Impact of target reproducibility on tumor dose in stereotactic radiotherapy of targets in the lung and liver

Radiotherapy and Oncology 66 (2003) 141–150 www.elsevier.com/locate/radonline

Impact of target reproducibility on tumor dose in stereotactic radiotherapy of targets in the lung and liver Jo¨rn Wulf*, Ulrich Ha¨dinger, Ulrich Oppitz, Wibke Thiele, Michael Flentje Department of Radiotherapy, University of Wu¨rzburg, Josef-Schneider-Strasse 11, D-97080 Wu¨rzburg, Germany Received 27 May 2002; received in revised form 4 October 2002; accepted 25 October 2002

Abstract Background and purpose: Previous analyses of target reproducibility in extracranial stereotactic radiotherapy have revealed standard security margins for planning target volume (PTV) definition of 5 mm in axial and 5–10 mm in longitudinal direction. In this study the reproducibility of the clinical target volume (CTV) of lung and liver tumors within the PTV over the complete course of hypofractionated treatment is evaluated. The impact of target mobility on dose to the CTV is assessed by dose–volume histograms (DVH). Materials and methods: Twenty-two pulmonary and 21 hepatic targets were treated with three stereotactic fractions of 10 Gy to the PTVenclosing 100%-isodose with normalization to 150% at the isocenter. A conformal dose distribution was related to the PTV, which was defined by margins of 5–10 mm added to the CTV. Prior to each fraction a computed tomography (CT)-simulation over the complete target volume was performed resulting in a total of 60 CT-simulations for lung and 58 CT-simulations for hepatic targets. The CTV from each CT-simulation was segmented and matched with the CT-study used for treatment planning. A DVH of the simulated CTV was calculated for each fraction. The target coverage (TC) of dose to the simulated CTV was defined as the proportion of the CTV receiving at least the reference dose (100%). Results: A decrease of TC to ,95% was found in 3/60 simulations (5%) of pulmonary and 7/58 simulations (12%) of hepatic targets. In two of 22 pulmonary targets (9%) and in four of 21 hepatic targets (19%) a TC of ,95% occurred in at least one fraction. At risk for a decreased TC ,95% were pulmonary targets with increased breathing mobility and hepatic targets with a CTV exceeding 100 cm 3. Conclusions: Target reproducibility was precise within the reference isodose in 91% of lung and 81% of liver tumors with a TC of the complete CTV $95% at each fraction of treatment. Pulmonary targets with increased breathing mobility and liver tumors .100 cm 3 are at risk for target deviation exceeding the standard security margins for PTV-definition at least for one fraction and require individual evaluation of sufficient margins. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Stereotactic radiotherapy; Stereotactic body frame; Conformal radiotherapy; Computed tomography simulation; Treatment accuracy; Dose–volume histogram

1. Introduction Stereotactic and conformal radiotherapy are performed to deliver dose as precisely as possible to a circumscribed target. Set-up inaccuracy and target mobility are reduced to a minimum to achieve a therapeutic benefit and to allow for dose escalation to increase tumor control probability without increase of normal tissue complication probability. But even with the use of patient immobilization devices as a stereotactic body frame (SBF) or efforts to decrease tumor mobility as breathing control systems, a certain amount of target deviation will remain during fractionated treatment, which has to be addressed by the planning target volume (PTV). In extracranial stereotactic radiotherapy (ESRT) of lung and liver tumors most authors use security margins for PTVdefinition of about 5–6 mm in axial and 5–10 mm in long-

itudinal direction [1–8,12–14,17,18], in some cases up to 10–20 mm [12–14], which are added to the clinical target volume (CTV). The security margins are based on metric analysis of target mobility and set-up inaccuracy due to computed tomography (CT)-simulation prior to treatment [1–7,17,18] or during treatment [8,12–14]. While this procedure seems to be adequate to define the PTV in general, it does not necessarily exclude an impact of target reproducibility on target dose. In ESRT a conformal dose distribution is planned to enclose the PTV with a certain isodose, e.g. 65%-isodose [1,2,5–7,17,18] or 80%-isodose [3,4]. A sufficient PTV should allow target mobility within the defined security margins without significant decrease of dose to the CTV. Therefore in the present study a new approach for evaluation of target reproducibility within the defined security margins was chosen: target reproducibility during hypofractionated treatment was measured as the impact on dose

* Corresponding author. 0167-8140/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0 167-8140(02)00 372-9

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to the CTV by analyzing dose–volume histograms (DVH) instead of a metric evaluation of security margins. Additionally several factors of potential influence on dose coverage of the CTV as breathing mobility, target volume or the quality of the initial dose plan are evaluated.

