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Purpose: To compare the pencil beam (PB) and collapsed cone (CC)-based three-dimensional dose calculation used for stereotactic irradiation of pulmonary targets.Methods and materials: Three-dimensional conformal dose distributions (using 6-MV and 18-MV photon beams) were generated for 33 pulmonary targets using the PB algorithm implemented in the Helax-TMS treatment planning system and then recalculated with the CC algorithm of TMS using an identical beam setup and parameters. The differences were analyzed by evaluating the dose–volume histograms for the planning target volume (PTV) and clinical target volume (CTV) and evaluating the computed absolute monitor units (MUs). The influence of the photon energy was also studied. For three cases, the results were compared with Monte-Carlo calculations.Results: Use of the CC model typically showed increased dose inhomogeneity. Owing to a more accurate modeling of secondary charged particle disequilibrium at the tumor–lung interface, the beam penumbra is broadened. The median and mean target dose decreased by 13.9% and 11.2% for the PTV and 9.2% and 9.4% for the CTV, respectively, using the CC algorithm. Consequently, the average PTV dose coverage decreased by 7.1% (SD, 6.5%). On average, the MUs calculated to achieve the prescribed dose were 5.4% (SD, 5.8%) greater for the CC algorithm. The difference in MUs between the PB and CC increased with decreasing PTV size and high photon energy (18 MV; r = -0.68), reaching 26% at the maximum.Conclusion: The absorbed dose at the lung–tumor interface calculated by the PB algorithm was considerably greater than the dose calculated using the CC algorithm. In small targets (PTV ≤100 cm3) and for 18-MV photons, the MUs calculated with PB may lead to an insufficient dose to the target volume. [Copyright &y& Elsevier]

Purpose: To report long-term outcome of fractionated stereotactic body radiation therapy (SBRT) for painful spinal metastases.Methods and Materials: This prospective, single-arm, multicenter phase 2 clinical trial enrolled 57 patients with 63 painful, unirradiated spinal metastases between March 2012 and July 2015. Patients were treated with 48.5 Gy in 10 SBRT fractions (long life expectancy [Mizumoto score ≤4]) or 35 Gy in 5 SBRT fractions (intermediate life expectancy [Mizumoto score 5-9]). Pain response was defined as pain improvement of a minimum of 2 points on a visual analog scale, and net pain relief was defined as the sum of time with pain response (complete and partial) divided by the overall follow-up time.Results: All 57 patients received treatment per protocol; 32 and 25 patients were treated with 10- and 5-fraction SBRT, respectively. The median follow-up of living patients was 60 months (range, 33-74 months). Of evaluable patients, 82% had complete or partial pain response (responders) at 3 months' follow-up (primary endpoint), and pain response remained stable over 5 years. Net pain relief was 74% (95% CI, 65%-80%). Overall survival rates of 1, 3, and 5 years were 59.6% (95% CI, 47%-72%), 33.3% (95% CI, 21%-46%), and 21% (95% CI, 10%-32%), respectively. Freedom from local spinal-metastasis progression was 82% at the last imaging follow-up. Late grade-3 toxicity was limited to pain in 2 patients (nonresponders). There were no cases of myelopathy. SBRT resulted in long-term improvements of all dimensions of the 5-level EuroQol 5-Dimension Questionnaire except anxiety/depression.Conclusions: Fractionated SBRT achieved durable pain response and improved quality of life at minimum late toxicity. [ABSTRACT FROM AUTHOR]

Purpose: Many technological and methodical advances have made stereotactic body radiotherapy (SBRT) more accurate and more efficient during the last years. This study aims to investigate whether experience in SBRT and technological innovations also translated into improved local control (LC) and overall survival (OS).Methods and Materials: A database of 700 patients treated with SBRT for lung metastases in 20 German centers between 1997 and 2014 was used for analysis. It was the aim of this study to investigate the impact of fluorodeoxyglucose positron-emission tomography (FDG-PET) staging, biopsy confirmation, image guidance, immobilization, and dose calculation algorithm, as well as the influence of SBRT experience, on LC and OS.Results: Median follow-up time was 14.3 months (range, 0-131.9 months), with 2-year LC and OS of 81.2% (95% confidence interval [CI] 75.8%-85.7%) and 54.4% (95% CI 50.2%-59.0%), respectively. In multivariate analysis, all treatment technologies except FDG-PET staging did not significantly influence outcome. Patients who received pre-SBRT FDG-PET staging showed superior 1- and 2-year OS of 82.7% (95% CI 77.4%-88.6%) and 64.8% (95% CI 57.5%-73.3%), compared with patients without FDG-PET staging resulting in 1- and 2-year OS rates of 72.8% (95% CI 67.4%-78.8%) and 52.6% (95% CI 46.0%-60.4%), respectively (P=.012). Experience with SBRT was identified as the main prognostic factor for LC: institutions with higher SBRT experience (patients treated with SBRT within the last 2 years of the inclusion period) showed superior LC compared with less-experienced centers (P≤.001). Experience with SBRT within the last 2 years was independent from known prognostic factors for LC.Conclusion: Investigated technological and methodical advancements other than FDG-PET staging before SBRT did not significantly improve outcome in SBRT for pulmonary metastases. In contrast, LC was superior with increasing SBRT experience of the individual center. [ABSTRACT FROM AUTHOR]

