Ricarda Seidensticker

Left‐liver hypertrophy after therapeutic right‐liver radioembolization is substantial but less than after portal vein embolization

In patients with liver malignancies potentially amenable to curative extended right hepatectomy but insufficient size of the future liver remnant (FLR), portal vein embolization (PVE) of the tumor‐bearing liver is used to induce contralateral liver hypertrophy but leaves the tumor untreated. Radioembolization (RE) treats the tumor in the embolized lobe along with contralateral hypertrophy induction. We performed a matched‐pair analysis to compare the capacity for hypertrophy induction of these two modalities. Patients with right‐hepatic secondary liver malignancies with no or negligible left‐hepatic tumor involvement who were treated by right‐lobar PVE (n = 141) or RE (n = 35) at two centers were matched for criteria known to influence liver regeneration following PVE: 1) baseline FLR/Total liver volume ratio (<25 versus ≥25%); 2) prior platinum‐containing systemic chemotherapy; 3) embolization of segments 5‐8 versus 4‐8; and 4) baseline platelet count (<200 versus ≥200 Gpt/L).The primary endpoint was relative change in FLR volume from baseline to follow‐up. Twenty‐six matched pairs were identified. FLR volume increase from baseline to follow‐up (median 33 [24‐56] days after PVE or 46 [27‐79] days after RE) was significant in both groups but PVE produced significantly more FLR hypertrophy than RE (61.5 versus 29%, P < 0.001). Time between treatment and follow‐up was not correlated with the degree of contralateral hypertrophy achieved in both groups. Although group differences in patient history and treatment setting were present and some bias cannot be excluded, this was minimized by the matched‐pair design, as remaining group differences after matching were found to have no significant influence on contralateral hypertrophy development. Conclusion: PVE induces significantly more contralateral hypertrophy than RE with therapeutic (nonlobectomy) doses. However, contralateral hypertrophy induced by RE is substantial and RE minimizes the risk of tumor progression in the treated lobe, possibly making it a suitable modality for selected patients. (Hepatology 2014;59:1864–1873)

Quantitative in vivo assessment of radiation injury of the liver using Gd-EOB-DTPA enhanced MRI: tolerance dose of small liver volumes

BackroundHepatic radiation toxicity restricts irradiation of liver malignancies. Better knowledge of hepatic tolerance dose is favourable to gain higher safety and to optimize radiation regimes in radiotherapy of the liver. In this study we sought to determine the hepatic tolerance dose to small volume single fraction high dose rate irradiation.Materials and methods23 liver metastases were treated by CT-guided interstitial brachytherapy. MRI was performed 3 days, 6, 12 and 24 weeks after therapy. MR-sequences were conducted with T1-w GRE enhanced by hepatocyte-targeted Gd-EOB-DTPA. All MRI data sets were merged with 3D-dosimetry data. The reviewer indicated the border of hypointensity on T1-w images (loss of hepatocyte function) or hyperintensity on T2-w images (edema). Based on the volume data, a dose-volume-histogram was calculated. We estimated the threshold dose for edema or function loss as the D90, i.e. the dose achieved in at least 90% of the pseudolesion volume.ResultsAt six weeks post brachytherapy, the hepatocyte function loss reached its maximum extending to the former 9.4Gy isosurface in median (i.e., ≥9.4Gy dose exposure led to hepatocyte dysfunction). After 12 and 24 weeks, the dysfunctional volume had decreased significantly to a median of 11.4Gy and 14Gy isosurface, respectively, as a result of repair mechanisms. Development of edema was maximal at six weeks post brachytherapy (9.2Gy isosurface in median), and regeneration led to a decrease of the isosurface to a median of 11.3Gy between 6 and 12 weeks. The dose exposure leading to hepatocyte dysfunction was not significantly different from the dose provoking edema.ConclusionHepatic injury peaked 6 weeks after small volume irradiation. Ongoing repair was observed up to 6 months. Individual dose sensitivity may differ as demonstrated by a relatively high standard deviation of threshold values in our own as well as all other published data.

Treatment of hepatic metastases of breast cancer with CT-guided interstitial brachytherapy - a phase II-study.

