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In vivo assessment of catheter positioning accuracy and prolonged irradiation time on liver tolerance dose after single-fraction 192Ir high-dose-rate brachytherapy

In vivo assessment of catheter positioning accuracy and prolonged irradiation time on liver... 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 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. * Correspondence: lutz.luedemann@charite.de † Contributed equally Department of Radiation Therapy, Charité Medical Center, Berlin, Germany Full list of author information is available at the end of the article © 2011 Lüdemann et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Lüdemann et al. Radiation Oncology 2011, 6:107 Page 2 of 10 http://www.ro-journal.com/content/6/1/107 Interventional technique 1 Background The interventional technique has been described in Single-fraction Ir high-dose-rate brachytherapy (HDR- detail elsewhere [9]. In brief, a T2-weighted (T2-w) BT) of the liver is an ablation technique which has respiratory-triggered ultrafast turbo spin echo (UTSE) shown promising results with respect to safety and and a T1-weighted (T1-w) breath-hold gradient echo efficacy in the treatment of nonresectable primary and (GRE) sequence with administration of the hepatocyte- secondary liver malignancies [1-3]. HDR-BT provides specific contrast agent gadobenate dimeglumine (Gd- steep dose gradients at the surface of the target volume BOPTA (Multihance), Bracco, Princeton, NJ) were due to the low g-ray energy of Ir and use of a point acquired to delineate primary and secondary liver source, and thus can be used to treat several malignan- lesions (see Follow-up section below). The brachyther- cies in one session or recurrent malignancies sequentially apy catheters were positioned using CT guidance without seriously impairing the functional hepatic reserve (Somatom 4, Siemens, Erlangen, Germany), i.e., CT [4]. To prevent recurrence at the tumor margins, catheter scans were acquired continuously during the interven- placement and dwell positions of the Ir point source tional procedure with an image reconstruction rate of have to be carefully planned [5]. The accuracy of dose 12 per second to monitor actual catheter location. They application is predominantly dependent on catheter posi- were placed in 6F angiographic sheaths (Radiofocus, tioning. Computed tomography (CT) was used to moni- Terumo, Japan), which were implanted in Seldinger tor catheter implantation, and 3D CT datasets acquired technique within the tumors.The angiographic sheaths in breath-hold were used for treatment planning. For were sutured to the skin. After catheter positioning, a irradiation patients were transferred from the CT unit to spiral CT scan of the liver (matrix size, 512 × 512; slice the brachytherapy unit. Dislocation of catheters during thickness, 5 mm; increment, 5 mm) enhanced by intra- patient transfer might be a potential source of error with venous administration of iodine contrast medium (100 respect to correct dose application at the target site. ml Ultravist 370; flow, 1 ml/s; start delay, 80s) was Additionally, the liver is an elastic organ and could be acquired in breath-hold technique for treatment plan- deformed between catheter implantation and irradiation. ning. Four catheters were implanted on average per The treatment of larger tumors with an Ir point HDR-BT session (range, 1 - 11 catheters). source requires the implantation of approximately 1 catheter for each 1 - 2 cm of tumor diameter. The con- Treatment planning and irradiation tributions of several catheters with numerous dwell Treatment was planned using the BrachyVision software positions to the planned dose in a large part of the tar- package, version 7.1 (Varian Medical Systems, Palo Alto, get volume lead to regional prolongation of irradiation. CA). The dwell positions and irradiation times were Several authors describe an increased normal tissue dose optimized to ensure delivery of the prescribed dose to tolerance for prolonged radiation therapy or pulsed dose the entire clinical target volume (CTV), see Figure 1. rate (PDR) radiation therapy [6,7] even if the total irra- The 24-channel HDR afterloading system (Gammamed diation time is less than one hour [8]. 12i, Varian, Charlottesville, VA) employed a Ir source The present study aims at addressing two methodical (nominal source strength, 370GBq). A dose of 15, 20, or aspects of HDR-BT: First, to investigate the limits of 25Gy was prescribed, which was planned to enclose the catheter positioning accuracy and its clinical importance. lesion (clinical target volume). Compromises were Second, to investigate if effects of prolonged irradiation necessary if organs of risk such as the stomach, small times on the tolerance dose of normal liver parenchyma intestine, or a large bile duct were very close to the tar- are important for clinical practice and may have to be get. No upper limit was defined for the dose within the taken into account in treatment planning. tumor volume. To preserve liver function after irradia- tion, one third of the liver parenchyma should receive a 2 Methods dose of less than 5Gy. The effective irradiation time Study population needed to apply the target dose with all catheters was In this study we retrospectively analyzed irradiation corrected according to the actual Ir source strength. effects on normal liver tissue in 50 consecutive patients We usually limit the maximum irradiation time to 60 who underwent CT-guided single-fraction HDR-BT as minutes to increase patient comfort. The catheters were part of a clinical phase II study prospectively assessing then sequentially connected to the afterloading system local tumor control. In 50 HDR-BT sessions a total of according to the prescribed enumeration, and irradiation 76 solid primary or secondary liver tumors were treated was started at the most distant dwell position in each (1 - 4 malignant tumors per session). The study was catheter. All dwell positions within one catheter were approved by the local ethics committee. Written sequentially irradiated without any delay. An interval of informed consent was obtained from all patients. Lüdemann et al. Radiation Oncology 2011, 6:107 Page 3 of 10 http://www.ro-journal.com/content/6/1/107 A) Figure 1 Geometry. The 3D visualization shows a CT slice with the Lesion B) calculated dose in Gy overlayed. The dose is applied using two catheters. The two catheters were visualized in 3D using surface 10 Gy rendering of the catheters labeled in the CT scan. approx. 2 - 3 minutes was required for connecting each 15 Gy catheter. Manual sequential connection of the catheters was necessary because only a single adapter was avail- 20 Gy able for connecting the catheters to the afterloader. The 5 Gy exposure times were in the range of 844 - 4432 seconds. Follow-up A total of 161 MRI examinations were performed 6 ± 2 weeks and 12 ± 2 weeks after HDR-BT. The MRI proto- Figure 2 Image registration. A) T2-w image coregistered with the col comprised the following sequences (Gyroscan NT planning CT. Note that only the liver was coregistered and Intera, Philips, The Netherlands) [10]: T2-w respiratory- therefore good matching of the images was only achieved for the liver. B) T2-w image showing segmented lesion and isodoses at 12- triggered UTSE (echo time/repetition time (TE/TR), 90/ week follow-up. A prononounced shift of the irradiation effect with 2100 ms; echo train length (ETL), 21; slice thickness, 8 respect to the planned dose distribution as shown in this example mm, acquired in interleaved mode with no gap) with fat was typically not found. suppression to assess the extent of interstitial edema and T1-w breath-hold GRE (TE/TR 5/30 ms; flip rotations, 3translations, 3scalings,and 3shears) by angle,30°; slice thickness, 8 mm, acquired in, interleaved exploring the normalized mutual information (NMI) [14], mode with no gap) 2 h after intravenous injection of 15 see Figure 2A. The liver including a 1-cm margin was seg- ml gadobenate dimeglumine (Gd-BOPTA (Multihance), mented in the treatment planning CT. The segmented Bracco, Princeton, NJ). The hepatocyte-specific contrast data served as reference for registration to optimize regis- agent gadobenate dimeglumine allowed visualization of tration accuracy for the liver. Registration accuracy was the extent of hepatocyte dysfunction. The underlying validated using intrahepatic vessel bifurcations as land- mechanism of intracellular uptake is a polyspecific marks. Three to four landmarks were set in the CT and organic anionic transport [11-13]. MRI image data of ten patients. Distances between the landmarks in the coregistered images (CT vs. MRI) were Image registration determined using the differences between the absolute Merging of the 3D dosimetry data calculated by BrachyVi- positions determined with Amira. A total of 120 coregis- sion with the corresponding follow-up MRI scans was tered landmark combinations were evaluated. accomplished using an independent image registration implementation within the 3D visualization software Calculation of normal liver tissue tolerance dose Amira 3.1 (Mercury Computer Systems, Berlin, Germany). The borders of hyperintensity on T2-w images (intersti- The image voxel-property-based registration method tial edema) and hypointensity on late Gd-BOPTA- allowed affine transformation (12 degrees of freedom: 3 Lüdemann et al. Radiation Oncology 2011, 6:107 Page 4 of 10 http://www.ro-journal.com/content/6/1/107 enhanced T1-w images (hepatocyte dysfuntion) around coordinate from the coordinates of the entry sites and the irradiated liver tumors were outlined, see Figure 2B. of the catheter tips was calculated. The direction vector The volume of each irradiation effect was determined. of catheter implantation was converted into a unit vec- As the next step, we used this volume to calculate the tor with unit length 1 cm. 3D-isodose, which was confined to the liver and encom- The shift vector  describing the shift between the passed a corresponding volume (± 1%). The calculated irradiation effect volume and the tolerance dose volume isodose was taken as a surrogate for the tolerance dose was calculated from the center coordinates of both of normal liver tissue assuming consistency between an volumes. The scalar product of the unit vector and the observed radiation effect and the dose applied [9]. The shift vector, , was taken as a measure of the S = e · S axial volume encompassed by the isodose surface will be shift between irradiation effect volume and tolerance referred to as tolerance dose volume in the following. dose volume axial to the direction vector of catheter The mismatch areas between both volumes were investi- implantation. It serves as a surrogate for catheter dislo- gated in detail for the effect of prolonged irradiation cation within the catheter track. The vector product of time, see Figure 3. both vectors,  , provides a measure of the S = |e × S| ortho orthogonal shift between the center coordinates of the Measurement of lesion volume shift in relation to irradiation effect volume and the tolerance dose volume planned volume in relation to the direction vector of catheter implanta- Potential inaccuracies of the treatment planning proce- tion. Since movement of the brachytherapy catheters dure or catheter dislocation were analyzed by calculating within the liver is limited to the catheter track the the shift between the center coordinates of the