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Aim To investigate the impact of pentoxifylline (PTX, 3 × 400 mg per day) and ursodeoxycholic acid (UDCA, 3 × 250 mg per day) administered for 12 weeks on radiation-induced liver toxicity. Materials and methods Inclusion criteria were liver metastases of extrahepatic malignancies undergoing HDR-BT. 36 patients were prospectively randomized to the medication (N = 18) or control arm (N = 18) and follow-up by hepatobiliary magnetic resonance imaging (MRI) was scheduled 6 and 12 weeks after local ablation by HDR-BT. We determined the threshold doses of fRILI by image fusion of MRI with the dosimetry data. Results 32 patients completed the study schedule. Per-protocol treatment was limited to 8 patients in the medication group and 16 patients in the control group. 22 adverse events of any grade likely or certainly related to PTX were recorded in 12 patients leading to the discontinuation of the study medication in 7 patients and to a dose reduction of PTX in 2 patients. In the per-protocol population, statistical analysis failed to prove a reduction of fRILI 6 and 12 weeks after HDR-BT. The incidence of adverse effects attributed to PTX (70.6%) was well above the data found in the literature for its approved indication. Conclusion The study endpoint was not met mainly attributed to the low statistical power of the small per-protocol cohort. Independently, PTX cannot be recommended for the reduction of radiation-induced liver toxicity in oncologic patients undergoing HDR-BT of liver metastases. Further studies might focus on a combination of UDCA with other potential drugs to help establish a preventive and tolerable regimen.

Background Locoregional therapies, as imaging-guided tumor-directed procedures, are emerging treatment strategies in the management of primary and secondary liver malignancies such as e.g. colorectal cancer liver metastases. As one of those, irradiation-based interstitial high dose rate brachytherapy (iBT) of liver metastases bears a risk of developing focal radiation-induced liver injury (fRILI). Since little is known about biological factors involved in hepatic dysfunction after irradiation, the aim of this study was to identify factors, that may play a role in the underlying mechanism of fRILI, and that potentially may serve as biomarkers for post-therapeutic fRILI to improve specific management and treatment of patients. Methods Twenty-two patients with hepatic malignancies (tumor patients, TP) underwent iBT with total ablative doses of radiation to the target volume ranging from e.g. 15 to 25 Gy. Hepatobiliary magnetic resonance imaging (MRI) was performed 6 weeks after iBT to quanitify fRILI. Blood samples were taken before (pre) and 6 weeks after (post) iBT from TP, and from ten healthy volunteers (HV controls) for the analyses of humoral mediators: monocyte chemoattractant protein-1 (MCP-1), chemokine (C-X3-C motif) ligand 1 (CX3CL1), vascular endothelial growth factor (VEGF) and beta-nerve growth factor (beta-NGF) using the Multi-Analyte Flow Assay via flow cytometry. Correlation analyses between the humoral mediators (pre and post iBT) with the tumor volume and fRILI were performed. Results While MCP-1 and CX3CL1 tended to decrease in TP vs. HV, VEGF was significantly decreased in TP vs. HV pre and post iBT (p p p p Conclusion Tumor volume and threshold dose of irradiation damage correlated positively with MCP-1 and VEGF as well as NGF and CX3CL, respectively. Thus, investigation of biological mediators in blood samples from tumor patients may provide an appropriate tool to predict fRILI after interstitial HDR brachytherapy of liver metastases.

Objectives To evaluate the correlation between liver enhancement on hepatobiliary phase and liver function parameters in a multicenter, multivendor study. Methods A total of 359 patients who underwent gadoxetic acid–enhanced MRI using a standardized protocol with various scanners within a prospective multicenter phase II trial (SORAMIC) were evaluated. The correlation between liver enhancement on hepatobiliary phase normalized to the spleen (liver-to-spleen ratio, LSR) and biochemical laboratory parameters, clinical findings related to liver functions, liver function grading systems (Child-Pugh and Albumin-Bilirubin [ALBI]), and scanner characteristics were analyzed using uni- and multivariate analyses. Results There was a significant positive correlation between LSR and albumin (rho = 0.193; p < 0.001), platelet counts (rho = 0.148; p = 0.004), and sodium (rho = 0.161; p = 0.002); and a negative correlation between LSR and total bilirubin (rho = −0.215; p < 0.001) and AST (rho = −0.191; p < 0.001). Multivariate analysis confirmed independent significance for each of albumin (p = 0.022), total bilirubin (p = 0.045), AST (p = 0.031), platelet counts (p = 0.012), and sodium (p = 0.006). The presence of ascites (1.47 vs. 1.69, p < 0.001) and varices (1.55 vs. 1.69, p = 0.006) was related to significantly lower LSR. Similarly, patients with ALBI grade 1 had significantly higher LSR than patients with grade 2 (1.74 ± 0.447 vs. 1.56 ± 0.408, p < 0.001); and Child-Pugh A patients had a significantly higher LSR than Child-Pugh B (1.67 ± 0.44 vs. 1.49 ± 0.33, p = 0.021). Also, LSR was negatively correlated with MELD-Na scores (rho = −0.137; p = 0.013). However, one scanner brand was significantly associated with lower LSR (p < 0.001). Conclusions The liver enhancement on the hepatobiliary phase of gadoxetic acid–enhanced MRI is correlated with biomarkers of liver functions in a multicenter cohort. However, this correlation shows variations between scanner brands. Key Points • The correlation between liver enhancement on the hepatobiliary phase of gadoxetic acid–enhanced MRI and liver function is consistent in a multicenter-multivendor cohort. • Signal intensity–based indices (liver-to-spleen ratio) can be used as an imaging biomarker of liver function. • However, absolute values might change between vendors.

