[en] Background and purpose: To assess the impact of both set-up errors and respiration-induced tumor motion on the cumulative dose delivered to a clinical target volume (CTV) in lung, for an irradiation based on current clinically applied field sizes. Materials and methods: A cork phantom, having a 50 mm spherically shaped polystyrene insertion to simulate a gross tumor volume (GTV) located centrally in a lung was irradiated with two parallel opposed beams. The planned 95% isodose surface was conformed to the planning target volume (PTV) using a multi leaf collimator. The resulting margin between the CTV and the field edge was 16 mm in beam's eye view. A dose of 70 Gy was prescribed. Dose area histograms (DAHs) of the central plane of the CTV (GTV+5 mm) were determined using radiographic film for different combinations of set-up errors and respiration-induced tumor motion. The DAHs were evaluated using the population averaged tumor control probability (TCP_pop) and the equivalent uniform dose (EUD) model. Results: Compared with dose volume histograms of the entire CTV, DAHs overestimate the impact of tumor motion on tumor control. Due to the choice of field sizes a large part of the PTV will receive a too low dose resulting in an EUD of the central plane of the CTV of 68.9 Gy for the static case. The EUD drops to 68.2, 66.1 and 51.1 Gy for systematic set-up errors of 5, 10 and 15 mm, respectively. For random set-up errors of 5, 10 and 15 mm (1 SD), the EUD decreases to 68.7, 67.4 and 64.9 Gy, respectively. For similar amplitudes of respiration-induced motion, the EUD decreases to 68.8, 68.5 and 67.7 Gy, respectively. For a clinically relevant scenario of 7.5 mm systematic set-up error, 3 mm random set-up error and 5 mm amplitude of breathing motion, the EUD is 66.7 Gy. This corresponds with a tumor control probability TCP_pop of 41.7%, compared with 50.0% for homogeneous irradiation of the CTV to 70 Gy. Conclusion: Systematic set-up errors have a dominant effect on the cumulative dose to the CTV. The effect of breathing motion and random set-up errors is smaller. Therefore the gain of controlling breathing motion during irradiation is expected to be small and efforts should rather focus on minimizing systematic errors. For the current clinically applied field sizes and a clinically relevant combination of set-up errors and breathing motion, the EUD of the central plane of the CTV is reduced by 3.3 Gy, at maximum, relative to homogeneous irradiation of the CTV to 70 Gy, for our worst case scenario

[en] Purpose: Measurements of oxygenation in the transplanted rodent KHT-C and SCC-VII tumors demonstrate significant heterogeneity from tumor to tumor as is observed in human tumors. This finding suggests that heterogeneity in oxygenation between tumors is likely related to factors associated with tumor growth rather than to intrinsic genetic differences. In this study we examined whether measurements of the oxygenation of individual KHT-C tumors were related to necrosis in the tumors or to tumor size and whether the more hypoxic tumors gave rise to more metastases. Methods: Tumors were grown in the gastrocnemius muscle of C3H mice and tumor oxygenation was measured at defined sizes (approx. 0.35 g, 1.0 g, and 2.0 g) using an Eppendorf polarographic oxygen probe. Necrosis was assessed by examining histological sections cut from tumors used for the oxygen measurements. Metastasis was assessed by counting macroscopic lung nodules in mice sacrificed when their tumors reached a size of approximately 2 g. Results: Tumor oxygenation in individual KHT-C tumors became poorer and necrosis became more extensive as the tumors grew larger but, at a size of 0.3-0.4 g, there was no relationship between oxygenation and extent of necrosis. In general, measurements of tumor pO₂ at a size of 0.3-0.4 g were predictive of tumor pO₂in the same tumor at a size of about 1 g, but by the time the tumors reached a size of about 2 g they were all very hypoxic. There was a trend suggesting a relationship between macroscopic metastases in the lung and degree of hypoxia in the KHT-C tumors but this was not statistically significant. Conclusion: The results indicate that the heterogeneity of oxygenation seen in KHT-C tumors is not explained by different degrees of necrosis in the individual tumors. The lack of a correlation between increased metastasis formation and increased levels of hypoxia in the KHT-C tumors is not consistent with results reported for human tumors