irradia- orthogonal shift results mainly from methodical limita- tion effect volume and the tolerance dose volume using tions of image registration due to local liver deforma- thecoordinatesystemof the planning CT.Onlythose tion. The vector product thus serves as an additional brachytherapies were evaluated in which the catheters surrogate for registration inaccuracy. were implanted unidirectionally, i.e., in parallel (n = 38). An asymmetry coefficient of the scalar and vector pro- The direction vector of an implanted catheter was cal- duct was calculated to differentiate between a systematic culated from the coordinates of the catheter skin entry shift and registration inaccuracy: site and the catheter tip in the treatment planning CT. |S |− S If more than one catheter was implanted, an average axial ortho AC = (1) 0.5(|S | + S ) axial ortho A positive value of the asymmetry coefficient indicates a shift predominantely parallel to the direction vector of the implanted catheter, whereas a negative value indi- cates a shift predominantly orthogonal to the direction MA+ Lesion vector of the implanted catheter. Evaluation of prolonged irradiation time Irradiation took up to 4432 seconds (≈ 74 minutes) using multiple catheters with numerous dwell positions MA- 192 of the Ir source. Therefore, in areas with significant 16.2 Gy isodose surface dose contribution of several catheters, dose delivery time was prolonged and may be characterized as pulsed dose administration. The effects of regionally longer, pulsed irradiation were investigated in areas where the extent of hepatocyte dysfunction and edema was not Figure 3 Mismatch areas. T2-w image showing segmented consistent with the applied dose. Only radiation effects irradiation effect and 16.2Gy isodose encompassing the induced by at least 2 brachytherapy catheters were corresponding tolerance dose volume. A very pronounced shift of assessed (n = 48). the irradiation effect with respect to the isodoses is shown to illus- We used a boolean tool implemented in Amira 3.1 to trate the likely maximum inaccuracy of catheter positioning. identify nonoverlapping areas of the irradiation effect Mismatch areas in which we observed a dose response at doses smaller than the tolerance dose of the total irradiation effect are volume and the corresponding tolerance dose isovolume indexed with “MA+” and mismatch areas in which we did not (confined to the liver). These areas will be referred to as observe a dose response at doses higher than the tolerance dose of mismatch areas in the following. Mismatch areas where the total irradiation effect are indexed with “MA- “. edema or hepatocyte dysfunction occurred at doses Lüdemann et al. Radiation Oncology 2011, 6:107 Page 5 of 10 http://www.ro-journal.com/content/6/1/107 smaller than the tolerance dose of the total irradiation effect are indexed with ‘"MA+”. Conversely, mismatch areas in which edema or hepatocyte dysfuntion did not manifest at doses exceeding the tolerance dose of the total irradiation effect are indexed with “MA-”,see Figure 3. The ‘"MA+” and “MA-” mismatch areas by definition have identical volumes. A comprehensive description of the time course of irradiation in brachytherapy is difficult since multiple catheters with numerous dwell positions contribute to dose fractionation in each voxel. First, the total voxel dose, D (x,y,z), depends on the voxel position. Second, tot thedosecontributionofeachcatheter, D (x, y, z), depends on the voxel position, (x,y,z), where i is the catheter number. Third, each voxel is irradiated with a different dose administration scheme, D (x,y,z)= ∑ tot n D (x,y,z), where n is the number of catheters. The Bra- chyVision software allows separation of the total dose map, D (x,y,z), into n separate dose maps, D (x,y,z), for tot i each catheter i, see Figure 4. We calculated a total of 202 separate treatment plans using the treatment plan- ning system to determine the contribution of each catheter to the total of 48 irradiation effects. To esti- mate the prolongation of irradiation by the Ir HDR source we calculated a catheter contribution index, I (x, y,z), that uses the number of dose contribution pulses: D (x, y, z) (2) |I (x, y, z)| = n − 2 · − 1 D (x, y, z) tot i=1 The irradiation of a single voxel is prolonged as the number of dose-contributing catheters increases. There- fore, the catheter contribution index increases with the number of contributing catheters. In case of a single con- tributing catheter, I = 0. In case of two equally contribut- ing catheters, D /D =0.5,and I =2.0. I is always in i tot P P the range between 0 and 2. The separate treatment plans were combined in a voxelwise approach using an arith- metic module implemented in Amira 3.1, see Figure 5. Catheter contribution index I (x,y,z) was then aver- aged over the 3D maps of the mismatch areas, I (MA+) and I (MA-). We calculated an asymmetry coefficient with the following formula I (MA+) − I (MA−) P P AC = (3) 0.5(I (MA+) + I (MA−)) P P Figure 4 Dose separation. The 3D visualization shows a coronal CT reconstruction with the calculated dose in Gy overlayed using to compare the averaged catheter contribution indices the patient in Fig. 1. The dose is applied using two catheters. The I (MA+) and I (MA-) calculated using Eq. 2. A value of two catheters were visualized in 3D using surface rendering of the P P catheters labeled in the CT scan. A) Total dose, D , overlayed. tot the asymmetry coefficient > 0 indicates that the catheter B) Dose applied by the cranial catheter, D . C) Dose applied by the contribution index in “MA+” is higher than in “MA-”, caudal catheter, D . vice versa a value of the asymmetry coefficient < 0 Lüdemann et al. Radiation Oncology 2011, 6:107 Page 6 of 10 http://www.ro-journal.com/content/6/1/107 Table 1 Normal liver tissue tolerance dose and volume of irradiation effect 6w T1-w 12w T1-w 6w T2-w 12w T2-w n = 44 36 48 33 Dose/Gy 13.7 ± 4.8 16.7 ± 5.0 14.3 ± 6.2 16.6 ± 6.4 Volume/ 190.3 ± 127.2 ± 190.0 ± 157.0 ± cm 158.6 118.8 166.4 143.5 Mean normal liver tissue tolerance dose and volume (± standard deviation) for interstitial edema assessed by hyperintensity on T2-w images and hepatocyte dysfunction assessed by hypointensity on T1-w images six/twelve weeks (6w and 12w) after HDR-BT (n: number of MRI examinations evaluated). A total of 96 follow-up MRI examinations of 30 patients with 38 irradiation effects were assessed to ana- lyze methodical limitations of catheter positioning accu- racy. Only patients with unidirectionally implanted, i.e., nearly parallel, catheters were included in the evaluation. Figure 5 Catheter contribution index.Theimageshowing the The median number of catheters inserted was 2 (Q :1, separated isodoses of two catheters for the patient in Fig. 1 and Fig. 4. The separated doses of the cranial and caudal catheter (Fig. Q : 3 catheters; range: 1-8 catheters). 4) are used to calculate the catheter contribution index (Eq. 2) Table 2 presents the axial, orthogonal, and total shifts shown in color coding. In case of two equally contributing (in mm) between the center coordinates of the irradiation catheters, D /D = 0.5 and I = 2.0. I is always in the range i tot P P effects and tolerance dose volumes in relation to the between 0 and 2. direction vectors of catheter implantation. The mean axial shift of hepatocyte dysfunction (T1-w images) was indicates that the catheter contribution index in “MA+” -5. 3 ± 5.4 mm and of interstitial edema (T2-w images) is lower than in “MA-”. -5. 6 ± 6.0 mm in plane, indicating a shift of the irradia- tion effect volume against the corresponding tolerance Statistical analysis dose volume in the direction of the catheter entry sites. The Generalized Estimating Equation (GEE) model was The orthogonal shift as a surrogate for registration inac- employed to statistically assess limits of catheter posi- curacy due to liver deformation was 4.0 ± 2.5 mm on tioning accuracy and the effects of prolonged irradiation T1-w images and 4.6 ± 2.6 mm on T2-w images. times on the tolerance dose of normal liver parenchyma. The orthogonal and axial shifts between the center For a dataset consisting of repeated measurements (2 coordinates of the irradiation effect volume and the tol- MRI sequences, 2 follow-up dates) of a variable of inter- erance dose volume in relation to the direction vector of est, a GEE model allows the correlation of outcomes catheter implantation were highly correlated in the T1- within one individual to be estimated and taken into w and T2-w MRI sequences (p = 0.003 and p <0.001, appropriate account in the equation which generates the respectively), as were the shifts between 6 and 12 weeks regression coefficients and their standard errors [15,16]. examinations (p = 0.001 and p = 0. 004, respectively). The GEE model was calculated with SAS, Version 9.1 The asymmetry coefficient of the orthogonal and axial (SAS Institute Inc., Cary, NC, USA). A p <0.05was shifts of the center coordinates of the irradiation effect considered significant. Table 2 Shift between irradiation effect and planned 3 Results dose distribution The validation of image registration accuracy using T1-w T2-w landmarks yielded a mean deviation of 2.64 mm (25% n = 47 49 quartile width (Q ): 0.28 mm, 75% quartile width Axial shift/mm -5.3 ± 5.4 -5.6 ± 6.0 (Q ): 4.51 mm). Thus registration accuracy proved to Orthogonal shift/mm 4.0 ± 2.5 4.6 ± 2.6 be sufficient for evaluating catheter positioning accuracy. Total shift/mm 7.7 ± 4.4 8.4 ± 4.4 A total of 161 MRI examinations of 62 irradiation AC 1.14 ± 0.43 1.04 ± 0.49 effects were performed 6 and 12 weeks after HDR-BT. Mean axial, orthogonal, and total shift between center coordinates of the Table 1 shows the mean volume and threshold dose of irradiation effect and planned dose distribution in relation to the direction hepatocyte dysfunction (T1-w images) and interstitial vector of catheter implantation for T1-w and T2-w MRI data. Both follow-up dates, 6w and 12w, were evaluated together. A negative value of the axial edema (T2-w images) and corresponding liver tolerance shift indicates a shift into the direction of the catheter entry site. T1-w = doses as well as the standard deviation between the hepatocyte dysfunction, T2-w = interstitial edema, n = number of MR examinations at 6 and 12 weeks (6W and 12W). examinations assessed. Lüdemann et al. Radiation Oncology 2011, 6:107 Page 7 of 10 http://www.ro-journal.com/content/6/1/107 and corresponding tolerance dose volume in relation to approximately 22-23Gy 6 weeks and 28Gy 12 weeks the direction vector of catheter implantation, AC ,was post intervention, see Table 3. The difference between 1.14 ± 0.43 for hepatocyte dysfunction and 1.04 ± 0.49 the average doses in the mismatch areas is significant (p for interstitial edema, indicating that the axial shift as a < 0.0001). The values for the catheter contribution surrogate for catheter dislocation within the catheter indices in the mismatch areas, I (MA+) and I (MA -), as P P track was predominant (p < 0.005). The asymmetry well as the asymmetry coefficients of the catheter contri- coefficient was significantly affected by the MRI bution indices in the mismatch areas, AC , with respect sequence used (p = 0.014) but not by the change in the to hepatocyte dysfunction and interstitial edema and the irradiation effect volume between the 6-week and 12- corresponding follow-up dates are displayed in Table 3. week examinations (p = 0.48). The mean of AC is > 0 in each subgroup, indicating A total of 129 follow-up MRI examinations of 44 that the catheter contribution index in “MA+” is slightly patients with 48 irradiation effects were assessed to ana- higher than in “MA-”. I (MA+) and I (MA-) are signifi- P P lyze the effect of prolonged irradiation time on the tol- cantly affected by the volume loss of the irradiation erance dose of normal liver parenchyma. All irradiation effect between the 6-week and 12-week follow-up exam- effects were induced by at least 2 brachytherapy cathe- inations and consecutive shifts of the mismatch areas ters. The median number of catheters per irradiation towards the high dose regions of the dose plan (p = effect was 4 (Q :3; Q : 6 catheters; range: 2-11 cathe- 0.0014). There is no significant difference between I 25 75 P ters). The average time for complete application of the (MA+) and I (MA-) with respect to hepatocyte dysfunc- radiation dose was 1865 ± 758 seconds (range: 844 - tion and interstitial edema (p = 0.9). 