Background/Aim: The aim of the present study was to determine whether the early systemic markers of inflammation, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), respond to high dose-rate (HDR) brachytherapy, and their possible correlation with radiation-induced liver injury of patients with liver metastases. Patients and Methods: This prospective study included 20 tumor patients (TP) undergoing irradiation-based interstitial HDR brachytherapy (iBT) of liver metastases, who received total radiation ablative doses to the planning target volume ranging from 15 to 25 Gy, depending on the tumor entity. Hepatobiliary magnetic resonance imaging (MRI) was performed 6 weeks after iBT to assess the maximum extent of focal radiation-induced liver injury (fRILI). Furthermore, blood samples for the pro-inflammatory cytokine response were taken one day prior to and 6 weeks after irradiation. IL-6 and TNF-α were measured by flow cytometry. Ten healthy volunteers (HV) were used as control group. Results: Compared to HV, TNF-α was significantly enhanced in TP before and after therapy (p

Funder: Sirtex, Funder: Bayer HealthCare; doi: http://dx.doi.org/10.13039/501100000801, Funder: Ludwig-Maximilians-Universität München (1024), PURPOSE: To explore the potential correlation between baseline interleukin (IL) values and overall survival or objective response in patients with hepatocellular carcinoma (HCC) receiving sorafenib. METHODS: A subset of patients with HCC undergoing sorafenib monotherapy within a prospective multicenter phase II trial (SORAMIC, sorafenib treatment alone vs. combined with Y90 radioembolization) underwent baseline IL-6 and IL-8 assessment before treatment initiation. In this exploratory post hoc analysis, the best cut-off points for baseline IL-6 and IL-8 values predicting overall survival (OS) were evaluated, as well as correlation with the objective response. RESULTS: Forty-seven patients (43 male) with a median OS of 13.8 months were analyzed. Cut-off values of 8.58 and 57.9 pg/mL most effectively predicted overall survival for IL-6 and IL-8, respectively. Patients with high IL-6 (HR, 4.1 [1.9-8.9], p < 0.001) and IL-8 (HR, 2.4 [1.2-4.7], p = 0.009) had significantly shorter overall survival than patients with low IL values. Multivariate analysis confirmed IL-6 (HR, 2.99 [1.22-7.3], p = 0.017) and IL-8 (HR, 2.19 [1.02-4.7], p = 0.044) as independent predictors of OS. Baseline IL-6 and IL-8 with respective cut-off values predicted objective response rates according to mRECIST in a subset of 42 patients with follow-up imaging available (IL-6, 46.6% vs. 19.2%, p = 0.007; IL-8, 50.0% vs. 17.4%, p = 0.011). CONCLUSION: IL-6 and IL-8 baseline values predicted outcomes of sorafenib-treated patients in this well-characterized prospective cohort of the SORAMIC trial. We suggest that the respective cut-off values might serve for validation in larger cohorts, potentially offering guidance for improved patient selection.

