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Purpose: To describe the evolution of external beam radiation therapy (EBRT) from EMBRACE-I (general guidelines for EBRT) to the initial phase of the EMBRACE-II study (detailed protocol for EBRT)., Methods and Materials: EMBRACE-I enrolled 1416 locally advanced cervical cancer patients treated with chemoradiation including image-guided adaptive brachytherapy during 2008 to 2015. From March 2016 until March 2018, 153 patients were enrolled in the ongoing EMBRACE-II study, which involves a comprehensive detailed strategy and accreditation procedure for EBRT target contouring, treatment planning, and image guidance. EBRT planning target volumes (PTVs), treated volumes (V43 Gy), and conformity index (CI; V43 Gy/PTV) were evaluated in both studies and compared., Results: For EMBRACE-I, conformal radiation therapy (60% of patients) or intensity-modulated radiation therapy (IMRT) and volumetric arc therapy (VMAT; 40%) was applied with 45 to 50 Gy over 25 to 30 fractions to the elective clinical target volume (CTV). For pelvic CTVs (82%), median PTV and V43 Gy volumes were 1549 and 2390 mL, respectively, and CI was 1.54. For pelvic plus paraortic nodal (PAN) CTVs (15%), median PTV and V43 Gy volumes were 1921 and 2895 mL, and CI was 1.51. For pelvic CTVs treated with 45 to 46 Gy, the use of conformal radiation therapy was associated with a median V43 Gy volume that was 546 mL larger than with IMRT/VMAT. For pelvic CTVs treated with IMRT, the use of a dose prescription ≥48 Gy was associated with a median V43 Gy volumes that was 428 mL larger than with a dose prescription of 45 to 46 Gy. For EMBRACE-II, all patients were treated with: IMRT/VMAT, daily IGRT, 45 Gy over 25 fractions for the elective CTV, and simultaneously integrated boost for pathologic lymph nodes. For pelvic CTVs (61%), median PTV and V43 Gy volumes were 1388 and 1418 mL, and CI was 1.02. For pelvic plus PAN CTVs (32%), median PTV and V43 Gy volumes were 1720 and 1765 mL, and CI was 1.03. From EMBRACE-I to initial II, median V43 Gy was decreased by 972 mL (41%) and 1130 mL (39%), and median CI decreased from 1.54 to 1.02 and 1.51 to 1.03 for pelvic and pelvic plus PAN irradiation, respectively., Conclusions: Application of IMRT/VMAT, IGRT, and a 45-Gy dose provides the potential of higher conformality inducing significant reduction of treated volume. Adherence to a detailed protocol including comprehensive accreditation, as in EMBRACE-II, reduces considerably V43 Gy and V50 Gy and improves conformality and interinstitutional consistency., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To investigate how dose distributions for liver stereotactic body radiation therapy (SBRT) can be improved by using automated, daily plan reoptimization to account for anatomy deformations, compared with setup corrections only., Methods and Materials: For 12 tumors, 3 strategies for dose delivery were simulated. In the first strategy, computed tomography scans made before each treatment fraction were used only for patient repositioning before dose delivery for correction of detected tumor setup errors. In adaptive second and third strategies, in addition to the isocenter shift, intensity modulated radiation therapy beam profiles were reoptimized or both intensity profiles and beam orientations were reoptimized, respectively. All optimizations were performed with a recently published algorithm for automated, multicriteria optimization of both beam profiles and beam angles., Results: In 6 of 12 cases, violations of organs at risk (ie, heart, stomach, kidney) constraints of 1 to 6 Gy in single fractions occurred in cases of tumor repositioning only. By using the adaptive strategies, these could be avoided (<1 Gy). For 1 case, this needed adaptation by slightly underdosing the planning target volume. For 2 cases with restricted tumor dose in the planning phase to avoid organ-at-risk constraint violations, fraction doses could be increased by 1 and 2 Gy because of more favorable anatomy. Daily reoptimization of both beam profiles and beam angles (third strategy) performed slightly better than reoptimization of profiles only, but the latter required only a few minutes of computation time, whereas full reoptimization took several hours., Conclusions: This simulation study demonstrated that replanning based on daily acquired computed