4432 seconds). The volumes of the mismatch areas, “MA+” and “MA- 4 Discussion ”, averaged over the 6-week and 12-week follow-up MRI In this study, we sought to assess two methodical examinations and T1-w and T2-w acquisitions, was 40.6 aspects of HDR-BT: first, limits of catheter positioning ±28.9cm (23.5 ± 10.1%). The differences between the accuracy and, second, effects of prolonged irradiation on mismatch area volumes with regard to 6-week and 12 the tolerance dose of normal liver parenchyma. The week follow-up examinations and T1-w and T2-w MRI mean shift between the center coordinates of the irra- are small, see Table 3. The average dose in “MA+” is diation effect volume and corresponding tolerance dose approximately 12Gy 6 weeks and 14Gy 12 weeks after volume in relation to the direction vector of catheter the intervention. The average dose in “MA-”,is implantation is ≈ - 5 mm in plane, indicating a shift of the irradiation effect in the direction of the catheter entry site. The shift is within the slice thickness of 5 mm of the treatment planning CT but larger than could Table 3 Mean dose, deviation of mean dose from normal liver tissue tolerance dose, and dose protraction in be explained by registration inaccuracy, which is ≈ 3 mismatch areas mm, and inaccuracy due to local liver deformation in 6W T1-w 12W T1-w 6W T2-w 12W T2-w the follow-up images, resulting in an overall registration inaccuracy of ≈ 4-5 mm. n 3527 4027 Determination of catheter positioning accuracy might D(MA+)/Gy 12.0 ± 4.3 14.1 ± 4.4 11.8 ± 5.4 14.0 ± 6.3 be limited by the delineation of the brachytherapy cathe- D(MA-)/Gy 23.2 ± 11.9 28.5 ± 11.0 22.2 ± 11.6 27.7 ± 15.1 ters in the treatment planning CT since applicator geo- ΔD(MA+)/Gy -2.1 ± 2.8 -3.2 ± 1.9 -2.1 ± 4.3 -3.0 ± 3.1 metry is entered manually. Partial volume effects in the ΔD(MA-)/Gy 9.1 ± 7.5 11.2 ± 6.8 8.3 ± 6.6 10.7 ± 8.8 treatment planning datasets could be a potential source I (MA+) 1.67 ± 0.33 1.69 ± 0.26 1.67 ± 0.31 1.70 ± 0.27 of error in the treatment planning procedure, especially I (MA-) 1.45 ± 0.39 1.35 ± 0.37 1.45 ± 0.37 1.39 ± 0.36 for catheters in oblique direction, since correct place- AC 0.17 ± 0.28 0.25 ± 0.27 0.16 ± 0.26 0.23 ± 0.22 ment of the starting point of the catheter is dependent V (MA +/MA-)/cm 42.0 ± 26.7 38.2 ± 31.2 40.8 ± 29.2 43.0 ± 33.1 on conspicuity of the catheter tip. V (MA +/MA-)/% 21.8 ± 11.1 23.9 ± 7.8 23.1 ± 0.8 27.0 ± 9.0 Another limitation is the dislocation of catheters D(MA+), D(MA-): Average dose in mismatch areas; “MA+” for response at doses smaller than the tolerance dose and “MA-” for missing response at doses between acquisition of the planning CT and irradiation. exceeding the tolerance dose. Although the angiographic sheaths containing the cathe- ΔD(MA+), ΔD(MA-): Difference between the average dose in “MA+"and “MA-” ters were secured to the skin by suture, retraction of the and corresponding tolerance dose of the irradiation effect. brachytherapy catheters within the catheter tracks might I (MA+), I (MA-): Catheter contribution index in “MA+” and “MA-”. P P AC : Asymmetry coefficient between the catheter contribution indices in “MA I potentially occur due to patient movement, e.g., when +” and “MA-”. the patient is transferred from the CT unit to the bra- V (MA +/MA-): Volume of the mismatch areas “MA+” and “MA-” in percent and chytherapy unit, and liver movement during respiration. absolute value which is per definition identical for both areas. However, the extent of the shift between an irradiation Errors are given as standard deviation. Lüdemann et al. Radiation Oncology 2011, 6:107 Page 8 of 10 http://www.ro-journal.com/content/6/1/107 effect and the center of the planned dose distribution liver targets. The authors showed that especially liver does not suggest a significant dislocation of the bra- tumors with a CTV exceeding 100 cm were susceptible chytherapy catheters within the catheter tracks. to target deviation exceeding the standard safety mar- The systematic shift between the irradiation effect gins for PTV definition. They suggested to increase the volume and planned dose distribution has to be consid- PTV by adding a larger safety margin to ensure ade- ered in treatment planning when defining the CTV to quatetargetdosedepositioninthese CTVs.Inbra- avoid underdosage of the tumor periphery. In our institu- chytherapy, the applicator moves to a certain extent tion, the CTV comprises the tumor volume visible on together with the target and there is no need to increase contrast-enhanced CT scans plus a 5-mm safety margin. the safety margin for larger tumors. With regard to treatment planning, we conclude that a Catheter dislocation in brachytherapy was mainly slice thickness exceeding 3 mm potentially impairs cathe- investigated in fractionated HDR brachytherapy of the ter positioning accuracy. We furthermore propose that it prostate, which differs from the technique used here in would be beneficial to increase the safety margin of the that a much larger number of catheters are implanted CTV in the direction of the catheter tips from 5 to 10 for more than one day. Imaging techniques (cone beam mm to avoid underdosage and consecutive recurrence at CT and CT) were used to assess catheter dislocation the tumor margin. The amount of mismatch (Table 3) between the first and second fraction, i.e., over 24 between planned dose distribution and irradiation effect hours. Foster et al. found a mean catheter displacement volume is determined by the registration accuracy or pos- of 5. 1 mm, resulting in a significantly (p <0.01) sibly by biological effects but does not allow to assess the decreased mean prostate V (volume receiving 100Gy reproducibility of the CTV. Two studies evaluated the or more) from 93.8% to 76.2% [20]. Five patients had accuracy of target positioning in extracranial stereotactic maximum catheter displacement exceeding 10 mm. radiotherapy (ESRT) using special patient fixation. For Simnor et al. found a mean movement in caudal direc- mobile soft tissue targets, such as liver metastasis, Wulf tion relative to the prostate base between the first and et al. [17] reported mean target deviations of 0.9 ± 4.5 second fraction of 7. 9 mm (range 0-21 mm). Planning mm, 0. 9 ± 3.0 mm, and 3.4 ± 3.2 mm in the craniocau- target volume dose D was reduced without move- 90% dal, anteroposterior, and lateral directions, respectively, ment correction by a mean of 27.8% [21]. Kim et al. when breathing control was applied. The mean 3D devia- found an average (range) magnitude of craniocaudal tion of the targets was 6.1 ± 4.6 mm. catheter displacement of 2.7 mm (- 6.0 to 13.5 mm) For single-fraction therapy, Herfarth et al. [18] using bone markers and 5.4 mm (-3.75 to 18.0 mm) reported mean target set-up deviations between treat- using the center of two gold markers [22]. Catheter dis- ment planning and treatment of 4. 0 ± 2.5 mm, 2.2 ± 1. location in fractionated HDR brachytherapy of the pros- 8 mm, and 2.2 ± 1.7 mm in the craniocaudal, anteropos- tate is in the same range as in the present study but, terior, and lateral directions, respectively. The mean 3D because of the much more complex irradiation geome- deviation of the targets was 5.7 ± 2.5 mm. try, the impact on dose coverage is much larger. The total in-plane deviation of the target location in We assessed the effect of prolonged irradiation times our study was slightly higher, 4-6 ± 2-6 mm. However, on the tolerance dose of normal liver tissue to determine we determined the effective positioning accuracy by its relevance for treatment planning. A catheter contribu- comparing the shift between the irradiation effect in fol- tion index served as a surrogate for prolonged pulsed low-up MRI and planned dose distribution. The authors dose administration in nonoverlapping areas of the irra- quoted above compared treatment planning images with diation effect volume and the corresponding tolerance control CT datasets acquired before treatment [17,18] dose volume. The catheter contribution index was and did not evaluate the treatment effect. slightly but significantly higher in “MA+” than in “MA-”, Based on metric analysis of target mobility and set-up indicating a prolongation of dose application in “MA+” inaccuracy in the CT simulation prior to or during compared to “MA-”. Based on published data, we would treatment, safety margins for defining the planning tar- have expected to find an increased tolerance dose of the get volume (PTV) of about 5 mm in axial and 5 - 10 liver parenchyma in areas irradiated for a longer time, i. mm in craniocaudal direction are commonly added to e., by several catheters [6,7], even if the overall irradiation the CTV in ESRT of lung and liver tumors [19]. In con- time is less than one hour [8]. However, we found a trast to the present study, Wulf et al. evaluated the decreased tolerance dose of the liver parenchyma in areas reproducibility of the CTV of lung and liver tumors where the radiation dose was applied by several catheters within the planning target volume (PTV) over the entire for a prolonged period of time. course of hypofractionated treatment in CT simulation We hypothesize that the effects of prolonged irradia- prior to application of each fraction [19]. The mean tion on the tolerance dose of normal liver tissue might volume ratio of the PTV to the CTV was 2.2 ± 0.6 in have been obscured by other factors. For instance, Lüdemann et al. Radiation Oncology 2011, 6:107 Page 9 of 10 http://www.ro-journal.com/content/6/1/107 biological effects such as reactive inflammatory changes Dose administration was considered highly prolonged if may mimic irradiation effects, or scarring of the liver the index was 2 (meaning that each catheter of the bra- tissue induced by catheter insertion may cause retrac- chytherapy implant contributed < 50% of the irradiation tion of the irradiation effect towards the catheter entry dose in the mismatch area). It was considered fairly pro- site. Furthermore, we propose that inaccuracies in the longed if the value was between 1 and 2 (indicating that positioning of the brachytherapy catheters are more pro- more than 25% of the total irradiation dose in the mis- nounced in areas where several catheters contribute to matchareawas appliedbymorethan1catheter),and the total irradiation dose and that the total applied nonprolonged if the value was ≤ 1 (meaning that 75% or effective dose in “MA+” was higher than would have more of the total irradiation dose in the mismatch area been expected from the treatment plan. Since steep was applied by 1 catheter only). Nevertheless, the tool is dose gradients are an inherent quality of interstitial sufficient to rule out practically relevant effects of pro- HDR-BT, the shift of active dwell positions of one or longed dose administration in HDR-BT in vivo. several catheters towards the tumor periphery would be sufficient to significantly increase the applied dose out- 5 Conclusions side the CTV. As the number of catheters increases, the In conclusion, positioning accuracy of brachytherapy probability of a dose shift due to slight inaccuracy in catheters is sufficiently precise with approx. 