Background High-dose-rate computed tomography (CT)-guided brachytherapy (HDR-BT) has shown promising results in patients with hepatocellular carcinoma (HCC). While growing evidence shows clear limitations of mRECIST, diffusion-weighted imaging (DWI) has relevant potential in improving the response assessment. Purpose To assess whether DWI allows evaluation of short- and long-term tumor response in patients with HCC after HDR-BT. Material and Methods A total of 22 patients with 11 non-responding HCCs (NR-HCC; local tumor recurrence within two years) and 24 responding HCCs (R-HCC; follow-up at least two years) were included in this retrospective bi-center study. HCCs were treated with HDR-BT and patients underwent pre- and post-interventional magnetic resonance imaging (MRI). Analyses of DWI were evaluated and compared between pre-interventional MRI, 1.follow-up after 3 months and 2.follow-up at the time of the local tumor recurrence (in NR-HCC) or after 12 months (in R-HCC). Results ADCmean of R-HCC increased significantly after HDR-BT on the first and second follow-up (ADCmean: 0.87 ± 0.18 × 10−3 mm2/s [pre-interventional]: 1.14 ± 0.23 × 10−3 mm2/s [1. post-interventional]; 1.42 ± 0.32 × 10−3 mm2/s [2. post-interventional]; P mean of NR-HCC did not show a significant increase from pre-intervention to 1. post-interventional MRI (ADCmean: 0.85 ± 0.24 × 10−3 mm2/s and 1.00 ± 0.30 × 10−3 mm2/s, respectively; P = 0.131). ADCmean increase was significant between pre-intervention and 2. follow-up (ADCmean: 1.03 ± 0.19 × 10−3 mm2/s; P = 0.018). There was no significant increase of ADCmean between the first and second follow-up. There was, however, a significant increase of ADCmin after 12 months (ADCmin: 0.87 ± 0.29 × 10−3 mm2/s) compared to pre-interventional MRI and first follow-up ( P Conclusion The tumor response after CT-guided HDR-BT was associated with a significantly higher increase in ADCmean and ADCmin in short- and long-term follow-up.

Purpose Evaluation of efficacy and safety of CT- or MRI-guided high-dose-rate interstitial brachytherapy (iBT) in the treatment of advanced, imatinib refractory, metastatic gastrointestinal stroma tumors (GISTs) was the objective of this retrospective study. Methods and Materials A cumulative number of 40 unresectable metastases (30 hepatic, 10 peritoneal) were treated with iBT in 10 selected patients with histologically proven GISTs. Six patients had peritoneal disease, and 5 patients were even progressing under sunitinib (second line)—thus iBT was applied as a salvage maneuver. IBT uses an interstitially introduced 192iridium source in a high-dose-rate irradiation regime to destroy vital cells in a single fraction. Response to treatment was assessed clinically and with acquisition of MRI/CT every 3 months. Results Local tumor control was reached in 97.5% of all treated metastases during a median time of 25 months—only one local relapse was observed during followup. The median diameter of the irradiated lesions was 2.4 cm (range 0.6–11.2 cm); a median dose of 15 Gy (range 6.7–21.96 Gy) was applied. The median progression-free survival after iBT was 6.8 (range 3.0–20.2) months; the median overall survival was 37.3 months (range 11.4–89.7). Two major complications (Common Terminology for Adverse Events grade 3) occurred following the intervention: local hemorrhage and pneumothorax, successfully dealt with by angiographic embolization and pleural drainage, respectively. Conclusions In selected patients with metastatic, imatinib refractory GISTs, iBT safely enables high rates of local tumor control and presents an alternative, anti-neoplastic treatment option even in a salvage situation.

A key limiting factor in the radiotherapy of liver malignancies is the relatively low tolerance of the liver parenchyma to radiation. This can lead to subclinical focal or generalized injury of the liver parenchyma under radiation treatment. It is of great importance to detect the rare complication of radiation-induced liver disease (RILD) early and to treat it symptomatically, as well as to protect patients with increased risk by preventive medication.

BACKGROUND/AIM Intraarterial Technetium-99m-Macroaggregated Albumin (99mTc-MAA) administration is an established method to predict particle distribution prior to radioembolization. This study aimed to analyse the impact of intraarterial administration of 99mTc-MAA on changes in liver-specific laboratory parameters and to assess whether such changes are associated with post-radioembolization hepatotoxicity. PATIENTS AND METHODS A total of 202 patients treated with radioembolization received prior mapping angiography with 99mTc-MAA administration. All patients underwent clinical and laboratory examinations, including liver-specific parameters at certain times before and after mapping angiography/99mTc-MAA administration, as well as before radioembolization and during follow-up. RESULTS Bilirubin increased temporarily after 99mTc-MAA administration (p

Hepatic tumors include hepatocellular cancer (HCC) and cholangiocarcinoma (CC), a small subgroup of tumors (approx. 1%) are classified as combined hepatocellularcholangiocellular carcinomas. Different stage-dependent therapeutic approaches comprise resection, local ablative techniques, locoregional therapies, systemic treatment, liver transplantation in selected cases and possible combination of these treatment modalities. This review summarizes current knowledge on multi-modal treatment strategies for liver cancer focusing on gastrointestinal side effects.

