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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.

Metastatic spread of the primary is still defined as the systemic stage of disease in treatment guidelines for various solid tumors. This definition is the rationale for systemic therapy. Interestingly and despite the concept of systemic involvement, surgical resection as a local treatment has proven to yield long-term outcomes in a subset of patients with limited metastatic disease, supporting the concept of oligometastatic disease. Radiofrequency ablation has yielded favorable outcomes in patients with hepatocellular carcinoma and colorectal metastases, and some studies indicate its prognostic potential in combined treatments with systemic therapies. However, some significant technical limitations apply, such as size limitation, heat sink effects, and unpredictable heat distribution to adjacent risk structures. Interventional and non-invasive radiotherapeutic techniques may overcome these limitations, expanding the options for oligometastatic patients and cytoreductive concepts. Current data suggest very high local control rates even in large tumors at any given location in the human body. The article focusses on the characteristics and possibilities of stereotactic body radiation therapy, interstitial high-dose-rate brachytherapy, and Yttrium-90 radioembolization. In this article, we discuss the differences of the technical preferences as well as their impact on indications. Current data is presented and discussed with a focus on application in oligometastatic or cytoreductive concepts in different tumor biologies.In den Leitlinien zur Behandlung verschiedener solider Tumoren wird die Metastasierung des Primärtumors nach wie vor als das systemische Stadium der Erkrankung definiert. Diese Definition begründet das Vorgehen für eine systemische Therapie. Interessanterweise, und trotz des Konzepts der systemischen Beteiligung, hat die chirurgische Resektion als lokale Behandlungsmöglichkeit langfristige Ergebnisse in einer Untergruppe von Patienten mit begrenzter Metastasierung zeigen können; dies bekräftigt das Konzept der oligometastatischen Erkrankung. Die Radiofrequenzablation hat günstige Ergebnisse bei Patienten mit Leberzellkarzinom und kolorektalen Metastasen gezeigt, und einige Studien weisen ihr prognostisches Potenzial bei mit systemischen Therapien kombinierten Behandlungen auf. Allerdings gelten hierbei einige wichtige technische Einschränkungen, wie z.B. Größenbeschränkung, «heat sink»-Effekte und unvorhersehbare Wärmeverteilung auf benachbarte Risikostrukturen. Interventionelle und nichtinvasive radiotherapeutische Techniken können diese Einschränkungen überwinden und hierdurch die Optionen für oligometastatische Patienten und für zytoreduktive Konzepte erweitern. Aktuelle Daten deuten auf sehr hohe lokale Kontrollraten auch bei großen Tumoren an jedem Ort im menschlichen Körper hin. Dieser Artikel befasst sich mit den Charakteristika und Möglichkeiten der stereotaktischen (Körper-)Radiotherapie, der interstitiellen hochdosierten Brachytherapie und der Yttrium-90-Radioembolisation. Wir diskutieren in diesem Beitrag die Unterschiede der technischen Präferenzen sowie ihre Auswirkungen auf die Indikationen. Aktuelle Daten werden vorgestellt und mit einem Fokus auf die Anwendung in oligometastatischen oder zytoreduktiven Konzepten bei unterschiedlichen Tumorbiologien diskutiert.

