Sorafenib therapy in patients with advanced hepatocellular carcinoma in advanced liver cirrhosis.

BACKGROUND AND AIM: Sorafenib has become the treatment standard for patients with advanced hepatocellular carcinoma (HCC). It is not clear whether patients with advanced liver function impairment (Child B) and patients undergoing additional locoregional therapy may tolerate treatment with sorafenib and benefit. We aimed to evaluate the tolerability and efficiency of sorafenib in patients with advanced HCC and different stages of liver cirrhosis, and in combination with locoregional therapy. METHODS: In 50 patients with advanced HCC treated with sorafenib tolerability and efficiency of the therapy with respect to stage of liver cirrhosis, existence of extrahepatic tumor spread, and additional locoregional therapy were evaluated. RESULTS: Fifty patients with advanced HCC were treated with sorafenib, and 13 received additional locoregional therapy. Tolerability of the systemic treatment was moderate in all patients, with no significant differences between the subgroups, while the median survival was better in patients with Child A than Child B cirrhosis. CONCLUSION: Tolerability and toxicity of a systemic treatment with sorafenib are moderate in patients with liver cirrhosis in Child A or B. Prospective randomized studies are required to evaluate the efficacy and tolerability of combined systemic and locoregional treatment approaches in patients with advanced HCC.

Detection of type II endoleak after endovascular aortic repair: comparison between magnetic resonance angiography and blood-pool contrast agent and dual-phase computed tomography angiography.

PURPOSE: This prospective study was designed to assess the diagnostic value of magnetic resonance angiography (MRA) with blood-pool contrast agent (gadofosveset) in the detection of type-II endoleak after endovascular aortic repair (EVAR). METHODS: Thirty-two patients with aortic aneurysms who had undergone EVAR were included in this study. All patients were examined by dual-phase computed tomography angiography (CTA) as well as MRA with gadofosveset in the first-pass and steady-state phases. Two independent readers evaluated the images of CTA and MRA in terms of endoleak type II, feeding vessel, and image quality. RESULTS: Median follow-up-time after EVAR was 22 months (range 4 to 59). Endoleak type II was detected by CTA in 12 of 32 patients (37.5%); MRA detected endoleak in all of these patients as well as in another 9 patients (n = 21, 65.6%), of whom the endoleaks in 6 patients showed an increasing diameter. Most endoleaks were detected in the steady-state phase (n = 14). The decrease in diameter of the aneurysmal sac was significantly greater in the patients without a visible endoleak that was visible on MRA (P = 0.004). In the overall estimation of diagnostic accuracy, MRA was judged superior to CTA in 66% of all examinations. CONCLUSION: MRA with gadofosveset appeared superior to CTA, and has higher diagnostic accuracy, in the detection of endoleak after EVAR.

Early prediction of anticancer effects with diffusion-weighted MR imaging in patients with colorectal liver metastases following selective internal radiotherapy.

OBJECTIVE: To prospectively evaluate diffusion-weighted imaging (DWI) for early prediction of tumour response in patients with colorectal liver metastases following selective internal radiotherapy (SIRT). METHODS: We evaluated 41 metastases in 21 patients, age 62.9 ± 9.9 years. All patients underwent magnetic resonance imaging (MRI) including breath-hold echoplanar DWI sequences. Imaging was performed before therapy (baseline MRI), 2 days after SIRT (early MRI) as well as 6 weeks later (follow-up MRI). Tumour volume (TV) and intratumoural apparent diffusion coefficient (ADC) were measured independently by two radiologists at all time points. RESULTS: Metastases were categorised as responding lesions (RL; n = 33) or non-responding lesions (NRL; n = 8) according to changes in TV after 6 weeks. We found an inverse correlation of changes in TV and ADC at follow-up MRI with a Pearson's correlation coefficient of r = -0.66 (p < 0.0001). On early MRI, no significant changes in TV were found for either RL or NRL. Conversely, ADC decreased significantly in RL by 10.7 ± 8.4% (p < 0.0001). ADC increased in NRL by 9.6 ± 20.8%, which was not statistically significant (p = 0.40). CONCLUSION: DWI was capable of predicting therapy effects of SIRT in patients with colorectal hepatic metastases as early as 2 days following treatment.