[en] Purpose: To investigate patient set-up, tumor movement and shrinkage during 3D conformal radiotherapy for non-small cell lung cancer. Materials and methods: In 97 patients, electronic portal images (EPIs) were acquired and corrected for set-up using an off-line correction protocol based on a shrinking action level. For 25 selected patients, the orthogonal EPIs (taken at random points in the breathing cycle) throughout the 6-7 week course of treatment were assessed to establish the tumor position in each image using both an overlay and a delineation technique. The range of movement in each direction was calculated. The position of the tumor in the digitally reconstructed radiograph (DRR) was compared to the average position of the lesion in the EPIs. In addition, tumor shrinkage was assessed. Results: The mean overall set-up errors after correction were 0, 0.6 and 0.2 mm in the x (left-right), y (cranial-caudal) and z (anterior-posterior) directions, respectively. After correction, the standard deviations (SDs) of systematic errors were 1.4, 1.5 and 1.3 mm and the SDs of random errors were 2.9, 3.1 and 2.0 mm in the x-, y- and z-directions, respectively. Without correction, 41% of patients had a set-up error of more than 5 mm vector length, but with the set-up correction protocol this percentage was reduced to 1%. The mean amplitude of tumor motion was 7.3 (SD 2.7), 12.5 (SD 7.3) and 9.4 mm (SD 5.2) in the x-, y- and z-directions, respectively. Tumor motion was greatest in the y-direction and in particular for lower lobe tumors. In 40% of the patients, the projected area of the tumor regressed by more than 20% during treatment in at least one projection. In 16 patients it was possible to define the position of the center of the tumor in the DRR. There was a mean difference of 6 mm vector length between the tumor position in the DRR and the average position in the portal images. Conclusions: The application of the correction protocol resulted in a significant improvement in the set-up accuracy. There was wide variation in the observed tumor motion with more movement of lower lobe lesions. Tumor shrinkage was observed. The position of the tumor on the planning CT scan did not always coincide with the average position as measured during treatment

[en] Background and purpose: The low density of lung tissue causes a reduced attenuation of photons and an increased range of secondary electrons, which is inaccurately predicted by the algorithms incorporated in some commonly available treatment planning systems (TPSs). This study evaluates the differences in dose in normal lung tissue computed using a simple and a more correct algorithm. We also studied the consequences of these differences on the dose-effect relations for radiation-induced lung injury. Materials and methods: The treatment plans of 68 lung cancer patients initially produced in a TPS using a calculation model that incorporates the equivalent-pathlength (EPL) inhomogeneity-correction algorithm, were recalculated in a TPS with the convolution-superposition (CS) algorithm. The higher accuracy of the CS algorithm is well-established. Dose distributions in lung were compared using isodoses, dose-volume histograms (DVHs), the mean lung dose (MLD) and the percentage of lung receiving >20 Gy (V20). Published dose-effect relations for local perfusion changes and radiation pneumonitis were re-evaluated. Results: Evaluation of isodoses showed a consistent overestimation of the dose at the lung/tumor boundary by the EPL algorithm of about 10%. This overprediction of dose was also reflected in a consistent shift of the EPL DVHs for the lungs towards higher doses. The MLD, as determined by the EPL and CS algorithm, differed on average by 17±4.5% (±1SD). For V20, the average difference was 12±5.7% (±1SD). For both parameters, a strong correlation was found between the EPL and CS algorithms yielding a straightforward conversion procedure. Re-evaluation of the dose-effect relations showed that lung complications occur at a 12-14% lower dose. The values of the TD₅₀ parameter for local perfusion reduction and radiation pneumonitis changed from 60.5 and 34.1 Gy to 51.1 and 29.2 Gy, respectively. Conclusions: A simple tissue inhomogeneity-correction algorithm like the EPL overestimates the dose to normal lung tissue. Dosimetric parameters for lung injury (e.g. MLD, V20) computed using both algorithms are strongly correlated making an easy conversion feasible. Dose-effect relations should be refitted when more accurate dose data is available