Methods: Fifteen patients (f, 6; m, 9; median age, 59 years; range, 32 to 72 years) with 28 liver metastases were included retrospectively. FDG-PET/CT imaging (median activity, 237 MBq; range, 231 to 252 MBq; median uptake, 61 min; range, 55 to 67 min) was performed on a Siemens Biograph mCT 64 followed by image reconstruction using 3D-ordered subset expectation maximization (3D-OSEM) or 3D-OSEM with PSF modeling - both with and without TOF information. Differences in SUVmax were analyzed using the Friedman test and Wilcoxon test for paired non-parametric data. The correlation of inter-method differences with the lesions’ TBR was studied using Spearman’s rank correlation coefficient (rho). Differences between lesions with low (4.8) TBR were analyzed using the Mann-Whitney U test (TBR measured with 3D-OSEM; binarized by its median). Background: The maximum standardized uptake value (SUVmax) is a common clinical parameter for quantification in F18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), but it is influenced by image reconstruction. The aim of this study was to analyze the association of SUVmax deviations related to point spread function (PSF) and time-of-flight (TOF) reconstruction with tumor-to-background ratios (TBR) in colorectal liver metastases (CRLM). Results: There was a significant correlation of the lesions’ TBR with relative SUVmax differences related to PSF (PSF + TOF vs. 3D-OSEM + TOF, rho = 0.61; PSF vs. 3D-OSEM, rho = 0.52) or TOF (PSF + TOF vs. PSF, rho = −0.58; 3D-OSEM + TOF vs. 3D-OSEM, rho = −0.61). Accordingly, PSF algorithms only showed higher SUVmax than non-PSF algorithms in lesions with a high TBR (median differences at low/high TBR, +2.6%/+9.1% [PSF + TOF vs. 3D-OSEM + TOF]; +0.7%/+6.4% [PSF vs. 3D-OSEM]). TOF integration also led to higher SUVmax but mainly at low TBR (low/high TBR, +10.4%/+1.8% [PSF + TOF vs. PSF]; +8.6%/−0.1% [3D-OSEM + TOF vs. 3D-OSEM]). Conclusions: Both PSF and TOF reconstruction resulted in a substantial alteration of SUVmax in CRLM. TOF provided the highest SUVmax increase in low-contrast lesions while - vice versa - PSF showed the most relevant increase in high-contrast lesions. Thus, one should be aware that quantitative analyses of lesions with varying TBR, e.g., in radiotherapy or follow-up studies, may be mainly affected by either PSF or TOF reconstruction, respectively.

Purpose: To prospectively assess a dose-response relationship for small volumes of liver parenchyma after single-fraction irradiation. Methods and Materials: Twenty-five liver metastases were treated by computed tomography (CT)-guided interstitial brachytherapy. Magnetic resonance imaging was performed 1 day before and 3 days and 6, 12, and 24 weeks after therapy. MR sequences included T1-w gradient echo (GRE) enhanced by hepatocyte-targeted gadobenate dimeglumine. All MRI data sets were merged with 3D dosimetry data and evaluated by two radiologists. The reviewers indicated the border of hyperintensity on T2-w images (edema) or hypointensity on T1-w images (loss of hepatocyte function). Based on the total 3D data, a dose-volume histogram was calculated. We estimated the threshold dose for either edema or function loss as the D 90 , i.e., the dose achieved in at least 90% of the pseudolesion volume. Results: Between 3 days and 6 weeks, the extension of the edema increased significantly from the 12.9 Gy isosurface to 9.9 Gy (standard deviation [SD], 3.3 and 2.6). No significant change was detected between 6 and 12 weeks. After 24 weeks, the edematous tissue had shrunk significantly to 14.7 Gy (SD, 4.2). Three days postbrachytherapy, the D 90 for hepatocyte function loss reached the 14.9 Gy isosurface (SD, 3.9). At 6 weeks, the respective zone had increased significantly to 9.9 Gy (SD, 2.3). After 12 and 24 weeks, the dysfunction volume had decreased significantly to the 11.9 Gy and 15.2 Gy isosurface, respectively (SD, 3 and 4.1). Conclusions: The 95% interval from 7.6 to 12.2 Gy found as the minimal hepatocyte tolerance after 6 weeks accounts for the radiobiologic variations found in CT-guided brachytherapy, including heterogeneous dose rates by variable catheter arrays.

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.