Purpose: Most radiobiological models for prediction of tumor control probability (TCP) do not account for the fact that many events could remain unobserved because of censoring. We therefore evaluated a set of TCP models that take into account this censoring.Methods and Materials: We applied 2 fundamental Bayesian cure rate models to a sample of 770 pulmonary metastasis treated with stereotactic body radiation therapy at German, Austrian, and Swiss institutions: (1) the model developed by Chen, Ibrahim and Sinha (the CIS99 model); and (2) a mixture model similar to the classic model of Berkson and Gage (the BG model). In the CIS99 model the number of clonogens surviving the radiation treatment follows a Poisson distribution, whereas in the BG model only 1 dominant recurrence-competent tissue mass may remain. The dose delivered to the isocenter, tumor size and location, sex, age, and pretreatment chemotherapy were used as covariates for regression.Results: Mean follow-up time was 15.5 months (range: 0.1-125). Tumor recurrence occurred in 11.6% of the metastases. Delivered dose, female sex, peripheral tumor location and having received no chemotherapy before RT were associated with higher TCP in all models. Parameter estimates of the CIS99 were consistent with the classical Cox proportional hazards model. The dose required to achieve 90% tumor control after 15.5 months was 146 (range: 114-188) Gy10 in the CIS99 and 133 (range: 101-164) Gy10 in the BG model; however, the BG model predicted lower tumor control at long (≳20 months) follow-up times and gave a suboptimal fit to the data compared to the CIS99 model.Conclusions: Biologically motivated cure rate models allow adding the time component into TCP modeling without being restricted to the follow-up period which is the case for the Cox model. In practice, application of such models to the clinical setting could allow for adaption of treatment doses depending on whether local control should be achieved in the short or longer term. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the accuracy of real-time couch tracking for prostate cancer. Methods and Materials: Intrafractional motion trajectories of 15 prostate cancer patients were the basis for this phantom study; prostate motion had been monitored with the Calypso System. An industrial robot moved a phantom along these trajectories, motion was detected via an infrared camera system, and the robotic HexaPOD couch was used for real-time counter-steering. Residual phantom motion during real-time tracking was measured with the infrared camera system. Film dosimetry was performed during delivery of 3-dimensional conformal radiation therapy (3D-CRT), step-and-shoot intensity modulated radiation therapy (IMRT), and volumetric modulated arc therapy (VMAT). Results: Motion of the prostate was largest in the anterior–posterior direction, with systematic (∑) and random (σ) errors of 2.3 mm and 2.9 mm, respectively; the prostate was outside a threshold of 5 mm (3D vector) for 25.0%±19.8% of treatment time. Real-time tracking reduced prostate motion to ∑=0.01 mm and σ = 0.55 mm in the anterior–posterior direction; the prostate remained within a 1-mm and 5-mm threshold for 93.9%±4.6% and 99.7%±0.4% of the time, respectively. Without real-time tracking, pass rates based on a γ index of 2%/2 mm in film dosimetry ranged between 66% and 72% for 3D-CRT, IMRT, and VMAT, on average. Real-time tracking increased pass rates to minimum 98% on average for 3D-CRT, IMRT, and VMAT. Conclusions: Real-time couch tracking resulted in submillimeter accuracy for prostate cancer, which transferred into high dosimetric accuracy independently of whether 3D-CRT, IMRT, or VMAT was used. [ABSTRACT FROM AUTHOR]

Purpose: The recognition of the true prevalence of cardiac toxicity after mediastinal radiotherapy requires very long follow-up and a precise diagnostic procedure. Cardiac magnetic resonance imaging (MRI) permits excellent quantification of cardiac function and identification of localized myocardial defects and has now been applied to a group of 20-year Hodgkin''s disease survivors. Methods and materials: Of 143 patients treated with anterior mediastinal radiotherapy (cobalt-60, median prescribed dose 40 Gy) for Hodgkin''s disease between 1978 and 1985, all 53 survivors were invited for cardiac MRI. Of those, 36 patients (68%) presented for MRI, and in 31 patients (58%) MRI could be performed 20–28 years (median, 24) after radiotherapy. The following sequences were acquired on a 1.5-T MRI: transversal T1-weighted TSE and T2-weighted half-fourier acquisition single-shot turbo-spin-echo sequences, a steady-state free precession (SSFP) cine sequence in the short heart axis and in the four-chamber view, SSFP perfusion sequences under rest and adenosine stress, and a SSFP inversion recovery sequence for late enhancement. The MRI findings were correlated with previously reconstructed doses to cardiac structures. Results: Clinical characteristics and reconstructed doses were not significantly different between survivors undergoing and not undergoing MRI. Pathologic findings were reduced left ventricular function (ejection fraction <55%) in 7 (23%) patients, hemodynamically relevant valvular dysfunction in 13 (42%), late myocardial enhancement in 9 (29%), and any perfusion deficit in 21 (68%). An association of regional pathologic changes and reconstructed dose to cardiac structures could not be established. Conclusions: In 20-year survivors of Hodgkin''s disease, cardiac MRI detects pathologic findings in approximately 70% of patients. Cardiac MRI has a potential role in cardiac imaging of Hodgkin''s disease patients after mediastinal radiotherapy. [Copyright &y& Elsevier]

