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Purpose: A method was recently developed for online-adaptive intensity modulated proton therapy (IMPT) in patients with cervical cancer. The advantage of this approach, relying on the use of tight margins, is challenged by the intrafraction target motion. The purpose of this study was to evaluate the dosimetric effect of intrafraction motion on the target owing to changes in bladder filling in patients with cervical cancer treated with online-adaptive IMPT., Methods and Materials: In 10 patients selected to have large uterus motion induced by bladder filling, the intrafraction anatomic changes were simulated for several prefraction durations for online (automated) contouring and planning. For each scenario, the coverage of the primary target was evaluated with margins of 2.5 and 5 mm., Results: Using a 5- mm planning target volume margin, median accumulated D98% was greater than 42.75 Gy RBE1.1 (95% of the prescribed dose) in the case of a prefraction duration of 5 and 10 minutes. For a prefraction duration of 15 minutes, this parameter deteriorated to 42.6 Gy RBE1.1 . When margins were reduced to 2.5 mm, only a 5-minute duration resulted in median target D98% above 42.75 Gy RBE1.1 . In addition, smaller bladders were found to be associated with larger dose degradations compared with larger bladders., Conclusions: This study indicates that intrafraction anatomic changes can have a substantial dosimetric effect on target coverage in an online-adaptive IMPT scenario for patients subject to large uterus motion. A margin of 5 mm was sufficient to compensate for the intrafraction motion due to bladder filling for up to 10 minutes of prefraction time. However, compensation for the uncertainties that were disregarded in this study, by using margins or robust optimization, is also required. Furthermore, a large bladder volume restrains intrafraction target motion and is recommended for treating patients in this scenario. Assuming that online-adaptive IMPT remains beneficial as long as narrow margins are used (5 mm or below), this study demonstrates its feasibility with regard to intrafraction motion., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: We aimed to derive a "robustness recipe" giving the range robustness (RR) and setup robustness (SR) settings (ie, the error values) that ensure adequate clinical target volume (CTV) coverage in oropharyngeal cancer patients for given gaussian distributions of systematic setup, random setup, and range errors (characterized by standard deviations of Σ, σ, and ρ, respectively) when used in minimax worst-case robust intensity modulated proton therapy (IMPT) optimization., Methods and Materials: For the analysis, contoured computed tomography (CT) scans of 9 unilateral and 9 bilateral patients were used. An IMPT plan was considered robust if, for at least 98% of the simulated fractionated treatments, 98% of the CTV received 95% or more of the prescribed dose. For fast assessment of the CTV coverage for given error distributions (ie, different values of Σ, σ, and ρ), polynomial chaos methods were used. Separate recipes were derived for the unilateral and bilateral cases using one patient from each group, and all 18 patients were included in the validation of the recipes., Results: Treatment plans for bilateral cases are intrinsically more robust than those for unilateral cases. The required RR only depends on the ρ, and SR can be fitted by second-order polynomials in Σ and σ. The formulas for the derived robustness recipes are as follows: Unilateral patients need SR = -0.15Σ(2) + 0.27σ(2) + 1.85Σ - 0.06σ + 1.22 and RR=3% for ρ = 1% and ρ = 2%; bilateral patients need SR = -0.07Σ(2) + 0.19σ(2) + 1.34Σ - 0.07σ + 1.17 and RR=3% and 4% for ρ = 1% and 2%, respectively. For the recipe validation, 2 plans were generated for each of the 18 patients corresponding to Σ = σ = 1.5 mm and ρ = 0% and 2%. Thirty-four plans had adequate CTV coverage in 98% or more of the simulated fractionated treatments; the remaining 2 had adequate coverage in 97.8% and 97.9%., Conclusions: Robustness recipes were derived that can be used in minimax robust optimization of IMPT treatment plans to ensure adequate CTV coverage for oropharyngeal cancer patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To evaluate a new type of marker and a new method of marker implantation and to assess interfraction cervix motion for a large population of patients with locally advanced cervical cancer by daily cone beam computed tomographic (CBCT) imaging., Methods and Materials: We investigated the position of markers in 50 patients treated in prone position during at least 23 fractions. To reduce