PURPOSE The aim of the study was the evaluation of feasibility, safety and effectiveness of interstitial brachytherapy for the treatment of hepatic metastases of breast cancer. MATERIALS AND METHODS Forty-one consecutive patients with 115 unresectable hepatic metastases of breast cancer were included in this phase-II-trial. They were treated in 69 interventions of CT-guided-interstitial-brachytherapy of the liver. Brachytherapy was applied as a single fraction high-dose-irradiation (15-25Gy (Gray)) using a (192)Ir-source of 10Ci. Nineteen patients presented systemically pretreated extrahepatic tumors. Primary endpoints were complications, local tumor control and progression-free survival. RESULTS The median tumor diameter was 4.6 cm (1.5-11 cm). The median irradiation time per intervention was 26.5 min (range: 7-47 min). The applied median minimal dose at the CTV (clinical target volume) margin was 18.5 Gy (12-25 Gy). In 69 interventions and during the postinterventional period, one major complication (symptomatic post-interventional bleeding) (1.5%) and six minor complications occurred (8.7%). The median follow-up time was 18 months (range: 1-56). After 6, 12 and 18 months, local tumor control was 97%, 93.5% and 93.5%, intra- and extrahepatic progression free survival was 53%, 40% and 27%, and overall survival was 97%, 79% and 60%, respectively. CONCLUSION CT-guided-brachytherapy is safe and effective for the treatment of liver metastases of breast cancer.

Malnutrition is a prognostic factor in patients with hepatocellular carcinoma (HCC).

BACKGROUND & AIMS Malnutrition is a common, hence frequently underdiagnosed condition in patients with liver cirrhosis as well as in patients with cancer and has been shown to have a negative impact on survival in these patients. Frequently applied screening tools including anthropometric measurements or laboratory parameters to screen for malnutrition are not suitable for patients with liver cirrhosis with additional pathophysiological mechanisms leading to hypoalbuminemia and edema. Prospective data on the prevalence and prognostic impact of malnutrition in patients with HCC are scarce. METHODS Fifty-one consecutive patients with hepatocellular carcinoma were prospectively enrolled into this study and screened for malnutrition by anthropometric measurements, the MNA score, the NRS score, laboratory work-up, and BIA measurement. The results of the different screening tools were compared to each other and with the BIA assessment and correlated with the outcome of patients. RESULTS The calculation of a body mass index (BMI) was not suitable to identify malnourished patients with HCC. The MNA identified 19, the NRS score 17 patients at a risk for malnutrition. BIA revealed a reduction in relative body cell mass in 12 patients. Univariate Cox regression analyses identified tumor stage, MNA score, and phase angle obtained by BIA as significant factors with influence on survival. Multivariate analyses confirmed the phase angle at a cut-off of 4.8 to be an independent factor. CONCLUSIONS A significant proportion of patients with HCC is malnourished or at risk for malnutrition. Screening questionnaires and BIA measurement are superior to pure anthropometric measurements to identify the condition that negatively influences survival. The phase angle derived from body impedance analysis is an independent prognostic factor in patients with HCC.

Prospective randomized trial of enoxaparin, pentoxifylline and ursodeoxycholic acid for prevention of radiation-induced liver toxicity.

Background/Aim Targeted radiotherapy of liver malignancies has found to be effective in selected patients. A key limiting factor of these therapies is the relatively low tolerance of the liver parenchyma to radiation. We sought to assess the preventive effects of a combined regimen of pentoxifylline (PTX), ursodeoxycholic acid (UDCA) and low-dose low molecular weight heparin (LMWH) on focal radiation-induced liver injury (fRILI). Methods and Materials Patients with liver metastases from colorectal carcinoma who were scheduled for local ablation by radiotherapy (image-guided high-dose-rate interstitial brachytherapy) were prospectively randomized to receive PTX, UDCA and LMWH for 8 weeks (treatment) or no medication (control). Focal RILI at follow-up was assessed using functional hepatobiliary magnetic resonance imaging (MRI). A minimal threshold dose, i.e. the dose to which the outer rim of the fRILI was formerly exposed to, was quantified by merging MRI and dosimetry data. Results Results from an intended interim-analysis made a premature termination necessary. Twenty-two patients were included in the per-protocol analysis. Minimal mean hepatic threshold dose 6 weeks after radiotherapy (primary endpoint) was significantly higher in the study treatment-group compared with the control (19.1 Gy versus 14.6 Gy, p = 0.011). Qualitative evidence of fRILI by MRI at 6 weeks was observed in 45.5% of patients in the treatment versus 90.9% of the control group. No significant differences between the groups were observed at the 12-week follow-up. Conclusions The post-therapeutic application of PTX, UDCA and low-dose LMWH significantly reduced the extent and incidence fRILI at 6 weeks after radiotherapy. The development of subsequent fRILI at 12 weeks (4 weeks after cessation of PTX, UDCA and LMWH during weeks 1–8) in the treatment group was comparable to the control group thus supporting the observation that the agents mitigated fRILI. Trial Registration EU clinical trials register 2008-002985-70 ClinicalTrials.gov NCT01149304

