Prevention of radiation-induced liver toxicity after interstitial HDR brachytherapy by pentoxifylline and ursodeoxycholic acid: patient compliance and outcome in a randomized trial.

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.

Planning Benchmark Study for Stereotactic Body Radiation Therapy of Liver Metastases: Results of the DEGRO/DGMP Working Group on Stereotactic Radiation Therapy and Radiosurgery.

PURPOSE: Our purpose was to investigate whether liver stereotactic body radiation therapy treatment planning can be harmonized across different treatment planning systems, delivery techniques, and institutions by using a specific prescription method and to minimize the knowledge gap concerning intersystem and interuser differences. We provide best practice guidelines for all used techniques. METHODS AND MATERIALS: A multiparametric specification of target dose (gross target volume [GTV]D50%, GTVD0.1cc, GTVV90%, planning target volume [PTV]V70%) with a prescription dose of GTVD50% = 3 × 20 Gy and organ-at-risk (OAR) limits were distributed with computed tomography and structure sets from 3 patients with liver metastases. Thirty-five institutions provided 132 treatment plans using different irradiation techniques. These plans were first analyzed for target and OAR doses. Four different renormalization methods were performed (PTVDmin, PTVD98%, PTVD2%, PTVDmax). The resulting 660 treatments plans were evaluated regarding target doses to study the effect of dose renormalization to different prescription methods. A relative scoring system was used for comparisons. RESULTS: GTVD50% prescription can be performed in all systems. Treatment plan harmonization was overall successful, with standard deviations for Dmax, PTVD98%, GTVD98%, and PTVDmean of 1.6, 3.3, 1.9, and 1.5 Gy, respectively. Primary analysis showed 55 major deviations from clinical goals in 132 plans, whereas in only <20% of deviations GTV/PTV dose was traded for meeting OAR limits. GTVD50% prescription produced the smallest deviation from target planning objectives and between techniques, followed by the PTVDmax, PTVD98%, PTVD2%, and PTVDmin prescription. Deviations were significant for all combinations but for the PTVDmax prescription compared with GTVD50% and PTVD98%. Based on the various dose prescription methods, all systems significantly differed from each other, whereas GTVD50% and PTVD98% prescription showed the least difference between the systems. CONCLUSIONS: This study showed the feasibility of harmonizing liver stereotactic body radiation therapy treatment plans across different treatment planning systems and delivery techniques when a sufficient set of clinical goals is given.

Functional and mutational analysis after radiation and cetuximab treatment on prostate carcinoma cell line DU145.

BACKGROUND: Epidermal Growth Factor Receptor is often overexpressed in advanced prostate carcinoma. In-vitro-studies in prostate carcinoma cell line DU145 have demonstrated increased sensibility to radiation after cetuximab treatment, but clinical data are not sufficient to date. METHODS: We analyzed effects of radiation and cetuximab in DU145 and A431 using proliferation, colony-forming-unit- and annexin-V-apoptosis-assays. Changes in protein expression of pEGFR and pERK1/2 after radiation and cetuximab treatment were analyzed. Using NGS we also investigated the impact of cetuximab long-term treatment. RESULTS: Cell counts in DU145 were reduced by 44% after 4 Gy (p = 0.006) and 55% after 4 Gy and cetuximab (p < 0.001). The surviving fraction (SF) was 0.69 after 2 Gy, 0.41 after 4 Gy and 0.15 after 6 Gy (each p < 0.001). Cetuximab treatment did not alter significantly growth reduction in 4 Gy radiated DU145 cells, p > 0.05 or SF, p > 0.05, but minor effects on apoptotic cell fraction in DU145 were detected. Using western blot, there were no detectable pEGFR and pERK1/2 protein signals after cetuximab treatment. No RAS mutation or HER2 amplification was detected, however a TP53 gen-mutation c.820G > T was found. CONCLUSIONS: Radiation inhibits cell-proliferation and colony-growth and induces apoptosis in DU145. Despite blocking MAP-Kinase-pathway using cetuximab, no significant radiation-sensitizing-effect was detected. Cetuximab treatment did not induce resistance-mutations. Further research must clarify which combination of anti-EGFR treatment strategies can increase radiation-sensitizing-effects.

A multi-institutional initiative on patient-related quality assurance: Independent computational dose verification of fluence-modulated treatment techniques.