The aim of this single-center, open-label phase II study was to assess the efficacy of image-guided high-dose-rate (HDR) brachytherapy (iBT) compared with conventional transarterial embolization (cTACE) in unresectable hepatocellular carcinoma. Seventy-seven patients were treated after randomization to iBT or cTACE, as single or repeated interventions. Crossover was allowed if clinically indicated. The primary endpoint was time to untreatable progression (TTUP). Eligibility criteria included a Child–Pugh score of ≤ 8 points, absence of portal vein thrombosis (PVT) at the affected liver lobe, and ≤ 4 lesions. Survival was analyzed by using the Cox proportional hazard model with stratification for Barcelona Clinic Liver Cancer (BCLC) stages. Twenty patients were classified as BCLC-A (iBT/cTACE 8/12), 35 as BCLC-B (16/19), and 22 as BCLC-C (13/9). The 1-, 2-, and 3-year TTUP probabilities for iBT compared with cTACE were 67.5% versus 55.2%, 56.0% versus 27.4%, and 29.5% versus 11.0%, respectively, with an adjusted hazard ratio (HR) of 0.49 (95% confidence interval 0.27–0.89; p = 0.019). The 1-, 2-, and 3-year TTPs for iBT versus cTACE were 56.0% versus 28.2%, 23.9% versus 6.3%, and 15.9% versus 6.3%, respectively, with an adjusted HR of 0.49 (0.29–0.85; p = 0.011). The 1-, 2-, and 3-year OS rates were 78.4% versus 67.7%, 62.0% versus 47.3%, and 36.7% versus 27.0%, respectively, with an adjusted HR of 0.62 (0.33–1.16; p = 0.136). This explorative phase II trial showed a superior outcome of iBT compared with cTACE in hepatocellular carcinoma and supports proceeding to a phase III trial.

To evaluate the course of pro- and anti-inflammatory cytokines after 90Y-radioembolization (RE) of liver malignancies and to identify prognosticators for liver-related adverse events and survival. In 34 consecutive patients with secondary or primary liver tumors scheduled for RE, the following cytokines were measured prior to and 2 h, 3 days, and 6 weeks after RE: interleukin (IL) -1, IL-2, IL-4, IL-6, IL-8, tumor necrosis factor alpha (TNF-α), and interferon-γ. Liver function impairment was defined as an elevation of liver-related laboratory values as graded by CTCAE ≥ 2 and/or serum bilirubin ≥30 µmol/l and/or development of ascites at 6-week follow-up. Significant changes over time were seen in IL-1 (increase from 0.4 pg/ml (±0.7) at baseline to 1.1 pg/ml (±1.4) 3 days after RE (p = 0.02)), and in IL-6 (increase from 16.8 pg/ml (±21.8) at baseline to 54.6 pg/ml (±78.2) 3 days after RE (p = 0.003)). Baseline values of IL-6 and IL-8 were independently associated with liver function impairment at follow-up as well as decreased survival with an optimal cutoff at 6.53 and 60.8 pg/ml, respectively. Expected changes in pro- and anti-inflammatory cytokines after RE were shown. Furthermore, baseline values of IL-6 and IL-8 were associated with later liver dysfunction and survival. We hypothesize that these biomarkers are potential prognosticators and might help in patient selection for RE.

Background: Radioembolization (RE) with yttrium-90 (90Y) resin microspheres yields heterogeneous response rates in with primary or secondary liver cancer. Radiation-induced liver disease (RILD) is a potentially life-threatening complication with higher prevalence in cirrhotics or patients exposed to previous chemotherapies. Advances in RILD prevention may help increasing tolerable radiation doses to improve patient outcomes. This study aimed to evaluate the impact of post-therapeutic RILD-prophylaxis in a cohort of intensely pretreated liver metastatic breast cancer patients, Methods: Ninety-three patients with liver metastases of breast cancer received RE between 2007 and 2016. All Patients received RILD prophylaxis for 8 weeks post-RE. From January 2014, RILD prophylaxis was changed from ursodeoxycholic acid (UDCA) and prednisolone (standard prophylaxis [SP], n = 59) to pentoxifylline (PTX), UDCA and low-dose low molecular weight heparin (LMWH) (modified prophylaxis (MP), n = 34). The primary endpoint was toxicity including symptoms of RILD, Results: Dose exposure of normal liver parenchyma was higher in the modified vs. standard prophylaxis group (47.2 Gy (17.8–86.8) vs. 40.2 Gy (12.5–83.5), p = 0.017). All grade RILD events (mild: bilirubin ≥ 21 µmol/L (but &lt, 30 μmol/L), severe: (bilirubin ≥ 30 µmol/L and ascites)) were observed more frequently in the SP group than in the MP group, albeit without significance (7/59 vs. 1/34, p = 0.140). Severe RILD occurred in the SP group only (n = 2, p &gt, 0.1). ALBI grade increased in 16.7% patients in the MP and in 27.1% patients in the SP group, respectively (group difference not significant), Conclusions: At established dose levels, mild or severe RILD events proved rare in our cohort. RILD prophylaxis with PTX, UDCA and LMWH appears to have an independent positive impact on OS in patients with metastatic breast cancer and may reduce the frequency and severity of RILD. Results of this study as well as pathophysiological considerations warrant further investigations of RILD prophylaxis presumably targeting combinations of anticoagulation (MP) and antiinflammation (SP) to increase dose prescriptions in radioembolization.