Safety of Repeated Radioembolizations in Patients with Advanced Primary and Secondary Liver Tumors and Progressive Disease After First Selective Internal Radiotherapy

The purpose of this study was to assess the safety of repeated 90Y radioembolization with resin microspheres in patients with extensive primary and secondary liver tumors after failure of first radioembolization. Methods: Between 2007 and 2011, 21 patients (12 women, 9 men; mean age, 61.0 y) with nonresectable advanced liver tumors (breast cancer liver metastases, n = 7; colorectal liver metastases, n = 5; hepatocellular carcinoma, n = 8; cholangiocellular carcinoma, n = 1) were repeatedly treated by radioembolization. Safety was the primary endpoint. Whole-liver treatment was achieved with sequential treatment sessions in most patients, with selective embolization of the left and right liver lobes within 6 wk. Toxicity was documented prospectively and according to Common Terminology Criteria for Adverse Events 4.0 criteria based on laboratory parameters; magnetic-resonance tomography; and clinical examinations 3 d, 6 wk, and every 3 mo after selective internal radiotherapy (SIRT). Metric variables were evaluated using the Student t test. Overall survival was assessed by Kaplan–Meier statistics. Results: Patients received an average of 1.6 whole-liver treatments performed in 3.0 unilobar radioembolizations (liver lobes sequentially). The mean total activity administered was 2.57 GBq. No radioembolization-induced liver disease was observed in any of the patients. Three patients showed reversible grade III to IV toxicities according to laboratory values, which returned to pretreatment levels after 6 wk. In 1 patient, a treatment-related duodenal ulcer occurred. Median overall survival was 18 mo after first radioembolization. Conclusion: In advanced liver tumors, repeated whole-liver treatments with 90Y radioembolization can be performed with an acceptable toxicity profile.

Clinical Characteristics and Time Trends in Etiology of Hepatocellular Cancer in Germany

Introduction: The incidence of hepatocellular cancer (HCC) continues to rise in Europe with a shift of the primary cause towards alcoholic and non-alcoholic fatty liver disease. Metabolic factors like diabetes mellitus and overweight have been identified as significant risk factors for HCC development. Patients and Methods: A retrospective analysis in a large single-center cohort of 650 patients diagnosed with HCC was performed. Demographic characteristics, risk factors, tumor stage at diagnosis and survival were evaluated. Results: Among 650 patients (aged 17-87 years, with a male: female ratio of 4:1), 80.8% had underlying liver cirrhosis. Alcohol abuse was identified as the only risk factor for liver cirrhosis in 52.2% of patients. Viral infection with hepatitis C and hepatitis B was present in 13.7 and 3.6% of patients, respectively. 66.1% of patients with HCC were overweight with a body mass index exceeding 25, 25.5% even exceeding 30; 52% of patients had diabetes mellitus. Conclusion: Strategies aiming at prevention and surveillance of patients at risk to develop HCC in the future need to widen the focus from patients with chronic viral hepatitis and a history of alcohol abuse to patients with metabolic risk factors.