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

Radiotherapy of liver malignancies shows promising results (radioembolization, stereotactic irradiation, interstitial brachytherapy). Regardless of the route of application, a certain amount of nontumorous liver parenchyma will be collaterally damaged by radiation. The functional reserve may be significantly reduced with an impact on further treatment planning. Monitoring of radiation-induced liver damage by imaging is neither established nor validated. We performed an analysis to correlate the histopathological presence of radiation-induced liver damage with functional magnetic resonance imaging (MRI) utilizing hepatobiliary contrast media (Gd-BOPTA). Patients undergoing local high-dose-rate brachytherapy for whom a follow-up hepatobiliary MRI within 120 days after radiotherapy as well as an evaluable liver biopsy from radiation-exposed liver tissue within 7 days before MRI were retrospectively identified. Planning computed tomography (CT)/dosimetry was merged to the CT-documentation of the liver biopsy and to the MRI. Presence/absence of radiation-induced liver damage (histopathology) and Gd-BOPTA uptake (MRI) as well as the dose applied during brachytherapy at the site of tissue sampling was determined. Fourteen biopsies from eight patients were evaluated. In all cases with histopathological evidence of radiation-induced liver damage (n = 11), no uptake of Gd-BOPTA was seen. In the remaining three, cases no radiation-induced liver damage but Gd-BOPTA uptake was seen. Presence of radiation-induced liver damage and absence of Gd-BOPTA uptake was correlated with a former high-dose exposition. Absence of hepatobiliary MRI contrast media uptake in radiation-exposed liver parenchyma may indicate radiation-induced liver damage. Confirmatory studies are warranted.

Noninvasive imaging has become the standard for hepatocellular carcinoma (HCC) diagnosis in cirrhotic patients. Typical imaging features of HCC such as arterial wash-in and venous wash-out deliver very high specificity and acceptable sensitivity even in nodules from 1 to 2 cm in diameter. However, limitations apply specifically in hypovascular HCC, for which the addition of new techniques such as diffusion-weighted magnetic resonance imaging (DW-MRI) or hepatobiliary MRI is helpful. Whereas DW-MRI adds to both the sensitivity and specificity, hepatobiliary MRI additionally contributes valuable information in cirrhotic patients on the histopathology of small lesions, including early HCC and high-grade dysplastic nodules. Biopsy of small, atypical lesions is associated with a high rate of false-negative findings and should be used only after careful consideration in selected patients. Here, we review the current international guidelines on HCC diagnosis as well as the latest developments in imaging that may contribute to safe detection and accurate characterization of suspicious nodules in patients with liver cirrhosis.

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 (

Background To assess brachytherapy catheter positioning accuracy and to evaluate the effects of prolonged irradiation time on the tolerance dose of normal liver parenchyma following single-fraction irradiation with 192 Ir. Materials and methods Fifty patients with 76 malignant liver tumors treated by computed tomography (CT)-guided high-dose-rate brachytherapy (HDR-BT) were included in the study. The prescribed radiation dose was delivered by 1 - 11 catheters with exposure times in the range of 844 - 4432 seconds. Magnetic resonance imaging (MRI) datasets for assessing irradiation effects on normal liver tissue, edema, and hepatocyte dysfunction, obtained 6 and 12 weeks after HDR-BT, were merged with 3D dosimetry data. The isodose of the treatment plan covering the same volume as the irradiation effect was taken as a surrogate for the liver tissue tolerance dose. Catheter positioning accuracy was assessed by calculating the shift between the 3D center coordinates of the irradiation effect volume and the tolerance dose volume for 38 irradiation effects in 30 patients induced by catheters implanted in nearly parallel arrangement. Effects of prolonged irradiation were assessed in areas where the irradiation effect volume and tolerance dose volume did not overlap (mismatch areas) by using a catheter contribution index. This index was calculated for 48 irradiation effects induced by at least two catheters in 44 patients. Results Positioning accuracy of the brachytherapy catheters was 5-6 mm. The orthogonal and axial shifts between the center coordinates of the irradiation effect volume and the tolerance dose volume in relation to the direction vector of catheter implantation were highly correlated and in first approximation identically in the T1-w and T2-w MRI sequences (p = 0.003 and p < 0.001, respectively), as were the shifts between 6 and 12 weeks examinations (p = 0.001 and p = 0.004, respectively). There was a significant shift of the irradiation effect towards the catheter entry site compared with the planned dose distribution (p < 0.005). Prolonged treatment time increases the normal tissue tolerance dose. Here, the catheter contribution indices indicated a lower tolerance dose of the liver parenchyma in areas with prolonged irradiation (p < 0.005). Conclusions Positioning accuracy of brachytherapy catheters is sufficient for clinical practice. Reduced tolerance dose in areas exposed to prolonged irradiation is contradictory to results published in the current literature. Effects of prolonged dose administration on the liver tolerance dose for treatment times of up to 60 minutes per HDR-BT session are not pronounced compared to effects of positioning accuracy of the brachytherapy catheters and are therefore of minor importance in treatment planning.