5-6 mm. catheter positioning likely increases as well. Accuracy was within the 5-mm slice thickness of the We conclude that the effects of prolonged irradiation treatment planning CT. Thus positioning accuracy is time are of minor importance for interstitial HDR-BT potentially affected by inaccuracy in the delineation of compared to other factors such as positioning accuracy the brachytherapy catheters during treatment planning of brachytherapy catheters and do not have to be taken due to partial volume effects in the planning CT. into account in treatment planning in HDR-BT if the Retraction of the catheters within the catheter tracks total irradiation time does not significantly exceed one during transfer of the patient from the CT unit to the hour. brachytherapy unit might occur; however, this retraction The study has several limitations. Obviously one key is not pronounced. Therefore, CT-guided HDR-BT can issue of the study is the registration accuracy. The vali- be safely performed, even if CT and brachytherapy are dation of registration accuracy was based on corre- not performed in the same unit. Effects of prolonged sponding vessel bifurcations identified in the planning irradiation times on the tolerance dose of normal liver CT and follow-up MR images by an experienced radiol- tissue are negligible compared to positioning accuracy ogist [23,24]. We applied affine registration, allowing 12 of brachytherapy catheters and do not have to be taken degrees of freedom, which compensates for whole organ into account in treatment planning if the total irradia- deformation and yielded an accuracy of ≈ 3mmwith tion time does not significantly exceed one hour. respect to vessel bifurcations within the central parts of the liver, comparable to other studies [25,26]. Affine 6 Competing interests registration has been proven to be precise and robust The authors declare that they have no competing for liver registration [25-27]. However, local liver defor- interests. mation resulting from compression by adjacent organs (such as the stomach), different respiration levels, or the 7 Authors’ contributions implanted catheters in the treatment planning CT data LL, CW: data analysis, manuscript preparation. might not be sufficiently compensated for. To ade- PW, JR: study coordination, study design. quately compensate for these effects a finite element MS, KM: data acquisition. model-based deformable image registration would have SK: data analysis been superior [23,24]. We tried to compensate for the All authors read and approved the final manuscript. limitations of affine registration by restricting the regis- tration to the liver [25]. Using this procedure, we Author details achieved a registration accuracy with a mean deviation 1 Department of Radiation Therapy, Charité Medical Center, Berlin, Germany. of 2.64 mm, which was smaller than that of the nonrigid Department of Radiology and Nuclear Medicine, Otto von Guericke University, Magdeburg, Germany. Department of Biometrics and Medical registration used by Elhawary et al. [28], for which the Informatics, Otto von Guericke University, Magdeburg, Germany. authors reported a mean target registration error of. 4.1 th mm and a mean 95 -percentile Hausdorff distance of 3. Received: 16 May 2011 Accepted: 5 September 2011 Published: 5 September 2011 3 mm. Second, the catheter contribution index has to be con- References sidered a rough simplification, merely providing a first 1. Ricke J, Mohnike K, Pech M, Seidensticker M, Rühl R, Wieners G, Gaffke G, estimate of the effect of prolonged dose administration. Kropf S, Felix R, Wust P: Local response and impact on survival after local Lüdemann et al. Radiation Oncology 2011, 6:107 Page 10 of 10 http://www.ro-journal.com/content/6/1/107 ablation of liver metastases from colorectal carcinoma by computed 21. Simnor T, Li S, Lowe G, Ostler P, Bryant L, Chapman C, Inchley D, Hoskin PJ: tomography-guided high-dose-rate brachytherapy. Int J Radiat Oncol Biol Justification for inter-fraction correction of catheter movement in Phys 2010, 78(2):479-485. fractionated high dose-rate brachytherapy treatment of prostate cancer. 2. Mohnike K, Wieners G, Schwartz F, Seidensticker M, Pech M, Ruehl R, Radiother Oncol 2009, 93(2):253-258. Wust P, Lopez-Hänninen E, Gademann G, Peters N, Berg T, Malfertheiner P, 22. Kim Y, Hsu IC, Pouliot J: Measurement of craniocaudal catheter Ricke J: Computed tomography-guided high-dose-rate brachytherapy in displacement between fractions in computed tomography-based high hepatocellular carcinoma: safety, efficacy, and effect on survival. Int J dose rate brachytherapy of prostate cancer. J Appl Clin Med Phys 2007, Radiat Oncol Biol Phys 2010, 78:172-179. 8(4):2415-2415. 3. Wieners G, Mohnike K, Peters N, Bischoff J, Kleine-Tebbe A, Seidensticker R, 23. Brock KK, Dawson LA, Sharpe MB, Moseley DJ, Jaffray DA: Feasibility of a Seidensticker M, Gademann G, Wust P, Pech M, Ricke J: Treatment of novel deformable image registration technique to facilitate classification, hepatic metastases of breast cancer with CT-guided interstitial targeting, and monitoring of tumor and normal tissue. Int J Radiat Oncol brachytherapy - A phase II-study. Radiother Oncol 2011. Biol Phys 2006, 64(4):1245-1254. 4. Rühl R, Lüdemann L, Czarnecka A, Streitparth F, Seidensticker M, Mohnike K, 24. Voroney JP, Brock KK, Eccles C, Haider M, Dawson LA: Prospective Pech M, Wust P, Ricke J: Radiobiological restrictions and tolerance doses comparison of computed tomography and magnetic resonance imaging of repeated single-fraction hdr-irradiation of intersecting small liver for liver cancer delineation using deformable image registration. Int J volumes for recurrent hepatic metastases. Radiat Oncol 2010, 5:44-44. Radiat Oncol Biol Phys 2006, 66(3):780-791. 5. Seidensticker M, Wust P, Rühl R, Mohnike K, Pech M, Wieners G, 25. van Dalen JA, Vogel W, Huisman HJ, Oyen WJ, Jager GJ, Karssemeijer N: Gademann G, Ricke J: Safety margin in irradiation of colorectal liver Accuracy of rigid CT-FDG-PET image registration of the liver. Phys Med metastases: assessment of the control dose of micrometastases. Radiat Biol 2004, 49(23):5393-5405. Oncol 2010, 5:24-24. 26. Carrillo A, Duerk JL, Lewin JS, Wilson DL: Semiautomatic 3-D image 6. Hall EJ: Weiss lecture. The dose-rate factor in radiation biology. Int J registration as applied to interventional MRI liver cancer treatment. IEEE Radiat Biol 1991, 59(3):595-610. Trans Med Imaging 2000, 19(3):175-185. 7. Fowler JF, Van Limbergen EF: Biological effect of pulsed dose rate 27. Christina Lee WC, Tublin ME, Chapman BE: Registration of MR and CT brachytherapy with stepping sources if short half-times of repair are images of the liver: comparison of voxel similarity and surface based present in tissues. Int J Radiat Oncol Biol Phys 1997, 37(4):877-883. registration algorithms. Comput Methods Programs Biomed 2005, 8. Pop LA, Millar WT, van der Plas M, van der Kogel AJ: Radiation tolerance of 78(2):101-114. rat spinal cord to pulsed dose rate (PDR-) brachytherapy: the impact of 28. Elhawary H, Oguro S, Tuncali K, Morrison PR, Tatli S, Shyn PB, Silverman SG, differences in temporal dose distribution. Radiother Oncol 2000, Hata N: Multimodality non-rigid image registration for planning, 55(3):301-315. targeting and monitoring during CT-guided percutaneous liver tumor 9. Wybranski C, Seidensticker M, Mohnike K, Kropf S, Wust P, Ricke J, cryoablation. Acad Radiol 2010, 17(11):1334-1344. Lüdemann L: In vivo assessment of dose volume and dose gradient doi:10.1186/1748-717X-6-107 effects on the tolerance dose of small liver volumes after single-fraction Cite this article as: Lüdemann et al.: In vivo assessment of catheter high-dose-rate 192Ir irradiation. Radiat Res 2009, 172(5):598-606. positioning accuracy and prolonged irradiation time on liver tolerance 10. Ricke J, Seidensticker M, Lüdemann L, Pech M, Wieners G, Hengst S, dose after single-fraction Ir high-dose-rate brachytherapy. Radiation Mohnike K, Cho CH, Hanninen EL, Al-Abadi H, Felix R, Wust P: In vivo Oncology 2011 6:107. assessment of the tolerance dose of small liver volumes after single- fraction HDR irradiation. Int J Radiat Oncol Biol Phys 2005, 62(3):776-84. 11. Clement O, Siauve N, Cuenod CA, Vuillemin-Bodaghi V, Leconte I, Frija G: Mechanisms of action of liver contrast agents: impact for clinical use. J Comput Assist Tomogr 1999, 23(Suppl 1):S45-52. 12. Kirchin MA, Pirovano GP, Spinazzi A: Gadobenate dimeglumine (Gd- BOPTA). An overview. Invest Radiol 1998, 33(11):798-809. 13. de Haen C, Ferla RL, Maggioni F: Gadobenate dimeglumine 0.5 M solution for injection (MultiHance) as contrast agent for magnetic resonance imaging of the liver: mechanistic studies in animals. J Comput Assist Tomogr 1999, 23(Suppl 1):S169-79. 14. Rohlfing T, West JB, Beier J, Liebig T, Taschner CA, Thomale UW: Registration of functional and anatomical MRI: accuracy assessment and application in navigated neurosurgery. Comput Aided Surg 2000, 5(6):414-25. 15. Burton P, Gurrin L, Sly P: Extending the simple linear regression model to account for correlated responses: an introduction to generalized estimating equations and multi-level mixed modelling. Stat Med 1998, 17(11):1261-91. 16. Zeger SL, Liang KY: Longitudinal data analysis for discrete and continuous outcomes. Biometrics 1986, 42:121-30. 17. Wulf J, Hadinger U, Oppitz U, Olshausen B, Flentje M: Stereotactic radiotherapy of extracranial targets: CT-simulation and accuracy of treatment in the stereotactic body frame. Radiother Oncol 2000, Submit your next manuscript to BioMed Central 57(2):225-36. and take full advantage of: 18. Herfarth KK, Debus J, Lohr F, Bahner ML, Fritz P, Hoss A, Schlegel W, Wannenmacher MF: Extracranial stereotactic radiation therapy: set-up • Convenient online submission accuracy of patients treated for liver metastases. Int J Radiat Oncol Biol Phys 2000, 46(2):329-35. • Thorough peer review 19. Wulf J, Hadinger U, Oppitz U, Thiele W, Flentje M: Impact of target • No space constraints or color figure charges reproducibility on tumor dose in stereotactic radiotherapy of targets in • Immediate publication on acceptance the lung and liver. Radiother Oncol 2003, 66(2):141-50. 20. Foster W, Cunha JA, Hsu IC, Weinberg V, Krishnamurthy D, Pouliot J: • Inclusion in PubMed, CAS, Scopus and Google Scholar Dosimetric impact of interfraction catheter movement in high-dose rate • Research which is freely available for redistribution prostate brachytherapy. Int J Radiat Oncol Biol Phys 2011, 80:85-90. Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

In vivo assessment of catheter positioning accuracy and prolonged irradiation time on liver tolerance dose after single-fraction 192Ir high-dose-rate brachytherapy

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Copyright © 2011 by Lüdemann et al; licensee BioMed Central Ltd.