2. Materials and methods ESRT is performed at our institution since 1997 and is based on the method first described by Blomgren and Lax from Karolinska Hospital, Stockholm, Sweden [1,2,5–7]. Circumscribed tumors in the lung and liver are irradiated in a hypofractionated treatment approach with three fractions of 10 Gy, prescribed to the PTV-enclosing 65%isodose. According to calculations of Lax [5] this inhomogeneous dose concept results in a 50% increased dose to the target without increase of dose to normal tissue outside the reference isodose, which is clinically intended to induce tumor necrosis and local control. In the present study this inhomogeneous dose concept was followed by dose prescription to the PTV-enclosing 100%-isodose (10 Gy) with normalization to 150% at the isocenter (15 Gy). This corresponds to the fraction dose described by Blomgren and Lax, who prescribed 10 Gy to the PTV-enclosing 65%isodose with normalization to 100% at the isocenter (15 Gy). The difference in describing (not prescribing) of dose compared to Blomgren and Lax was chosen to address International Commission on Radiological Units (ICRU)standards, where the minimum target dose should be at least 95%. For patient immobilization and stereotactic setup, a SBF was used (ELEKTA Oncology Systems). In the SBF the patient is immobilized by the use of a vacuum pillow. Repeated patient positioning is supported by two laser systems attached to the SBF, which have to be aligned to small tattoos at the patient’s trunk and legs defined at first positioning in the SBF. Breathing mobility of targets in the lung and liver can be reduced mechanically by the use of a template (‘diaphragm control’, DC), which is attached to the SBF and pressed on the patient’s epigastrium to increase abdominal pressure with the effect of decreased diaphragmatic motion. Technical details of the SBF, the procedure of patient positioning and repositioning, results of treatment accuracy related to different types of targets and treatment results from irradiation of lung and liver targets at our institution have been described previously [17,18]. The SBF represents an external reference system to locate the isocenter and target position by stereotactic coordinates instead of skin markers or bony reference structures. The stereotactic coordinates are calculated using fiducials visible in each CT-slice, which correspond to a system of horizontal and oblique copper wires integrated in the body frames sidewalls. Because these fiducials are reproducible and objective, they can also be used as matching points independent from anatomical landmarks.

2.1. Patient and target characteristics Twenty-one consecutive patients with 22 targets in the lung and 17 patients with 21 targets in the liver were evaluated in the study. Pulmonary targets were primary lung cancer ðn ¼ 11Þ, local recurrences of lung cancer ðn ¼ 3Þ and pulmonary metastases ðn ¼ 8Þ of bronchial carcinoma ðn ¼ 4Þ, colorectal cancer ðn ¼ 2Þ, malignant thymoma ðn ¼ 1Þ and malignant neurinoma ðn ¼ 1Þ. Twenty of 21 hepatic targets were metastases of colorectal cancer ðn ¼ 9Þ, breast cancer ðn ¼ 6Þ, ovarian cancer ðn ¼ 4Þ and pancreas cancer ðn ¼ 1Þ. One patient was treated for a surgically inoperable cholangiocarcinoma. One patient with two pulmonary and one patient with two hepatic metastases were treated simultaneously for both targets, three patients with hepatic metastases were sequentially irradiated for a second manifestation, which occurred during follow-up. The breathing control was used if the target mobility (measured by dynamic CT-scans at the same table position) was larger than 5 mm in any direction due to diaphragmatic motions. Patient and target characteristics are shown in Table 1. 2.2. Treatment planning and CT-simulation The CT-scan for treatment planning was performed in 5 mm slices with or without oral and/or intravenous (i.v.) contrast media. While for hepatic targets i.v. contrast was Table 1 Patient and treatment characteristics for targets in the lung (21 patients with 22 targets) and liver (17 patients with 21 targets)

No. of targets Gender Male Female Age (years) Range Median/mean Karnofsky-Index prior to treatment Range Median/mean Treatment intention Primary stereotactic radiotherapy Stereotactic boost Re-irradiation after previous radiotherapy Treatment volume (cm 3) CTV (min/max) CTV (median/mean/SD) PTV (min/max) PTV (median/mean/SD) Breathing control used (number) Location of lung targets Central in the lung Close to mediastinum Close to thoracic wall Fractionation 3 £ 10 Gy/100%-isodose (150%/isocenter)

Lung

Liver

n ¼ 22

n ¼ 21

18 4

6 15

48–77 65/66

15–78 57/56

70–100 90/86

80–100 90/93

18 1 3

21 0 0

5/277 64/78/66 17/343 127/144/90 8 (36%)

9/516 64/95/116 42/772 130/174/165 21 (100%)