90Y-radioembolization (RE) is a promising technique for delivering high doses of radiation to liver tumors but may result in compromise of liver function. To gain further perspective, we evaluated the toxicity rates of sequential lobar versus “whole liver” 90Y-radioembolization. Thirty-four patients with liver malignancy in noncirrhotic livers were included; 90Y-radioembolization was performed as either whole liver or sequential lobar treatment in 17 patients each. Standard clinical and liver specific laboratory parameters as well as MR imaging before treatment and at follow-up (6 and 12 weeks) after radioembolization were evaluated for toxicity using the Common Terminology Criteria for Adverse Events (CTCAE). Volumetry of the liver, tumor, and spleen and measurement of portal vein diameter also were performed. Three months after whole liver RE, 14 liver-related grade 3/4 events were recorded versus 2 events after sequential lobar treatment (P

We 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. Results from 50 embolization procedures conducted with the VP IV in 44 patients are summarized. All 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. With 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.

Background To assess radiobiological restrictions and tolerance doses as well as other toxic effects derived from repeated applications of single-fraction high dose rate irradiation of small liver volumes in clinical practice. Methods Twenty patients with liver metastases were treated repeatedly (2 - 4 times) at identical or intersecting locations by CT-guided interstitial brachytherapy with varying time intervals. Magnetic resonance imaging using the hepatocyte selective contrast media Gd-BOPTA was performed before and after treatment to determine the volume of hepatocyte function loss (called pseudolesion), and the last acquired MRI data set was merged with the dose distributions of all administered brachytherapies. We calculated the BED (biologically equivalent dose for a single dose d = 2 Gy) for different α/β values (2, 3, 10, 20, 100) based on the linear-quadratic model and estimated the tolerance dose for liver parenchyma D90 as the BED exposing 90% of the pseudolesion in MRI. Results The tolerance doses D90 after repeated brachytherapy sessions were found between 22 - 24 Gy and proved only slightly dependent on α/β in the clinically relevant range of α/β = 2 - 10 Gy. Variance analysis showed a significant dependency of D90 with respect to the intervals between the first irradiation and the MRI control (p < 0.05), and to the number of interventions. In addition, we observed a significant inverse correlation (p = 0.037) between D90 and the pseudolesion's volume. No symptoms of liver dysfunction or other toxic effects such as abscess formation occurred during the follow-up time, neither acute nor on the long-term. Conclusions Inactivation of liver parenchyma occurs at a BED of approx. 22 - 24 Gy corresponding to a single dose of ~10 Gy (α/β ~ 5 Gy). This tolerance dose is consistent with the large potential to treat oligotopic and/or recurrent liver metastases by CT-guided HDR brachytherapy without radiation-induced liver disease (RILD). Repeated small volume irradiation may be applied safely within the limits of this study.

Backround Micrometastases of colorectal liver metastases are present in up to 50% of lesions. In this study we sought to determine the threshold dose for local control of occult micrometastases in patients undergoing CT (computed tomography)-guided brachytherapy of colorectal liver metastases. Materials and methods Nineteen patients demonstrated 34 local tumor recurrences originating from micrometastases after CT-guided brachytherapy of 27 colorectal liver metastases. We considered a local tumor recurrence as originating from a micrometastasis if tumor regrowth occurred adjacent to a formerly irradiated lesion and the distance of the 3D isocenter of the new lesion was ≤ 23.5 mm from the previous tumor margin. Follow-up MRI was fused with the planning-CT and dosimetry data. Two reviewers independently indicated the dose exposure at the isocenter of the micrometastases. Statistical analysis included an analysis of variance (ANOVA) using backward selection. 95% tolerance intervals with coverage of 87.5 and 75% of the data of the normal distribution were calculated. Results The median distance of the micrometastases to the margin of the originating colorectal metastases was 8.75 mm (1-21 mm). Dose exposure at the isocenter was 12.25 Gy (7-19.8) in median. We stratified according to the distance from the isocenter to the initial tumor margin: ≤ 9 mm, > 9-15 mm and > 15 mm. The median dose in the according isocenters was 13.18, 11.6 and 11.85 Gy. The threshold dose failing to prevent micrometastasis growth was sigificantly higher in a subgroup of lesions with ≤ 9 mm distance as compared to > 15 mm (13.18 vs 11.85 Gy). Adjuvant chemotherapy correlated with greater distance of micrometastasis growth to the tumor but not with the threshold dose. Conclusion To prevent loss of local tumor control by continuous growth of micrometastases a threshold dose of 15,4 Gy (single fraction) should be delivered at a distance of 21 mm to the gross tumor margin.