PURPOSE: This multi-institutional study investigates whether computational verification of fluence-modulated treatment plans using independent software with its own Strahlerkopfmodel is an appropriate method for patient-related quality assurance (PRQA) in the context of various combinations of linear accelerators (linacs), treatment techniques and treatment planning systems (TPS). MATERIALS AND METHODS: The PRQA-software's (Mobius3D) recalculations of 9 institutions' treatment plans were analyzed for a horseshoe-shaped planning target volume (PTV) inside a phantom. The recomputed dose distributions were compared to a) the dose distributions as calculated by all TPS's and b) the measured dose distributions, which were acquired using the same independent measuring system for all institutions. Furthermore, dose volume histograms were examined. The penumbra deviations and mean gamma values were quantified using Verisoft (PTW). Additionally, workflow requirements for computational verification were discussed. RESULTS: Mobius3D is compatible with all examined TPSs, treatment techniques and linacs. The mean PTV dose differences (Mobius3D-TPS, <3.0%) and 3D gamma passing rates (>95.0%) led to a positive plan acceptance result in all cases. These results are similar to the outcome of the dosimetric measurements with one exception. The mean gamma values (<0.5) show a good agreement between Mobius3D and the TPS dose distributions. CONCLUSION: Using Mobius3D was proven to be an appropriate computational PRQA method for the tested combinations of linacs, treatment techniques and TPS's. The clinical use of Mobius3D has to be complemented with regular dosimetric measurements and thorough linac and TPS QA. Mobius3D's computational verification reduced measurement effort and personnel needs in comparison to dosimetric verifications.

Comparative analysis between interstitial brachytherapy and stereotactic body irradiation for local ablation in liver malignancies.

PURPOSE: Interstitial high-dose-rate brachytherapy (BT) is an alternative treatment option to stereotactic body radiotherapy (SBRT) for the ablative treatment of liver malignancies. The aim of the present comparative planning study was to reveal the possibilities and limitations of both techniques with regard to dosimetric properties. METHODS AND MATERIALS: Eighty-five consecutive patients with liver malignancy diagnosis were treated with interstitial BT between 12/2008 and 09/2009. The prescription dose of BT varied between 15 and 20 Gy, depending on histology. For dosimetric comparison, virtual SBRT treatment plans were generated using the original BT planning CTs. Additional margins reflecting the respiratory tumor motion were added to the target volumes for SBRT planning. RESULTS: The mean PTVBT was 34.7 cm3 (0.5-410.0 cm3) vs. a mean PTVSBRT of 73.2 cm3 (6.1-593.4 cm3). Regarding the minimum peripheral dose (D99.9), BT achieved the targeted prescription dose of 15 Gy/20 Gy better without violating organ at risk constraints. The dose exposure of the liver was significantly influenced by treatment modality. The liver exposure to 5 Gy was statistically lower with 611 ± 43 cm3 for BT as compared with 694 ± 37 cm3 for SBRT plans (20-Gy group, p = 0.001), corresponding to 41.8% vs. 45.9% liver volume, respectively. CONCLUSIONS: To the best of our knowledge, this is the first report on the comparison of clinically treated liver BT treatments with virtually planned SBRT treatments. The planning study showed a superior outcome of BT regarding dose coverage of the target volume and exposed liver volume. Nevertheless, further studies are needed to determine ideal applicability for each treatment approach.

First report on extended distance between tumor lesion and adjacent organs at risk using interventionally applied balloon catheters: a simple procedure to optimize clinical target volume covering effective isodose in interstitial high-dose-rate brachytherapy of liver malignomas.

PURPOSE: Organs at risk (OARs), which are very close to a clinical target volume (CTV), can compromise effective tumor irradiation. The present study investigated the feasibility and safety of a novel approach, in particular, the extent of the dosimetric effect of distancing CTV from adjacent OARs by means of interventionally applied balloon catheters. MATERIAL AND METHODS: Patients with peripheral hepatic malignancies, in whom the critical proximity of an OAR to the CTV in the assessment by contrast-enhanced magnetic resonance imaging (MRI) scans and the preplanning process were included. Additionally, patients underwent placement of an interventional balloon catheter during computed tomography (CT)-guided application of interstitial brachytherapy (iBT) catheters inserted into the tissue between hepatic capsule and adjacent OAR. The virtual position of an OAR without balloon catheter was anticipated and contoured in addition to contouring of CTV and OAR. The calculated dose values for CTV as well as 1 cc of the relevant OAR (D1cc) with and without balloon were recorded. The D1cc of the realized irradiation plan was statistically compared to the D1cc of the virtually contoured OARs. RESULTS: In 31 cases, at least one balloon catheter was administered. The mean D1cc of the OAR in the group with balloon(s) was 12.6 Gy compared with 16 Gy in the virtual cohort without the device, therefore significantly lower (p < 0.001). Overall, there were no acute complications. Severe (> 2 CTCAEv4.03) late complications observed in 3/31 (9.6%) patients during follow-up period after brachytherapy were most certainly not due to the balloon application. Side effects were probably associated with pre-existing serious diseases and potentially additional local late effects of the irradiation in general rather than with the balloon catheters. CONCLUSIONS: The distancing of the adjacent OARs allows a higher D100 value of CTV, therefore allowing for more efficient local control.