13 4 5 22

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used generally in the arterial and portal-venous phase to receive an optimal visibility of the target, for pulmonary targets i.v. contrast was only necessary, if the target had to be distinguished from structures in the mediastinum or thoracic wall. Breathing mobility of the target was evaluated by repeated slices (dynamic scans) at the same longitudinal SBF-coordinate ( ¼ without couch movement) with an interval of 2 s. The breathing mobility of the target in axial direction was measured by using a grid of 10 mm, which was projected digitally over the target contour in each of the dynamic CT-slices. The longitudinal mobility was evaluated by repeating the procedure cranial and caudal to the first position. If the patient did not tolerate the increased abdominal pressure, the maximum breathing mobility of the target was measured and taken into account for PTV-definition. Three-dimensional (3D)-treatment planning was performed by Helax-TMSw versions 4.01A, 4.01B and 5.1 (MDS Nordion). The target was segmented as CTV including the macroscopic tumor with a margin of 2–3 mm. Targets in the lung were segmented in the lung window (1600, 2400 HU), tumors in the liver depending on the largest diameter of hypodensity and peripheral contrast enhancement in the arterial and/or portal-venous phase. For PTVdefinition, security margins of 5 mm in anterior–posterior and lateral and 5–10 mm in longitudinal direction were added to the CTV using an automatic tool of TMS. This tool not only added the longitudinal margin cranial and caudal to the CTV, but also calculated the longitudinal margin in each slice of the volume to ensure a sufficient security margin continuously over the complete CTV. A conformal dose distribution was achieved by five to nine static fields and/or rotational fields using irregular shapes achieved by customized blocks or multileaf-collimator (10 mm leaf-width). Prior to each fraction CT-simulation was performed covering the complete target volume. The anatomic target structure of the planned isocenter slice was reproduced at CT-simulation. The difference between the planned longitudinal stereotactic coordinate to the anatomically corresponding slice at CT-simulation was measured as longitudinal correction. The subsequent CT-slices covering the CTV included the longitudinal correction, but no correction of the target position in lateral or anterior–posterior direction for the evaluation. This approach was chosen, because results of a former analysis revealed that CT-simulation should be performed prior to each fraction for mobile targets as tumors in the lung and liver [17]. Therefore performing a study without longitudinal correction would not meet practical clinical conditions. Lateral and anterior corrections were not performed because axial correction at the isocenter level might not necessarily be representative for the complete target. It is the purpose of the present study to evaluate target reproducibility under these conditions. In each CT-simulation study the CTV was segmented de novo using Helax-TMSw. Segmentation of the CTV and PTV for treatment planning and for CT-simulation was

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performed by only one person (J.W.) to avoid interindividual variability. Intraindividual variability was reduced by keeping the same strategy for target definition for simulation as for treatment planning using anatomical landmarks as hepatic or portal veins, organ surface, ligaments, pulmonary vessels or bronchi. The reproducibility of CTV-segmentation from CT-simulations 1–3 (CTV-sim1–3) was evaluated by comparing the size of the different volumes. The segmented CTV from CT-simulation was projected into the corresponding CT-slices of the treatment planning study using a digital matching-tool (Helax-TMSw). The matching procedure was simple and reliable because of the use of the fiducials in the SBF side walls. After the matching procedure a DVH was calculated for the simulated CTV. The procedure of matching, segmentation of the CTV and a schematic model of the simulated CTV are shown in Fig. 1. 2.3. Evaluation of the PTV and reference isodose to cover CTV-mobility A total of 60 CT-simulations for 22 pulmonary targets and 58 CT-simulations for 21 hepatic targets were evaluated resulting in an average of 2.7 and 2.8 of a maximum of three possible CT-simulations for each type of target. In 77% (17/ 22 targets) of lung targets and 76% (16/21 targets) of liver targets the complete treatment course was covered by three CT-simulations. Four patients in each group had two, one patient in each group had only one CT-simulation (in these patients CT-simulation could not be performed due to technical problems or due to the digital data being lost). The impact of CTV reproducibility during hypofractionated treatment was evaluated by comparison of DVHs for the planned and simulated CTV (CTV-plan, CTV-sim1–3), which were calculated according to the projection of the CTVs from CT-simulations into the initial dose plan. The impact of dose to the CTV was measured by evaluation of the different DVHs to calculate the target coverage (TC), which is defined as proportion of the CTV within the reference isodose. The TC is 100%, if the TC is complete. A TC of 95% indicates that only 95% of the CTV receives at least the reference dose of 100% (10 Gy). This approach allows interpretation of the impact of target mobility in a dose– volume relation compared to the minimum dose alone, which has no relation to a specific volume. A complete TC of 100% will be achieved easily, if the reference isodose exceeds the target volume by a large amount. Therefore a parameter describing the conformity of the dose distribution relative to the PTV is necessary. According to Van’t Riet et al. [15] the conformity of dose distribution can be described by a conformity number (CN), which is defined as the ratio of the proportion of the PTV within the reference (100%) isodose (PTVref) to the complete PTV, multiplied by the ratio of the (PTVref) to the reference volume (volume of the 100%-isodose, Vref): CN ¼ ðPTVref =PTVÞ £ ðPTVref =Vref Þ:

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The first factor (PTVref/PTV) describes the TC of the PTV, the second factor (PTVref/Vref) describes the dose load to normal tissue (volume outside the PTV). The CN decreases with decreased TC and to the amount the refer-

ence volume exceeds the PTV within the reference volume. An example of a conformal dose distribution relative to the PTV is shown in Fig. 2. Several factors may influence the TC of the CTV. These