streaking artifacts in the planning CT scan, a new type of polymeric marker was used and compared with conventional gold markers. In addition, a new method of implantation was used in an attempt to reduce marker loss. In each fraction, a CT scan was acquired before dose delivery and aligned to the bony anatomy of the planning CT scan, simulating the clinical setup protocol. First, sufficient visibility of the markers was verified. Then, systematic and random displacement of the marker centroids was recorded and analyzed in 3 directions with regard to the planning CT and the first CBCT (to evaluate the presence of a vaginal catheter in the planning CT). Streaking artifacts were quantified with the standard deviation of the mean squared intensity difference in a radius around the marker., Results: Marker loss was minimal during treatment: in only 3 of the 50 patients 1 marker was lost. Streaking artifacts for the new markers were reduced compared with conventional gold markers. For the planning CT, M/Σ/σ were 0.4/3.4/2.2 mm, 1.0/5.5/4.5 mm, and -3.9/5.1/3.6 mm for the left-right, anterior-posterior, and cranial-caudal directions, respectively. With regard to the first CBCT scan, M/Σ/σ were 0.8/2.8/2.1, 0.6/4.4/4.4, and -1.3/4.5/3.6 mm., Conclusions: A new type of marker and implantation method was shown to have significantly reduced marker loss and streaking artifacts compared with gold fiducial markers. The recorded marker displacement confirms results reported in the existing literature but for a larger dataset., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To assess, in a phase 2 study, the efficacy and toxicity of stereotactic body radiation therapy for oligometastases to the lung in inoperable patients., Methods and Materials: Patients with lung metastases were included in this study if (1) the primary tumor was controlled; (2) patients were ineligible for or refused surgery and chemotherapy; and (3) patients had 5 or fewer metastatic lesions in no more than 2 organs. Large peripheral tumors were treated with a dose of 60 Gy (3 fractions), small peripheral tumors with 30 Gy (1 fraction), central tumors received 60 Gy (5 fractions), and mediastinal tumors or tumors close to the esophagus received 56 Gy (7 fractions)., Results: Thirty patients with 57 metastatic lung tumors from various primary cancers were analyzed. The median follow-up was 36 months (range, 4-60 months). At 2 years, local control for the 11 central tumors was 100%, for the 23 peripheral tumors treated to 60 Gy it was 91%, and for the 23 tumors treated in a single 30-Gy fraction it was 74% (P=.13). This resulted in an overall local control rate at 1 year of 79%, with a 2-sided 80% confidence interval of 67% to 87%. Because the hypothesized value of 70% lies within the confidence interval, we cannot reject the hypothesis that the true local control rate at 1 year is ≤70%, and therefore we did not achieve the goal of the study: an actuarial local control of the treated lung lesions at 1 year of 90%. The 4-year overall survival rate was 38%. Grade 3 acute toxicity occurred in 5 patients. Three patients complained of chronic grade 3 toxicity, including pain, fatigue, and pneumonitis, and 3 patients had rib fractures., Conclusions: The local control was promising, and the 4-year overall survival rate was 38%. The treatment was well tolerated, even for central lesions., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To investigate the dosimetric impact of intrafraction prostate motion and the effect of robot correction strategies for hypofractionated CyberKnife treatments with a simultaneously integrated boost., Methods and Materials: A total of 548 real-time prostate motion tracks from 17 patients were available for dosimetric simulations of CyberKnife treatments, in which various correction strategies were included. Fixed time intervals between imaging/correction (15, 60, 180, and 360 seconds) were simulated, as well as adaptive timing (ie, the time interval reduced from 60 to 15 seconds in case prostate motion exceeded 3 mm or 2° in consecutive images). The simulated extent of robot corrections was also varied: no corrections, translational corrections only, and translational corrections combined with rotational corrections up to 5°, 10°, and perfect rotational correction. The correction strategies were evaluated for treatment plans with a 0-mm or 3-mm margin around the clinical target volume (CTV). We recorded CTV coverage (V100%) and dose-volume parameters of the peripheral zone (boost), rectum, bladder, and urethra., Results: Planned dose parameters were increasingly preserved with larger extents of robot corrections. A time interval between corrections of 