tomography scans can improve liver stereotactic body radiation therapy dose delivery., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To compare pathology macroscopic tumor dimensions with magnetic resonance imaging (MRI) measurements and to establish the microscopic tumor extension of colorectal liver metastases., Methods and Materials: In a prospective pilot study we included patients with colorectal liver metastases planned for surgery and eligible for MRI. A liver MRI was performed within 48 hours before surgery. Directly after surgery, an MRI of the specimen was acquired to measure the degree of tumor shrinkage. The specimen was fixed in formalin for 48 hours, and another MRI was performed to assess the specimen/tumor shrinkage. All MRI sequences were imported into our radiotherapy treatment planning system, where the tumor and the specimen were delineated. For the macroscopic pathology analyses, photographs of the sliced specimens were used to delineate and reconstruct the tumor and the specimen volumes. Microscopic pathology analyses were conducted to assess the infiltration depth of tumor cell nests., Results: Between February 2009 and January 2010 we included 13 patients for analysis with 21 colorectal liver metastases. Specimen and tumor shrinkage after resection and fixation was negligible. The best tumor volume correlations between MRI and pathology were found for T1-weighted (w) echo gradient sequence (r(s) = 0.99, slope = 1.06), and the T2-w fast spin echo (FSE) single-shot sequence (r(s) = 0.99, slope = 1.08), followed by the T2-w FSE fat saturation sequence (r(s) = 0.99, slope = 1.23), and the T1-w gadolinium-enhanced sequence (r(s) = 0.98, slope = 1.24). We observed 39 tumor cell nests beyond the tumor border in 12 metastases. Microscopic extension was found between 0.2 and 10 mm from the main tumor, with 90% of the cases within 6 mm., Conclusions: MRI tumor dimensions showed a good agreement with the macroscopic pathology suggesting that MRI can be used for accurate tumor delineation. However, microscopic extensions found beyond the tumor border indicate that caution is needed in selecting appropriate tumor margins., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: We investigated the potentials and limitations of guiding liver stereotactic body radiation therapy (SBRT) set-up on liver-implanted fiducial markers., Methods and Materials: Twelve patients undergoing compression-supported SBRT in a stereotactic body frame received fluoroscopy at treatment preparation and before each treatment fraction. In fluoroscopic videos we localized the markers and diaphragm tip at expiration and the spine (measurements on free-breathing and abdominal compression). Day-to-day displacements, rotations (markers only), and deformations were determined. Marker guidance was compared to conventional set-up strategies in treatment set-up simulations., Results: For compression, day-to-day motion of markers with respect to their centers of mass (COM) was sigma = 0.9 mm (random error SD), Sigma = 0.4 mm (systematic error SD), and <2.1 mm (maximum). Consequently, assuming that markers were closely surrounding spherical tumors, marker COM-guided set-up would have required safety margins of approximately 2 mm. Using marker COM as the gold standard, other set-up methods (using no correction, spine registration, and diaphragm tip craniocaudal registration) resulted in set-up errors of 1.4 mm < sigma < 2.8 mm, 2.6 mm < Sigma < 5.1 mm, and 6.3 mm < max < 12.4 mm. Day-to-day intermarker motion of <16.7%, 2.2% median, and rotations between 3.5 degrees and 7.2 degrees were observed. For markers not surrounding the tumor, e.g., 5 cm between respective COMs, these changes could effect residual tumor set-up errors up to 8.4 mm, 1.1 mm median (deformations), and 3.1 mm to 6.3 mm (rotations). Compression did not systematically contribute to deformations and rotations, since similar results were observed for free-breathing., Conclusions: If markers can be implanted near and around the tumor, residual set-up errors by marker guidance are small compared to those of conventional set-up methods, allowing high-precision tumor radiation set-up. However, substantial errors may result if markers are not implanted precisely, requiring further research to obtain adequate safety margins., (Copyright 2010 Elsevier Inc. All rights reserved.)