Radiobiological restrictions and tolerance doses of repeated single-fraction hdr-irradiation of intersecting small liver volumes for recurrent hepatic metastases.

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 alpha/beta 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 alpha/beta in the clinically relevant range of alpha/beta = 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 (alpha/beta ~ 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.

Safety margin in irradiation of colorectal liver metastases: assessment of the control dose of micrometastases.

BACKGROUND: 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 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 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.

Local response and impact on survival after local ablation of liver metastases from colorectal carcinoma by computed tomography-guided high-dose-rate brachytherapy.

PURPOSE: To determine local tumor control after CT-guided brachytherapy at various dose levels and the prognostic impact of extensive cytoreduction in colorectal liver metastases. METHODS AND MATERIALS: Seventy-three patients were treated on a single-center prospective trial that was initially designed to be randomized to three dose levels of 15 Gy, 20 Gy, or 25 Gy per lesion, delivered in a single fraction. However, because there was a high rate of cross-over of subjects from higher to lower dose levels, this study is better understood as a prospective trial with three dose levels. No upper size limit for the metastases was applied. We assessed time to local progression, progression-free survival, and overall survival. RESULTS: According to safety constraints cross-over was performed. The final assignment was n = 98, n = 68, and n = 33 in the 15-Gy, 20-Gy, and 25-Gy groups, respectively. Median diameter of the largest tumor lesion in each patient was 5 cm (range, 1-13.5 cm). Estimated mean local recurrence-free survival for all lesions was 34 months (median not reached). The group assigned to 15 Gy after cross-over displayed 34 local recurrences out of 98 lesions; 20 Gy, 15 out of 68 lesions; 25 Gy, 1 out of 33 lesions. The difference between the 25-Gy and the 20-Gy or 15-Gy group was significant (p < 0.05). Repeated local tumor ablations were the most prominent factor for increased survival and dominated additional systemic antitumor treatments. CONCLUSIONS: Local tumor control after CT-guided brachytherapy of colorectal liver metastases demonstrated a strong dose dependency. The role of extensive minimally invasive tumor ablation in metastatic colorectal cancer needs to be further established.

Value of combined PET/CT for radiation planning in CT-guided percutaneous interstitial high-dose-rate single-fraction brachytherapy for colorectal liver metastases.

PURPOSE: To determine the additional value of fluorodeoxyglucose-positron emission tomography (PET) for clinical target volume definition in the planning of computed tomography (CT)-guided interstitial brachytherapy for liver metastases. PATIENTS AND METHODS: A total of 19 patients with liver metastases from colorectal cancer treated in 25 sessions were included in the present study. All patients had undergone fluorodeoxyglucose-PET for patient evaluation before interstitial CT-guided brachytherapy. A contrast-enhanced CT scan of the upper abdomen was obtained for radiation planning. The clinical target volume (CTV) was defined by a radiation oncologist and radiologist. After registration of the CT scan with the PET data set, the target volume was defined again using the fusion images. RESULTS: PET revealed one additional liver lesion that was not visible on CT. The median CT-CTV (defined using CT and magnetic resonance imaging) was 68 cm(3) (range 4-260). The PET/CT-CTV (median, 78 cm(3); range, 4-273) was significantly larger, with a median gain of 24.5% (interquartile range, 2.1-71.5%; p = .022). An increased CTV was observed in 15 cases and a decrease in 6; in 4 cases, the CT-CTV and PET/CT-CTV were equal. Incomplete dose coverage of PET/CT-CTVs was indicative of early local progression (p = .004); however, CT-based radiation plans did not show significant differences in the local control rates when stratified by dose coverage. CONCLUSION: Retrospective implementation of fluorodeoxyglucose-PET for CTV specification for CT-guided brachytherapy for colorectal liver metastases revealed a significant change in the CTVs. Additional PET-positive tumor regions with incomplete dose coverage could explain unexpected early local progression.

Image-guided interstitial high-dose-rate brachytherapy in hepatocellular carcinoma.

