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Purpose: In CyberKnife® respiratory tracking, tumor positions are predicted from external marker positions using correlation models. With available models, prediction accuracy may deteriorate when respiratory motion baseline drifts occur. Previous investigations have demonstrated that for linear models this can be mitigated by adding a time-dependent term. In this study, we have focused on added value of time-dependent terms for the available non-linear correlation models, and on phase shifts between internal and external motion tracks., Methods: Treatment simulations for tracking with and without time-dependent terms were performed using computer generated respiratory motion tracks for 60.000 patients with variable baseline drifts and phase shifts. The protocol for acquisition of X-ray images was always the same. Tumor position prediction accuracies in simulated treatments were largely based on cumulative error-time histograms and quantified with R95: in 95% of time the prediction error is < R95 mm., Results: For all available correlation models, prediction accuracy improved by adding a time-dependent term in case of occurring baseline drifts, with and without phase shifts present. For the most accurate model and 150 s between model updates, adding time dependency reduced R95 from 3.9 to 3.1 mm and from 5.4 to 3.3 mm for 0.25 and 0.50 mm/min drift, respectively. Tumor position prediction accuracy improvements with time-dependent models were obtained without increases in X-ray imaging., Conclusions: Using available correlation models with an added time-dependent term could largely mitigate negative impact of respiratory motion baseline drifts on tumor position prediction accuracy, also in case of large phase shifts., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This work was in part funded by a research grant of Accuray Inc. Erasmus MC Cancer Institute also has research collaborations with Elekta AB Stockholm, Sweden and Varian Medical Systems, Palo Alto, USA. No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, and decisions on preparation of the manuscript and publication., (Copyright © 2024 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

The benefits of using Synchrony Respiratory Tracking System (RTS) in conjunction with the CyberKnife robotic treatment device to treat a "breathing tumor" in an anthropomorphic, tissue-equivalent, thoracic phantom have been investigated. The following have been studied: (a) Synchrony's ability to allow the CyberKnife to deliver accurately a planned dose distribution to the free-breathing phantom and (b) the dosimetric implications when irregularities in the breathing cycle and phase differences between internal (tumor) and external (chest) motion exist in the course of one treatment fraction. The breathing phantom PULMONE (phantom used in lung motion experiments) has been used, which can imitate regular or irregular breathing patterns. The breathing traces from two patients with lung cancer have been selected as input. Both traces were irregular in amplitude, frequency, and base line. Patient B demonstrated a phase difference between internal and external motion, whereas patient A did not. The experiment was divided into three stages: In stage I-static, the treatment was delivered to the static phantom. In stage II-motion, the phantom was set to breathe, following the breathing trace of each of the two patients. Synchrony was switched off, so no motion compensation was made. In stage III-compensation, the phantom was set to breathe and Synchrony was switched on. A linear correspondence model was chosen to allow for phase differences between internal and external motion. Gafchromic EBT film was inserted in the phantom tumor to measure dose. To eradicate small errors in film alignment during readout, a gamma comparison with pass criteria of 3%/3 mm was selected. For a more quantitative approach, the percentage of pixels in each gamma map that exceeded the value of 1 (P1) was also used. For both breathing signals, the dose blurring caused by the respiratory motion of the tumor in stage II was degraded considerably compared with stage I (P1 = 15% for patient A and 8% for patient B). The motion compensation via the linear correspondence model was sufficient to provide a dose distribution that satisfied the set gamma criteria (P1=3% for patient A and 2% for patient B). Synchrony RTS has been found satisfactory in recovering the initial detail in dose distribution, for realistic breathing signals, even in the case where a phase delay between internal tumor motion and external chest displacement exists. For the signals applied here, a linear correspondence model provided an acceptable degree of motion compensation.

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.

Three-dimensional (3D) dose distribution has been improved by 3D conformation and intensity modulation in external radiotherapy. Interfractional uncertainty has been reduced by image-guided setup techniques. Reduction of ambiguity because of intrafractional target motion is the next step forward. Respiratory organ motion is known to be the largest intrafractional organ motion. Radiotherapy techniques controlling, gating, or tracking respiratory motion are under investigation to use smaller safety margins and higher doses for moving tumors. However, data on intrafractional tumor motion are sparse. We developed a fluoroscopic real-time tracking system and implantation techniques of fiducial markers for moving organs and have been accumulating knowledge about internal tumor motion. We also found the importance of 4-dimensional treatment planning to account for tumor motion in precision radiotherapy. This article reviews the current basic knowledge on respiratory physiology and summarizes the accumulating knowledge on internal motion of lung and liver tumors.

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-path length (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 TD(50) 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.

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.

Synchronized moving aperture radiation therapy (SMART) is a new technique for treating mobile tumours under development at Massachusetts General Hospital (MGH). The basic idea of SMART is to synchronize the moving radiation beam aperture formed by a dynamic multileaf collimator (DMLC) with the tumour motion induced by respiration. SMART is based on the concept of the average tumour trajectory (ATT) exhibited by a tumour during respiration. During the treatment simulation stage, tumour motion is measured and the ATT is derived. Then, the original IMRT MLC leaf sequence is modified using the ATT to compensate for tumour motion. During treatment, the tumour motion is monitored. The treatment starts when leaf motion and tumour motion are synchronized at a specific breathing phase. The treatment will halt when the tumour drifts away from the ATT and will resume when the synchronization between tumour motion and radiation beam is re-established. In this paper, we present a method to derive the ATT from measured tumour trajectory data. We also investigate the validity of the ATT concept for lung tumours during normal breathing. The lung tumour trajectory data were acquired during actual radiotherapy sessions using a real-time tumour-tracking system. SMART treatment is simulated by assuming that the radiation beam follows the derived ATT and the tumour follows the measured trajectory. In simulation, the treatment starts at exhale phase. The duty cycle of SMART delivery was calculated for various treatment times and gating thresholds, as well as for various exhale phases where the treatment begins. The simulation results show that in the case of free breathing, for 4 out of 11 lung datasets with tumour motion greater than 1 cm from peak to peak, the error in tumour tracking can be controlled to within a couple of millimetres while maintaining a reasonable delivery efficiency. That is to say, without any breath coaching/control, the ATT is a valid concept for some lung tumours. However, to make SMART an efficient technique in general, it is found that breath coaching techniques are required.

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 or=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.

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.

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.

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.