Purpose: To assess day-to-day differences between planned and delivered target volume (TV) and organ-at-risk (OAR) dose distributions in liver stereotactic body radiation therapy (SBRT), and to investigate the dosimetric impact of setup corrections., Methods and Materials: For 14 patients previously treated with SBRT, the planning CT scan and three treatment scans (one for each fraction) were included in this study. For each treatment scan, two dose distributions were calculated: one using the planned setup for the body frame (no correction), and one using the clinically applied (corrected) setup derived from measured tumor displacements. Per scan, the two dose distributions were mutually compared, and the clinically delivered distribution was compared with planning. Doses were recalculated in equivalent 2-Gy fraction doses. Statistical analysis was performed with the linear mixed model., Results: With setup corrections, the mean loss in TV coverage relative to planning was 1.7%, compared with 6.8% without corrections. For calculated equivalent uniform doses, these figures were 2.3% and 15.5%, respectively. As for the TV, mean deviations of delivered OAR doses from planning were small (between -0.4 and +0.3 Gy), but the spread was much larger for the OARs. In contrast to the TV, the mean impact of setup corrections on realized OAR doses was close to zero, with large positive and negative exceptions., Conclusions: Daily correction of the treatment setup is required to obtain adequate TV coverage. Because of day-to-day patient anatomy changes, large deviations in OAR doses from planning did occur. On average, setup corrections had no impact on these doses. Development of new procedures for image guidance and adaptive protocols is warranted.

Purpose: To study regional differences in lung radiosensitivity by evaluating the incidence of radiation pneumonitis (RP) in relation to regional dose distributions., Methods and Materials: Registered chest CT and single photon emission CT lung perfusion scans were obtained in 106 patients before curative or radical radiotherapy for non-small-cell lung cancer. The mean lung dose (MLD) was calculated. The single photon-emission CT perfusion data were used to weigh the MLD with perfusion, resulting in the mean perfusion-weighted lung dose. In addition, the lungs were geometrically divided into different subvolumes. The mean regional dose (MRD) for each region was calculated and weighted with the perfusion of each region to obtain the mean perfusion-weighted regional dose. RP was defined as respiratory symptoms requiring steroids. The incidence of RP for patients with tumors in a specific subvolume was calculated. The normal tissue complication probability (NTCP) parameter values for the TD(50), and an offset NTCP parameter for tumor location were fitted for both lungs and for each lung subvolume to the observed data using maximum likelihood analysis., Results: The incidence of RP correlated significantly with the MLD and MRD of the posterior, caudal, ipsilateral, central, and peripheral lung subvolumes (p between 0.05 and 0.002); no correlation was seen for the anterior, cranial, and contralateral regions Similarly, a statistically significant correlation was observed between the incidence of RP and the perfusion-weighted MLD and perfusion-weighted MRD for all regions, except the anterior lung region. For this region, the dose-effect relation improved remarkably after weighting the local dose with the local perfusion. A statistically significant difference (p = 0.01) in the incidence of RP was found between patients with cranial and caudal tumors (11% and 40%, respectively). Therefore, a dose-independent offset NTCP parameter for caudal tumors was included in the NTCP model, improving most correlations significantly, confirming that patients with caudal tumors have a greater probability of developing RP., Conclusion: The incidence of RP correlated significantly with the MLD and MRD of most lung regions, except for the anterior, cranial, and contralateral regions. Weighting the local dose with the local perfusion improved the dose-effect relation for the anterior lung region. Irradiation of caudally located lung tumors resulted in a greater risk of RP than irradiation of tumors located in other parts of the lungs.