Treating hepatocellular carcinoma (HCC) remains a challenge; its incidence is increasing worldwide, and the disease is frequently diagnosed in an advanced stage in which curative treatment cannot be provided. According to the Milan criteria and Barcelona Clinic Liver Cancer staging scheme, only a minority of patients are candidates for potentially curative liver transplantation or, in patients without evidence of severe liver cirrhosis, for resection or radiofrequency ablation (1–4). Transarterial chemoembolization (TACE) is accepted as the therapy of choice (1, 2, 5–7) in intermediate disease stages or as a bridging treatment for patients on the waiting list for transplantation. When TACE is contraindicated and in advanced disease, systemic therapy with sorafenib, a multikinase inhibitor, is the only available effective treatment for patients with preserved liver function (8). Depending on patient selection and the embolic agent used, the median survival after TACE ranges from 15.6 to 23.2 months, and the treatment has demonstrated a proven benefit in controlled studies (compared with best supportive care), especially in early intermediate stage patients (5–7, 9–12). In a phase III trial comparing sorafenib with a placebo in advanced-stage HCC in Child A patients, treatment with sorafenib yielded a median survival benefit of 10.7 vs. 7.9 months (8). Through its embolic effect, TACE may induce the release of angiogenic factors, which in turn may promote the outgrowth of surviving tumor cells into tumor recurrence and metastatic spread. Therefore, combining TACE with systemic sorafenib treatment may be an attractive concept (13, 14). Clinical data still remain inconclusive (15–17). Although the toxicity of such a combined regimen (TACE plus sorafenib) does not seem to exceed the toxicity conferred by each of the two modalities alone, the overall toxicity of systemic sorafenib remains high. Common adverse events include diarrhea, hand-foot skin reaction, and fatigue, presenting at grade 3 intensity in approximately 25% of cases (8, 18). These observations have led to the idea of locally administering sorafenib in combination with ethiodized oil to increase the sorafenib concentration in the tumor while reducing the systemic concentration, and thus, toxicity. Recent pilot experiments by Gaba et al. (19) and Chatziioannou et al. (20) revealed transarterial sorafenib chemoembolization to be feasible in non-tumor-bearing rabbits, where favorable pharmacokinetics were observed. The sorafenib concentrations found in the treated lobe were significantly higher than the concentrations reported for systemic therapy, while no immediate histopathologic tissue toxicity was found in animal necropsy (19, 20). In this study, we performed a modified TACE using an emulsion of sorafenib and ethiodized oil (referred to as SORATACE) for the treatment of experimental VX-2 liver tumors in rabbits. Efficacy and safety were measured using contrast-enhanced computed tomography (CT) and histopathologic examinations. Two groups of rabbits receiving either no treatment or oral sorafenib served as controls.

Purpose To evaluate efficacy and safety of CT-guided iBT in patients with primary and secondary malignancies of the pancreas. Material and methods 13 patients with 13 lesions of the pancreatic corpus and tail were included: 8 secondary malignancies (metastatic lesions = ML) and 5 primary malignancies, including 3 primary tumors (PT) and 2 isolated locoregional recurrences (ILR) after surgical resection were treated with image-guided iBT using a 192iridium source (single fraction irradiation). Every 3 months after treatment clinical and imaging follow-up were conducted to evaluate efficacy. Peri- and postinterventional complications were assessed descriptively. Results The median diameter of the gross tumor volume (GTV) was 3 cm (range 1–6.5 cm), treated with a median D100 (minimal enclosing tumor dose) of 15.3 Gy (range 9.2–25.4 Gy). Local tumor control (LTC) was 92.3% within a median follow-up period of 6.7 months (range 3.2–55.7 months). Cumulative median progression free survival (PFS) was 6.2 months (range 2.8–25.7 months; PFS of primary and secondary malignancies was 5.8 and 6.2 months, respectively). Cumulative median over all survival (OS) after iBT was 16.2 months (range 3.3–55.7 months; OS of primary and secondary malignancies was 7.4 months and 45.6 months, respectively). 1 patient developed mild acute pancreatits post iBT, spontanously resolved within 1 week. No severe adverse events (grade 3+) were recorded. Conclusion Image-guided iBT is a safe and particularly effective treatment in patients with primary and secondary malignancies of the pancreas and might provide a well-tolerated additional therapeutic option in the multidisciplinary management of selected patients.