Fig. 1. (a) The CT-studies for treatment planning and simulation of the CTV prior to irradiation are matched using fiducials in the SBF sidewalls as external reference system. (b) The CTV-contour is segmented slice by slice in the CT-study for simulation (right), digitally transferred into the CT-study for treatment planning (left), where the complete CTV sim is defined as new VOI. (c) A schematic view of the three simulated CTVs relative to the CTV of the planning study, the PTV and the reference isodose is shown. (d) While CTV deviation within the PTV and the reference isodose remains without effect on target dose (CTV sim 1–2), insufficient CTV reproducibility with parts of the CTV beyond the reference isodose results in decreased target dose (CTV sim 3). The impact of target reproducibility on target dose is calculated by DVH for the CTV prior to each fraction of irradiation.

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Fig. 2. Axial, coronal and sagittal dose distribution for extracranial stereotactic irradiation of a lung metastasis in the right lower lobe (CTV-plan 21 cm 3, PTV 59 cm 3). The planned dose in the CTV was 117% at minimum and 155% at maximum (median 147%, mean 145%, SD 8%) and in the PTV was 90% at minimum and 155% at maximum (median 135%, mean 132%, SD 15%). The PTV (thin white line) is optimal enclosed by the 100%-reference isodose (arrows), resulting in a CN of 0.83. TC of the planned and the three simulated CTVs was 100% and of the PTV 98%. The dose distribution was achieved by three individually shaped rotational fields over 708 each and two static beams to increase the gradient at the trachea.

factors are related to the target itself as the volume of the CTV and the PTV. Other factors are related to the estimated target mobility as the use of the DC, the longitudinal security margin of 5 mm (LSM 5) versus 10 mm (LSM 10) and the ratio of the PTV to the CTV, which increases with larger security margins, e.g. due to the intolerance of the DC or target mobility .5 mm despite the use of the DC. A third group of factors is related to the treatment plan as the TC of the planned CTV and PTV, which occasionally has been accepted despite a TC ,100%, e.g. because an organ at risk had to be spared. The correlation of these factors to the TC for the simulated CTV was statistically evaluated by the Pearson-Product-Moment analysis [11] using a level for statistical significance of 5%.

3. Results 3.1. Longitudinal correction Longitudinal correction prior to the matching procedure ranged from 0 to 10 mm, median 2.5 mm, mean 2.8 mm (standard deviation (SD) 2.6 mm) in pulmonary targets and from 0 to 10 mm, median 2 mm, mean 3.6 mm (SD 3.9 mm) in hepatic targets. In none of the lung targets but in three of 58 simulations for liver targets (5%) the longitudinal correction exceeded the LSM. These three corrections of 10 mm each occurred in three different targets with a LSM of 5 mm. A

longitudinal correction ranging within the LSM was necessary in 49/60 (82%) simulations of pulmonary targets and in 41/58 (71%) of hepatic targets. A LSM equal to the longitudinal correction was found in 11/60 (18%) of lung and in 14/58 (24%) of hepatic targets. While the majority of these cases 10/11 in lung tumors occurred in targets with a LSM of 5 mm, in hepatic tumors 5/14 cases occurred in a LSM of 5 mm and 9/14 cases in a LSM of 10 mm. 3.2. Reproducibility of the CTV Median and mean differences of the intraobserver reproducibility of CTV segmentation from different CT-studies compared to the initial CTV from treatment planning were 3 cm 3 for lung and 2 cm 3 for liver targets (max/min 30/ 213 cm 3 lung and 29/233 cm 3 liver) with a SD of 7 cm 3 for pulmonary and 8 cm 3 for hepatic targets. Compared to a median CTV of 64 cm 3 the median and mean deviations are ,5%. Major differences were observed in single cases (numbers 4, 15 and 18 of pulmonary targets and numbers 12, 19 and 20 of hepatic targets) indicating that individual factors in certain patients like increased breathing mobility might be responsible. 3.3. CN of the dose distribution relative to the PTV The CN of the dose distribution ranged from 0.58 to 0.85 (median 0.74, mean 0.73, SD 0.09) in pulmonary targets and

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,100% ranged between 54 and 93% (median 80%, mean 78%, SD 12%) of the prescribed fraction dose for targets in the lung and between 42 and 94% (median 74%, mean 72%, SD 18%) for targets in the liver. These minimum doses are not related to a specific volume and might be of questionable significance. 3.5. Analysis of factors influencing TC of the simulated CTV 3.5.1. Target related factors The CTV of pulmonary targets ranged from 5 to 277 cm 3 (median 64 cm 3, mean 78 cm 3, SD 67 cm 3), the CTV of hepatic targets from 9 to 516 cm 3 (median 64 cm 3, mean 95 cm 3, SD 116 cm 3). The PTV of pulmonary targets ranged from 17 to 343 cm 3 (median 127 cm 3, mean 144 cm 3, SD 90 cm 3) and from 42 to 772 cm 3 (median 130 cm 3, mean 174 cm 3, SD 165 cm 3) in hepatic targets.

