy, and 25 m (95% CI: 15-34.7 m) for TD ≥205 Gy (P=.0391). PVT patients exhibited a 4.35 m median OS (95% CI: 2-8 m) for TD<205 Gy, and 15.7 m (95% CI: 9.5-25.5 m) for TD ≥205 Gy, (P=.0004), with HR of 6.99. PVT patients exhibited a median OS of 3.6 m (95% CI: 2-8 m) when PVT MAA targeting was poor or with TD <205 Gy (poor candidate), vs 17.5 m (95% CI: 11-26.5 m) for the others identified as good candidates (P<.0001), with HR of 12.85. CONCLUSION: This study confirms the highly predictive value of MAA-based TD evaluation for response and OS. TD evaluation and PVT MAA targeting should be further evaluated in ongoing trials, whereas personalized dosimetry should be implemented in new trial designs.

Occupational radiation exposure of medical staff performing 9°Y-loaded microsphere radioembolization.

PURPOSE: Radioembolization of liver cancer with (90)Y-loaded microspheres is increasingly used but data regarding hospital staff exposure are scarce. We evaluated the radiation exposure of medical staff while preparing and injecting (90)Y-loaded glass and resin microspheres especially in view of the increasing use of these products. METHODS: Exposure of the chest and finger of the radiopharmacist, nuclear medicine physician and interventional radiologist during preparation and injection of 78 glass microsphere preparations and 16 resin microsphere preparations was monitored. Electronic dosimeters were used to measure chest exposure and ring dosimeters were used to measure finger exposure. RESULTS: Chest exposure was very low for both products used (<10 µSv from preparation and injection). In our experience, finger exposure was significantly lower than the annual limit of 500 mSv for both products. With glass microspheres, the mean finger exposure was 13.7 ± 5.2 µSv/GBq for the radiopharmacist, and initially 17.9 ± 5.4 µSv/GBq for the nuclear medicine physician reducing to 13.97 ± 7.9 µSv/GBq with increasing experience. With resin microspheres, finger exposure was more significant: mean finger exposure for the radiopharmacist was 295.1 ± 271.9 µSv/GBq but with a reduction with increasing experience to 97.5 ± 35.2 µSv/GBq for the six most recent dose preparations. For administration of resin microspheres, the greatest mean finger exposure for the nuclear medicine physician (the most exposed operator) was 235.5 ± 156 µSv/GBq. CONCLUSION: Medical staff performing (90)Y-loaded microsphere radioembolization procedures are exposed to safe levels of radiation. Exposure is lower than that from treatments using (131)I-lipiodol. The lowest finger exposure is from glass microspheres. With resin microspheres finger exposure is acceptable but could be optimized in accordance with the ALARA principle, and especially in view of the increasing use of radioembolization.

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.

Multidisciplinary approach of lumbo-sacral chordoma: From oncological treatment to reconstructive surgery.

Lumbo-sacral chordoma is a rare, slow-growing tumor, arising from embryonic nothocordal remnants. Wide en bloc excision with clear margins remains mandatory to achieve satisfactory recurrence rates and disease-free survival. No chemotherapy has been demonstrated to be effective and radiotherapy is only marginally effective. Tyrosine kinase receptor inhibitors have showed encouraging results in locally advanced and metastatic chordoma. Reconstructive surgery may become very complex. Multidisciplinary approach in tertiary hospitals is always necessary.

Volumetric changes after (90)y radioembolization for hepatocellular carcinoma in cirrhosis: an option to portal vein embolization in a preoperative setting?

BACKGROUND: Contralateral hypertrophy after (90)Y radioembolization has been described in case reports, but the incidence and quantitative extent of liver volume modifications after this therapy are unknown. METHODS: This retrospective study examined patients with hepatocellular carcinoma and underlying cirrhosis treated by (90)Y radioembolization. The main inclusion criteria were unilateral treatment, no prior liver surgery, and computed tomographic scans allowing for volumetric assessments. Treated, tumor, and contralateral liver volumes were measured. Whole liver volume and the ratio of contralateral to total functional liver volume after a virtual hepatectomy were calculated. RESULTS: Data of 34 patients were analyzed. Response rates were 26 % according to Response Evaluation Criteria in Solid Tumors (RECIST) and 63 % according to modified RECIST. Median overall survival was 13.5 months. Median treated volume decreased from 938 mL (interquartile range [IQR] = 719) to 702 mL (IQR = 656) (p < 0.001), while median contralateral volume increased from 724 mL (IQR = 541) to 920 mL (IQR = 530) (p < 0.001). The whole liver volume remained stable, with a median volume of 1,702 mL (IQR = 568) versus 1,577 mL (IQR 670), respectively (p = 0.55). The mean maximal increase in contralateral volume was 42 % (95 % confidence interval 16-67). Overall, 13 patients (38.2 %) exhibited increases greater than 30 %, while 13 patients (38.2 %) showed no increase or showed increases less than 10 %. The median ratio of contralateral to total functional liver volume increased from 48.5 to 64.9 % (p < 0.001), with the proportion of patients with a ratio of ≥50 % increasing from 47.1 to 67.6 % (p = 0.013). CONCLUSIONS: (90)Y radioembolization induced frequent and similar increases in functional liver remnant volume compared with portal vein embolization. This technique should be tested in a prospective study phase 2 study before liver resection.

Intrahepatic cholangiocarcinoma: impact of genetic hemochromatosis on outcome and overall survival after surgical resection.

BACKGROUND: The influence of genetic hemochromatosis (GH) on outcomes following surgical resections for intrahepatic cholangiocarcinoma (ICC) has not been evaluated. METHODS: All patients with ICC who underwent a surgical resection between January 1997 and August 2011 were analyzed retrospectively. Risk factors were assessed by univariate and multivariate analyses. RESULTS: Eighty-seven patients were analyzed; 16 of these patients (18.4%) had GH. Among the 71 non-GH patients, 52 (73.2%) and 19 (26.8%) had normal or cirrhotic parenchyma, respectively. There was no significant difference in survival between the GH and non-GH patients. A univariate analysis showed that major hepatectomy (P = 0.012), intraoperative blood transfusion (P = 0.007), tumor size >5 cm (P = 0.006), several nodules (P < 0.001), and microvascular invasion (P = 0.04) were significantly associated with poor survival. A multivariate analysis showed that intraoperative blood infusion (HR 0.37; CI 95% [0.19; 0.71]) and more than one nodule (HR 2.5; CI 95% [1.06; 5.8]) were associated with a lower survival rate. CONCLUSION: Although the incidence of GH was high in our series, the presence of GH did not affect the outcomes after a liver hepatectomy for ICC. GH does not appear to increase recurrences or worsen the overall and disease-free survival.

[Immunotherapy: a therapeutic revolution against prostate cancer?]. / Immunothérapie: une nouvelle arme contre le cancer de la prostate.

The interaction between the immune system and cancer was an area of research interest for several decades. The recent U.S. Food and Drug Administration approval of sipuleucel-T and ipilimumab stimulated broader interest in manipulating immunity to fight cancer. In the context of prostate cancer, the immunotherapy strategies under development are therapeutic vaccination strategies, such as sipuleucel-T and PROSTVAC-VF, or immune checkpoint blockade of CTLA-4. Improved understanding of the immune responses generated by the development of predictive biomarkers for patient selection will guide rational combinations of these treatments and provide new treatment options in prostate cancer.

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.