Joint deformable liver registration and bias field correction for MR-guided HDR brachytherapy.

PURPOSE: In interstitial high-dose rate brachytherapy, liver cancer is treated by internal radiation, requiring percutaneous placement of applicators within or close to the tumor. To maximize utility, the optimal applicator configuration is pre-planned on magnetic resonance images. The pre-planned configuration is then implemented via a magnetic resonance-guided intervention. Mapping the pre-planning information onto interventional data would reduce the radiologist's cognitive load during the intervention and could possibly minimize discrepancies between optimally pre-planned and actually placed applicators. METHODS: We propose a fast and robust two-step registration framework suitable for interventional settings: first, we utilize a multi-resolution rigid registration to correct for differences in patient positioning (rotation and translation). Second, we employ a novel iterative approach alternating between bias field correction and Markov random field deformable registration in a multi-resolution framework to compensate for non-rigid movements of the liver, the tumors and the organs at risk. In contrast to existing pre-correction methods, our multi-resolution scheme can recover bias field artifacts of different extents at marginal computational costs. RESULTS: We compared our approach to deformable registration via B-splines, demons and the SyN method on 22 registration tasks from eleven patients. Results showed that our approach is more accurate than the contenders for liver as well as for tumor tissues. We yield average liver volume overlaps of 94.0 ± 2.7% and average surface-to-surface distances of 2.02 ± 0.87 mm and 3.55 ± 2.19 mm for liver and tumor tissue, respectively. The reported distances are close to (or even below) the slice spacing (2.5 - 3.0 mm) of our data. Our approach is also the fastest, taking 35.8 ± 12.8 s per task. CONCLUSION: The presented approach is sufficiently accurate to map information available from brachytherapy pre-planning onto interventional data. It is also reasonably fast, providing a starting point for computer-aidance during intervention.

Assessment of Iterative Closest Point Registration Accuracy for Different Phantom Surfaces Captured by an Optical 3D Sensor in Radiotherapy.

An optical 3D sensor provides an additional tool for verification of correct patient settlement on a Tomotherapy treatment machine. The patient's position in the actual treatment is compared with the intended position defined in treatment planning. A commercially available optical 3D sensor measures parts of the body surface and estimates the deviation from the desired position without markers. The registration precision of the in-built algorithm and of selected ICP (iterative closest point) algorithms is investigated on surface data of specially designed phantoms captured by the optical 3D sensor for predefined shifts of the treatment table. A rigid body transform is compared with the actual displacement to check registration reliability for predefined limits. The curvature type of investigated phantom bodies has a strong influence on registration result which is more critical for surfaces of low curvature. We investigated the registration accuracy of the optical 3D sensor for the chosen phantoms and compared the results with selected unconstrained ICP algorithms. Safe registration within the clinical limits is only possible for uniquely shaped surface regions, but error metrics based on surface normals improve translational registration. Large registration errors clearly hint at setup deviations, whereas small values do not guarantee correct positioning.

Patient-related quality assurance with different combinations of treatment planning systems, techniques, and machines : A multi-institutional survey.

PURPOSE: This project compares the different patient-related quality assurance systems for intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) techniques currently used in the central Germany area with an independent measuring system. MATERIALS AND METHODS: The participating institutions generated 21 treatment plans with different combinations of treatment planning systems (TPS) and linear accelerators (LINAC) for the QUASIMODO (Quality ASsurance of Intensity MODulated radiation Oncology) patient model. The plans were exposed to the ArcCHECK measuring system (Sun Nuclear Corporation, Melbourne, FL, USA). The dose distributions were analyzed using the corresponding software and a point dose measured at the isocenter with an ionization chamber. RESULTS: According to the generally used criteria of a 10 % threshold, 3 % difference, and 3 mm distance, the majority of plans investigated showed a gamma index exceeding 95 %. Only one plan did not fulfill the criteria and three of the plans did not comply with the commonly accepted tolerance level of ±3 % in point dose measurement. CONCLUSION: Using only one of the two examined methods for patient-related quality assurance is not sufficiently significant in all cases.

The association of tumor-to-background ratios and SUVmax deviations related to point spread function and time-of-flight F18-FDG-PET/CT reconstruction in colorectal liver metastases.