Purpose: To evaluate the potential of adaptive radiotherapy (ART) for advanced-stage non–small cell lung cancer (NSCLC) in terms of lung sparing and dose escalation. Methods and Materials: In 13 patients with locally advanced NSCLC, weekly CT images were acquired during radio- (n = 1) or radiochemotherapy (n = 12) for simulation of ART. Three-dimensional (3D) conformal treatment plans were generated: conventionally fractionated doses of 66 Gy were prescribed to the planning target volume without elective lymph node irradiation (Plan_3D). Using a surface-based algorithm of deformable image registration, accumulated doses were calculated in the CT images acquired during the treatment course (Plan_4D). Field sizes were adapted to tumor shrinkage once in week 3 or 5 and twice in weeks 3 and 5. Results: A continuous tumor regression of 1.2% per day resulted in a residual gross tumor volume (GTV) of 49% ± 15% after six weeks of treatment. No systematic differences between Plan_3D and Plan_4D were observed regarding doses to the GTV, lung, and spinal cord. Plan adaptation to tumor shrinkage resulted in significantly decreased lung doses without compromising GTV coverage: single-plan adaptation in Week 3 or 5 and twice-plan adaptation in Weeks 3 and 5 reduced the mean lung dose by 5.0% ± 4.4%, 5.6% ± 2.9% and 7.9% ± 4.8%, respectively. This lung sparing with twice ART allowed an iso–mean lung dose escalation of the GTV dose from 66.8 Gy ± 0.8 Gy to 73.6 Gy ± 3.8 Gy. Conclusions: Adaptation of radiotherapy to continuous tumor shrinkage during the treatment course reduced doses to the lung, allowed significant dose escalation and has the potential of increased local control. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the potential of adaptive radiotherapy (ART) for advanced-stage non-small cell lung cancer (NSCLC) in terms of lung sparing and dose escalation. Methods and Materials: In 13 patients with locally advanced NSCLC, weekly CT images were acquired during radio- (n=1) or radiochemotherapy (n=12) for simulation of ART. Three-dimensional (3D) conformal treatment plans were generated: conventionally fractionated doses of 66 Gy were prescribed to the planning target volume without elective lymph node irradiation (Plan_3D). Using a surface-based algorithm of deformable image registration, accumulated doses were calculated in the CT images acquired during the treatment course (Plan_4D). Field sizes were adapted to tumor shrinkage once in week 3 or 5 and twice in weeks 3 and 5. Results: A continuous tumor regression of 1.2% per day resulted in a residual gross tumor volume (GTV) of 49%±15% after six weeks of treatment. No systematic differences between Plan_3D and Plan_4D were observed regarding doses to the GTV, lung, and spinal cord. Plan adaptation to tumor shrinkage resulted in significantly decreased lung doses without compromising GTV coverage: single-plan adaptation in Week 3 or 5 and twice-plan adaptation in Weeks 3 and 5 reduced the mean lung dose by 5.0%±4.4%, 5.6%±2.9% and 7.9%±4.8%, respectively. This lung sparing with twice ART allowed an iso-mean lung dose escalation of the GTV dose from 66.8 Gy±0.8 Gy to 73.6 Gy±3.8 Gy. Conclusions: Adaptation of radiotherapy to continuous tumor shrinkage during the treatment course reduced doses to the lung, allowed significant dose escalation and has the potential of increased local control. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the feasibility and accuracy of a method for markerless tracking of lung tumors in electronic portal imaging device (EPID) movies and to analyze intra- and interfractional variations in tumor motion. Methods and Materials: EPID movies were acquired during stereotactic body radiotherapy (SBRT) given to 40 patients with 49 pulmonary targets and retrospectively analyzed. Tumor visibility and tracking accuracy were determined by three observers. Tumor motion of 30 targets was analyzed in detail via four-dimensional computed tomography (4DCT) and EPID in the superior-inferior direction for intra- and interfractional variations. Results: Tumor visibility was sufficient for markerless tracking in 47% of the EPID movies. Tumor size and visibility in the DRR were correlated with visibility in the EPID images. The difference between automatic and manual tracking was a maximum of 2 mm for 98.3% in the x direction and 89.4% in the y direction. Motion amplitudes in 4DCT images (range, 0.7-17.9 mm; median, 4.9 mm) were closely correlated with amplitudes in the EPID movies. Intrafractional and interfractional variability of tumor motion amplitude were of similar magnitude: 1 mm on average to a maximum of 4 mm. A change in moving average of more than ±1 mm, ±2 mm, and ±4 mm were observed in 47.1%, 17.1%, and 4.5% of treatment time for all trajectories, respectively. Mean tumor velocity was 3.4 mm/sec, to a maximum 61 mm/sec. Conclusions: Tracking of pulmonary tumors in EPID images without implanted markers was feasible in 47% of all treatment beams. 4DCT is representative of the evaluation of mean breathing motion on average, but larger deviations occurred in target motion between treatment planning and delivery effort a monitoring during delivery. [Copyright &y& Elsevier]

Purpose: To investigate the influence of continuous table motion on patient breathing patterns for compensation of moving targets by a robotic treatment couch. Methods and Materials: Fifteen volunteers were placed on a robotic treatment couch, and the couch was moved on different breathing-correlated and -uncorrelated trajectories. External abdominal breathing motion of the patients was measured using an infrared camera system. The influence of table motion on breathing range and pattern was analyzed. Results: Continuous table motion was tolerated well by all test persons. Volunteers reacted differently to table motion. Four test persons showed no change of breathing range and pattern. Increased irregular breathing was observed in 4 patients; however, irregularity was not correlated with table motion. Only 4 test persons showed an increase in mean breathing amplitude of more than 2mm during motion of the couch. The mean cycle period decreased by more than 1 s for 2 test persons only. No abrupt changes in amplitude or cycle period could be observed. Conclusions: The observed small changes in breathing patterns support the application of motion compensation by a robotic treatment couch. [Copyright &y& Elsevier]

Purpose: To evaluate the outcomes after dose-escalated radiotherapy (RT) for spinal metastases and paraspinal tumors. Methods and Materials: A total of 14 patients, 12 with spinal metastases and a long life expectancy and 2 with paraspinal tumors, were treated for 16 lesions with intensity-modulated, image-guided RT. A median biologic effective dose of 74 Gy10 (range, 55–86) in a median of 20 fractions (range, 3–34) was prescribed to the target volume. The spinal canal was treated to 40 Gy in 20 fractions using a second intensity-modulated RT dose level in the case of epidural involvement. Results: After median follow-up of 17 months, one local recurrence was observed, for an actuarial local control rate of 88% after 2 years. Local control was associated with rapid and long-term pain relief. Of 11 patients treated for a solitary spinal metastasis, 6 developed systemic disease progression. The actuarial overall survival rate for metastatic patients was 85% and 63% after 1 and 2 years, respectively. Acute Grade 2-3 skin toxicity was seen in 2 patients with no late toxicity greater than Grade 2. No radiation-induced myelopathy was observed. Conclusion: Dose-escalated irradiation of spinal metastases was safe and resulted in excellent local control. Oligometastatic patients with a long life expectancy and epidural involvement are considered to benefit the most from fractionated RT. [Copyright &y& Elsevier]