60 to 180 seconds provided optimal preservation of CTV coverage. To achieve 98% CTV coverage in 98% of the treatments, translational and rotational corrections up to 10° were required for the 0-mm margin plans, whereas translational and rotational corrections up to 5° were required for the 3-mm margin plans. Rectum and bladder were spared considerably better in the 0-mm margin plans. Adaptive timing did not improve delivered dose., Conclusions: Intrafraction prostate motion substantially affected the delivered dose but was compensated for effectively by robot corrections using a time interval of 60 to 180 seconds. A 0-mm margin required larger extents of additional rotational corrections than a 3-mm margin but resulted in lower doses to rectum and bladder., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To design and evaluate individualized nonadaptive and online-adaptive strategies based on a pretreatment established motion model for the highly deformable target volume in cervical cancer patients., Methods and Materials: For 14 patients, nine to ten variable bladder filling computed tomography (CT) scans were acquired at pretreatment and after 40 Gy. Individualized model-based internal target volumes (mbITVs) accounting for the cervix and uterus motion due to bladder volume changes were generated by using a motion-model constructed from two pretreatment CT scans (full and empty bladder). Two individualized strategies were designed: a nonadaptive strategy, using an mbITV accounting for the full-range of bladder volume changes throughout the treatment; and an online-adaptive strategy, using mbITVs of bladder volume subranges to construct a library of plans. The latter adapts the treatment online by selecting the plan-of-the-day from the library based on the measured bladder volume. The individualized strategies were evaluated by the seven to eight CT scans not used for mbITVs construction, and compared with a population-based approach. Geometric uniform margins around planning cervix-uterus and mbITVs were determined to ensure adequate coverage. For each strategy, the percentage of the cervix-uterus, bladder, and rectum volumes inside the planning target volume (PTV), and the clinical target volume (CTV)-to-PTV volume (volume difference between PTV and CTV) were calculated., Results: The margin for the population-based approach was 38 mm and for the individualized strategies was 7 to 10 mm. Compared with the population-based approach, the individualized nonadaptive strategy decreased the CTV-to-PTV volume by 48% ± 6% and the percentage of bladder and rectum inside the PTV by 5% to 45% and 26% to 74% (p < 0.001), respectively. Replacing the individualized nonadaptive strategy by an online-adaptive, two-plan library further decreased the percentage of bladder and rectum inside the PTV (0% to 10% and -1% to 9%; p < 0.004) and the CTV-to-PTV volume (4-96 ml)., Conclusions: Compared with population-based margins, an individualized PTV results in better organ-at-risk sparing. Online-adaptive radiotherapy further improves organ-at-risk sparing., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To quantify the clinical accuracy of the respiratory motion tracking system of the CyberKnife treatment device., Methods and Materials: Data in log files of 44 lung cancer patients treated with tumor tracking were analyzed. Errors in the correlation model, which relates the internal target motion with the external breathing motion, were quantified. The correlation model error was compared with the geometric error obtained when no respiratory tracking was used. Errors in the prediction method were calculated by subtracting the predicted position from the actual measured position after 192.5 ms (the time lag to prediction in our current system). The prediction error was also measured for a time lag of 115 ms and a new prediction method., Results: The mean correlation model errors were less than 0.3 mm. Standard deviations describing intrafraction variations around the whole-fraction mean error were 0.2 to 1.9 mm for cranio-caudal, 0.1 to 1.9 mm for left-right, and 0.2 to 2.5 mm for anterior-posterior directions. Without the use of respiratory tracking, these variations would have been 0.2 to 8.1 mm, 0.2 to 5.5 mm, and 0.2 to 4.4 mm. The overall mean prediction error was small (0.0 +/- 0.0 mm) for all directions. The intrafraction standard deviation ranged from 0.0 to 2.9 mm for a time delay of 192.5 ms but was halved by using the new prediction method., Conclusions: Analyses of the log files of real clinical cases have shown that the geometric error caused by respiratory motion is substantially reduced by the application of respiratory motion tracking.

