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To identify factors predictive for chronic urinary toxicity secondary to high-dose adaptive three-dimensional conformal radiation.From 1999 to 2002, 331 consecutive patients with clinical Stage II-III prostate cancer were prospectively treated (median dose, 75.6 Gy). The bladder was contoured, and the bladder wall was defined as the outer 3 mm of the bladder solid volume. Toxicity was quantified according to the National Cancer Institute Common Toxicity Criteria 2.0. Median follow-up was 1.6 years.The 3-year rates of Gradeor =2 and Grade 3 chronic urinary toxicity were 17.0% and 3.6%, respectively. Prostate volume, confidence-limited patient-specific planning target volume, bladder wall volume, and acute urinary toxicity were all found to be accurate predictors for chronic urinary toxicity. The volume of bladder wall receivingor =30 Gy (V30) andor =82 Gy (V82), along with prostate volume, were all clinically useful predictors of Gradeor =2 and Grade 3 chronic urinary toxicity and chronic urinary retention. Both Gradeor =2 (p = 0.001) and Grade 3 (p = 0.03) acute urinary toxicity were predictive for the development of Gradeor =2 (p = 0.001, p = 0.03) and Grade 3 (p = 0.05, p0.001) chronic urinary toxicity. On Cox multivariate analysis the development of acute toxicity was independently predictive for the development of both Gradeor =2 and Grade 3 chronic urinary toxicity.Acute urinary toxicity and bladder wall dose-volume endpoints are strong predictors for the development of subsequent chronic urinary toxicity. Our recommendation is to attempt to limit the bladder wall V30 to30 cm(3) and the V82 to7 cm(3) when possible. If bladder wall information is not available, bladder solid V30 and V82 may be used.

In our Phase II prostate cancer Adaptive Radiation Therapy (ART) study, the highest possible dose was selected on the basis of normal tissue tolerance constraints. We analyzed rectal toxicity rates in different dose levels and treatment groups to determine whether equivalent toxicity rates were achieved as hypothesized when the protocol was started.From 1999 to 2002, 331 patients with clinical stage T1 to T3, node-negative prostate cancer were prospectively treated with three-dimensional conformal adaptive RT. A patient-specific confidence-limited planning target volume was constructed on the basis of 5 CT scans and 4 sets of electronic portal images after the first 4 days of treatment. For each case, the rectum (rectal solid) was contoured in its entirety. The rectal wall was defined by use of a 3-mm wall thickness (median volume: 29.8 cc). The prescribed dose level was chosen using the following rectal wall dose constraints: (1) Less than 30% of the rectal wall volume can receive more than 75.6 Gy. (2) Less than 5% of the rectal wall can receive more than 82 Gy. Low-risk patients (PSA10, Stageor = T2a, Gleason score7) were treated to the prostate alone (Group 1). All other patients, intermediate and high risk, where treated to the prostate and seminal vesicles (Group 2). The risk of chronic toxicity (NCI Common Toxicity Criteria 2.0) was assessed for the different dose levels prescribed. HIC approval was acquired for all patients. Median follow-up was 1.6 years.Grade 2 chronic rectal toxicity was experienced by 34 patients (10%) (9% experienced rectal bleeding, 6% experienced proctitis, 3% experienced diarrhea, and 1% experienced rectal pain) at a median interval of 1.1 year. Nine patients (3%) experienced grade 3 or higher chronic rectal toxicity (1 Grade 4) at a median interval of 1.2 years. The 2-year rates of Grade 2 or higher and Grade 3 or higher chronic rectal toxicity were 17% and 3%, respectively. No significant difference by dose level was seen in the 2-year rate of Grade 2 or higher chronic rectal toxicity. These rates were 27%, 15%, 14%, 17%, and 24% for dose levels equal to or less than 72, 73.8, 75.6, 77.4, and 79.2 Gy, respectively (p = 0.3). Grade 2 or higher chronic rectal bleeding was significantly greater for Group 2 than for Group 1, 17% vs. 8% (p = 0.035).High doses (79.2 Gy) were safely delivered in selected patients by our adaptive radiotherapy process. Under the rectal dose-volume histogram constraints for the dose level selection, the risk of chronic rectal toxicity is similar among patients treated to different dose levels. Therefore, rectal chronic toxicity rates reflect the dose-volume cutoff used and are independent of the actual dose levels. On the other hand, a larger PTV will increase the rectal wall dose and chronic rectal toxicity rates. PTV volume and dose constraints should be defined, considering their potential benefit.