[en] Purpose: To compare different normal tissue complication probability (NTCP) models to predict the incidence of radiation pneumonitis on the basis of the dose distribution in the lung. Methods and Materials: The data from 382 breast cancer, malignant lymphoma, and inoperable non-small-cell lung cancer patients from two centers were studied. Radiation pneumonitis was scored using the Southwestern Oncology Group criteria. Dose-volume histograms of the lungs were calculated from the dose distributions that were corrected for dose per fraction effects. The dose-volume histogram of each patient was reduced to a single parameter using different local dose-effect relationships. Examples of single parameters were the mean lung dose (MLD) and the volume of lung receiving more than a threshold dose (V_Dth). The parameters for the different NTCP models were fit to patient data using a maximum likelihood analysis. Results: The best fit resulted in a linear local dose-effect relationship, with the MLD as the resulting single parameter. The relationship between the MLD and NTCP could be described with a median toxic dose (TD₅₀) of 30.8 Gy and a steepness parameter m of 0.37. The best fit for the relationship between the V_Dth and the NTCP was obtained with a D_th of 13 Gy. The MLD model was found to be significantly better than the V_Dth model (p <0.03). However, for 85% of the studied patients, the difference in NTCP calculated with both models was <10%, because of the high correlation between the two parameters. For dose distributions outside the range of the studied dose-volume histograms, the difference in NTCP, using the two models could be >35%. For arbitrary dose distributions, an estimate of the uncertainty in the NTCP could be determined using the probability distribution of the parameter values of the Lyman-Kutcher-Burman model. Conclusion: The maximum likelihood method revealed that the underlying local dose-effect relation for radiation pneumonitis was linear (the MLD model), rather than a step function (the V_Dth model). Thus, for the studied patient population, the MLD was the most accurate predictor for the incidence of radiation pneumonitis

[en] The aim of this study was to develop a technique for axillary radiotherapy that minimizes the risk of radiation-induced damage to the surrounding normal tissue (i.e., arm, shoulder, lung, esophagus, and spinal cord) while keeping the risk of a nodal recurrence to a minimum. A planning study was performed in 20 breast cancer patients. The target volume of the axillary treatment encompassed the periclavicular and axillary lymph node areas. The 3-dimensional (3D) computed tomography (CT) information in this study was used to outline the lymph node areas and the organs at risk (i.e., the esophagus, spinal cord, brachial plexus, and lung). A conventional AP-PA technique (with a transmission plate placed in the AP beam) was evaluated. In addition, a new single-isocenter technique consisting of AP/PA fields using a gantry rotation of ±20 deg. and a medial AP segment was developed. Both techniques were compared by evaluation of the calculated dose distributions and the dose-volume histograms of the target volume and surrounding organs at risk. The field borders and humeral shielding were redefined based on the 3D anatomical references. Adapting the humeral shielding reduced the irradiated volume by 19% and might contribute to a reduction of the incidence of arm edema and impairment of shoulder function. The maximum radiation dose in the esophagus and spinal cord was reduced by more than 50% using the single-isocenter technique. The difference between both techniques with respect to the mean doses in the target volume and lung, and the maximum dose in brachial plexus, was not statistically significant. Moreover, the single-isocenter technique allowed a fast and easy treatment preparation and reduced the execution time considerably (with approximately 10 minutes per fraction)

