[en] Purpose: To investigate whether Dose-Volume Histogram (DVH) parameters can be used to identify risk groups for developing late gastrointestinal (GI) and genitourinary (GU) complications after conformal radiotherapy for prostate cancer. Methods and Materials: DVH parameters were analyzed for 130 patients with localized prostate cancer, treated with conformal radiotherapy in a dose-escalating protocol (70-78 Gy, 2 Gy per fraction). The incidence of late (>6 months) GI and GU complications was classified using the RTOG/EORTC and the SOMA/LENT scoring system. In addition, GI complications were divided in nonsevere and severe (requiring one or more laser treatments or blood transfusions) rectal bleeding. The median follow-up time was 24 months. We investigated whether rectal and bladder wall volumes, irradiated to various dose levels, correlated with the observed actuarial incidences of GI and GU complications, using volume as a continuous variable. Subsequently, for each dose level in the DVH, the rectal wall volumes were dichotomized using different volumes as cutoff levels. The impact of the total radiation dose, and the maximum radiation dose in the rectal and bladder wall was analyzed as well. Results: The actuarial incidence at 2 years for GI complications ≥Grade II was 14% (RTOG/EORTC) or 20% (SOMA/LENT); for GU complications ≥Grade III 8% (RTOG/EORTC) or 21% (SOMA/LENT). Neither for GI complications ≥Grade II (RTOG/EORTC or SOMA/LENT), nor for GU complications ≥Grade III (RTOG/EORTC or SOMA/LENT), was a significant correlation found between any of the DVH parameters and the actuarial incidence of complications. For severe rectal bleeding (actuarial incidence at 2 years 3%), four consecutive volume cutoff levels were found, which significantly discriminated between high and low risk. A trend was observed that a total radiation dose ≥ 74 Gy (or a maximum radiation dose in the rectal wall >75 Gy) resulted in a higher incidence of severe rectal bleeding (p = 0.07). Conclusions: These data show that dose escalation up to 78 Gy, using a conformal technique, is feasible. However, these data have also demonstrated that the incidence of severe late rectal bleeding is increased above certain dose-volume thresholds

[en] Purpose: To develop a model that predicts possible rectum configurations that can occur during radiotherapy of prostate cancer on the basis of a planning CT scan and patient group data. Materials and Methods: We used a stochastic shape description model with a limited number of parameters (area, area difference, and curvature) on a slice-by-slice basis to simulate rectum motion. The probability distributions of the chosen parameters were obtained from a group of 9 reference patients, who each received 15-17 repeat CT scans. We used a Monte Carlo technique to generate different rectum configurations from the probability distributions. We verified the model by comparing dose-wall histograms (DWHs) of the originally delineated rectal contours and simulated rectums for a three-field treatment technique with a prescription dose of 78 Gy. The 15-17 sets of rectal contours of each patient are regarded as the golden standard and provide a good estimate of the actual dose received during the treatment. We determined the equivalent uniform dose (EUD) for a quantitative comparison between the actual dose, the dose predicted on the basis of the simulations, and the dose predicted on the basis of a single planning CT scan. Results: The simulated rectum configurations yield a better estimate of the actual dose in the rectal wall than the rectum in the planning CT scan alone. The differences between the EUD based on the planning CT scan and the actual EUD ranged between -1.1 Gy and 2.1 Gy, with respect to a mean actual EUD of 69.8 Gy. This range is smaller for the EUD based on the simulated rectums, namely -0.4 Gy to 0.6 Gy. Furthermore, the simulation generates a set of rectum configurations that provides an estimate of the variation in DWHs during the course of the treatment. This estimate can be used in addition to the DWH of the planning CT scan in the analysis of gastrointestinal toxicity. Conclusions: To simulate rectum shapes, we have developed a model that can be used in addition to the information available in the planning CT scan in the analysis of the received dose to the rectal wall during radiotherapy of prostate cancer

[en] Purpose: To evaluate the feasibility of dose escalation in non-small cell lung cancer (NSCLC) using three-dimensional conformal radiation therapy. Patients and methods: The main eligibility criteria of the trial were: pathologically proven inoperable NSCLC, ECOG performance status ≤2, weight loss <10% and no chemotherapy within 6 weeks prior to the start of the radiotherapy treatment. No elective nodal irradiation was given. Patients were treated 5 days a week with 2.25 Gy per fraction and a 6 weeks overall treatment time; two fractions a day were given if more than 30 fractions were prescribed. Five risk groups were defined according to the relative mean lung dose (rMLD). Within each group the dose was escalated with three fractions per step (6.75 Gy). The next dose level opened after a toxicity-free follow-up of 6 months in three patients. The maximum tolerable dose has been reached if two out of six patients experience a dose-limiting toxicity (pneumonitis ≥grade 3 (SWOG), grade 3 early and grade 2 late esophageal toxicity or any other (RTOG) grade 3 or 4 complications). Results: Fifty-five patients were included. Tumor stage was I/II in 47%, IIIA in 33% and IIIB in 20%. The majority of the patients received a dose of 74.3 Gy (n=17) or 81.0 Gy (n=23). Radiation pneumonitis occurred in seven patients: four patients developed a grade 2, two patients grade 3 and one patient a grade 4. Esophageal toxicity was mild. In 50 patients tumor response at 3 months follow-up was evaluable. In six patients a complete response was recorded, in 38 a partial response, five patients had stable disease and one patient experienced progressive disease. Only one patient developed an isolated failure in an uninvolved nodal area. So far the radiation dose was safely escalated to 87.8 Gy in group 1 (lowest rMLD), 81.0 Gy in groups 2 and 3 and 74.3 Gy in group 4. Conclusion: Three-dimensional conformal radiotherapy enables significant dose escalation in NSCLC. The maximum tolerable dose has not yet been reached in any risk group