New interventional options especially for patients with HCC and BCLC scores B and C give rise to disputes about the optimal therapeutic management. CT-guided brachytherapy complements established interventional techniques like RFA and TACE since it may also be used successfully in tumors much greater than 5 cm in diameter. In addition, unlike thermal ablation, the brachytherapy technique may be applied in tumors located nearby risk structures such as liver hilum or gallbladder and it is independent of cooling effects such as through large blood vessels or strong tumor perfusion. Depending on tumor size, geometry and visibility, MRI or CT guidance may be used. 15 Gy minimal target dose can be applied safely in a single or--in case of very large tumors--a sequential approach targeting different tumor portions. Local recurrence rates will be very low, and the rate of complications is moderate despite the fact that most patients present with underlying cirrhosis and related comorbidities. Preliminary data suggest a positive impact on overall survival. Randomized controlled trials are on their way to assess combination schemes with systemic treatments such as sorafenib.

Hepatocellular carcinoma and liver cirrhosis: assessment of the liver function after Yttrium-90 radioembolization with resin microspheres or after CT-guided high-dose-rate brachytherapy.

PURPOSE: To identify changes of liver function after single-fraction irradiation or yttrium-90 radioembolization ((90)Y-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 (90)Y-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 gamma-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 <0.05. 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.

Assessment of the tolerance dose of the hepatic reticulo-endothelial system (RES) after single fraction HDR-irradiation: an in-vivo study employing SSPIO.

PURPOSE: 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. MATERIALS AND METHODS: 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). RESULTS: 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. CONCLUSION: 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.

CT-guided interstitial brachytherapy of primary and secondary lung malignancies: results of a prospective phase II trial.

BACKGROUND AND PURPOSE: CT-guided interstitial brachytherapy of primary lung malignancies and pulmonary metastases represents a novel interventional technique, combining conventional high-dose-rate (HDR) iridium-192 ((192)Ir) brachytherapy with modern CT guidance for applicator positioning and computer-aided 3-D radiation treatment planning. The purpose of this study was to assess safety and efficacy of this technique. PATIENTS AND METHODS: 30 patients with 83 primary or secondary lung malignancies were recruited in a prospective nonrandomized trial (Table 1). After catheter positioning under CT fluoroscopy, a spiral CT was acquired for treatment planning (Figure 1). All but two patients received a defined single dose (coverage > 99%) of at least 20 Gy from a (192)Ir source in HDR technique. RESULTS: Adverse effects were nausea (n = 3, 6%), minor (n = 6, 12%) and one major pneumothorax (2%). Post intervention, no changes of vital capacity and forced expiratory volume could be detected. The median follow-up period was 9 months (1-21 months) with a local tumor control of 91% at 12 months (Figure 2). CONCLUSION: CT-guided interstitial brachytherapy proved to be safe and effective for the treatment of primary and secondary lung malignancies.

CT-guided brachytherapy (CTGB) versus interstitial laser ablation (ILT) of colorectal liver metastases: an intraindividual matched-pair analysis.

PURPOSE: To compare local tumor control after percutaneous tumor ablation by interstitial laser therapy (ILT) or CT-guided brachytherapy (CTGB). PATIENTS AND METHODS: In a matched pair analysis including 18 patients with 36 liver metastases of colorectal primary, both ILT and CTGB were performed in different lesions. The following matching factors were considered: (i) tumor size < or = 5 cm, and (ii) execution of chemotherapy after tumor ablation. Primary endpoint was local tumor control. RESULTS: Treated lesions were identical in terms of tumor size and all matching criteria were fulfilled in all patients except for the performance of adjuvant chemotherapy. Median follow-up was 14 months (3-24 months) for both groups. Only five of 18 patients (28%) demonstrated local tumor progression after CTGB, whereas in ten of 18 patients (56%) tumor progression was found after ILT. Differences encountered were significant for all patients (p = 0.04), whereas in those who fulfilled all matching criteria (n = 14) the level of statistical significance was not reached (p = 0.23). CONCLUSION: CTGB demonstrated superior local tumor control compared to ILT in long-term follow-up.