[en] Purpose: To evaluate the changes in pulmonary function after high-dose radiotherapy (RT) for non-small-cell lung cancer in patients with a long-term disease-free survival. Methods and Materials: Pulmonary function was measured in 34 patients with inoperable non-small-cell lung cancer before RT and at 3 and 18 months of follow-up. Thirteen of these patients had a pulmonary function test (PFT) 36 months after RT. The pulmonary function parameters (forced expiratory volume in 1 s [FEV₁], diffusion capacity [T_lcoc], forced vital capacity, and alveolar volume) were expressed as a percentage of normal values. Changes were expressed as relative to the pre-RT value. We evaluated the impact of chronic obstructive pulmonary disease, radiation pneumonitis, mean lung dose, and PFT results before RT on the changes in pulmonary function. Results: At 3, 18, and 36 months, a significant decrease was observed for the T_lcoc (9.5%, 14.6%, and 22.0%, respectively) and the alveolar volume (5.8%, 6.6%, and 15.8%, respectively). The decrease in FEV₁ was significant at 18 and 36 months (8.8% and 13.4%, respectively). No recovery of any of the parameters was observed. Chronic obstructive pulmonary disease was an important risk factor for larger PFT decreases. FEV₁ and T_lcoc decreases were dependent on the mean lung dose. Conclusion: A significant decrease in pulmonary function was observed 3 months after RT. No recovery in pulmonary function was seen at 18 and 36 months after RT. The decrease in pulmonary function was dependent on the mean lung dose, and patients with chronic obstructive pulmonary disease had larger reductions in the PFTs

[en] Purpose: The aim of this study was to determine the maximum tolerated dose (MTD) delivered within 6 weeks in patients with non-small-cell lung cancer (NSCLC). The impact of tumor volume and delivered dose on failure-free interval (FFI) and overall survival (OS) were also studied. Methods and Materials: A Phase I/II trial was performed including inoperable NSCLC patients. According to the relative mean lung dose (rMLD), five risk groups with different starting doses were defined: Group 1, rMLD 0.0 to 0.12; Group 2, rMLD 0.12 to 0.18; Group 3, rMLD 0.18 to 0.24; Group 4, rMLD 0.24 to 0.31; and Group 5, rMLD 0.31 to 0.40. Patients underwent irradiation with 2.25 Gy per fraction and a fixed overall treatment time of 6 weeks. The dose was escalated with 6.75 Gy after 6 months follow-up without dose-limiting toxicity. If more than 30 fractions were prescribed, twice-daily irradiation was performed with at least a 6-h interval. Results: A total of 88 patients were included. Tumor Stage I or II was found in 53%, IIIA in 31%, and IIIB in 17%. The MTD was not achieved in risk Group 1 (reached dose, 94.5 Gy). For risk Groups 2 and 3 the MTD was 81 Gy. The 74.3-Gy dose was determined to be safe for Group 4 and the 60.8-Gy dose for Group 5. In 2 patients (5%) an isolated nodal relapse occurred. Based on multivariable analysis, higher doses significantly increased the FFI (p = 0.02) for the total group. The OS was increased in the lower risk groups (p = 0.05) but not in the higher risk groups (p = 0.4). Conclusion: Dose escalation is safe up to 94.5 Gy in 42 fractions in 6 weeks in patients with an MLD 13.6 Gy or less. Higher doses are associated with a better FFI and OS for smaller tumor volumes. Involved-field irradiation results in a low percentage of isolated nodal relapses