Ziele: Evaluierung des Uptakes von Tc99m markierten Glucosemolekulen, 1-Thio-β-D-Glucose (1-TG) und 5-Thio-β-D-Glucose (5-TG), in den Tumorzelllinien HCT-116 und A549. Methode: Kultivierung der humanen Karzinomzelllinien HCT-116 (kolorektales-Ca.) und A549 (Adeno-Ca. der Lunge) unter Standardbedingungen. 12h vor Versuch Umsetzen auf glucosefreie Medien. Inkubation von je 1 Mio. Zellen mit 1 MBq F-18-FDG, 1-TG und 5-TG unter verschiedenen Glucose- (0; 2,5; 5 und 10mmol/l) und Insulinkonzentrationen (0,5; 1 und 2 IE/ml mit 5mmol/l Glucose) zu 3 definierten Inkubationszeiten (0,5; 2 und 4h). Zudem Bestimmung des Traceruptakes nach Blockierung der Glucosetransporter GLUT 1–12 mit Cytochalasin B (5, 10 and 20µmol/l) unter glucosefreien Bedingungen. Waschen der Zellen und Messung des Uptakes im Bohrloch. Ergebnis: Es zeigte sich ein maximaler Uptake von 1- und 5-TG nach 4h. Der Uptake betrug maximal 100,4% (1-TG, HCT-116), bzw. 67,4% (5-TG, HCT-116) vom Uptake von F-18-FDG unter glucosefreien Bedingungen. Mit zunehmender Inkubationszeit zeigte sich ein Anstieg des Uptakes, maximal um 492,7% fur F-18-FDG (A549), um 420,5% fur 1-TG (HCT-116) und um 294,2% fur 5-TG (HCT-116) unter glucose- und insulinfreien Bedingungen. Unter glucosefreien Bedingungen konnte der hochste Uptake fur alle Tracer beobachtet werden. Unter Glucosezusatz (10mmol/l) zeigte sich die maximale Reduktion des Uptakes um 95,9% bei F-18-FDG (A549), 41,6% bei 1-TG (HCT-116) und 39,1% bei 5-TG (A549). Insulinzusatz bewirkte eine Zunahme des Uptakes um maximal 135,8% bei F-18-FDG, 17,4% bei 1-TG und 18,7% bei 5-TG (alle HCT-116). Bei Blockade mittels Cytochalasin B Reduktion des Uptakes um 34,8% bei 1-TG (HCT-116) und 38,1% bei 5-TG (A 549). Schlussfolgerung: 1- und 5-TG zeigen einen Uptake in A549 und HCT-116 Zellen. Die Aufnahme ist im Gegensatz zum FDG allerdings geringer ausgepragt. Es zeigen sich Hinweise auf eine glucosetransporterabhangige Aufnahme. Ein Nutzen in der Tumorbildgebung muss in vivo uberpruft werden. Korrespondierender Autor: Seidensticker M Universitatsklinikum Magdeburg, Klinik fur Radiologie und Nuklearmedizin, Leipziger Str. 44, 39120 Magdeburg E-Mail: max.seidensticker@med.ovgu.de