Purpose: To evaluate the accuracy of direct reconstruction of mid-ventilation and peak-phase four-dimensional (4D) computed tomography (CT) frames based on the external breathing signal. Methods and Materials: For 11 patients with 15 pulmonary targets, a respiration-correlated CT study (4D CT) was acquired for treatment planning. After retrospective time-based sorting of raw projection data and reconstruction of eight CT frames equally distributed over the breathing cycle, mean tumor position (Pmean), mid-ventilation frame, and breathing motion were evaluated based on the internal tumor trajectory. Analysis of the external breathing signal (pressure sensor around abdomen) with amplitude-based sorting of projections was performed for direct reconstruction of the mid-ventilation frame and frames at peak phases of the breathing cycle. Results: On the basis of the eight 4D CT frames equally spaced in time, tumor motion was largest in the craniocaudal direction, with 12 ± 7 mm on average. Tumor motion between the two frames reconstructed at peak phases was not different in the craniocaudal and anterior–posterior directions but was systematically smaller in the left–right direction by 1 mm on average. The 3-dimensional distance between Pmean and the tumor position in the mid-ventilation frame based on the internal tumor trajectory was 1.2 ± 1 mm. Reconstruction of the mid-ventilation frame at the mean amplitude position of the external breathing signal resulted in tumor positions 2.0 ± 1.1 mm distant from Pmean. Breathing-induced motion artifacts in mid-ventilation frames caused negligible changes in tumor volume and shape. Conclusions: Direct reconstruction of the mid-ventilation frame and frames at peak phases based on the external breathing signal was reliable. This makes the reconstruction of only three 4D CT frames sufficient for application of the mid-ventilation technique in clinical practice. [Copyright &y& Elsevier]

Purpose: To evaluate outcome after image-guided stereotactic body radiotherapy (SBRT) for early-stage non-small-cell lung cancer (NSCLC) and pulmonary metastases. Methods and Materials: A total of 124 patients with 159 pulmonary lesions (metastases n = 118; NSCLC, n = 41; Stage IA, n = 13; Stage IB, n = 19; T3N0, n = 9) were treated with SBRT. Patients were treated with hypofractionated schemata (one to eight fractions of 6-26 Gy); biologic effective doses (BED) to the clinical target volume (CTV) were calculated based on four-dimensional (4D) dose calculation. The position of the pulmonary target was verified using volume imaging before all treatments. Results: With mean/median follow-up of 18/14 months, actuarial local control was 83% at 36 months with no difference between NSCLC and metastases. The dose to the CTV based on 4D dose calculation was closely correlated with local control: local control rates were 89% and 62% at 36 months for >100 Gy and <100 Gy BED (p = 0.0001), respectively. Actuarial freedom from regional and systemic progression was 34% at 36 months for primary NSCLC group; crude rate of regional failure was 15%. Three-year overall survival was 37% for primary NSCLC and 16% for metastases; no dose-response relationship for survival was observed. Exacerbation of comorbidities was the most frequent cause of death for primary NSCLC. Conclusions: Doses of >100 Gy BED to the CTV based on 4D dose calculation resulted in excellent local control rates. This cutoff dose is not specific to the treatment technique and protocol of our study and may serve as a general recommendation. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate outcome after image-guided stereotactic body radiotherapy (SBRT) for early-stage non–small-cell lung cancer (NSCLC) and pulmonary metastases. Methods and Materials: A total of 124 patients with 159 pulmonary lesions (metastases n = 118; NSCLC, n = 41; Stage IA, n = 13; Stage IB, n = 19; T3N0, n = 9) were treated with SBRT. Patients were treated with hypofractionated schemata (one to eight fractions of 6–26 Gy); biologic effective doses (BED) to the clinical target volume (CTV) were calculated based on four-dimensional (4D) dose calculation. The position of the pulmonary target was verified using volume imaging before all treatments. Results: With mean/median follow-up of 18/14 months, actuarial local control was 83% at 36 months with no difference between NSCLC and metastases. The dose to the CTV based on 4D dose calculation was closely correlated with local control: local control rates were 89% and 62% at 36 months for >100 Gy and <100 Gy BED (p = 0.0001), respectively. Actuarial freedom from regional and systemic progression was 34% at 36 months for primary NSCLC group; crude rate of regional failure was 15%. Three-year overall survival was 37% for primary NSCLC and 16% for metastases; no dose–response relationship for survival was observed. Exacerbation of comorbidities was the most frequent cause of death for primary NSCLC. Conclusions: Doses of >100 Gy BED to the CTV based on 4D dose calculation resulted in excellent local control rates. This cutoff dose is not specific to the treatment technique and protocol of our study and may serve as a general recommendation. [Copyright &y& Elsevier]

Purpose: To evaluate a novel four-dimensional (4D) image-guided radiotherapy (IGRT) technique in stereotactic body RT for liver tumors. Methods and Materials: For 11 patients with 13 intrahepatic tumors, a respiratory-correlated 4D computed tomography (CT) scan was acquired at treatment planning. The target was defined using CT series reconstructed at end-inhalation and end-exhalation. The liver was delineated on these two CT series and served as a reference for image guidance. A cone-beam CT scan was acquired after patient positioning; the blurred diaphragm dome was interpreted as a probability density function showing the motion range of the liver. Manual contour matching of the liver structures from the planning 4D CT scan with the cone-beam CT scan was performed. Inter- and intrafractional uncertainties of target position and motion range were evaluated, and interobserver variability of the 4D-IGRT technique was tested. Results: The workflow of 4D-IGRT was successfully practiced in all patients. The absolute error in the liver position and error in relation to the bony anatomy was 8 ± 4 mm and 5 ± 2 mm (three-dimensional vector), respectively. Margins of 4–6 mm were calculated for compensation of the intrafractional drifts of the liver. The motion range of the diaphragm dome was reproducible within 5 mm for 11 of 13 lesions, and the interobserver variability of the 4D-IGRT technique was small (standard deviation, 1.5 mm). In 4 patients, the position of the intrahepatic lesion was directly verified using a mobile in-room CT scanner after application of intravenous contrast. Conclusion: The results of our study have shown that 4D image guidance using liver contour matching between respiratory-correlated CT and cone-beam CT scans increased the accuracy compared with stereotactic positioning and compared with IGRT without consideration of breathing motion. [Copyright &y& Elsevier]