CsI-detector-based dual-exposure dual energy in chest radiography for lung nodule detection: results of an international multicenter trial.

To assess both sensitivity and specificity of digital chest radiography alone and in conjunction with dual-exposure dual-energy chest radiography for the detection and classification of pulmonary nodules. One hundred patients with a total of 149 lung nodules (3-45 mm; median, 11 mm) confirmed by CT were included in this study. Dual-exposure dual-energy chest radiographies of each patient were obtained using a CsI detector system. Experienced board-certified chest radiologists from four different medical centers in Europe reviewed standard chest radiographs alone and in conjunction with dual-energy images blinded and in random order. The reviewers rated the probability of presence, calcification and malignancy of all lung nodules on a five-point rating scale. Lesions detected were identified by applying a specific coordinate system to enable precise verification by the study leader. A receiver-operating characteristic (ROC) analysis was performed. In addition to the 149 true-positive CT proven lesions, 236 false-positive lung nodules were described in digital chest radiographies in conjunction with dual-energy chest radiographies. The cumulative sensitivity of chest radiography in conjunction with dual energy was 43%, specificity was 55%. For digital radiography alone, sensitivity was 35% and specifity was 83%. For the dual energy system, positive predictive value was 58%, and negative predictive value was 66% compared to the digital radiography with a positive predictive value of 59% and a negative predictive value of 65%. Areas under the curve in a ROC analysis resulted in 0.631 (95% confidence interval =0.61 to 0.65) for radiography with dual energy and 0.602 (95% confidence interval =0.58 to 0.63) for digital radiography alone. This difference was not statistically significant. For the detection of lesion calcification or the determination of malignancy, ROC analysis also failed to show significant differences. CsI-based flat-panel dual-exposure dual-energy imaging added to standard chest radiography did not show statistically significant improvement for the detection of pulmonary nodules, nor the identification of calcifications, nor the determination of malignancy.

Planning transarterial radioembolization of colorectal liver metastases with Yttrium 90 microspheres: evaluation of a sequential diagnostic approach using radiologic and nuclear medicine imaging techniques.

The purpose of the study was to establish a diagnostic approach to the preparation of patients with colorectal liver metastases considered for transarterial radioembolization (RE). Twenty-two patients sequentially underwent computed tomography (CT; thorax/abdomen), magnetic resonance imaging (MRI; liver; hepatocyte-specific contrast), positron emission tomography (PET/PET-CT; F18-fluoro-desoxy-glucose), and angiography with perfusion scintigraphy [planar imaging; tomography with integrated CT (SPECT-CT)]. The algorithm was continued when no contraindication or alternative treatment option was found. The impact of each test on the therapy decision and RE management was recorded. Patient evaluation using CT revealed contraindications for RE in 4/22 patients (18%). Of the remaining 18 patients, 2 were excluded and 3 were assigned to locally ablative treatment based on MRI and PET results (28%). The remaining 13 patients entered the planning algorithm: SPECT-CT revealed gastrointestinal tracer accumulations in 4 (31%) patients [SPECT, 2 (15%)], making a modified application necessary. In five patients (38%), planar scintigraphy revealed relevant hepatopulmonary shunting. Therapy was finally administered to all 13 patients without therapy-related pulmonary or gastrointestinal morbidity. Each part of the diagnostic algorithm showed a relevant impact on patient management. The sequential approach appears to be suitable and keeps the number of unnecessary treatments and therapy risks to a minimum.

Image-guided micro-therapy for tumor ablation: from thermal coagulation to advanced irradiation techniques.

Image-guided tumor ablation has been established as a valuable adjunct in oncological treatment concepts. The majority of micro-therapeutic procedures is performed by applying thermal ablation, such as radiofrequency or laser. However, in view of the limitations of thermal ablation regarding tumor size or adjacent risk structures, novel techniques combining brachytherapy with modern interventional techniques have demonstrated favorable outcomes. In addition, advances in non-invasive percutaneous irradiation, such as extracranial stereotaxy, have demonstrated very competitive preliminary results. In this article, state-of-the-art techniques for micro-therapeutic tumor ablation are being described.