Purpose : The rectal dose/volume relationship and inherent variations thereof are fundamental parameters to guide dose escalation in prostate cancer treatment. This study evaluates the effect of rectal dose/volume variation on the risk of rectal complication for different planning target volume (PTV) constructions. Methods and Materials : Thirty prostate patients with multiple daily CT scans obtained during the treatment course were included in this retrospective study. The dose distribution was calculated based on the pretreatment CT image alone. Treatment plans were generated by applying the four-field-box beam arrangement to each of three different PTVs: PTVs with 0.5-cm and 1.0-cm uniform margins, and a patient-specific PTV constructed using treatment imaging feedback. For each of the 30 patients, the rectal wall as manifested on each of multiple CT images was delineated after image bony registration to the pretreatment CT image, and applied to the corresponding treatment plan to obtain the rectal wall dose-volume histogram (DVH). Interpatient and intrapatient rectal dose/volume variations were quantified accordingly. The corresponding uncertainty and sensitivity of the risk of rectal complication to the variations were evaluated for each of the three PTVs. Finally, the efficacy of using multiple CT images to reduce uncertainty in planning evaluation was examined. Results : Sensitivity of the risk of rectal complication to rectal dose/volume variation strongly depends on the clinical target volume (CTV)-to-PTV margin or prescription dose, or both. Compared to the conventional two-dimensional (2D) prostate cancer treatment, the sensitivity for a conformal treatment can be 3 times higher or more. Due to the interpatient rectal dose/volume variation, the individual normal tissue complication probability (NTCP) was distributed from 10% to 37% when a common prescription dose was applied for all patients. The intrapatient rectal dose/volume variation introduces at least ± 25% uncertainty in the NTCP calculation for at least 10% or 25% of the patients treated with the PTV of 1.0- or 0.5-cm margin, respectively. These uncertainties were larger for the smaller PTV, with the standard deviation up to 20%. By applying multiple CT image feedback, the NTCP uncertainty could be reduced by a factor of 2. Conclusions : Shape and position variation of rectum has less influence on treatment planning in the conventional 2D treatment of prostate cancer. However, this influence is quickly growing with high treatment dose or small CTV-to-PTV margins. To reduce the variation and uncertainties in the treatment planning evaluation associated with the inter- and intrapatient rectal dose/volume variation, the iso-NTCP model and treatment image feedback technique can be applied in dose escalation trials of prostate cancer treatment.

Purpose: Advances in technology allow the creation of complex treatment plans with tightly conforming doses. However, variations in positioning of the organ/patient with respect to treatment beams necessitate the use of an appreciable margin, potentially limiting dose escalation in many patients. To (1) reduce this margin and (2) test the hypothesis that the achievable level of dose escalation is patient dependent, a patient-specific, confidence-limited planning target volume (cl-PTV) was constructed using an adaptive radiotherapy (ART) process for prostate cancer treatment developed in-house. The potential dose escalation achievable with this ART process is quantified for both conformal radiotherapy (CRT) delivery and intensity-modulated radiotherapy (IMRT) delivery. Material and Methods: Patients with organ confined prostate cancer were entered prospectively into an ART process developed in-house. This ART process has been designed to improve accuracy and precision of dose delivery, consequently enhancing dose escalation. In this process, a cl-PTV is constructed for each patient in the second week of treatment based upon on-line portal and CT images acquired during the first week of treatment. The treatment prescription dose, defined as the minimum dose to the cl-PTV, is selected based on predefined dose-volume constraints for rectum/bladder and derived from the pretreatment planning CT image. In addition, the treatment modality (CRT or IMRT) is determined based on the level of dose escalation achievable and the risk of inaccurate targeting. The potential for both dose escalation and the application of IMRT was evaluated by comparing the prescription doses delivered using the ART process, with the cl-PTV, to those in the traditional treatment process, with a conventional generic PTV. In addition, the distributions of potential geometric target underdosing and normal tissue overdosing were also calculated to evaluate the quality of the conventional treatment plans. Results: One hundred and fifty patients have been treated with the ART process. When compared to the treatment dose delivered with the conventional treatment process (generic PTV), an average 5% (2.5–10%) more dose could be delivered using the ART process with CRT, and 7.5% (2.5–15%) more dose could be delivered with IMRT. Of the 150 patients, 70% were treated to a minimum cl-PTV dose ≥ 77.4 Gy (81.3 Gy ICRU isocenter dose). Dosimetric analysis revealed that 81 Gy to the cl-PTV (or 86.7 Gy ICRU) could be prescribed to at least 50% of patients if IMRT was applied using the ART process. In contrast, IMRT did not yield an obvious dose escalation gain if patients were treated using the generic PTV. Our results also demonstrate that the cl-PTV is significantly smaller than the conventional generic PTV for most patients, with a mean volume reduction of 24% (range, 5–43%). Conclusion: These results support our hypothesis that the achievable level of dose escalation using ART is patient dependent. By using the ART process to develop a cl-PTV, one can (1) optimize the dose level, (2) increase the applicability of IMRT, and (3) improve the quality of dose delivery. The ART process provides the foundation to identify a suitable option (CRT or IMRT) for the delivery of a safe treatment and dose escalation. It is now our standard of practice for prostate cancer treatment.