Purpose: In dose-escalation studies of radiotherapy (RT) for non-small-cell lung cancer (NSCLC), radiation pneumonitis (RP) is the most important dose-limiting complication. Transforming growth factor-beta1 (TGF-beta1) has been reported to be associated with the incidence of RP. It has been proposed that serial measurements of plasma TGF-beta1 can be valuable to estimate the risk of RP and to decide whether additional dose-escalation can be safely applied. The aim of this study was to evaluate prospectively the time course of TGF-beta1 levels in patients irradiated for NSCLC in relation to the development of RP and dose-volume parameters., Methods and Materials: Plasma samples were obtained in 68 patients irradiated for medically inoperable or locally advanced NSCLC (dose range, 60.8-94.5 Gy) before and 4, 6, and 18 weeks after the start of RT. Plasma TGF-beta1 levels were determined using a bioassay on the basis of TGF-beta1-induced plasminogen activator inhibitor-1 expression in mink lung cells. All patients underwent chest computed tomography scans before RT that were repeated at 18 weeks after RT. The computed tomography data were used to calculate the mean lung dose (MLD) and to score the radiation-induced radiologic changes. RP was defined on the basis of the presence of either radiographic changes or clinical symptoms. Symptomatic RP was scored according to the Common Toxicity Criteria (Grade 1 or worse) and the Southwestern Oncology Group criteria (Grade 2 or worse). Multivariate analyses were performed to investigate which factors (pre- or posttreatment TGF-beta1 level, MLD) were associated with the incidence of RP. To improve our understanding of the time course of TGF-beta1 levels, we performed a multivariate analysis to investigate which factors (pre-RT TGF-beta1 level, MLD, RP) were independently associated with the posttreatment TGF-beta1 levels., Results: The pre-RT TGF-beta1 levels were increased in patients with NSCLC (median 21 ng/mL, range, 5-103 ng/mL) compared with healthy individuals (range, 4-12 ng/mL). On average, the TGF-beta1 levels normalized toward the end of treatment and remained stable until 18 weeks after RT. In 29 patients, however, TGF-beta1 was increased at the end of RT with respect to the pre-RT value. The multivariate analyses revealed that the MLD was the only variable that correlated significantly with the risk of both radiographic RP (p = 0.05) and symptomatic RP, independent of the scoring system used (p = 0.05 and 0.03 for Southwestern Oncology Group and Common Toxicity Criteria systems, respectively). The TGF-beta1 level at the end of RT was significantly associated with the MLD (p <0.001) and pre-RT TGF-beta1 level (p = 0.001)., Conclusion: The MLD correlated significantly with the incidence of both radiographic and symptomatic RP. The results of our study did not confirm the reports that increased levels of TGF-beta1 at the end of RT are an independent additional risk factor for developing symptomatic RP. However, the TGF-beta1 level at the end of a RT was significantly associated with the MLD and the pre-RT level.

Purpose: To investigate the three-dimensional (3D) intrafractional motion of liver tumors during real-time tumor-tracking radiotherapy (RTRT)., Materials and Methods: The data of 20 patients with liver tumors were analyzed. Before treatment, a 2-mm gold marker was implanted near the tumor. The RTRT system used fluoroscopy image processor units to determine the 3D position of the implanted marker. A linear accelerator was triggered to irradiate the tumor only when the marker was located within a permitted region. The automatically recorded tumor-motion data were analyzed to determine the amplitude of the tumor motion, curve shape of the tumor motion, treatment efficiency, frequency of movement, and hysteresis. Each of the following clinical factors was evaluated to determine its contribution to the amplitude of movement: tumor position, existence of cirrhosis, surgical history, tumor volume, and distance between the isocenter and the marker., Results: The average amplitude of tumor motion in the 20 patients was 4 +/- 4 mm (range 1-12), 9 +/- 5 mm (range 2-19), and 5 +/- 3 mm (range 2-12) in the left-right, craniocaudal, and anterior-posterior (AP) direction, respectively. The tumor motion of the right lobe was significantly larger than that of the left lobe in the left-right and AP directions (p = 0.01). The tumor motion of the patients with liver cirrhosis was significantly larger than that of the patients without liver cirrhosis in the left-right and AP directions (p < 0.004). The tumor motion of the patients who had received partial hepatectomy was significantly smaller than that of the patients who had no history of any operation on the liver in the left-right and AP directions (p < 0.03). Thus, three of the five clinical factors examined (i.e., tumor position in the liver, cirrhosis, and history of surgery on the liver) significantly affected the tumor motion of the liver in the transaxial direction during stereotactic irradiation. Frequency analysis revealed that for 9 (45%) of the 20 tumors, the cardiac beat caused measurable motion. The 3D trajectory of the tumor showed hysteresis for 4 (20%) of the 20 tumors. The average treatment efficiency of RTRT was 40%., Conclusions: Tumor location, cirrhosis, and history of surgery on the liver all had an impact on the intrafractional tumor motion of the liver in the transaxial direction. This finding should be helpful in determining the smallest possible margin in individual cases of radiotherapy for liver malignancy.