The aim of this study was to assess the dependence of the normal liver tissue threshold dose on the volume exposed and the catheter geometry-dependent dose gradients for single-fraction high-dose-rate brachytherapy of malignant liver lesions. A total of 50 patients with malignant liver tumors treated with CT-guided high-dose-rate 192Ir brachytherapy were included. Dose planning was performed using a three-dimensional CT data set acquired after percutaneous applicator positioning. Magnetic resonance imaging (MRI), performed 6 and 12 weeks after therapy, was analyzed retrospectively. All MRI data sets were merged with 3D dosimetry data. The border of hyperintensity on T2-weighted images (edema) and of hypointensity on T1-weighted images (impaired hepatocyte function) were analyzed to assess the radiation effect. The threshold isodose surface of the volume exposed was calculated from the 3D dosimetry data. The relationships between irradiated volume and threshold isodose surface as well as dose gradient and threshold isodose surface were evaluated over time. The median threshold dose of the volume exposed, characterized by hepatocyte dysfunction and edema, was approximately 13 Gy 6 weeks after irradiation and approximately 16 Gy at 12 weeks. We found a significant correlation between the normal liver tissue threshold dose and volume exposed (P0.0001). The 12-week threshold dose was estimated between approximately 14 Gy for 500 cm(3), approximately 16 Gy for 100 cm(3), and approximately 18 Gy for 10 cm(3) of irradiated volume. The results indicate that the dose gradient has no effect on the threshold liver dose. There was a significant shift of the threshold doses from regions of lower to regions of higher-dose exposure in the course of follow-up (P0.0001). Thus the normal liver tissue threshold dose is dependent on the volume exposed but not on the dose gradient.

Image guided minimally invasive local and locoregional tumor ablation techniques like radiofrequency ablation, interstitial brachytherapy, transarterial chemoembolization (TACE) and selective internal radiotherapy (SIRT) with (90)Yttrium ( (90)Y) microspheres have been established as valuable amendments in oncologic therapy concepts. These techniques allow the destruction of extensive liver tumors with an acceptable toxicity profile. Necessity for a safe performance of these procedures is a close collaboration between interventional radiologist and anesthetist.

Purpose: To identify changes of liver function after single-fraction irradiation or yttrium-90 radioembolization (90Y-RE) of hepatocellular carcinoma associated with liver cirrhosis on the basis of laboratory data. Methods and Materials: 24 patients with primary liver carcinoma and liver cirrhosis classified Child-Pugh A or B were treated either by image-guided high-dose-rate brachytherapy (HDR-BT) (12 patients) or by 90Y-RE (12 patients). The following laboratory parameters were assessed 1 day before and 3 days, 6 weeks and 3 months after the intervention: total bilirubin and γ-glutamyl transpeptidase (GGTP) as parameters of detoxification function, albumin and cholinesterase (ChE) as direct synthesis parameters, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (AP) as indicators of liver tissue damage. Preinterventional values were taken as baseline, following values were calculated as percentage changes from the baseline value. Statistical analysis was performed using the Wilcoxon-matched pairs test, comparing postinterventional with preinterventional values. Differences were considered statistically significant with a p value Results: In all patients the median bilirubin, ALT, AP and albumin values remained within normal limits at any time of follow-up. AST levels in the RE group and GGTP in both groups have been already elevated over a normal range before the intervention, and in both groups both parameters showed a slight increase after interventions. ChE activity was lowered already in the baseline values and showed a further decrease 3 days after BT as well as 3 days and 6 weeks after RE, with final reconstitution to baseline values. All liver function test parameters showed mild changes shortly after radiation therapy but floating laboratory values recovering within 12 weeks to baseline values. Radiation or RE-induced liver disease was recorded in no patient. Conclusions: Liver function parameters show only mild changes shortly after intervention with recovery within 6–12 weeks to baseline values.