Purpose: To determine the influence of observer variation and treatment planner variation on the dose delivered to the target and normal structures when irradiating paranasal sinus carcinomas., Patients and Methods: Nine patients with paranasal sinus tumors underwent debulking surgery and subsequent radiation therapy. Two observers from two different institutions delineated the clinical target volumes (CTVs) for the elective and the boost volumes. These volumes were expanded in three dimensions with a 5-mm margin. At both institutions, a three-dimensional conformal treatment plan of 46 Gy to the elective volumes, plus 20 Gy to the boost target volumes, was designed. The delineated volumes and treatment plans were compared., Results: The mean volume ratio between institutions of the elective CTVs was 0.9 (standard error = 0.05). The differences were located mainly at the bottom of the nasal cavity and at the frontal border of the target areas. The differences in boost CTVs were large; the mean volume ratio was 2.6 (standard error = 0.58). After expansion of the CTV, the mean distance between the planning target volume (PTV) and the chiasm differed by 0.5 cm between the two institutions. Cases with smaller distances between the PTV and the chiasm had more underdosage to the PTV. This effect was less pronounced for institution A (1 vol.%/cm) than for institution B (10 vol.%/cm) treatment plans, which were less conformal. When the treatment plan was designed for the PTV of institution B, 23 volume % of the PTV of institution A received <95% of the prescribed dose. If the treatment plan was designed for the (on average larger) PTV of institution A, the underdosed volume of PTV at institution B was 17%. The relative underdosage to the "other" PTV was larger when the original treatment plan was more conformal., Conclusion: In the irradiation of paranasal sinus cancer, both the treatment planner and the observer have a significant influence on the dose to the target and organs at risk. Both effects are similar in magnitude. The observer effect increases with more conformal treatment plans. Minimizing the observer variation is important for adequate irradiation of paranasal sinus cancer.

Purpose: To develop an accurate method to generate a dose-volume histogram (DVH) of the rectum wall, solely based on the outer contours of the rectum wall., Methods and Materials: A mathematical model for the rectum wall is developed, incorporating the stretching of the rectum wall due to variable rectal filling and neighboring structures. The model is based on the assumption that the amount of intersected rectum wall tissue normal to the central axis of the rectum is constant. The main objective of the model is to determine the thickness of the rectum wall in each wall element. Two approaches are described, each yielding a DVH of the rectum wall, based only on the delineated outer contours of the rectum. In the first approach, the model is used to create a set of inner contours out of the axial outer contours. Both sets of contours are used to derive a dose-wall histogram (DWH) of the rectum. In the second approach, the model is used to generate a normalized 2D sampling space, which is subsequently binned into a normalized dose-surface histogram (NDSH). The model is verified using 20 sets of CT data (5 patients x 4 scans) in which both outer and inner contours of the rectum are carefully delineated. The DWHs and NDSHs are compared with DVHs of the rectum wall, which require contouring of the outer and inner surfaces of the rectum wall, and with DVHs of the total rectum (including rectal filling). The variation between DWHs, NDSHs, and DVHs is investigated using normal tissue complication probability (NTCP) calculations., Results: The local wall thickness of the rectum as outlined on CT data was in conformity with the described rectum model. The amount of rectum wall tissue per unit length rectum varied considerably between patients (27%, 1 SD). In all analyzed patients, the DWHs and NDSHs corresponded well to the DVHs of the rectum wall. Much more discrepancies were observed between the DVHs of the total rectum and the DVHs of the rectum wall., Conclusion: The applied methods yield accurate dose distributions of the rectum wall, without delineating the inner surface of the rectum. This reduces both the workload and variations due to inaccurate delineation of the rectum wall. The DWH and NDSH are effective tools to evaluate 3D dose distributions of the rectum wall and to estimate the complication probability of the rectum in high-dose conformal radiotherapy.