Fig. 3. Comparison of the TC of the CTV for treatment planning and the CTV evaluated by CT-simulation prior to the first, second and third irradiation for targets in the lung (a) and the liver (b). While in pulmonary targets a decreased TC of ,95% due to target deviation was observed in three of 60 simulations (5%) without correlation to volume, in hepatic targets six of the seven cases out of 58 simulations with a TC ,95% (12%) occurred in targets with a CTV .100 cm 3. The targets are shown in order of increasing volume of the planned CTV.

from 0.45 to 0.91 (median 0.79, mean 0.77, SD 0.1) in hepatic targets. 3.4. TC of the CTV at treatment planning and CT-simulation The TC of the CTV in the original treatment plan ranged from 99 to 100% (median 100%, mean 99%, SD 0.3%) for lung targets and from 95 to 100% (median 100%, mean 99%, SD 1%) for liver targets. The projection of the CTVs from CT-simulation into the treatment plan resulted in a TC ranging from 86 to 100% (median 100%, mean 99%, SD 3%) for pulmonary targets and from 85 to 100% (median 100%, mean 98%, SD 3%) for hepatic targets. A TC of ,95% was found in two patients in 3/60 simulations (5%) for lung targets and in four patients in 7/58 simulations (12%) for hepatic targets. Related to treatment fractions in 95% of fractions for pulmonary and 88% of fraction for hepatic targets, dose to the CTV was not impaired. Related to targets, a TC ,95% occurred in 9% (2/22 targets) of targets in the lung and in 19% (4/21 targets) of targets in the liver at least in one fraction. The TC for pulmonary and hepatic targets in relation to the CTV are shown in Fig. 3a, b. The minimum dose to the CTVs with a TC

3.5.2. Mobility related factors The volume ratio of the PTV to the planned CTV ranged from 1.7 to 3.5 in pulmonary and from 1.4 to 3.3 in hepatic targets. Median and mean were 2.1 and 2.3 (SD 0.5) in lung and 2.2 and 2.2 (SD 0.6) in liver targets. The security margin for PTV-definition in longitudinal direction was decreased from 10 mm (LSM 10) to 5 mm (LSM 5) in 11/22 lung targets (50%) and in 10/21 liver targets (48%). The DC to reduce breathing mobility was always used for hepatic targets and for eight of 22 pulmonary targets (36%), which were located in the lower lobes and were not attached to the mediastinum or thoracic wall. 3.5.3. Treatment plan related factors The TC of the PTV ranged from 90 to 100% (median and mean 96%, SD 2%) for lung targets and 83 to 100% (median 97%, mean 95%, SD 5%) for liver targets. The spatial relationship of the target to an organ at risk or the attempt to save functional organ tissue may lead to the acceptance of a treatment plan with a per se decreased TC for the PTV of ,95%, which occurred in 6/22 (27%) lung and in 7/21 (33%) liver targets. 3.5.4. Correlation to TC of the CTV The factors with significant correlation (5% level at Pearson-Product-Moment analysis) to a decreased TC of the simulated CTV were different for targets in the lung and liver: the TC of tumors in the lung correlated negatively with parameters indicating increased target mobility as the use of the DC ðr ¼ 20:49Þ, a large PTV/CTV-ratio ðr ¼ 20:39Þ (Fig. 4a) and an increased LSM of 10 mm ðr ¼ 20:29Þ. The other factors as the target volume itself (CTV r ¼ 0:13 and PTV r ¼ 0:12), the TC of the planned CTV ðr ¼ 0:02Þ and PTV ðr ¼ 0:14Þ or the CN ðr ¼ 20:17Þ showed no correlation to the TC of the simulated CTV. The TC of hepatic targets correlated negatively with an increased volume of the CTV ðr ¼ 20:35Þ and the PTV ðr ¼ 20:34Þ and positively to an initially sufficient treat-

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Fig. 4. (a) The TC of the simulated CTV in pulmonary targets correlated negatively with factors associated with increased target mobility. The strongest correlation was evaluated for the use of the DC (r ¼ 20:49; right) and a high PTV/CTV-ratio (r ¼ 20:39; left). Using the DC as increasing the PTV relative to the CTV indicate the attempt to address for increased target mobility. The regression curves are shown with its 95% confidence interval. (The small number of visible compared to the total number of 60 plot points is due to projection of several points at the same position, e.g. TC ¼ 1 without use of the DC n ¼ 36). (b) In hepatic targets the TC of the simulated CTV correlated positively with an initially sufficient treatment plan indicated by a high TC of the planned CTV (top left; r ¼ 0:40) and the PTV (top right; r ¼ 0:54) and for sufficient security margins indicated by a high PTV/CTV-ratio (bottom; r ¼ 0:41). These factors again were negatively correlated to increased volume of the CTV and PTV (r ¼ 20:35 and r ¼ 20:34; not shown). The regression curves are shown with its 95% confidence interval. (The small number of visible compared to the total number of 58 plot points is due to projection of several points at the same position, e.g. TC ¼ 1 in the simulated and planned CTV n ¼ 23).