Purpose To determine the saftety and efficacy of computed tomography (CT)–guided brachytherapy in hepatocellular carcinoma (HCC). Methods and Materials A total of 83 patients were recruited, presenting with 140 HCC- lesions. Treatment was performed by CT-guided high-dose-rate (HDR) brachytherapy with an iridium—192 source. The primary endpoint was time to progression; secondary endpoints included local tumor control and overall survival (OS). A matched-pair analysis with patients not receiving brachytherapy was performed. Match criteria included the Cancer of the Liver Italian Program (CLIP) score, alpha-fetoprotein, presence, and extent of multifocal disease. For statistical analysis, Kaplan-Meier and Cox regression were performed. Results Mean and median cumulative TTP for all patients (n = 75) were 17.7 and 10.4 months. Five local recurrences were observed. The OS after inclusion reached median times of 19.4 months (all patients), 46.3 months (CLIP score, 0), 20.6 months (CLIP score, 1) 12.7 months, (CLIP score, 2), and 8.3 months (CLIP score, ≥3). The 1— and 3—year OS were 94% and 65% (CLIP score, 0), 69% and 12% (CLIP score, 1), and 48% and 19% (CLIP score, 2), respectively. Nine complications requiring intervention were encountered in 124 interventions. Matched-pair analysis revealed a significantly longer OS for patients undergoing CT-guided brachytherapy. Conclusion Based on our results the study treatment could be safely performed. The study treatment had a beneficial effect on OS in patients with advanced HCC, with respect to (and depending on) the CLIP score and compared with OS in a historical control group. A high rate of local control was also observed, regardless of applied dose in a range of 15 to 25 Gy.

The aim of this study was to evaluate the feasibility, safety, and efficacy of combined treatment with hepatic interstitial brachytherapy (HIB) and hepatic arterial infusion (HAI) of chemotherapy after interventional implantation of port catheter systems. Thirty-three patients with unresectable “liver-only” metastases of colorectal cancer were treated with both HIB and HAI during the course of their disease. All 33 patients had recurrent disease and 27 had received previous chemotherapy. Of these, 15 received HAI first and were then consolidated with HIB, 9 started with HIB and were continued with HAI, and 9 received first HIB and subsequently HAI after hepatic disease progression. Patients were evaluated for treatment characteristics, side effects, and efficacy. Comparisons between treatment groups were also performed. The median tumor diameter of metastases treated with brachytherapy was 4.6 cm (range: 1–12 cm). The median minimal irradiation dose inside the tumor margin was 18 Gy administered to a mean of two metastases in 69 interventions. Minor (n = 4) and major (n = 3) complications occurred in 10% of interventions. WHO grade III adverse events of the regional chemotherapy were observed in seven patients; grade IV, in one patient. At a median follow-up of 28 months (range: 7–74 months), the median time to disease progression after first treatment was 10.5 months (range: 1–35 months). Of 138 metastases treated by brachytherapy, 16 local recurrences were seen (mean, 12.3 months; range, 3–45 months). No signs of hepatic failure were observed in any of our patients. In conclusion, combinations of two minimally invasive therapeutic methods are feasible, with acceptable complication rates, and provide promising results in colorectal cancer patients with unresectable hepatic metastases.

To prospectively assess a dose-response relationship for the hepatic reticulo-endothelial system (RES) after small volume single fraction irradiation of liver parenchyma in vivo.Twenty-five liver tumors were treated by computed tomography (CT)-guided interstitial brachytherapy. Magnetic resonance imaging (MRI) was performed 1 day before and 3 days, 6, 12 and 24 weeks after therapy. MR-sequences included T2-w Turbo Spin Echo (TSE) enhanced by hepatic RES targeted Standard Superparamagnetic Iron Oxide (SSPIO). All MRI data sets were merged with three dimensional (3D) dosimetry data and evaluated by two radiologists. We estimated the threshold dose for either edema or function loss as the D90. A match-pair analysis was performed with another 25 liver tumors, which were treated the same but had MRI follow-up using the hepatocyte specific MRI contrast media Gadobenate dimeglumine (Gd-BOPTA).Three days post brachytherapy the D90 for hepatic RES function loss reached the 18.3 Gray (Gy) isosurface (Standard Deviation (SD) 7.7). At 6 weeks, the respective zone had increased significantly to the 12.9 Gy isosurface (SD 4.4). After 12 and 24 weeks, the dysfunction of liver volume decreased significantly to the 15 Gy and 20.4 Gy isosurface respectively (SD 7.1 and 10.0). Comparison to the hepatocyte function loss indicates a higher minimal threshold dose of the hepatic RES.Hepatic RES demonstrated a high regenerative capacity and a higher minimal threshold dose than hepatocytes. Temporary function loss was found from the 13 Gy isosurface.