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). 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) and high (>4.8) TBR were analyzed using the Mann-Whitney U test (TBR measured with 3D-OSEM; binarized by its median). 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.

Accuracy of applicator tip reconstruction in MRI-guided interstitial 192Ir-high-dose-rate brachytherapy of liver tumors.

BACKGROUND AND PURPOSE: To evaluate the reconstruction accuracy of brachytherapy (BT) applicators tips in vitro and in vivo in MRI-guided (192)Ir-high-dose-rate (HDR)-BT of inoperable liver tumors. MATERIALS AND METHODS: Reconstruction accuracy of plastic BT applicators, visualized by nitinol inserts, was assessed in MRI phantom measurements and in MRI (192)Ir-HDR-BT treatment planning datasets of 45 patients employing CT co-registration and vector decomposition. Conspicuity, short-term dislocation, and reconstruction errors were assessed in the clinical data. The clinical effect of applicator reconstruction accuracy was determined in follow-up MRI data. RESULTS: Applicator reconstruction accuracy was 1.6±0.5 mm in the phantom measurements. In the clinical MRI datasets applicator conspicuity was rated good/optimal in ⩾72% of cases. 16/129 applicators showed not time dependent deviation in between MRI/CT acquisition (p>0.1). Reconstruction accuracy was 5.5±2.8 mm, and the average image co-registration error was 3.1±0.9 mm. Vector decomposition revealed no preferred direction of reconstruction errors. In the follow-up data deviation of planned dose distribution and irradiation effect was 6.9±3.3 mm matching the mean co-registration error (6.5±2.5 mm; p>0.1). CONCLUSION: Applicator reconstruction accuracy in vitro conforms to AAPM TG 56 standard. Nitinol-inserts are feasible for applicator visualization and yield good conspicuity in MRI treatment planning data. No preferred direction of reconstruction errors were found in vivo.

The influence of different signal-to-background ratios on spatial resolution and F18-FDG-PET quantification using point spread function and time-of-flight reconstruction.

BACKGROUND: F18-fluorodeoxyglucose positron-emission tomography (FDG-PET) reconstruction algorithms can have substantial influence on quantitative image data used, e.g., for therapy planning or monitoring in oncology. We analyzed radial activity concentration profiles of differently reconstructed FDG-PET images to determine the influence of varying signal-to-background ratios (SBRs) on the respective spatial resolution, activity concentration distribution, and quantification (standardized uptake value [SUV], metabolic tumor volume [MTV]). METHODS: Measurements were performed on a Siemens Biograph mCT 64 using a cylindrical phantom containing four spheres (diameter, 30 to 70 mm) filled with F18-FDG applying three SBRs (SBR1, 16:1; SBR2, 6:1; SBR3, 2:1). Images were reconstructed employing six algorithms (filtered backprojection [FBP], FBP + time-of-flight analysis [FBP + TOF], 3D-ordered subset expectation maximization [3D-OSEM], 3D-OSEM + TOF, point spread function [PSF], PSF + TOF). Spatial resolution was determined by fitting the convolution of the object geometry with a Gaussian point spread function to radial activity concentration profiles. MTV delineation was performed using fixed thresholds and semiautomatic background-adapted thresholding (ROVER, ABX, Radeberg, Germany). RESULTS: The pairwise Wilcoxon test revealed significantly higher spatial resolutions for PSF + TOF (up to 4.0 mm) compared to PSF, FBP, FBP + TOF, 3D-OSEM, and 3D-OSEM + TOF at all SBRs (each P < 0.05) with the highest differences for SBR1 decreasing to the lowest for SBR3. Edge elevations in radial activity profiles (Gibbs artifacts) were highest for PSF and PSF + TOF declining with decreasing SBR (PSF + TOF largest sphere; SBR1, 6.3%; SBR3, 2.7%). These artifacts induce substantial SUVmax overestimation compared to the reference SUV for PSF algorithms at SBR1 and SBR2 leading to substantial MTV underestimation in threshold-based segmentation. In contrast, both PSF algorithms provided the lowest deviation of SUVmean from reference SUV at SBR1 and SBR2. CONCLUSIONS: At high contrast, the PSF algorithms provided the highest spatial resolution and lowest SUVmean deviation from the reference SUV. In contrast, both algorithms showed the highest deviations in SUVmax and threshold-based MTV definition. At low contrast, all investigated reconstruction algorithms performed approximately equally. The use of PSF algorithms for quantitative PET data, e.g., for target volume definition or in serial PET studies, should be performed with caution - especially if comparing SUV of lesions with high and low contrasts.