Purpose: To investigate the influence of tumor motion on the calculation of four-dimensional (4D) dose distributions of the gross tumor volume (GTV) in pulmonary stereotactic body radiotherapy. Methods and Materials: For 7 patients with eight pulmonary tumors, a respiratory-correlated 4D-computed tomography study was acquired. The internal target volume was the sum of all tumor positions in the planning 4D-computed tomography study, and a 5-mm margin was used for generation of the planning target volume. Three-dimensional (3D) treatment plans were generated with a dose prescription of 3 x 12.5 Gy to the planning target volume enclosing the 65% and 80% isodose. After model-based nonrigid image registration, the 4D dose distributions were calculated. Results: No significant difference was found in the dose to the GTV with the tumor in the end-exhalation, end-inhalation, or mid-ventilation phase of the breathing cycle. The high-dose region was confined to the solid tumor, and lower doses were delivered to the surrounding pulmonary tissue of lower density. This nonstatic, variant dose distribution increased the 4D dose to the GTV by 6.2%, on average, compared with calculations using on a static dose distribution during the breathing cycle. The 4D accumulation resulted in a biologic effective dose (BED) of 143 +/- 8 Gy and 106 +/- 4 Gy to the GTV in the plan-65% and plan-80%, respectively. The dose to the ipsilateral lung was not different between the 3D and 4D dose calculations or between plan-65% and plan-80%. Conclusions: In this study, the dose to the GTV was not decreased or blurred in the 4D plan compared with the 3D plan. The 3D doses to the GTV, internal target volume, and dose at the isocenter were good approximations of the 4D dose calculations. The 3D dose at the planning target volume margin underestimated the 4D dose significantly. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate whether the position of brain metastases remains stable between planning and treatment in cranial stereotactic radiotherapy (SRT). Methods and Materials: Eighteen patients with 20 brain metastases were treated with single-fraction (17 lesions) or hypofractionated (3 lesions) image-guided SRT. Median time interval between planning and treatment was 8 days. Before treatment a cone-beam CT (CBCT) and a conventional CT after application of i.v. contrast were acquired. Setup errors using automatic bone registration (CBCT) and manual soft-tissue registration of the brain metastases (conventional CT) were compared. Results: Tumor size was not significantly different between planning and treatment. The three-dimensional setup error (mean +/- SD) was 4.0 +/- 2.1 mm and 3.5 +/- 2.2 mm according to the bony anatomy and the lesion itself, respectively. A highly significant correlation between automatic bone match and soft-tissue registration was seen in all three directions (r >/= 0.88). The three-dimensional distance between the isocenter according to bone match and soft-tissue registration was 1.7 +/- 0.7 mm, maximum 2.8 mm. Treatment of intracranial pressure with steroids did not influence the position of the lesion relative to the bony anatomy. Conclusion: With a time interval of approximately 1 week between planning and treatment, the bony anatomy of the skull proved to be an excellent surrogate for the target position in image-guided SRT. [ABSTRACT FROM AUTHOR]

Purpose: Respiratory correlated computed tomography has been shown to be effective for evaluation of breathing-induced motion of pulmonary tumors. This study investigated whether a single four-dimensional CT study (4D-CT) is representative and sufficient for treatment planning in stereotactic body radiotherapy (SBRT). Methods and Materials: Four repeated helical 4D-CT studies were acquired every 10 min for 10 patients with 14 pulmonary metastases. Patients remained immobilized in a stereotactic body frame (SBF) for 30 min; abdominal compression was applied to seven patients. Using amplitude based sorting, eight phases equally distributed over the breathing cycle were reconstructed for each 4D-CT study. Tumor position was defined in a total of 406 CT series and variability of breathing motion and mean tumor position were evaluated. Results: Peak-to-peak tumor motion was 9.9 mm +/- 6.8 mm (mean +/- standard deviation) and 9.0 mm +/- 7.4 mm at time point 0 min (t(0)) and t(30), respectively. In one patient with poor pulmonary function, continuous increase of breathing motion from 17.4 mm at t(0) to 28.3 mm at t(30) was seen. In five and two lesions, respectively, a drift of the mean tumor position greater than 3 mm and 5 mm was observed. A borderline significance was calculated for larger tumor position variability in midventilation phases compared with peak-ventilation phases of the breathing cycle (p = 0.08). Conclusion: Treatment planning based on a single 4D-CT study is reliable for the majority of patients. Increased intrafractional uncertainties were seen for patients with poor pulmonary function and with tumors located in the lower lobe. [ABSTRACT FROM AUTHOR]

Purpose: To scrutinize the positioning accuracy and reproducibility of a commercial hexapod robot treatment table (HRTT) in combination with a commercial cone-beam computed tomography system for image-guided radiotherapy (IGRT). Methods and Materials: The mechanical stability of the X-ray volume imaging (XVI) system was tested in terms of reproducibility and with a focus on the moveable parts, i.e., the influence of kV panel and the source arm on the reproducibility and accuracy of both bone and gray value registration using a head-and-neck phantom. In consecutive measurements the accuracy of the HRTT for translational, rotational, and a combination of translational and rotational corrections was investigated. The operational range of the HRTT was also determined and analyzed. Results: The system performance of the XVI system alone was very stable with mean translational and rotational errors of below 0.2 mm and below 0.2°, respectively. The mean positioning accuracy of the HRTT in combination with the XVI system summarized over all measurements was below 0.3 mm and below 0.3° for translational and rotational corrections, respectively. The gray value match was more accurate than the bone match. Conclusion: The XVI image acquisition and registration procedure were highly reproducible. Both translational and rotational positioning errors can be corrected very precisely with the HRTT. The HRTT is therefore well suited to complement cone-beam computed tomography to take full advantage of position correction in six degrees of freedom for IGRT. The combination of XVI and the HRTT has the potential to improve the accuracy of high-precision treatments. [Copyright &y& Elsevier]