ment plan indicated by a large PTV/CTV-ratio ðr ¼ 0:41Þ, a high TC of the planned CTV ðr ¼ 0:40Þ and PTV ðr ¼ 0:54Þ (Fig. 4b). The LSM ðr ¼ 0:18Þ and the CN ðr ¼ 20:13Þ showed no significant correlation. In liver targets a large PTV/CTV-ratio represented adequate security margins and not targets at risk for deviation. Contrary to the results in pulmonary tumors a small PTV/CTV-ratio in the liver indicated adjacent critical structures, which led to decreased security margins in certain regions of the PTV.

4. Discussion The purpose of the present study was to evaluate target reproducibility in hypofractionated ESRT over the complete target volume and the complete course of treatment and to describe the impact of target deviation on dose to the CTV. The analysis is aimed not only to verify the previously evaluated security margins for PTV-definition, but also to assess its reliability to achieve the most important goal in

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ESRT: the dose to the CTV. Additionally factors were evaluated, which might be associated with decreased target dose. This should provide data to avoid underdosage in tumors characterized by these factors, e.g. by eventually increased security margins or improved efforts to reduce breathing mobility. Prior to evaluation of these factors the reproducibility of segmentation of the simulated CTV without use of contrast media had to be addressed. Because it seemed unreasonable to apply contrast media to the patient for only scientific reasons the intraobserver reliability was evaluated by comparison of the volume of planned CTV to the simulated CTV. The target reproducibility revealed median and mean differences of 2–3 cm 3 (SD 7–8 cm 3), which was acceptable compared to the median and mean CTV volumes (64/ 78 cm 3 lung and 64/95 cm 3 liver). Nevertheless in single cases the differences of CTV-definition were remarkable up to 130 cm 3 and 233 cm 3. These differences were mainly due to individual parameters as increased or decreased breathing mobility with the consequence that tumor was visible in more or fewer CT-slices compared to the planning situation with the consequence of a substantially changed volume. Choosing the approach to measure the influence of target mobility and reproducibility in hypofractionated stereotactic treatment in terms of dose to the CTV, two conditions are essential: the security margins for PTV-definition and the conformity of dose distribution. Using large security margins or a reference isodose exceeding the PTV to a large amount will reduce the risk for underdosage to the CTV significantly but also increase unnecessarily high dose loads to normal tissue. The security margins for PTV-definition in the present study are in accordance with most other authors, who use 5 mm in axial and 5–10 mm in longitudinal direction [1–8,12–14,17,18]. Basis for these margins were measurements of Lax and Blomgren, who found a mean reproducibility of the target in the SBF of 3.1–3.7 mm in transverse and 5.7 mm in longitudinal direction [1,2,6,7]. Other authors published similar results [3,13,14,17]. For targets in the liver and lower lung these margins require reduced breathing mobility. For this purpose most authors increase the abdominal pressure by the use of a mechanical breathing control device [1– 7,17,18] or more advanced techniques such as breathing triggered irradiation [16]. On conformity of dose distribution in ESRT no data is published yet. The CN described by Van’t Riet et al. [13] relates the TC of the PTV (PTVref/PTV) to conformity of the dose distribution (PTVref/Vref). According to an example by Van’t Riet a CN of 0.65 for a four-field technique with irregular beam shapes in teletherapy of the prostate and of 0.72 for prostate brachytherapy with seeds can be achieved. Compared to these results the CN in the present study are remarkably high and indicate that high TC of the CTV is not due to a generous reference isodose: the median and mean of CN was 0.74 and 0.73 (SD 0.09) in pulmonary targets and