Delayed Diagnosis of HCC with Chronic Alcoholic Liver Disease

Background: Adherence to surveillance recommendations for patients at risk of developing hepatocellular carcinoma (HCC) is influenced by several factors, including the etiology of chronic liver disease. Aim: The aim of this study was to analyze whether tumor stage at diagnosis and prognosis differ in patients with alcohol-related HCC compared to those with chronic viral hepatitis-related HCC. Patients and Methods: Medical records of 650 patients diagnosed with HCC between 1994 and 2011 were analyzed retrospectively. Groups were formed from patients having either alcohol abuse or viral hepatitis (chronic hepatitis B or C virus infection) as the only known HCC risk factors. Demographic data (age and gender), tumor stage at diagnosis, survival, liver function [Child–Pugh–Turcotte (CPT) score] in patients with liver cirrhosis, complications of liver cirrhosis, and serologic parameters were compared between the two groups. Results: A total of 393 HCC cases (male 84%, median age 65 years) were identified, with alcohol abuse as the causative factor in 76.8% and chronic viral hepatitis in 23.2%. In patients with alcohol abuse, 278 (92.1%) were diagnosed with liver cirrhosis (CPT A 49.3%, CPT B 31.1%, CPT C 9.6%), while in patients with viral hepatitis, 84 (92.3%) suffered from liver cirrhosis (CPT A 59.3%, CPT B 23.1%, CPT C 8.8%). Tumor stage in patients with alcohol abuse was Barcelona Clinic Liver Cancer (BCLC) C in 43.7%, BCLC B in 30.5%, and BCLC A in 14.6%. Patients with viral hepatitis showed a trend toward diagnosis at an earlier tumor stage (BCLC B 35.2%, BCLC C 34.1%, BCLC A 22.2%). Etiology of liver cirrhosis did not significantly influence survival in intermediate and advanced tumor stages, but BCLC-A patients with alcohol-related disease demonstrated prolonged survival compared to patients with viral hepatitis. Conclusion: Tumor stage at diagnosis of HCC is influenced by the etiology of underlying chronic liver disease and is more progressed in patients having a disease with alcoholic etiology. Majority of HCC patients are not diagnosed at a curable stage, which underlines the need for specialized care for all patients with chronic liver disease, independent of etiology and consequent adherence to current surveillance guidelines.

Advantages and Disadvantages of the Amplatzer Vascular Plug IV in Visceral Embolization: Report of 50 Placements

PurposeWe describe our initial clinical experience in artificial embolization with the Amplatzer Vascular Plug IV (VP IV), a further development of the Vascular Plug family already in routine use.MethodsResults from 50 embolization procedures conducted with the VP IV in 44 patients are summarized.ResultsAll 50 embolizations were successful, although two required the technique to be modified because of problems with jamming of the screw thread and thus with disconnection of the plug. This was associated with large branching angles.ConclusionsWith experience, the VP IV can be used safely and effectively, and it expands the spectrum of possible embolizations in interventional radiology. Its greatest disadvantage is its relatively poor positional controllability.

Prophylactic Embolization of the Cystic Artery Prior to Radioembolization of Liver Malignancies—An Evaluation of Necessity

PurposePrior to radioembolization (RE) of hepatic tumors, many centers prophylactically occlude the cystic artery (CA) during evaluation angiography (EVA) to prevent radiation-induced cholecystitis. There is no conclusive evidence for the protective effect of CA embolization and it bears the risk of inducing ischemic cholecystitis. The aim of this study is to evaluate the justification for CA embolization by comparing clinical and morphologic imaging parameters between patients undergoing coil occlusion of the cystic artery (COCA) and those with uncoiled CA (UCCA).Materials and MethodsRetrospective comparison of 37 patients with UCCA versus 68 patients with COCA in terms of clinical findings (CRP, leukocyte count, body temperature, upper abdominal pain) and morphologic imaging parameters associated with cholecystitis (gallbladder (GB) wall thickness, free fluid in GB bed, bremsstrahlung SPECT) after EVA, after RE, and at 6-week follow-up.ResultsAt none of the 3 time points (EVA, RE, 6-week follow-up) was there any significant difference in CRP, leukocyte count, body temperature, or upper abdominal pain between the UCCA and COCA group. There was also no significant difference between the two groups with regard to GB wall thickness, fluid in the GB bed, and bremsstrahlung in SPECT. One patient of the UCCA group and two patients of the COCA developed cholecystitis requiring treatment.ConclusionComparison of clinical and imaging findings between patients with and without CA embolization prior to RE identified no predictors of radiogenic or ischemic cholecystitis after RE. Our study provides no evidence for a benefit of prophylactic CA embolization before RE.