[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 determine local dose-effect relations for lung perfusion and density changes due to irradiation for patients with non-small-cell lung cancer (NSCLC) and to quantify the effect of reperfusion. Methods and Materials: For 25 NSCLC patients and a reference group of 81 patients with healthy lungs, registered single photon emission computed tomography (SPECT) lung perfusion and CT scans were made, before and after radiotherapy. Average dose-effect relations for perfusion and CT-density changes were calculated and compared with the dose-effect relation of the reference group. On the basis of these dose-effect relations, the post-RT perfusion was predicted for each patient and compared to the measured post-RT perfusion. Results: Well-perfused lung regions of the NSCLC patients showed the same dose-effect relation as the reference patients. By comparing predicted and measured post-treatment perfusion scans, regions of reperfusion could be determined for 18 of 25 NSCLC patients but for none of the reference patients. Conclusion: Well-perfused lung tissue of patients with NSCLC behaves like healthy lung tissue with respect to radiation. The dose-effect relation for perfusion and CT density was extended for doses up to 80 Gy. Radiation damage in poorly perfused lung regions was less than predicted as a consequence of local reperfusion

[en] Purpose: To assess the recovery from early local pulmonary injury after irradiation and to determine whether regional differences exist. Methods: For 110 patients treated for breast cancer or malignant lymphoma, single photon emission computed tomography (SPECT) perfusion and ventilation scans and CT scans were made before, 3, 18, and 48 months after radiotherapy. Dose-effect relations for changes in local perfusion, ventilation, and density were determined for each individual patient using spatially correlated SPECT and CT data sets, for each follow-up period. Average dose-effect relations for both subgroups were determined, as well as dose-effect relations for different regions. Results: In general, partial improvement of local pulmonary injury was observed between 3 and 18 months for each of the three endpoints. After 18 months, no further improvement was seen. Patients with breast cancer and malignant lymphoma showed a similar improvement (except for the perfusion parameter), which was attributed to a recovery from the early radiation response and could not be explained by contraction effects of fibrosis of lung parenchyma. No regional differences in radiosensitivity 18 months after treatment were observed, except for the dorsal versus ventral region. This difference was attributed to a gravity-related effect in the measuring procedure. Conclusion: For all patients, a partial recovery from early local perfusion, ventilation, and density changes, was seen between 3 and 18 months after radiotherapy. After 18 months, local lung function did not further improve (lymphoma patients)

[en] Purpose: To study the impact of incorporation of lung perfusion information in the optimization of radical radiotherapy (RT) treatment plans for patients with medically inoperable non-small cell lung cancer (NSCLC). Materials and methods: The treatment plans for a virtual phantom and for five NSCLC patients with typical defects of pre-RT lung perfusion were optimized to minimize geometrically determined parameters as the mean lung dose (MLD), the lung volume receiving more than 20 Gy (V20), and the functional equivalent of the MLD, using perfusion-weighted dose-volume histograms. For the patients the (perfusion-weighted) optimized plans were compared to the clinically applied treatment plans. Results: The feasibility of perfusion-weighted optimization was demonstrated in the phantom. Using perfusion information resulted in an increase of the weights of those beams that were directed through the hypo-perfused lung regions both for the phantom and for the studied patients. The automatically optimized dose distributions were improved with respect to lung toxicity compared with the clinical treatment plans. For patients with one hypo-perfused hemi-thorax, the estimated gain in post-RT lung perfusion was 6% of the prescribed dose compared to the geometrically optimized plan. For patients with smaller perfusion defects, perfusion-weighted optimization resulted in the same plan as the geometrically optimized plan. Conclusion: Perfusion-weighted optimization resulted in clinically well applicable treatment plans, which cause less radiation damage to functioning lung for patients with large perfusion defects

[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] Aim. To determine the additional value of FDG-PET-CT as compared to conventional staging (CS) in high-risk breast cancer patients. Patients and methods. Thirty-one high-risk breast cancer patients, 14 of whom had recurrent breast cancer, were included in this study, which took place between June 2005 and March 2008. None of the patients had clinical signs of distant metastases. FDG-PET-CT scanning was added to CS, which consisted of a chest x-ray, liver ultrasonography or CT, and bone scintigraphy. Median follow-up was 17 months (6-41 months). FDG-PET-CT was considered to have additional value to CS if it led to a change in treatment plan or if it made additional examinations to confirm or deny findings on CS unnecessary. Results. FDG-PET-CT was considered to have additional value to CS in 13 patients (42% [95% CI: 23-61]). In five patients (16% [95% CI: 1-31]), FDG-PET-CT led to a change in treatment plan by identifying nodal metastases in the internal mammary chain (IMC; N = 3) or in the mediastinum (N = 2). In nine patients (29% [95% CI: 11-47]), FDG-PET-CT would have prevented the need for additional examinations; in seven of these nine patients, distant metastases were suggested in bone or liver on CS, but these did not show FDG uptake. Conclusions. FDG-PET-CT was found to have additional value to CS in 42% of the patients. To optimize cost-effectiveness, the main challenge now is to improve the selection of patients in whom FDG-PET-CT has additional value to CS