0.79 and 0.77 (SD 0.1) in hepatic targets. Only in single cases the CN was considerably lower with a minimal CN of 0.58 in lung and 0.45 in hepatic targets. This was mainly due to the attempt to achieve a very steep dose gradient e.g. at organs at risk with the consequence of decreased conformity in the vicinity of less sensitive structures. The high CN in the present study is not only achieved by an elaborated field arrangement, but also due to the spherical or ellipsoid target shape in the majority of cases. Another factor is the policy in our clinic to position the steep dose gradient at the PTV border, which resulted in acceptance of treatment plans with an a priori slightly decreased TC of the PTV ,100%: accordingly the TC of the PTV ranged from 90 to 100% (median and mean 96%, SD 2%) for lung targets and from 83 to 100% (median 97%, mean 95%, SD 5%) for liver targets. In summary, both the security margins for PTV-definition and the achieved conformity of dose distribution allow the evaluation of target reproducibility by analysis of the dose to the CTV. The analysis revealed that only in three of 60 CT-simulations of lung targets (5%) and seven of 58 CTsimulations for liver targets (12%) the TC decreased to ,95% indicating that in 95% of pulmonary and 88% of hepatic tumors target reproducibility was precise enough to ensure dose coverage of the CTV $95% in any fraction. Nevertheless decreased TC of the CTV ,95% did not occur randomly but was cumulated in certain targets: the three cases of TC ,95% occurred in two of 22 pulmonary targets (9%) and the seven cases of TC ,95% occurred in four of 21 hepatic targets (19%). Despite the fact that statistical analysis of factors with influence on TC must remain preliminary because of the small numbers of cases with a TC ,95% it was performed to achieve data for potential improvements in PTV-definition. The statistical analysis of pulmonary targets revealed negative correlation of a decreased TC ,95% to mobility related factors as use of breathing control ðr ¼ 20:49Þ, large PTV/CTV-ratio ðr ¼ 20:39Þ and a large LSM of 10 mm ðr ¼ 20:29Þ. In hepatic targets a decreased TC ,95% correlated negatively to a large CTV ðr ¼ 20:35Þ and PTV ðr ¼ 20:34Þ and positively to a initially sufficient TC to the CTV ðr ¼ 0:40Þ and PTV ðr ¼ 0:54Þ and to a sufficient PTV/CTV-ratio ðr ¼ 0:41Þ. Even if these results have to be interpreted with care they are consistent with clinical observations. Uematsu et al. [12–14] reported security margins usually about 5–10 mm, but occasionally up to 20 mm necessary for stereotactic irradiation of lung and liver targets with oxygen supported shallow breathing. Without (sufficient) breathing control target mobility will be increased: Shimizu et al. examined unreduced breathing motions of lung targets ranging between 8.1 and 14.6 mm in anterior–posterior, 5.5 and 10 mm in lateral and 6.8 and 15.9 mm in longitudinal direction [10] and a mean target deviation for liver targets of 9 mm in anterior–posterior, 8 mm in lateral and 21 mm in longitudinal direction [9].

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The effect of uncontrolled breathing mobility of pulmonary targets is demonstrated in the present evaluation by the example of one patient (number 4, Fig. 3a) in whom two of the three fractions with a TC ,95% accumulated. The patient was treated for a pulmonary metastasis in the left lower lobe after pneumonectomy for the primary tumor. Mechanical reduction of breathing mobility was difficult to achieve due to the small remaining lung volume. Despite the use of the DC, increased security margins (10 mm) and consecutively the largest PTV/CTV-ratio (3.5) of the complete study, the PTV was not sufficient for reliable dose coverage. The PTV of 66 cm 3 enclosing a CTV of 19 cm 3 could not be further increased because of the limitation of functional lung volume after pneumonectomy. The example of this patient indicates the importance of breathing control, which unfortunately was not achieved sufficiently by mechanical devices and emphasizes the role of different methods as breathing triggered irradiation [10,16] or jet-ventilation [3] in those patients. The analysis of clinical parameters in patients with a low TC in liver targets revealed that three of the four targets including six of the seven simulations with a TC ,95% were among the five targets with the largest volume exceeding a CTV of 100 cm 3 (target numbers 17, 18 and 20; Fig. 3b). The PTV/CTV-ratio was low (2.4, 1.8 and 1.4) and the TC was already decreased in the treatment plan for the CTV 100, 99 and 95% and for the PTV 96, 93 and 83%. In these cases an increase of the PTV was not performed due to the clinical limitations as functional liver tissue or close organs at risk. This observation stresses the importance of a sufficient PTV especially in large liver targets even if dose to functional liver volume becomes a limiting factor. In these cases the effectiveness of treatment and dose delivery has to be balanced to potential side effects and in large liver tumors it will remain a clinical decision, whether stereotactic irradiation can be performed both sufficiently and safely. The clinical impact of a decreased TC on local control rates cannot be assessed at this time, because for ESRT with its high fraction doses no data on dose–volume effects are available yet. The published local control rates of stereotactically treated lung and liver tumors range from 78 to 100% and are reported on a database of 17–66 targets [1,2,4,8,12,18]. Accordingly only few local recurrences have been observed with the difficulty to draw reliable conclusions from local failure. Due to the lack of clinical data and the variety of dose concepts the clinical importance of the minimum, maximum or median dose to the CTV cannot be assessed. Considerations whether a more homogeneous dose distribution with a less steep dose gradient as achieved by a PTV-enclosing 80%-isodose [3,4,12] is superior to an inhomogeneous dose distribution with a very steep dose gradient [1,2,5–7,17,18] as used in the present study have to be discussed on the base of clinical data. At this time it remains unclear whether the slightly increased risk for a decreased TC due to a steep dose gradient is clinically more important than the additional dose