Purpose: To establish volume imaging using an on-board cone-beam CT (CB-CT) scanner for evaluation of three-dimensional patient setup errors. Methods and Materials: The data from 24 patients were included in this study, and the setup errors using 209 CB-CT studies and 148 electronic portal images were analyzed and compared. The effect of rotational errors alone, translational errors alone, and combined rotational and translational errors on target coverage and sparing of organs at risk was investigated. Results: Translational setup errors using the CB-CT scanner and an electronic portal imaging device differed <1 mm in 70.7% and <2 mm in 93.2% of the measurements. Rotational errors >2° were recorded in 3.7% of pelvic tumors, 26.4% of thoracic tumors, and 12.4% of head-and-neck tumors; the corresponding maximal rotational errors were 5°, 8°, and 6°. No correlation between the magnitude of translational and rotational setup errors was observed. For patients with elongated target volumes and sharp dose gradients to adjacent organs at risk, both translational and rotational errors resulted in considerably decreased target coverage and highly increased doses to the organs at risk compared with the initial treatment plan. Conclusions: The CB-CT scanner has been successfully established for the evaluation of patient setup errors, and its feasibility in day-to-day clinical practice has been demonstrated. Our results have indicated that rotational errors are of clinical significance for selected patients receiving high-precision radiotherapy. [Copyright &y& Elsevier]

Purpose: To prove an expected benefit of concurrent radiochemotherapy (RCT), a two-arm randomized multicentric study was performed. In a subgroup analysis the influence of pretherapeutical hemoglobin level (p-Hb) on survival under locoregional control (SLC) was tested. Patients and Methods: The study included primarily untreated Stage III/IV (International Union Against Cancer [UICC]) oropharyngeal and hypopharyngeal carcinomas. Patients were randomized to receive either hyperfractionated (hf) and accelerated (acc) RCT with two cycles 5-fluorouracil (600 mg/m2/day) and carboplatin (70 mg/m2/day) on Days 1–5 and 29–33 or hf-acc radiotherapy (RT) alone. Total RT dose in both arms was 69.9 Gy in 38 days in concomitant boost technique. Results: After a median follow-up time of 57 months, SLC is significantly better in RCT than in RT (p = 0.01), with median SLC of 17 months and 11 months, respectively. Also overall survival (OS) shows a benefit for RCT (p = 0.016), with a median survival of 23 months for RCT and 16 months for RT. However, the benefit in SLC and OS is not seen in hypopharyngeal carcinomas. In a multivariate analysis of oropharyngeal cancer patients, p-Hb levels lower than 12.7 g/dL resulted in lower SLC compared with higher p-Hb levels up to 13.8 g/dL. P-Hb levels >13.8 g/dL did not further improve SLC. Conclusions: Hyperfractionated-accelerated RCT is superior to hf-acc RT in oropharyngeal carcinomas. P-Hb levels >13.8 g/dL do not further improve SLC. [Copyright &y& Elsevier]

Purpose: To analyze the radiation-induced levels of gammaH2AX and its decay kinetics in 10 human cell lines covering a wide range of cellular radiosensitivity (SF2, 0.06-0.63).Methods and Materials: Five tumor cell lines included Colo-800 melanoma, two glioblastoma (MO59J and MO59K), fibrosarcoma HT 1080, and breast carcinoma MCF7. Five primary skin fibroblasts lines included two normal strains, an ataxia telangiectasia strain, and two fibroblast strains from breast cancer patients with an adverse early skin reaction to radiotherapy. Cellular radiosensitivity was assessed by colony-forming test. Deoxyribonucleic acid damage and repair were analyzed according to nuclear gammaH2AX foci intensity, with digital image analysis.Results: The cell lines tested showed a wide degree of variation in the background intensity of immunostained nuclear histone gammaH2AX, which was higher for the tumor cell lines compared with the fibroblast strains. It was not possible to predict clonogenic cell survival (SF2) for the 10 cell lines studied from the radiation-induced gammaH2AX intensity. In addition, the slopes of the dose-response (0-4 Gy) curves, the rates of gammaH2AX disappearance, and its residual expression (Conclusions: The results from 10 cell lines showed that measurements of immunofluorescence intensity by digital image analysis of phosphorylated histone H2AX as a surrogate marker of DNA double-strand breaks did not allow reliable ranking of cell strains according to their clonogenic survival after irradiation. [ABSTRACT FROM AUTHOR]

Purpose: Published clinical studies provide conflicting data regarding the prognostic significance of carbonic anhydrase IX (CA IX) overexpression as an endogenous marker of tumor hypoxia and its comparability with other methods of hypoxia detection. We performed a systematic analysis of CA IX protein levels under various in vitro conditions of tumor hypoxia in HT 1080 human fibrosarcoma and FaDu human pharyngeal carcinoma cells. Because sorting of live CA IX positive cells from tumors provides a tool to study the radiosensitivity of chronically hypoxic cells, we modified and tested a CA IX flow cytometry protocol on mixed hypoxic/aerobic suspensions of HT 1080 and FaDu cells. Methods and Materials: HT 1080 and FaDu cells were treated with up to 24 h of in vitro hypoxia and up to 96 h of reoxygenation. To test the effect of nonhypoxic stimuli, glucose and serum availability, pH and cell density were modified. CA IX protein was quantified in Western blots of whole-cell lysates. Mixed suspensions with known percentages of hypoxic cells were prepared for CA IX flow cytometry. The same mixtures were assayed for clonogenic survival after 10 Gy. Results: Hypoxia-induced CA IX protein expression was seen after >6 h at < or =5% O(2), and protein was stable over 96 h of reoxygenation in both cell lines. Glucose deprivation abolished the hypoxic CA IX response, and high cell density caused CA IX induction under aerobic conditions. Measured percentages of CA IX-positive cells in mixtures closely reflected known percentages of hypoxic cells in HT 1080 and were associated with radioresistance of mixtures after 10 Gy. Conclusion: CA IX is a stable marker of current or previous chronic hypoxia but influenced by nonhypoxic stimuli. Except the time course of accumulation, all properties of this marker resembled our previous findings for hypoxia-inducible factor-1alpha. A modified flow cytometry protocol provided good separability of CA IX-negative and -positive cells in vitro and can be applied to sort chronically hypoxic cells from tumors. [ABSTRACT FROM AUTHOR]