Purpose: To study changes of pulmonary function tests (PFTs) after radiotherapy (RT) of non-small-cell lung cancer (NSCLC) in relation to radiation dose, tumor regression, and changes in lung perfusion., Methods and Materials: Eighty-two patients with inoperable NSCLC were evaluated with PFTs (forced expiratory volume in 1 s [FEV(1)] and diffusion capacity [T(L,COc)]), a computed tomography (CT) scan of the chest, and a single photon emission CT (SPECT) lung perfusion scan, before and 3-4 months after RT. The reductions of PFTs and tumor volume were calculated. The lung perfusion was measured from pre- and post-RT SPECT scans, and the difference was defined as the measured perfusion reduction (MPR). In addition, the perfusion post-RT was estimated from the dose distribution using a dose-effect relation for regional lung perfusion, and compared with the pre-RT lung perfusion to obtain the predicted perfusion reduction (PPR). The difference between the actually measured and the PPR was defined as reperfusion. The mean lung dose (MLD) was computed and weighted with the pre-RT perfusion, resulting in the mean perfusion-weighted lung dose (MpLD). Changes of PFTs were evaluated in relation to tumor dose, MLD, MpLD, tumor regression, and parameters related to perfusion changes., Results: In a multivariate analysis, the total tumor dose and MLD were not associated with reductions of PFTs. Tumor regression resulted in a significant improvement of FEV(1) (p = 0.02), but was associated with a reduction of T(L,COc) (p = 0.05). The MpLD and the PPR showed a significant (p = 0.01 to 0.04) but low correlation (r = 0.24 to 0.31) with the reduction of both PFTs. The other parameters for perfusion changes, the MPR and reperfusion were not correlated with changes in PFTs., Conclusion: The perfusion-related dose variables, the MpLD or the PPR, are the best parameters to estimate PFTs after RT. Tumor regression is associated with an improvement of FEV(1) and a decline of T(L,COc). Reperfusion was not associated with an improvement of global pulmonary function.

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 (TD(50)) 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.