[en] Background and purpose: To evaluate the process of target volume delineation in lung cancer for optimization of imaging, delineation protocol and delineation software. Patients and methods: Eleven radiation oncologists (observers) from five different institutions delineated the Gross Tumor Volume (GTV) including positive lymph nodes of 22 lung cancer patients (stages I-IIIB) on CT only. All radiation oncologist-computer interactions were recorded with a tool called 'Big Brother'. For each radiation oncologist and patient the following issues were analyzed: delineation time, number of delineated points and corrections, zoom levels, level and window (L/W) settings, CT slice changes, use of side windows (coronal and sagittal) and software button use. Results: The mean delineation time per GTV was 16 min (SD 10 min). The mean delineation time for lymph node positive patients was on average 3 min larger (P=0.02) than for lymph node negative patients. Many corrections (55%) were due to L/W change (e.g. delineating in mediastinum L/W and then correcting in lung L/W). For the lymph node region, a relatively large number of corrections was found (3.7 corr/cm²), indicating that it was difficult to delineate lymph nodes. For the tumor-atelectasis region, a relative small number of corrections was found (1.0 corr/cm²), indicating that including or excluding atelectasis into the GTV was a clinical decision. Inappropriate use of L/W settings was frequently found (e.g. 46% of all delineated points in the tumor-lung region were delineated in mediastinum L/W settings). Despite a large observer variation in cranial and caudal direction of 0.72 cm (1 SD), the coronal and sagittal side windows were not used in 45 and 60% of the cases, respectively. For the more difficult cases, observer variation was smaller when the coronal and sagittal side windows were used. Conclusions: With the 'Big Brother' tool a method was developed to trace the delineation process. The differences between observers concerning the delineation style were large. This study led to recommendations on how to improve delineation accuracy by adapting the delineation protocol (guidelines for L/W use) and delineation software (double window with lung and mediastinum L/W settings at the same time, enforced use of coronal and sagittal views) and including FDG-PET information (lymph nodes and atelectasis)

[en] Purpose: Target delineation using only CT information introduces large geometric uncertainties in radiotherapy for lung cancer. Therefore, a reduction of the delineation variability is needed. The impact of including a matched CT scan with 2-[¹⁸F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) and adaptation of the delineation protocol and software on target delineation in lung cancer was evaluated in an extensive multi-institutional setting and compared with the delineations using CT only. Methods and Materials: The study was separated into two phases. For the first phase, 11 radiation oncologists (observers) delineated the gross tumor volume (GTV), including the pathologic lymph nodes of 22 lung cancer patients (Stages I-IIIB) on CT only. For the second phase (1 year later), the same radiation oncologists delineated the GTV of the same 22 patients on a matched CT-FDG-PET scan using an adapted delineation protocol and software (according to the results of the first phase). All delineated volumes were analyzed in detail. The observer variation was computed in three dimensions by measuring the distance between the median GTV surface and each individual GTV. The variation in distance of all radiation oncologists was expressed as a standard deviation. The observer variation was evaluated for anatomic regions (lung, mediastinum, chest wall, atelectasis, and lymph nodes) and interpretation regions (agreement and disagreement; i.e., >80% vs. <80% of the radiation oncologists delineated the same structure, respectively). All radiation oncologist-computer interactions were recorded and analyzed with a tool called 'Big Brother.' Results: The overall three-dimensional observer variation was reduced from 1.0 cm (SD) for the first phase (CT only) to 0.4 cm (SD) for the second phase (matched CT-FDG-PET). The largest reduction in the observer variation was seen in the atelectasis region (SD 1.9 cm reduced to 0.5 cm). The mean ratio between the common and encompassing volume was 0.17 and 0.29 for the first and second phases, respectively. For the first phase, the common volume was 0 in 4 patients (i.e., no common point for all GTVs). In the second phase, the common volume was always >0. For all anatomic regions, the interpretation differences among the radiation oncologists were reduced. The amount of disagreement was 45% and 18% for the first and second phase, respectively. Furthermore, the mean delineation time (12 vs. 16 min, p < 0.001) and mean number of corrections (25 vs. 39, p < 0.001) were reduced in the second phase compared with the first phase. Conclusion: For high-precision radiotherapy, the delineation of lung target volumes using only CT introduces too great a variability among radiation oncologists. Implementing matched CT-FDG-PET and adapted delineation protocol and software reduced observer variation in lung cancer delineation significantly with respect to CT only. However, the remaining observer variation was still large compared with other geometric uncertainties (setup variation and organ motion)