Purpose: The clinical results of dose escalation using stereotactic radiotherapy to increase local tumor control in medically inoperable patients with Stage I-II non–small-cell lung cancer or pulmonary metastases were evaluated.Methods and materials: Twenty patients with Stage I-II non–small-cell lung cancer and 41 patients with 51 pulmonary metastases not amenable to surgery were treated with stereotactic radiotherapy at 3 × 10 Gy (n = 19), 3 × 12–12.5 Gy to the planning target volume enclosing 100%–isodose, with normalization to 150% at the isocenter; n = 26) or 1 × 26 Gy to the planning target volume enclosing 80%–isodose (n = 26). The median follow-up was 11 months (range, 2–61 months) for primary lung cancer patients and 9 months (range, 2–37 months) for patients with metastases.Results: The actuarial local control rate was 92% for lung cancer patients and 80% for metastasis patients ≥1 year after treatment and was significantly improved by increasing the dose from 3 × 10 Gy to 3 × 12–12.5 Gy or 1 × 26 Gy (p = 0.038). The overall survival rate after 1 and 2 years was 52% and 32%, respectively, for lung cancer patients and 85% and 33%, respectively, for metastasis patients, impaired because of systemic disease progression. After 12 months, 60% of patients with primary lung cancer and 35% of patients with pulmonary metastases were without systemic progression. No severe acute or late toxicity was observed, and only 2 patients (3%) developed symptomatic Grade 2 pneumonitis, which was successfully treated with oral steroids.Conclusion: Stereotactic radiotherapy for lung tumors offers a very effective treatment option locally without significant complications in medically impaired patients who are not amenable to surgery. Patient selection is important, because those with a low risk of systemic progression are more likely to benefit from this approach. [Copyright &y& Elsevier]

: PurposeThe transcription factor subunit hypoxia-inducible factor-1α (HIF-1α) is currently discussed as a potential endogenous marker of tumor hypoxia to select patients for modified treatment. Despite an association of immunohistochemical HIF-1α overexpression and poor prognosis after radiotherapy in many tumor entities, the reported pattern of HIF-1α staining was often not consistent with tumor hypoxia. To explain this discrepancy, we studied the in vitro conditions under which HIF-1α protein accumulates.: Methods and materialsFaDu human pharyngeal carcinoma and HT 1080 human fibrosarcoma cells were treated with different schedules of in vitro hypoxia at 5%, 1%, and 0.1% O2 and reoxygenation. HIF-1α protein levels were determined in nuclear extracts. Cellular radiation sensitivity was assessed by clonogenic survival assay after single-dose irradiation at the above oxygen concentrations.: ResultsIn both cell lines, weak HIF-1α expression was observed at 20% O2 and after 10 min of hypoxia. Increased HIF-1α protein levels were observed at 1 h of hypoxia, remained stable over 24 h, and decreased to baseline within 15 min of reoxygenation. HIF-1α protein at 5% O2 was half-maximal in FaDu but indistinguishable from 0.1% O2 in HT 1080. A good correlation of HIF-1α protein level and hypoxic radiation resistance, with equal ranking of data points by both assays, was observed in FaDu cells but not in HT 1080 cells.: ConclusionsThe ability of HIF-1α to indicate radiobiologically relevant levels of tumor hypoxia seems to be cell type specific. This finding may explain the inconsistent results regarding the pattern of HIF-1α expression in tumor sections. [Copyright &y& Elsevier]

Purpose: Type II cells and the surfactant system have been proposed to play a central role in pathogenesis of radiation pneumonitis. We analyzed the secretory function and proliferation parameters of alveolar type II cells in the early (until 24 h) and late phase (1–5 weeks) after irradiation (RT) in vitro and in vivo.Methods and Materials: Type II cells were isolated from rats according to the method of Dobbs. Stimulation of secretion was induced with terbutaline, adenosine triphosphate (ATP), and 12-O-tetradecanoylphorbol-13-acetate (TPA) for a 2-h period. Determination of secretion was performed using 3H-labeled phosphatidylcholine. For the early-phase analysis, freshly isolated and adherent type II cells were irradiated in vitro with 9–21 Gy (stepwise increase of 3 Gy). Secretion stimulation was initiated 1, 6, 24, and 48 h after RT. For late-phase analysis, type II cells were isolated 1–5 weeks after 18 Gy whole lung or sham RT. Each experiment was repeated at least fivefold. Flow cytometry was used to determine cell cycle distribution and proliferating cell nuclear antigen index.Results: During the early-phase (in vitro) analysis, we found a normal stimulation of surfactant secretion in irradiated, as well as unirradiated, cells. No change in basal secretion and no dose effect were seen. During the late phase, 1–5 weeks after whole lung RT, we observed enhanced secretory activity for all secretagogues and a small increase in basal secretion in Weeks 3 and 4 (pneumonitis phase) compared with controls. The total number of isolated type II cells, as well as the rate of viable cells, decreased after the second post-RT week. Cell cycle alterations suggesting an irreversible G2/M block occurred in the second post-RT week and did not resolve during the observation period. The proliferating cell nuclear antigen index of type II cells from irradiated rats did not differ from that of controls.Conclusion: In contrast to literature data, we observed no direct effect of radiation on secretory activity in the early phase after RT. In our study of isolated type II cells, as well as in intact animals, RT did not result in an impaired surfactant secretion up to 5 weeks after RT. Our in vivo experiments even showed an increased response of phosphatidylcholine secretion to all known secretagogues at Weeks 3 and 4 after whole lung RT, possibly due to inflammatory cytokines. Cell cycle alterations with G2/M block and cell loss in the late post-RT period may contribute more to the manifestation of radiation-induced lung damage than functional impairment in type II cells. [Copyright &y& Elsevier]