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Medicine & Public Health; Oncology; Radiotherapy
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1748-717X
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10.1186/1748-717X-6-107
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21892943
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Abstract

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 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. * Correspondence: lutz.luedemann@charite.de † Contributed equally Department of Radiation Therapy, Charité Medical Center, Berlin, Germany Full list of author information is available at the end of the article © 2011 Lüdemann et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Lüdemann et al. Radiation Oncology 2011, 6:107 Page 2 of 10 http://www.ro-journal.com/content/6/1/107 Interventional technique 1 Background The interventional technique has been described in Single-fraction Ir high-dose-rate brachytherapy (HDR- detail elsewhere [9]. In brief, a T2-weighted (T2-w) BT) of the liver is an ablation technique which has respiratory-triggered ultrafast turbo spin echo (UTSE) shown promising results with respect to safety and and a T1-weighted (T1-w) breath-hold gradient echo efficacy in the treatment of nonresectable primary and (GRE) sequence with administration of the hepatocyte- secondary liver malignancies [1-3]. HDR-BT provides specific contrast agent gadobenate dimeglumine (Gd- steep dose gradients at the surface of the target volume BOPTA (Multihance), Bracco, Princeton, NJ) were due to the low g-ray energy of Ir and use of a point acquired to delineate primary and secondary liver source, and thus can be used to treat several malignan- lesions (see Follow-up section below). The brachyther- cies in one session or recurrent malignancies sequentially apy catheters were positioned using CT guidance without seriously impairing the functional hepatic reserve (Somatom 4, Siemens, Erlangen, Germany), i.e., CT [4]. To prevent recurrence at the tumor margins, catheter scans were acquired continuously during the interven- placement and dwell positions of the Ir point source tional procedure with an image reconstruction rate of have to be carefully planned [5]. The accuracy of dose 12 per second to monitor actual catheter location. They application is predominantly dependent on catheter posi- were placed in 6F angiographic sheaths (Radiofocus, tioning. Computed tomography (CT) was used to moni- Terumo, Japan), which were implanted in Seldinger tor catheter implantation, and 3D CT datasets acquired technique within the tumors.The angiographic sheaths in breath-hold were used for treatment planning. For were sutured to the skin. After catheter positioning, a irradiation patients were transferred from the CT unit to spiral CT scan of the liver (matrix size, 512 × 512; slice the brachytherapy unit. Dislocation of catheters during thickness, 5 mm; increment, 5 mm) enhanced by intra- patient transfer might be a potential source of error with venous administration of iodine contrast medium (100 respect to correct dose application at the target site. ml Ultravist 370; flow, 1 ml/s; start delay, 80s) was Additionally, the liver is an elastic organ and could be acquired in breath-hold technique for treatment plan- deformed between catheter implantation and irradiation. ning. Four catheters were implanted on average per The treatment of larger tumors with an Ir point HDR-BT session (range, 1 - 11 catheters). source requires the implantation of approximately 1 catheter for each 1 - 2 cm of tumor diameter. The con- Treatment planning and irradiation tributions of several catheters with numerous dwell Treatment was planned using the BrachyVision software positions to the planned dose in a large part of the tar- package, version 7.1 (Varian Medical Systems, Palo Alto, get volume lead to regional prolongation of irradiation. CA). The dwell positions and irradiation times were Several authors describe an increased normal tissue dose optimized to ensure delivery of the prescribed dose to tolerance for prolonged radiation therapy or pulsed dose the entire clinical target volume (CTV), see Figure 1. rate (PDR) radiation therapy [6,7] even if the total irra- The 24-channel HDR afterloading system (Gammamed diation time is less than one hour [8]. 12i, Varian, Charlottesville, VA) employed a Ir source The present study aims at addressing two methodical (nominal source strength, 370GBq). A dose of 15, 20, or aspects of HDR-BT: First, to investigate the limits of 25Gy was prescribed, which was planned to enclose the catheter positioning accuracy and its clinical importance. lesion (clinical target volume). Compromises were Second, to investigate if effects of prolonged irradiation necessary if organs of risk such as the stomach, small times on the tolerance dose of normal liver parenchyma intestine, or a large bile duct were very close to the tar- are important for clinical practice and may have to be get. No upper limit was defined for the dose within the taken into account in treatment planning. tumor volume. To preserve liver function after irradia- tion, one third of the liver parenchyma should receive a 2 Methods dose of less than 5Gy. The effective irradiation time Study population needed to apply the target dose with all catheters was In this study we retrospectively analyzed irradiation corrected according to the actual Ir source strength. effects on normal liver tissue in 50 consecutive patients We usually limit the maximum irradiation time to 60 who underwent CT-guided single-fraction HDR-BT as minutes to increase patient comfort. The catheters were part of a clinical phase II study prospectively assessing then sequentially connected to the afterloading system local tumor control. In 50 HDR-BT sessions a total of according to the prescribed enumeration, and irradiation 76 solid primary or secondary liver tumors were treated was started at the most distant dwell position in each (1 - 4 malignant tumors per session). The study was catheter. All dwell positions within one catheter were approved by the local ethics committee. Written sequentially irradiated without any delay. An interval of informed consent was obtained from all patients. Lüdemann et al. Radiation Oncology 2011, 6:107 Page 3 of 10 http://www.ro-journal.com/content/6/1/107 A) Figure 1 Geometry. The 3D visualization shows a CT slice with the Lesion B) calculated dose in Gy overlayed. The dose is applied using two catheters. The two catheters were visualized in 3D using surface 10 Gy rendering of the catheters labeled in the CT scan. approx. 2 - 3 minutes was required for connecting each 15 Gy catheter. Manual sequential connection of the catheters was necessary because only a single adapter was avail- 20 Gy able for connecting the catheters to the afterloader. The 5 Gy exposure times were in the range of 844 - 4432 seconds. Follow-up A total of 161 MRI examinations were performed 6 ± 2 weeks and 12 ± 2 weeks after HDR-BT. The MRI proto- Figure 2 Image registration. A) T2-w image coregistered with the col comprised the following sequences (Gyroscan NT planning CT. Note that only the liver was coregistered and Intera, Philips, The Netherlands) [10]: T2-w respiratory- therefore good matching of the images was only achieved for the liver. B) T2-w image showing segmented lesion and isodoses at 12- triggered UTSE (echo time/repetition time (TE/TR), 90/ week follow-up. A prononounced shift of the irradiation effect with 2100 ms; echo train length (ETL), 21; slice thickness, 8 respect to the planned dose distribution as shown in this example mm, acquired in interleaved mode with no gap) with fat was typically not found. suppression to assess the extent of interstitial edema and T1-w breath-hold GRE (TE/TR 5/30 ms; flip rotations, 3translations, 3scalings,and 3shears) by angle,30°; slice thickness, 8 mm, acquired in, interleaved exploring the normalized mutual information (NMI) [14], mode with no gap) 2 h after intravenous injection of 15 see Figure 2A. The liver including a 1-cm margin was seg- ml gadobenate dimeglumine (Gd-BOPTA (Multihance), mented in the treatment planning CT. The segmented Bracco, Princeton, NJ). The hepatocyte-specific contrast data served as reference for registration to optimize regis- agent gadobenate dimeglumine allowed visualization of tration accuracy for the liver. Registration accuracy was the extent of hepatocyte dysfunction. The underlying validated using intrahepatic vessel bifurcations as land- mechanism of intracellular uptake is a polyspecific marks. Three to four landmarks were set in the CT and organic anionic transport [11-13]. MRI image data of ten patients. Distances between the landmarks in the coregistered images (CT vs. MRI) were Image registration determined using the differences between the absolute Merging of the 3D dosimetry data calculated by BrachyVi- positions determined with Amira. A total of 120 coregis- sion with the corresponding follow-up MRI scans was tered landmark combinations were evaluated. accomplished using an independent image registration implementation within the 3D visualization software Calculation of normal liver tissue tolerance dose Amira 3.1 (Mercury Computer Systems, Berlin, Germany). The borders of hyperintensity on T2-w images (intersti- The image voxel-property-based registration method tial edema) and hypointensity on late Gd-BOPTA- allowed affine transformation (12 degrees of freedom: 3 Lüdemann et al. Radiation Oncology 2011, 6:107 Page 4 of 10 http://www.ro-journal.com/content/6/1/107 enhanced T1-w images (hepatocyte dysfuntion) around coordinate from the coordinates of the entry sites and the irradiated liver tumors were outlined, see Figure 2B. of the catheter tips was calculated. The direction vector The volume of each irradiation effect was determined. of catheter implantation was converted into a unit vec- As the next step, we used this volume to calculate the tor with unit length 1 cm. 3D-isodose, which was confined to the liver and encom- The shift vector  describing the shift between the passed a corresponding volume (± 1%). The calculated irradiation effect volume and the tolerance dose volume isodose was taken as a surrogate for the tolerance dose was calculated from the center coordinates of both of normal liver tissue assuming consistency between an volumes. The scalar product of the unit vector and the observed radiation effect and the dose applied [9]. The shift vector, , was taken as a measure of the S = e · S axial volume encompassed by the isodose surface will be shift between irradiation effect volume and tolerance referred to as tolerance dose volume in the following. dose volume axial to the direction vector of catheter The mismatch areas between both volumes were investi- implantation. It serves as a surrogate for catheter dislo- gated in detail for the effect of prolonged irradiation cation within the catheter track. The vector product of time, see Figure 3. both vectors,  , provides a measure of the S = |e × S| ortho orthogonal shift between the center coordinates of the Measurement of lesion volume shift in relation to irradiation effect volume and the tolerance dose volume planned volume in relation to the direction vector of catheter implanta- Potential inaccuracies of the treatment planning proce- tion. Since movement of the brachytherapy catheters dure or catheter dislocation were analyzed by calculating within the liver is