Image-guided high-dose-rate interstitial brachytherapy (iBT) with iridium-192 is an effective treatment option for patients with liver malignancies. Little is known about long-term radiation effects on the bile duct system when central hepatic structures are exposed to iBT. This retrospective analysis investigates the occurrence of posthepatic cholestasis (PHC) and associated complications in patients undergoing iBT. We identified patients who underwent iBT of hepatic malignancies and had point doses of ≥1 Gy to central bile duct structures. Patients with known bile duct-related diseases or prior bile duct manipulation were excluded. 102 patients were retrospectively included. Twenty-two patients (22%) developed morphologic PHC after a median of 17 (3–54) months; 18 of them were treated using percutaneous transhepatic cholangiopancreatography drainage or endoscopic retrograde cholangiopancreatography. The median point dose was 24.8 (4.4–80) Gy in patients with PHC versus 14.2 (1.8–61.7) Gy in those without PHC (p = 0.028). A dose of 20.8 Gy (biological effective dose, BED3/10 = 165/64.1 Gy) was identified to be the optimal cutoff dose (p = 0.028; 59% sensitivity, 24% specificity). Abscess/cholangitis was more common in patients with PHC compared to those without (4 of 22 vs. 2 of 80; p = 0.029). Median survival did not differ between patients with and without PHC (43 vs. 36 months; p = 0.571). iBT of liver malignancies located near the hilum can cause PHC when the central bile ducts are exposed to high point doses. Given the long latency and absence of impact of iBT-induced PHC on median survival, the rate of cholestasis and complications seen in our patients appears to be acceptable.

Purpose Computed tomography (CT) or magnetic resonance imaging (MRI) guided brachytherapy provides high tumor control rates in hepatocellular carcinoma (HCC) and colorectal liver metastases. In contrast to thermal ablation methods such as radiofrequency ablation (RFA), much less restrictions apply with respect to tumor location or size. In this study, we determined the efficacy and safety of CT- or MRI-guided brachytherapy in metastatic melanoma. Material and methods Fifty-two metastases of malignant melanoma in 14 patients were included in this retrospective study. Local tumor control and safety were evaluated as primary and secondary endpoints. Furthermore, we evaluated overall survival and progression free survival. Tumor locations were liver (n = 31), lung (n = 15), adrenal (n = 3), lymph nodes (n = 2), and kidney (n = 1). Treatment planning was performed using three-dimensional CT or MRI data acquired after percutaneous applicator positioning under CT or open MRI guidance. Subsequently, single fraction high-dose-rate (HDR) brachytherapy was applied using a (192)Iridium source. Clinical and cross-sectional follow-up were performed every 3 months post intervention. Results The median diameter of treated lesions was 1.5 cm (range: 0.7-10 cm). Doses between 15 and 20 Gy were applied (median dose: 19.9 Gy). The mean irradiation time ranged between 7-45 minutes. After treatment, there was one patient with a cholangitis. After a median follow up of five months, the median local tumor control was 90%. The median overall survival of the patients was 8 months. The median progression free survival of the patients was 6 months. Conclusions Image-guided HDR brachytherapy is a safe and effective treatment procedure in metastatic malignant melanoma.

To assess the efficacy, safety, and outcome of image-guided high-dose-rate (HDR) brachytherapy in patients with adrenal gland metastases (AGM). From January 2007 to April 2014, 37 patients (7 female, 30 male; mean age 66.8 years, range 41.5–82.5 years) with AGM from different primary tumors were treated with CT-guided HDR interstitial brachytherapy (iBT). Primary endpoint was local tumor control (LTC). Secondary endpoints were time to untreatable progression (TTUP), time to progression (TTP), overall survival (OS), and safety. In a secondary analysis, risk factors with an influence on survival were identified. The median biological equivalent dose (BED) was 37.4 Gy. Mean LTC after 12 months was 88%; after 24 months this was 74%. According to CTCAE criteria, one grade 3 adverse event occurred. Median OS after first diagnosis of AGM was 18.3 months. Median OS, TTUP, and TTP after iBT treatment were 11.4, 6.6, and 3.5 months, respectively. Uni- and multivariate Cox regression analyses revealed significant influences of synchronous disease, tumor diameter, and the total number of lesions on OS or TTUP or both. Image-guided HDR-iBT is safe and effective. Treatment- and primary tumor-independent features influenced survival of patients with AGM after HDR-iBR treatment.