Background: To evaluate the influence of total dose and tumor volume on local control and survival in primary radiotherapy of non-small-cell lung cancer (NSCLC).Methods and Materials: We retrospectively analyzed the clinical course and CT-derived pre- and post-therapeutic tumor volume data of 135 patients with NSCLC undergoing primary radiotherapy at our department between 1989 and 1996. Among these, a total of 192 spatially separated tumor volumes (135 primary tumors, 1 additional intrapulmonary tumor, and 56 involved lymph nodes) were available for analysis. In all patients, treatment was planned using CT-based three-dimensional treatment planning. The dose to each tumor volume was derived from the individual dose plans. Mean total dose was 59.9 Gy (range: 30–80 Gy). All but 3 patients were followed until death. For local control analysis, each tumor was analyzed separately, and its remission status was determined in serial follow-up CT scans. A total of 784 CT scans were analyzed. Actuarial local control analysis was performed for the 192 separated tumor volumes, and survival analysis was performed for the 135 patients. Tumor control probability was calculated using a Poisson statistical model.Results: Overall 1- and 2-year local control rate was 50% and 37%, respectively. The 2-year local control rate for tumors <50 ccm, 50–200 ccm, and >200 ccm was 51%, 22%, and 10%, respectively (p = 0.02). The 2-year local control rate for dose levels ≤60 Gy and >60 Gy was 28% and 43% (p < 0.001). For the subgroup of 147 tumors smaller than 100 ccm, the local control rate increased up to 70% (1 year) and 51% (2 years) with doses of more than 60 Gy. For tumors larger than 100 ccm, no dose effect was seen. Only 2 of 45 tumors >100 ccm were controlled more than 2 years. Multivariate analysis revealed tumor volume, total dose, histopathologic type, and grading as significant and independent prognostic factors for local control. The number of delay days by split course (if used) and application of chemotherapy was not found to influence local control. Overall 1- and 2-year survival rate was 42% and 13%. Total radiation dose, chemotherapy, and T and N stage—but not tumor volume—were found to be independent and significant prognostic factors for survival in multivariate analysis.Conclusion: Tumor volume is an important predictor of local control in NSCLC. We found a clear dose effect for local control and survival in NSCLC. Long-term local control for a significant proportion of patients seems possible for small tumors only (<100 ccm, i.e., maximum diameter 6 cm) with doses of 70 Gy and more. Tumors of ≥100 ccm are unlikely to be controlled long term by conventional doses up to 70 Gy. These results support dose escalation in patients with NSCLC. [Copyright &y& Elsevier]

Purpose: To evaluate doses to the microscopic disease (MD) in adaptive radiotherapy (ART) for locally advanced non-small-cell lung cancer (NSCLC) and to model tumor control probability (TCP).Methods and Materials: In a retrospective planning study, three-dimensional conformal treatment plans for 13 patients with locally advanced NSCLC were adapted to shape and volume changes of the gross tumor volume (GTV) once or twice during conventionally fractionated radiotherapy with total doses of 66 Gy; doses in the ART plans were escalated using an iso-mean lung dose (MLD) approach compared to non-adapted treatment. Dose distributions to the volumes of suspect MD were simulated for a scenario with synchronous shrinkage of the MD and GTV and for a scenario of a stationary MD despite GTV shrinkage; simulations were performed using deformable image registration. TCP calculations considering doses to the GTV and MD were performed using three different models.Results: Coverage of the MD at 50 Gy was not compromised by ART. Coverage at 60 Gy in the scenario of a stationary MD was significantly reduced from 92% ± 10% to 73% ± 19% using ART; however, the coverage was restored by iso-MLD dose escalation. Dose distributions in the MD were sufficient to achieve a TCP >80% on average in all simulation experiments, with the clonogenic cell density the major factor influencing TCP. The combined TCP for the GTV and MD was 19.9% averaged over all patients and TCP models in non-adaptive treatment with 66 Gy. Iso-MLD dose escalation achieved by ART increased the overall TCP by absolute 6% (adapting plan once) and by 8.7% (adapting plan twice) on average. Absolute TCP values were significantly different between the TCP models; however, all TCP models suggested very similar TCP increase by using ART.Conclusions: Adaptation of radiotherapy to the shrinking GTV did not compromise dose coverage of volumes of suspect microscopic disease and has the potential to increase TCP by >40% compared with radiotherapy planning without ART. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate doses to the microscopic disease (MD) in adaptive radiotherapy (ART) for locally advanced non–small-cell lung cancer (NSCLC) and to model tumor control probability (TCP). Methods and Materials: In a retrospective planning study, three-dimensional conformal treatment plans for 13 patients with locally advanced NSCLC were adapted to shape and volume changes of the gross tumor volume (GTV) once or twice during conventionally fractionated radiotherapy with total doses of 66 Gy; doses in the ART plans were escalated using an iso-mean lung dose (MLD) approach compared to non-adapted treatment. Dose distributions to the volumes of suspect MD were simulated for a scenario with synchronous shrinkage of the MD and GTV and for a scenario of a stationary MD despite GTV shrinkage; simulations were performed using deformable image registration. TCP calculations considering doses to the GTV and MD were performed using three different models. Results: Coverage of the MD at 50 Gy was not compromised by ART. Coverage at 60 Gy in the scenario of a stationary MD was significantly reduced from 92% ± 10% to 73% ± 19% using ART; however, the coverage was restored by iso-MLD dose escalation. Dose distributions in the MD were sufficient to achieve a TCP >80% on average in all simulation experiments, with the clonogenic cell density the major factor influencing TCP. The combined TCP for the GTV and MD was 19.9% averaged over all patients and TCP models in non-adaptive treatment with 66 Gy. Iso-MLD dose escalation achieved by ART increased the overall TCP by absolute 6% (adapting plan once) and by 8.7% (adapting plan twice) on average. Absolute TCP values were significantly different between the TCP models; however, all TCP models suggested very similar TCP increase by using ART. Conclusions: Adaptation of radiotherapy to the shrinking GTV did not compromise dose coverage of volumes of suspect microscopic disease and has the potential to increase TCP by >40% compared with radiotherapy planning without ART. [ABSTRACT FROM AUTHOR]