limited to the catheter track the the shift between the center coordinates of the irradia- orthogonal shift results mainly from methodical limita- tion effect volume and the tolerance dose volume using tions of image registration due to local liver deforma- thecoordinatesystemof the planning CT.Onlythose tion. The vector product thus serves as an additional brachytherapies were evaluated in which the catheters surrogate for registration inaccuracy. were implanted unidirectionally, i.e., in parallel (n = 38). An asymmetry coefficient of the scalar and vector pro- The direction vector of an implanted catheter was cal- duct was calculated to differentiate between a systematic culated from the coordinates of the catheter skin entry shift and registration inaccuracy: site and the catheter tip in the treatment planning CT. |S |− S If more than one catheter was implanted, an average axial ortho AC = (1) 0.5(|S | + S ) axial ortho A positive value of the asymmetry coefficient indicates a shift predominantely parallel to the direction vector of the implanted catheter, whereas a negative value indi- cates a shift predominantly orthogonal to the direction MA+ Lesion vector of the implanted catheter. Evaluation of prolonged irradiation time Irradiation took up to 4432 seconds (≈ 74 minutes) using multiple catheters with numerous dwell positions MA- 192 of the Ir source. Therefore, in areas with significant 16.2 Gy isodose surface dose contribution of several catheters, dose delivery time was prolonged and may be characterized as pulsed dose administration. The effects of regionally longer, pulsed irradiation were investigated in areas where the extent of hepatocyte dysfunction and edema was not Figure 3 Mismatch areas. T2-w image showing segmented consistent with the applied dose. Only radiation effects irradiation effect and 16.2Gy isodose encompassing the induced by at least 2 brachytherapy catheters were corresponding tolerance dose volume. A very pronounced shift of assessed (n = 48). the irradiation effect with respect to the isodoses is shown to illus- We used a boolean tool implemented in Amira 3.1 to trate the likely maximum inaccuracy of catheter positioning. identify nonoverlapping areas of the irradiation effect Mismatch areas in which we observed a dose response at doses smaller than the tolerance dose of the total irradiation effect are volume and the corresponding tolerance dose isovolume indexed with “MA+” and mismatch areas in which we did not (confined to the liver). These areas will be referred to as observe a dose response at doses higher than the tolerance dose of mismatch areas in the following. Mismatch areas where the total irradiation effect are indexed with “MA- “. edema or hepatocyte dysfunction occurred at doses Lüdemann et al. Radiation Oncology 2011, 6:107 Page 5 of 10 http://www.ro-journal.com/content/6/1/107 smaller than the tolerance dose of the total irradiation effect are indexed with ‘"MA+”. Conversely, mismatch areas in which edema or hepatocyte dysfuntion did not manifest at doses exceeding the tolerance dose of the total irradiation effect are indexed with “MA-”,see Figure 3. The ‘"MA+” and “MA-” mismatch areas by definition have identical volumes. A comprehensive description of the time course of irradiation in brachytherapy is difficult since multiple catheters with numerous dwell positions contribute to dose fractionation in each voxel. First, the total voxel dose, D (x,y,z), depends on the voxel position. Second, tot thedosecontributionofeachcatheter, D (x, y, z), depends on the voxel position, (x,y,z), where i is the catheter number. Third, each voxel is irradiated with a different dose administration scheme, D (x,y,z)= ∑ tot n D (x,y,z), where n is the number of catheters. The Bra- chyVision software allows separation of the total dose map, D (x,y,z), into n separate dose maps, D (x,y,z), for tot i each catheter i, see Figure 4. We calculated a total of 202 separate treatment plans using the treatment plan- ning system to determine the contribution of each catheter to the total of 48 irradiation effects. To esti- mate the prolongation of irradiation by the Ir HDR source we calculated a catheter contribution index, I (x, y,z), that uses the number of dose contribution pulses: D (x, y, z) (2) |I (x, y, z)| = n − 2 · − 1 D (x, y, z) tot i=1 The irradiation of a single voxel is prolonged as the number of dose-contributing catheters increases. There- fore, the catheter contribution index increases with the number of contributing catheters. In case of a single con- tributing catheter, I = 0. In case of two equally contribut- ing catheters, D /D =0.5,and I =2.0. I is always in i tot P P the range between 0 and 2. The separate treatment plans were combined in a voxelwise approach using an arith- metic module implemented in Amira 3.1, see Figure 5. Catheter contribution index I (x,y,z) was then aver- aged over the 3D maps of the mismatch areas, I (MA+) and I (MA-). We calculated an asymmetry coefficient with the following formula I (MA+) − I (MA−) P P AC = (3) 0.5(I (MA+) + I (MA−)) P P Figure 4 Dose separation. The 3D visualization shows a coronal CT reconstruction with the calculated dose in Gy overlayed using to compare the averaged catheter contribution indices the patient in Fig. 1. The dose is applied using two catheters. The I (MA+) and I (MA-) calculated using Eq. 2. A value of two catheters were visualized in 3D using surface rendering of the P P catheters labeled in the CT scan. A) Total dose, D , overlayed. tot the asymmetry coefficient > 0 indicates that the catheter B) Dose applied by the cranial catheter, D . C) Dose applied by the contribution index in “MA+” is higher than in “MA-”, caudal catheter, D . vice versa a value of the asymmetry coefficient < 0 Lüdemann et al. Radiation Oncology 2011, 6:107 Page 6 of 10 http://www.ro-journal.com/content/6/1/107 Table 1 Normal liver tissue tolerance dose and volume of irradiation effect 6w T1-w 12w T1-w 6w T2-w 12w T2-w n = 44 36 48 33 Dose/Gy 13.7 ± 4.8 16.7 ± 5.0 14.3 ± 6.2 16.6 ± 6.4 Volume/ 190.3 ± 127.2 ± 190.0 ± 157.0 ± cm 158.6 118.8 166.4 143.5 Mean normal liver tissue tolerance dose and volume (± standard deviation) for interstitial edema assessed by hyperintensity on T2-w images and hepatocyte dysfunction assessed by hypointensity on T1-w images six/twelve weeks (6w and 12w) after HDR-BT (n: number of MRI examinations evaluated). A total of 96 follow-up MRI examinations of 30 patients with 38 irradiation effects were assessed to ana- lyze methodical limitations of catheter positioning accu- racy. Only patients with unidirectionally implanted, i.e., nearly parallel, catheters were included in the evaluation. Figure 5 Catheter contribution index.Theimageshowing the The median number of catheters inserted was 2 (Q :1, separated isodoses of two catheters for the patient in Fig. 1 and Fig. 4. The separated doses of the cranial and caudal catheter (Fig. Q : 3 catheters; range: 1-8 catheters). 4) are used to calculate the catheter contribution index (Eq. 2) Table 2 presents the axial, orthogonal, and total shifts shown in color coding. In case of two equally contributing (in mm) between the center coordinates of the irradiation catheters, D /D = 0.5 and I = 2.0. I is always in the range i tot P P effects and tolerance dose volumes in relation to the between 0 and 2. direction vectors of catheter implantation. The mean axial shift of hepatocyte dysfunction (T1-w images) was indicates that the catheter contribution index in “MA+” -5. 3 ± 5.4 mm and of interstitial edema (T2-w images) is lower than in “MA-”. -5. 6 ± 6.0 mm in plane, indicating a shift of the irradia- tion effect volume against the corresponding tolerance Statistical analysis dose volume in the direction of the catheter entry sites. The Generalized Estimating Equation (GEE) model was The orthogonal shift as a surrogate for registration inac- employed to statistically assess limits of catheter posi- curacy due to liver deformation was 4.0 ± 2.5 mm on tioning accuracy and the effects of prolonged irradiation T1-w images and 4.6 ± 2.6 mm on T2-w images. times on the tolerance dose of normal liver parenchyma. The orthogonal and axial shifts between the center For a dataset consisting of repeated measurements (2 coordinates of the irradiation effect volume and the tol- MRI sequences, 2 follow-up dates) of a variable of inter- erance dose volume in relation to the direction vector of est, a GEE model allows the correlation of outcomes catheter implantation were highly correlated in the T1- within one individual to be estimated and taken into w and T2-w MRI sequences (p = 0.003 and p <0.001, appropriate account in the equation which generates the respectively), as were the shifts between 6 and 12 weeks regression coefficients and their standard errors [15,16]. examinations (p = 0.001 and p = 0. 004, respectively). The GEE model was calculated with SAS, Version 9.1 The asymmetry coefficient of the orthogonal and axial (SAS Institute Inc., Cary, NC, USA). A p <0.05was shifts of the center coordinates of the irradiation effect considered significant. Table 2 Shift between irradiation effect and planned 3 Results dose distribution The validation of image registration accuracy using T1-w T2-w landmarks yielded a mean deviation of 2.64 mm (25% n = 47 49 quartile width (Q ): 0.28 mm, 75% quartile width Axial shift/mm -5.3 ± 5.4 -5.6 ± 6.0 (Q ): 4.51 mm). Thus registration accuracy proved to Orthogonal shift/mm 4.0 ± 2.5 4.6 ± 2.6 be sufficient for evaluating catheter positioning accuracy. Total shift/mm 7.7 ± 4.4 8.4 ± 4.4 A total of 161 MRI examinations of 62 irradiation AC 1.14 ± 0.43 1.04 ± 0.49 effects were performed 6 and 12 weeks after HDR-BT. Mean axial, orthogonal, and total shift between center coordinates of the Table 1 shows the mean volume and threshold dose of irradiation effect and planned dose distribution in relation to the direction hepatocyte dysfunction (T1-w images) and interstitial vector of catheter implantation for T1-w and T2-w MRI data. Both follow-up dates, 6w and 12w, were evaluated together. A negative value of the axial edema (T2-w images) and corresponding liver tolerance shift indicates a shift into the direction of the catheter entry site. T1-w = doses as well as the standard deviation between the hepatocyte dysfunction, T2-w = interstitial edema, n = number of MR examinations at 6 and 12 weeks (6W and 12W). examinations assessed. Lüdemann et al. Radiation Oncology 2011, 6:107 Page 7 of 10 http://www.ro-journal.com/content/6/1/107 and corresponding tolerance dose volume in relation to approximately 22-23Gy 6 weeks and 28Gy 12 weeks the direction vector of catheter implantation, AC ,was post intervention, see Table 3. The difference between 1.14 ± 0.43 for hepatocyte dysfunction and 1.04 ± 0.49 the average doses in the mismatch areas is significant (p for interstitial edema, indicating that the axial shift as a < 0.0001). The values for the catheter contribution surrogate for catheter dislocation within the catheter indices in the mismatch areas, I (MA+) and I (MA -), as P P track was predominant (p < 0.005). The asymmetry well as the asymmetry coefficients of the catheter contri- coefficient was significantly affected by the MRI bution indices in the mismatch areas, AC , with respect sequence used (p = 0.014) but not by the change in the to hepatocyte dysfunction and interstitial edema and the irradiation effect volume between the 6-week and 12- corresponding follow-up dates are displayed in Table 3. week examinations (p = 0.48). The mean of AC is > 0 in each subgroup, indicating A total of 129 follow-up MRI examinations of 44 that the catheter contribution index in “MA+” is slightly patients with 48 irradiation effects were assessed to ana- higher than in “MA-”. I (MA+) and I (MA-) are signifi- P P lyze the effect of prolonged irradiation time on the tol- cantly affected by the volume loss of the irradiation erance dose of normal liver parenchyma. All irradiation effect between the 6-week and 12-week follow-up exam- effects were induced by at least 2 brachytherapy cathe- inations and consecutive shifts of the mismatch areas ters. The median number of catheters per irradiation towards the high dose regions of the dose plan (p = effect was 4 (Q :3; Q : 6 catheters; range: 2-11 cathe- 0.0014). There is no significant difference between I 25 75 P ters). The average time for complete application of the (MA+) and I (MA-) with respect to hepatocyte dysfunc- radiation dose was 1865 ± 758 seconds (range: 844 - tion and interstitial edema (p = 0.9). 