The aim of this study was to assess the rates of haemorrhagic and thrombotic complications in patients undergoing interventional tumour ablation with and without peri-interventional low-molecular-weight heparin (LMWH) thrombosis prophylaxis. Patients presented with primary and secondary neoplastic lesions in the liver, lung, kidney, lymph nodes and other locations. A total of 781 tumour ablations (radiofrequency ablation, n = 112; interstitial brachytherapy, n = 669) were performed in 446 patients over 22 months; 260 were conducted under peri-interventional thrombosis prophylaxis with LMWH (H-group;) and 521 without this (NH-group, in 143 of these, LMWH was given post-interventionally). Sixty-three bleeding events occurred. There were significantly more bleedings in the H-group than in the NH-group (all interventions, 11.66 and 6.26 %, p = 0.0127; liver ablations, 12.73 and 7.1 %, p = 0.0416). The rate of bleeding events Grade ≥ III in all procedures was greater by a factor of >2.6 in the H-group than in the NH-group (4.64 and 1.73 %, p = 0.0243). In liver tumour ablations, the corresponding factor was about 3.3 (5.23 and 1.54 %, p = 0.028). In uni- and multivariate analyses including covariates, the only factor constantly and significantly associated with the rate of haemorrhage events was peri-interventional LMWH prophylaxis. Only one symptomatic lung embolism occurred in the entire cohort (NH-group). The 30- and 90-day mortalities were significantly greater in the H-group than in the NH-group. Peri-interventional LMWH thrombosis prophylaxis should be considered with caution. The rate of clinically relevant thrombotic events was extremely low.

Background In treatment-refractory liver dominant metastatic colorectal cancer, the role of liver directed therapies still is unclear. We sought to determine a prognostic score for Y90 radioembolization in these patients. Methods We analyzed 106 patients with refractory liver dominant mCRC who had undergone a total of 178 Y90 radioembolizations with resin microspheres was collected. Potential factors influencing survival were analyzed using a Cox regression. The Log rank test served to establish prognostic factors and to form a clinical score for outcome prediction after Y90 radioembolization. Results Median survival of all patients was 6.7 months. Neither age nor prior surgical or systemic therapy nor metastatic spread had an effect on survival. In contrast, hepatic tumor load, Karnofsky index as well as CEA and CA19-9 serums level had a significant influence (p 20 %, CEA >130 ng/ml or CA19-9 > 200U/ml and Karnofsky index

Zusammenfassung Die intraarterielle Selektive Interne Radiotherapie (SIRT) mit 90 Y-markierten Mikrospharen ist mittlerweile eine wichtige lokal-ablative Therapieoption fur die Behandlung onkologischer Patienten geworden. Die SIRT stellt gegenwartig einen palliativen Therapieansatz fur die Behandlung von Lebermalignomen dar. Infolge der Art des 90 Y-Zerfalls als β - -Strahler ohne eine begleitende Gammaemission, bedarf es zur Validierung der erzielten Verteilung des Radioembolisates einer Bremsstrahlungsbildgebung. Dieser Artikel demonstriert durch eine Phantommessung diese Art der Bildgebung und zeigt anhand einer Patientenstudie die Vorteile einer posttherapeutischen Schnittbildgebung. Es werden Ansatzpunkte fur weitere Optimierungen der Bremsstrahlungsbildgebung aufgezeigt.

This study was designed to evaluate overall survival after radioembolization or best supportive care (BSC) in patients with chemotherapy-refractory liver-dominant metastatic colorectal cancer (mCRC). This was a matched-pair comparison of patients who received radioembolization plus BSC or BSC alone for extensive liver disease. Twenty-nine patients who received radioembolization were retrospectively matched with a contemporary cohort of >500 patients who received BSC from 3 centers in Germany. Using clinical databases, patients were initially matched for prior treatments and tumor burden and then 29 patients were consecutively identified with two or more of four matching criteria: synchronous/metachronous metastases, tumor burden, increased ALP, and/or CEA >200 U/ml. Survival was calculated from date of progression before radioembolization or BSC by using Kaplan–Meier analysis. Of 29 patients in each study arm, 16 pairs (55.2%) matched for all four criteria, and 11 pairs (37.9%) matched three criteria. Patients in both groups had a similar performance status (Karnofsky index, median 80% [range, 60–100%]). Compared with BSC alone, radioembolization prolonged survival (median, 8.3 vs. 3.5 months; P