Purpose: To quantify three-dimensional (3D) movement of the prostate gland with the patient in the supine and prone positions and to analyze the movement frequency for each treatment position., Methods and Materials: The real-time tumor-tracking radiotherapy (RTRT) system was developed to identify the 3D position of a 2-mm gold marker implanted in the prostate 30 times/s using two sets of fluoroscopic images. The linear accelerator was triggered to irradiate the tumor only when the gold marker was located within the region of the planned coordinates relative to the isocenter. Ten patients with prostate cancer treated with RTRT were the subjects of this study. The coordinates of the gold marker were recorded every 0.033 s during RTRT in the supine treatment position for 2 min. The patient was then moved to the prone position, and the marker was tracked for 2 min to acquire data regarding movement in this position. Measurements were taken 5 times for each patient (once a week); a total of 50 sets for the 10 patients was analyzed. The raw data from the RTRT system were filtered to reduce system noise, and the amplitude of movement was then calculated. The discrete Fourier transform of the unfiltered data was performed for the frequency analysis of prostate movement., Results: No apparent difference in movement was found among individuals. The amplitude of 3D movement was 0.1-2.7 mm in the supine and 0.4-24 mm in the prone positions. The amplitude in the supine position was statistically smaller in all directions than that in the prone position (p < 0.0001). The amplitude in the craniocaudal and AP directions was larger than in the left-right direction in the prone position (p < 0.0001). No characteristic movement frequency was detected in the supine position. The respiratory frequency was detected for all patients regarding movement in the craniocaudal and AP directions in the prone position. The results of the frequency analysis suggest that prostate movement is affected by the respiratory cycle and is influenced by bowel movement in the prone position., Conclusion: The results of this study have confirmed that internal organ motion is less frequent in the supine position than in the prone position in the treatment of prostate cancer. RTRT would be useful in reducing uncertainty due to the effects of the respiratory cycle, especially in the prone position.

Purpose: In this work, three-dimensional (3D) motion of lung tumors during radiotherapy in real time was investigated. Understanding the behavior of tumor motion in lung tissue to model tumor movement is necessary for accurate (gated or breath-hold) radiotherapy or CT scanning., Methods: Twenty patients were included in this study. Before treatment, a 2-mm gold marker was implanted in or near the tumor. A real-time tumor tracking system using two fluoroscopy image processor units was installed in the treatment room. The 3D position of the implanted gold marker was determined by using real-time pattern recognition and a calibrated projection geometry. The linear accelerator was triggered to irradiate the tumor only when the gold marker was located within a certain volume. The system provided the coordinates of the gold marker during beam-on and beam-off time in all directions simultaneously, at a sample rate of 30 images per second. The recorded tumor motion was analyzed in terms of the amplitude and curvature of the tumor motion in three directions, the differences in breathing level during treatment, hysteresis (the difference between the inhalation and exhalation trajectory of the tumor), and the amplitude of tumor motion induced by cardiac motion., Results: The average amplitude of the tumor motion was greatest (12 +/- 2 mm [SD]) in the cranial-caudal direction for tumors situated in the lower lobes and not attached to rigid structures such as the chest wall or vertebrae. For the lateral and anterior-posterior directions, tumor motion was small both for upper- and lower-lobe tumors (2 +/- 1 mm). The time-averaged tumor position was closer to the exhale position, because the tumor spent more time in the exhalation than in the inhalation phase. The tumor motion was modeled as a sinusoidal movement with varying asymmetry. The tumor position in the exhale phase was more stable than the tumor position in the inhale phase during individual treatment fields. However, in many patients, shifts in the exhale tumor position were observed intra- and interfractionally. These shifts are the result of patient relaxation, gravity (posterior direction), setup errors, and/or patient movement.The 3D trajectory of the tumor showed hysteresis for 10 of the 21 tumors, which ranged from 1 to 5 mm. The extent of hysteresis and the amplitude of the tumor motion remained fairly constant during the entire treatment. Changes in shape of the trajectory of the tumor were observed between subsequent treatment days for only one patient. Fourier analysis revealed that for 7 of the 21 tumors, a measurable motion in the range 1-4 mm was caused by the cardiac beat. These tumors were located near the heart or attached to the aortic arch. The motion due to the heartbeat was greatest in the lateral direction. Tumor motion due to hysteresis and heartbeat can lower treatment efficiency in real-time tumor tracking-gated treatments or lead to a geographic miss in conventional or active breathing controlled treatments., Conclusion: The real-time tumor tracking system measured the tumor position in all three directions simultaneously, at a sampling rate that enabled detection of tumor motion due to heartbeat as well as hysteresis. Tumor motion and hysteresis could be modeled with an asymmetric function with varying asymmetry. Tumor motion due to breathing was greatest in the cranial-caudal direction for lower-lobe unfixed tumors.