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within the reference isodose achieved by the inhomogeneous dose distribution. Because of the lack of this data it should be demanded from stereotactic treatment to deliver the prescribed dose to the target in a reproducible and predictable way. The evaluation of the stereotactic approach to meet this requirement for targets in lung and liver was the purpose of the present study. In summary the dose to the CTV was not affected by target reproducibility over the complete volume and the complete course of treatment in 95% of lung and 88% of liver tumors, if security margins of 5 mm in axial and 5– 10 mm in longitudinal direction were used for PTV definition. The results of CT-simulation are reliable even for large volumes and for a hypofractionated treatment approach. Nevertheless the analysis revealed two subgroups at risk for decreased TC of dose: pulmonary tumors with increased breathing mobility, which cannot be reduced by mechanical breathing control and liver tumors with a CTV exceeding 100 cm 3. Under these circumstances an increase of the PTV to achieve adequate target dose has to be balanced against the risk to harm the functional organ reserve of the patient and therefore these targets should be treated with care.

References [1] Blomgren H, Lax I, Na¨ slund I, Svanstro¨ m R. Stereotactic high dose fractionation radiation therapy of extracranial tumors using an accelerator. Acta Oncol 1995;34:861–870. [2] Blomgren H, Lax I, Go¨ ranson H, et al. Radiosurgery for tumors in the body: clinical experience using a new method. J Radiosurg 1998;1(1):63–74. [3] Herfarth KK, Debus J, Lohr F, et al. Extracranial stereotactic radiation therapy: set-up accuracy of patients treated for liver metastases. Int J Radiat Oncol Biol Phys 2000;46(2):329–335. [4] Herfarth KK, Debus J, Lohr F, et al. Stereotactic single dose radiation therapy of liver tumors: results of a phase I/II trial. J Clin Oncol 2001;19(1):164–170. [5] Lax I. Target dose versus extra-target dose in stereotactic radiosurgery. Acta Oncol 1993;32(4):453–457. [6] Lax I, Blomgren H, Na¨ slund I, Svanstro¨ m R. Stereotactic radiotherapy of malignancies in the abdomen. Methodological aspects. Acta Oncol 1994;33:677–683. [7] Lax I, Blomgren H, Larson D, Na¨ slund D. Extracranial stereotactic radiosurgery of localized targets. J Radiosurg 1998;1(2):135–148. [8] Nakagawa K, Aoki Y, Tago M, Terahara A, Ohtomo K. Megavoltage CT-assisted stereotactic radiosurgery for thoracic tumors: original research in the treatment of thoracic neoplasms. Int J Radiat Oncol Biol Phys 2000;48(2):449–457. [9] Shimizu S, Shirato H, Xo B, et al. Three dimensional movement of a liver tumor detected by high-speed magnetic resonance. Radiother Oncol 1999;50:367–370. [10] Shimizu S, Shirato H, Ogura S, et al. Detection of lung tumor movement in real-time tumor-tracking radiotherapy. Int J Radiat Oncol Biol Phys 2001;51(2):304–310. [11] StatSoft, Inc. STATISTICA fu¨ r Windows [Computer- ProgrammHandbuch]. StatSoft, Inc., 2300 East 14th Street, Tulsa, OK 74104, Tel.: 11-918-749-1119, fax: 11-918-749-2217, e-mail: [email protected], WEB: http://www.statsoft.com. Tulsa, OK, 1998. [12] Uematsu M, Shioda A, Tahara K, et al. Focal, high dose, and fractio-

150

J. Wulf et al. / Radiotherapy and Oncology 66 (2003) 141–150

nated modified stereotactic radiation therapy for lung carcinoma patients. Cancer 1998;82:1062–1070. [13] Uematsu M, Sonderegger M, Shioda A, et al. Daily positioning accuracy of frameless stereotatctic radiation therapy with a fusion of computed tomography and linear accellarator (focal) unit: evaluation of z-axis with a z-marker. Radiother Oncol 1999;50:337–339. [14] Uematsu M, Shioda M, Suda A, et al. Intrafractional tumor position stability during computed tomography (CT)-guided frameless stereotactic radiation therapy for lung or liver cancers with a fusion of CT and linear accelerator (focal) unit. Int J Radiat Oncol Biol Phys 2000;48(2):443–448. [15] Van’t Riet A, Mak ACA, Moerland MA, Elders LH, Van der Zee W. A conformation number to quantify the degree of conformality in

brachytherapy and external beam irradiation: application to the prostate. Int J Radiat Oncol Biol Phys 1997;37(3):731–736. [16] Wong JW, Sharpe MB, Jaffray DA, et al. The use of active breathing control (ABC) to reduce margin for breathing motion. Int J Radiat Oncol Biol Phys 1999;44(4):911–919. [17] Wulf J, Haedinger 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;57:225–236. [18] Wulf J, Haedinger U, Oppitz U, Thiele W, Ness-Dourdoumas R, Flentje M. Stereotactic radiotherapy of targets in the lung and liver. Strahlenther Onkol 2001;177:645–655.