4432 seconds). The volumes of the mismatch areas, “MA+” and “MA- 4 Discussion ”, averaged over the 6-week and 12-week follow-up MRI In this study, we sought to assess two methodical examinations and T1-w and T2-w acquisitions, was 40.6 aspects of HDR-BT: first, limits of catheter positioning ±28.9cm (23.5 ± 10.1%). The differences between the accuracy and, second, effects of prolonged irradiation on mismatch area volumes with regard to 6-week and 12 the tolerance dose of normal liver parenchyma. The week follow-up examinations and T1-w and T2-w MRI mean shift between the center coordinates of the irra- are small, see Table 3. The average dose in “MA+” is diation effect volume and corresponding tolerance dose approximately 12Gy 6 weeks and 14Gy 12 weeks after volume in relation to the direction vector of catheter the intervention. The average dose in “MA-”,is implantation is ≈ - 5 mm in plane, indicating a shift of the irradiation effect in the direction of the catheter entry site. The shift is within the slice thickness of 5 mm of the treatment planning CT but larger than could Table 3 Mean dose, deviation of mean dose from normal liver tissue tolerance dose, and dose protraction in be explained by registration inaccuracy, which is ≈ 3 mismatch areas mm, and inaccuracy due to local liver deformation in 6W T1-w 12W T1-w 6W T2-w 12W T2-w the follow-up images, resulting in an overall registration inaccuracy of ≈ 4-5 mm. n 3527 4027 Determination of catheter positioning accuracy might D(MA+)/Gy 12.0 ± 4.3 14.1 ± 4.4 11.8 ± 5.4 14.0 ± 6.3 be limited by the delineation of the brachytherapy cathe- D(MA-)/Gy 23.2 ± 11.9 28.5 ± 11.0 22.2 ± 11.6 27.7 ± 15.1 ters in the treatment planning CT since applicator geo- ΔD(MA+)/Gy -2.1 ± 2.8 -3.2 ± 1.9 -2.1 ± 4.3 -3.0 ± 3.1 metry is entered manually. Partial volume effects in the ΔD(MA-)/Gy 9.1 ± 7.5 11.2 ± 6.8 8.3 ± 6.6 10.7 ± 8.8 treatment planning datasets could be a potential source I (MA+) 1.67 ± 0.33 1.69 ± 0.26 1.67 ± 0.31 1.70 ± 0.27 of error in the treatment planning procedure, especially I (MA-) 1.45 ± 0.39 1.35 ± 0.37 1.45 ± 0.37 1.39 ± 0.36 for catheters in oblique direction, since correct place- AC 0.17 ± 0.28 0.25 ± 0.27 0.16 ± 0.26 0.23 ± 0.22 ment of the starting point of the catheter is dependent V (MA +/MA-)/cm 42.0 ± 26.7 38.2 ± 31.2 40.8 ± 29.2 43.0 ± 33.1 on conspicuity of the catheter tip. V (MA +/MA-)/% 21.8 ± 11.1 23.9 ± 7.8 23.1 ± 0.8 27.0 ± 9.0 Another limitation is the dislocation of catheters D(MA+), D(MA-): Average dose in mismatch areas; “MA+” for response at doses smaller than the tolerance dose and “MA-” for missing response at doses between acquisition of the planning CT and irradiation. exceeding the tolerance dose. Although the angiographic sheaths containing the cathe- ΔD(MA+), ΔD(MA-): Difference between the average dose in “MA+"and “MA-” ters were secured to the skin by suture, retraction of the and corresponding tolerance dose of the irradiation effect. brachytherapy catheters within the catheter tracks might I (MA+), I (MA-): Catheter contribution index in “MA+” and “MA-”. P P AC : Asymmetry coefficient between the catheter contribution indices in “MA I potentially occur due to patient movement, e.g., when +” and “MA-”. the patient is transferred from the CT unit to the bra- V (MA +/MA-): Volume of the mismatch areas “MA+” and “MA-” in percent and chytherapy unit, and liver movement during respiration. absolute value which is per definition identical for both areas. However, the extent of the shift between an irradiation Errors are given as standard deviation. Lüdemann et al. Radiation Oncology 2011, 6:107 Page 8 of 10 http://www.ro-journal.com/content/6/1/107 effect and the center of the planned dose distribution liver targets. The authors showed that especially liver does not suggest a significant dislocation of the bra- tumors with a CTV exceeding 100 cm were susceptible chytherapy catheters within the catheter tracks. to target deviation exceeding the standard safety mar- The systematic shift between the irradiation effect gins for PTV definition. They suggested to increase the volume and planned dose distribution has to be consid- PTV by adding a larger safety margin to ensure ade- ered in treatment planning when defining the CTV to quatetargetdosedepositioninthese CTVs.Inbra- avoid underdosage of the tumor periphery. In our institu- chytherapy, the applicator moves to a certain extent tion, the CTV comprises the tumor volume visible on together with the target and there is no need to increase contrast-enhanced CT scans plus a 5-mm safety margin. the safety margin for larger tumors. With regard to treatment planning, we conclude that a Catheter dislocation in brachytherapy was mainly slice thickness exceeding 3 mm potentially impairs cathe- investigated in fractionated HDR brachytherapy of the ter positioning accuracy. We furthermore propose that it prostate, which differs from the technique used here in would be beneficial to increase the safety margin of the that a much larger number of catheters are implanted CTV in the direction of the catheter tips from 5 to 10 for more than one day. Imaging techniques (cone beam mm to avoid underdosage and consecutive recurrence at CT and CT) were used to assess catheter dislocation the tumor margin. The amount of mismatch (Table 3) between the first and second fraction, i.e., over 24 between planned dose distribution and irradiation effect hours. Foster et al. found a mean catheter displacement volume is determined by the registration accuracy or pos- of 5. 1 mm, resulting in a significantly (p <0.01) sibly by biological effects but does not allow to assess the decreased mean prostate V (volume receiving 100Gy reproducibility of the CTV. Two studies evaluated the or more) from 93.8% to 76.2% [20]. Five patients had accuracy of target positioning in extracranial stereotactic maximum catheter displacement exceeding 10 mm. radiotherapy (ESRT) using special patient fixation. For Simnor et al. found a mean movement in caudal direc- mobile soft tissue targets, such as liver metastasis, Wulf tion relative to the prostate base between the first and et al. [17] reported mean target deviations of 0.9 ± 4.5 second fraction of 7. 9 mm (range 0-21 mm). Planning mm, 0. 9 ± 3.0 mm, and 3.4 ± 3.2 mm in the craniocau- target volume dose D was reduced without move- 90% dal, anteroposterior, and lateral directions, respectively, ment correction by a mean of 27.8% [21]. Kim et al. when breathing control was applied. The mean 3D devia- found an average (range) magnitude of craniocaudal tion of the targets was 6.1 ± 4.6 mm. catheter displacement of 2.7 mm (- 6.0 to 13.5 mm) For single-fraction therapy, Herfarth et al. [18] using bone markers and 5.4 mm (-3.75 to 18.0 mm) reported mean target set-up deviations between treat- using the center of two gold markers [22]. Catheter dis- ment planning and treatment of 4. 0 ± 2.5 mm, 2.2 ± 1. location in fractionated HDR brachytherapy of the pros- 8 mm, and 2.2 ± 1.7 mm in the craniocaudal, anteropos- tate is in the same range as in the present study but, terior, and lateral directions, respectively. The mean 3D because of the much more complex irradiation geome- deviation of the targets was 5.7 ± 2.5 mm. try, the impact on dose coverage is much larger. The total in-plane deviation of the target location in We assessed the effect of prolonged irradiation times our study was slightly higher, 4-6 ± 2-6 mm. However, on the tolerance dose of normal liver tissue to determine we determined the effective positioning accuracy by its relevance for treatment planning. A catheter contribu- comparing the shift between the irradiation effect in fol- tion index served as a surrogate for prolonged pulsed low-up MRI and planned dose distribution. The authors dose administration in nonoverlapping areas of the irra- quoted above compared treatment planning images with diation effect volume and the corresponding tolerance control CT datasets acquired before treatment [17,18] dose volume. The catheter contribution index was and did not evaluate the treatment effect. slightly but significantly higher in “MA+” than in “MA-”, Based on metric analysis of target mobility and set-up indicating a prolongation of dose application in “MA+” inaccuracy in the CT simulation prior to or during compared to “MA-”. Based on published data, we would treatment, safety margins for defining the planning tar- have expected to find an increased tolerance dose of the get volume (PTV) of about 5 mm in axial and 5 - 10 liver parenchyma in areas irradiated for a longer time, i. mm in craniocaudal direction are commonly added to e., by several catheters [6,7], even if the overall irradiation the CTV in ESRT of lung and liver tumors [19]. In con- time is less than one hour [8]. However, we found a trast to the present study, Wulf et al. evaluated the decreased tolerance dose of the liver parenchyma in areas reproducibility of the CTV of lung and liver tumors where the radiation dose was applied by several catheters within the planning target volume (PTV) over the entire for a prolonged period of time. course of hypofractionated treatment in CT simulation We hypothesize that the effects of prolonged irradia- prior to application of each fraction [19]. The mean tion on the tolerance dose of normal liver tissue might volume ratio of the PTV to the CTV was 2.2 ± 0.6 in have been obscured by other factors. For instance, Lüdemann et al. Radiation Oncology 2011, 6:107 Page 9 of 10 http://www.ro-journal.com/content/6/1/107 biological effects such as reactive inflammatory changes Dose administration was considered highly prolonged if may mimic irradiation effects, or scarring of the liver the index was 2 (meaning that each catheter of the bra- tissue induced by catheter insertion may cause retrac- chytherapy implant contributed < 50% of the irradiation tion of the irradiation effect towards the catheter entry dose in the mismatch area). It was considered fairly pro- site. Furthermore, we propose that inaccuracies in the longed if the value was between 1 and 2 (indicating that positioning of the brachytherapy catheters are more pro- more than 25% of the total irradiation dose in the mis- nounced in areas where several catheters contribute to matchareawas appliedbymorethan1catheter),and the total irradiation dose and that the total applied nonprolonged if the value was ≤ 1 (meaning that 75% or effective dose in “MA+” was higher than would have more of the total irradiation dose in the mismatch area been expected from the treatment plan. Since steep was applied by 1 catheter only). Nevertheless, the tool is dose gradients are an inherent quality of interstitial sufficient to rule out practically relevant effects of pro- HDR-BT, the shift of active dwell positions of one or longed dose administration in HDR-BT in vivo. several catheters towards the tumor periphery would be sufficient to significantly increase the applied dose out- 5 Conclusions side the CTV. As the number of catheters increases, the In conclusion, positioning accuracy of brachytherapy probability of a dose shift due to slight inaccuracy in catheters is sufficiently precise with approx. 