Aim. To assess the outcomes of patients with unresectable intrahepatic cholangiocellular carcinoma (ICC) treated by a tailored therapeutic approach, combining systemic with advanced image-guided local or locoregional therapies.Materials and Methods. Treatment followed an algorithm established by a multidisciplinary GI-tumor team. Treatment options comprised ablation (RFA, CT-guided brachytherapy) or locoregional techniques (TACE, radioembolization, i.a. chemotherapy).Results. Median survival was 33.1 months from time of diagnosis and 16.0 months from first therapy. UICC stage analysis showed a median survival of 15.9 months for stage I, 9 months for IIIa, 18.4 months for IIIc, and 13 months for IV. Only the number of lesions, baseline serum CEA and serum CA19-9, and objective response (RECIST) were independently associated with survival. Extrahepatic metastases had no influence.Conclusion. Patients with unresectable ICC may benefit from hepatic tumor control provided by local or locoregional therapies. Future prospective study formats should focus on supplementing systemic therapy by classes of interventions (“toolbox”) rather than specific techniques, that is, local ablation leading to complete tumor destruction (such as RFA) or locoregional treatment leading to partial remission (such as radioembolization). This trial is registered with German Clinical Trials Registry (Deutsche Register Klinischer Studien), DRKS-ID:DRKS00006237.

To evaluate complications and identify risk factors for adverse events in patients undergoing high-dose-rate interstitial brachytherapy (iBT). Data from 192 patients treated in 343 CT- or MRI-guided interventions from 2006–2009 at our institution were analyzed. In 41 %, the largest tumor treated was ≥ 5 cm, 6 % of the patients had tumors ≥ 10 cm. Prior to iBT, 60 % of the patients had chemotherapy, 22 % liver resection, 19 % thermoablation or transarterial chemoembolization (TACE). Safety was the primary endpoint; survival data were obtained as the secondary endpoints. During follow-up, MRI or CT imaging was performed and clinical and laboratory parameters were obtained. The rate of major complications was below 5 %. Five major bleedings (1.5 %) occurred. The frequency of severe bleeding was significantly higher in patients with advanced liver cirrhosis. One patient developed signs of a nonclassic radiation-induced liver disease. In 3 patients, symptomatic gastrointestinal (GI) ulcers were detected. A dose exposure to the GI wall above 14 Gy/ml was a reliable threshold to predict ulcer formation. A combination of C-reactive protein ≥ 165 mg/l and/or leukocyte count ≥ 12.7 Gpt/l on the second day after the intervention predicted infection (sensitivity 90.0 %; specificity 92.8 %.) Two patients (0.6 %) died within 30 days. Median overall survival after the first liver treatment was 20.1 months for all patients and the local recurrence-free surviving proportion was 89 % after 12 months. Image-guided iBT yields a low rate of major complications and is effective.

Over the last decade radioembolization and transarterial chemoembolization have been shown to be effective in unresectable intrahepatic cholangiocellular carcinoma. Unfortunately, up to now the evidence is not high with most of the conclusions drawn from single center retrospective analyses with small sample sizes treated in the salvage situation. However, the results are promising and suggest a survival benefit in the treatment of unresectable cholangiocellular carcinoma, even in an advanced stage with extrahepatic disease. In the following, available results of the treatment of unresectable cholangiocellular carcinoma by radioembolization and transarterial chemoembolization will be summarized. Special attention will be given to prognostic factors and efficacy as measured by response criteria. The potential integration of these therapies into multimodal treatment concepts will be discussed with focus on the intensification of therapy and a staged concept of therapy.

Prior 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). Retrospective 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. At 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. Comparison 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.

Summary 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.

Transarterial chemoembolization (TACE) is established as bridging therapy of HCC listed for transplantation (LT). CT-guided brachytherapy (CTB) has not been evaluated as a bridging concept. We compared CTB and TACE for bridging before LT in HCC patients. Twelve patients with HCC received LT after CTB (minimal tumour dose, 15–20 Gy). Patients were matched (CTB:TACE, 1:2) by sex, age, number and size of lesions, and underlying liver disease with patients who received TACE before transplantation. Study endpoints were extent of necrosis at histopathology and recurrence rate after OLT. There were no significant differences between the CTB and TACE groups regarding Child-Pugh category (p = 0.732), AFP (0.765), time on waiting list (p = 0.659), number (p = 0.698) and size (p = 0.853) of HCC lesions, fulfilment of Milan-criteria (p = 0.638), or previous liver-specific treatments. CTB achieved higher tumour necrosis rates than TACE (p = 0.018). The 1- and 3-year recurrence rate in the CTB group was 10 and 10 % vs. TACE, 14 and 30 % (p = 0.292). Our data show comparable or even better response and post-LT recurrence rates of CTB compared to TACE for treating HCC in patients prior to LT. CTB should be further evaluated as an alternative bridging modality, especially for patients not suited for TACE. • CT-guided interstitial brachytherapy (CTB) is a promising alternative to transarterial chemoembolization (TACE). • CTB instead of TACE is possible for bridging to liver transplantation in HCC patients. • HCC recurrence was not associated with CTB despite potential tumour seeding.