5-6 mm. catheter positioning likely increases as well. Accuracy was within the 5-mm slice thickness of the We conclude that the effects of prolonged irradiation treatment planning CT. Thus positioning accuracy is time are of minor importance for interstitial HDR-BT potentially affected by inaccuracy in the delineation of compared to other factors such as positioning accuracy the brachytherapy catheters during treatment planning of brachytherapy catheters and do not have to be taken due to partial volume effects in the planning CT. into account in treatment planning in HDR-BT if the Retraction of the catheters within the catheter tracks total irradiation time does not significantly exceed one during transfer of the patient from the CT unit to the hour. brachytherapy unit might occur; however, this retraction The study has several limitations. Obviously one key is not pronounced. Therefore, CT-guided HDR-BT can issue of the study is the registration accuracy. The vali- be safely performed, even if CT and brachytherapy are dation of registration accuracy was based on corre- not performed in the same unit. Effects of prolonged sponding vessel bifurcations identified in the planning irradiation times on the tolerance dose of normal liver CT and follow-up MR images by an experienced radiol- tissue are negligible compared to positioning accuracy ogist [23,24]. We applied affine registration, allowing 12 of brachytherapy catheters and do not have to be taken degrees of freedom, which compensates for whole organ into account in treatment planning if the total irradia- deformation and yielded an accuracy of ≈ 3mmwith tion time does not significantly exceed one hour. respect to vessel bifurcations within the central parts of the liver, comparable to other studies [25,26]. Affine 6 Competing interests registration has been proven to be precise and robust The authors declare that they have no competing for liver registration [25-27]. However, local liver defor- interests. mation resulting from compression by adjacent organs (such as the stomach), different respiration levels, or the 7 Authors’ contributions implanted catheters in the treatment planning CT data LL, CW: data analysis, manuscript preparation. might not be sufficiently compensated for. To ade- PW, JR: study coordination, study design. quately compensate for these effects a finite element MS, KM: data acquisition. model-based deformable image registration would have SK: data analysis been superior [23,24]. We tried to compensate for the All authors read and approved the final manuscript. limitations of affine registration by restricting the regis- tration to the liver [25]. Using this procedure, we Author details achieved a registration accuracy with a mean deviation 1 Department of Radiation Therapy, Charité Medical Center, Berlin, Germany. of 2.64 mm, which was smaller than that of the nonrigid Department of Radiology and Nuclear Medicine, Otto von Guericke University, Magdeburg, Germany. Department of Biometrics and Medical registration used by Elhawary et al. [28], for which the Informatics, Otto von Guericke University, Magdeburg, Germany. authors reported a mean target registration error of. 4.1 th mm and a mean 95 -percentile Hausdorff distance of 3. Received: 16 May 2011 Accepted: 5 September 2011 Published: 5 September 2011 3 mm. Second, the catheter contribution index has to be con- References sidered a rough simplification, merely providing a first 1. Ricke J, Mohnike K, Pech M, Seidensticker M, Rühl R, Wieners G, Gaffke G, estimate of the effect of prolonged dose administration. Kropf S, Felix R, Wust P: Local response and impact on survival after local Lüdemann et al. Radiation Oncology 2011, 6:107 Page 10 of 10 http://www.ro-journal.com/content/6/1/107 ablation of liver metastases from colorectal carcinoma by computed 21. Simnor T, Li S, Lowe G, Ostler P, Bryant L, Chapman C, Inchley D, Hoskin PJ: tomography-guided high-dose-rate brachytherapy. Int J Radiat Oncol Biol Justification for inter-fraction correction of catheter movement in Phys 2010, 78(2):479-485. fractionated high dose-rate brachytherapy treatment of prostate cancer. 2. Mohnike K, Wieners G, Schwartz F, Seidensticker M, Pech M, Ruehl R, Radiother Oncol 2009, 93(2):253-258. Wust P, Lopez-Hänninen E, Gademann G, Peters N, Berg T, Malfertheiner P, 22. Kim Y, Hsu IC, Pouliot J: Measurement of craniocaudal catheter Ricke J: Computed tomography-guided high-dose-rate brachytherapy in displacement between fractions in computed tomography-based high hepatocellular carcinoma: safety, efficacy, and effect on survival. Int J dose rate brachytherapy of prostate cancer. J Appl Clin Med Phys 2007, Radiat Oncol Biol Phys 2010, 78:172-179. 8(4):2415-2415. 3. Wieners G, Mohnike K, Peters N, Bischoff J, Kleine-Tebbe A, Seidensticker R, 23. Brock KK, Dawson LA, Sharpe MB, Moseley DJ, Jaffray DA: Feasibility of a Seidensticker M, Gademann G, Wust P, Pech M, Ricke J: Treatment of novel deformable image registration technique to facilitate classification, hepatic metastases of breast cancer with CT-guided interstitial targeting, and monitoring of tumor and normal tissue. Int J Radiat Oncol brachytherapy - A phase II-study. Radiother Oncol 2011. Biol Phys 2006, 64(4):1245-1254. 4. Rühl R, Lüdemann L, Czarnecka A, Streitparth F, Seidensticker M, Mohnike K, 24. Voroney JP, Brock KK, Eccles C, Haider M, Dawson LA: Prospective Pech M, Wust P, Ricke J: Radiobiological restrictions and tolerance doses comparison of computed tomography and magnetic resonance imaging of repeated single-fraction hdr-irradiation of intersecting small liver for liver cancer delineation using deformable image registration. Int J volumes for recurrent hepatic metastases. Radiat Oncol 2010, 5:44-44. Radiat Oncol Biol Phys 2006, 66(3):780-791. 5. Seidensticker M, Wust P, Rühl R, Mohnike K, Pech M, Wieners G, 25. van Dalen JA, Vogel W, Huisman HJ, Oyen WJ, Jager GJ, Karssemeijer N: Gademann G, Ricke J: Safety margin in irradiation of colorectal liver Accuracy of rigid CT-FDG-PET image registration of the liver. Phys Med metastases: assessment of the control dose of micrometastases. Radiat Biol 2004, 49(23):5393-5405. Oncol 2010, 5:24-24. 26. Carrillo A, Duerk JL, Lewin JS, Wilson DL: Semiautomatic 3-D image 6. Hall EJ: Weiss lecture. The dose-rate factor in radiation biology. Int J registration as applied to interventional MRI liver cancer treatment. IEEE Radiat Biol 1991, 59(3):595-610. Trans Med Imaging 2000, 19(3):175-185. 7. Fowler JF, Van Limbergen EF: Biological effect of pulsed dose rate 27. Christina Lee WC, Tublin ME, Chapman BE: Registration of MR and CT brachytherapy with stepping sources if short half-times of repair are images of the liver: comparison of voxel similarity and surface based present in tissues. Int J Radiat Oncol Biol Phys 1997, 37(4):877-883. registration algorithms. Comput Methods Programs Biomed 2005, 8. Pop LA, Millar WT, van der Plas M, van der Kogel AJ: Radiation tolerance of 78(2):101-114. rat spinal cord to pulsed dose rate (PDR-) brachytherapy: the impact of 28. Elhawary H, Oguro S, Tuncali K, Morrison PR, Tatli S, Shyn PB, Silverman SG, differences in temporal dose distribution. Radiother Oncol 2000, Hata N: Multimodality non-rigid image registration for planning, 55(3):301-315. targeting and monitoring during CT-guided percutaneous liver tumor 9. Wybranski C, Seidensticker M, Mohnike K, Kropf S, Wust P, Ricke J, cryoablation. Acad Radiol 2010, 17(11):1334-1344. Lüdemann L: In vivo assessment of dose volume and dose gradient doi:10.1186/1748-717X-6-107 effects on the tolerance dose of small liver volumes after single-fraction Cite this article as: Lüdemann et al.: In vivo assessment of catheter high-dose-rate 192Ir irradiation. Radiat Res 2009, 172(5):598-606. positioning accuracy and prolonged irradiation time on liver tolerance 10. Ricke J, Seidensticker M, Lüdemann L, Pech M, Wieners G, Hengst S, dose after single-fraction Ir high-dose-rate brachytherapy. Radiation Mohnike K, Cho CH, Hanninen EL, Al-Abadi H, Felix R, Wust P: In vivo Oncology 2011 6:107. assessment of the tolerance dose of small liver volumes after single- fraction HDR irradiation. Int J Radiat Oncol Biol Phys 2005, 62(3):776-84. 11. Clement O, Siauve N, Cuenod CA, Vuillemin-Bodaghi V, Leconte I, Frija G: Mechanisms of action of liver contrast agents: impact for clinical use. J Comput Assist Tomogr 1999, 23(Suppl 1):S45-52. 12. Kirchin MA, Pirovano GP, Spinazzi A: Gadobenate dimeglumine (Gd- BOPTA). An overview. Invest Radiol 1998, 33(11):798-809. 13. de Haen C, Ferla RL, Maggioni F: Gadobenate dimeglumine 0.5 M solution for injection (MultiHance) as contrast agent for magnetic resonance imaging of the liver: mechanistic studies in animals. J Comput Assist Tomogr 1999, 23(Suppl 1):S169-79. 14. Rohlfing T, West JB, Beier J, Liebig T, Taschner CA, Thomale UW: Registration of functional and anatomical MRI: accuracy assessment and application in navigated neurosurgery. Comput Aided Surg 2000, 5(6):414-25. 15. Burton P, Gurrin L, Sly P: Extending the simple linear regression model to account for correlated responses: an introduction to generalized estimating equations and multi-level mixed modelling. Stat Med 1998, 17(11):1261-91. 16. Zeger SL, Liang KY: Longitudinal data analysis for discrete and continuous outcomes. Biometrics 1986, 42:121-30. 17. Wulf J, Hadinger U, Oppitz U, Olshausen B, Flentje M: Stereotactic radiotherapy of extracranial targets: CT-simulation and accuracy of treatment in the stereotactic body frame. Radiother Oncol 2000, Submit your next manuscript to BioMed Central 57(2):225-36. and take full advantage of: 18. Herfarth KK, Debus J, Lohr F, Bahner ML, Fritz P, Hoss A, Schlegel W, Wannenmacher MF: Extracranial stereotactic radiation therapy: set-up • Convenient online submission accuracy of patients treated for liver metastases. Int J Radiat Oncol Biol Phys 2000, 46(2):329-35. • Thorough peer review 19. Wulf J, Hadinger U, Oppitz U, Thiele W, Flentje M: Impact of target • No space constraints or color figure charges reproducibility on tumor dose in stereotactic radiotherapy of targets in • Immediate publication on acceptance the lung and liver. Radiother Oncol 2003, 66(2):141-50. 20. Foster W, Cunha JA, Hsu IC, Weinberg V, Krishnamurthy D, Pouliot J: • Inclusion in PubMed, CAS, Scopus and Google Scholar Dosimetric impact of interfraction catheter movement in high-dose rate • Research which is freely available for redistribution prostate brachytherapy. Int J Radiat Oncol Biol Phys 2011, 80:85-90. Submit your manuscript at www.biomedcentral.com/submit

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Radiation OncologySpringer Journals

Published: Sep 5, 2011

References