Purpose: We hypothesize that the difference in image quality between the traditional kilovoltage (kV) prescription radiographs and megavoltage (MV) treatment radiographs is a major factor hindering our ability to accurately measure, thus correct, setup error in radiation therapy. The objective of this work is to study the accuracy of on-line correction of setup errors achievable using either kV- or MV-localization (i.e., open-field) radiographs. Methods and Materials: Using a gantry mounted kV and MV dual-beam imaging system, the accuracy of on-line measurement and correction of setup error using electronic kV- and MV-localization images was examined based on anthropomorphic phantom and patient imaging studies. For the phantom study, the user’s ability to accurately detect known translational shifts was analyzed. The clinical study included 14 patients with disease in the head and neck, thoracic, and pelvic regions. For each patient, 4 orthogonal kV radiographs acquired during treatment simulation from the right lateral, anterior-to-posterior, left lateral, and posterior-to-anterior directions were employed as reference prescription images. Two-dimensional (2D) anatomic templates were defined on each of the 4 reference images. On each treatment day, after positioning the patient for treatment, 4 orthogonal electronic localization images were acquired with both kV and 6-MV photon beams. On alternate weeks, setup errors were determined from either the kV- or MV-localization images but not both. Setup error was determined by aligning each 2D template with the anatomic information on the corresponding localization image, ignoring rotational and nonrigid variations. For each set of 4 orthogonal images, the results from template alignments were averaged. Based on the results from the phantom study and a parallel study of the inter- and intraobserver template alignment variability, a threshold for minimum correction was set at 2 mm in any direction. Setup correction was applied by translating the treatment couch in the lateral, superior-to-inferior and vertical directions only. During treatment, kV open-field images were acquired for off-line treatment verification and analysis. Each patient study spanned 2–6 weeks. The 14 patient studies were completed with 8248 electronic images acquired and analyzed. Results: Results from the phantom studies showed that the users were able to detect the applied translational shift to better than 2 mm, and mostly to within 1 mm. The intraobserver variability of template alignment was on the order of 1 mm using a sample of either MV or kV patient images. The difference between using MV or kV images was significant for only a few cases. However in most cases, interobserver alignment variability was larger when using MV images than kV. For on-line setup correction, the study procedure added 10 min. to conventional treatment time. Setup variation measured with either kV- or MV-localization images was similar. The initial magnitude of setup error was appreciable, with a mean displacement of about 6.6 ± 2.4 mm for the 14 patients. On-line correction using either kV- or MV-localization images improved setup accuracy. Over all study patients, setup errors occurred with standard deviations greater than 2 mm in any direction with a frequency of 48% before correction, and were reduced to 16% after correction. On average, kV image-based correction reduced radial setup variation to 2.6 ± 1.6 mm compared to the 3.3 ± 1.8 mm attained using MV images. The difference detected between the kV and MV data was not statistically significant when averaged over all patients. However, for on-line corrections in the neck and thoracic regions, using kV-localization images reduced setup error significantly more than using MV images. Conclusions: In our anatomic template alignment study, interobserver variability was smaller using kV images than MV images. Intraobserver variability was smaller for alignments on kV images than MV images for a few cases. On-line correction improved patient setup accuracy. Kilovoltage image-based corrections were qualitatively more effective than MV image-based corrections, but results were site dependent. We posit that the largely indifferent results using kV and MV images were due primarily to the prevalence of rotational and nonrigid setup variations, which were not addressed with our limited model of setup error. Nevertheless, the use of a kV beam offers the significant advantage of low imaging dose that will greatly enhance the potential for more frequent on-line correction.

Purpose Previous work has found a highly significant relationship between the irradiated small-bowel volume and development of Grade 3 small-bowel toxicity in patients with rectal cancer. This study tested the previously defined parameters in a much larger group of patients. Methods and Materials A total of 96 consecutive patients receiving pelvic radiation therapy for rectal cancer had treatment planning computed tomographic scans with small-bowel contrast that allowed the small bowel to be outlined with calculation of a small-bowel dose–volume histogram for the initial intended pelvic treatment to 45 Gy. Patients with at least one parameter above the previously determined dose–volume parameters were considered high risk, whereas those with all parameters below these levels were low risk. The grade of diarrhea and presence of liquid stool was determined prospectively. Results There was a highly significant association with small-bowel dose–volume and Grade 3 diarrhea ( p ≤ 0.008). The high-risk and low-risk parameters were predictive with Grade 3 diarrhea in 16 of 51 high-risk patients and in 4 of 45 low-risk patients ( p = 0.01). Patients who had undergone irradiation preoperatively had a lower incidence of Grade 3 diarrhea than those treated postoperatively (18% vs. 28%; p = 0.31); however, the predictive ability of the high-risk/low-risk parameters was better for preoperatively ( p = 0.03) than for postoperatively treated patients ( p = 0.15). Revised risk parameters were derived that improved the overall predictive ability ( p = 0.004). Conclusions The highly significant dose–volume relationship and validity of the high-risk and low-risk parameters were confirmed in a large group of patients. The risk parameters provided better modeling for the preoperative patients than for the postoperative patients.

Purpose: To evaluate an online image-guidance strategy for conformal treatment of prostate cancer and to estimate margin-reduction benefits. Methods and Materials: Twenty-eight patients with at least 16 helical computed tomography scans were each used in this study. Two prostate soft-tissue registration methods, including sagittal rotation, were evaluated. Setup errors and rigid organ motion were corrected online; non-rigid and intrafraction motion were included in offline analysis. Various clinical target volume-planning target volume (CTV-PTV) margins were applied. Geometrical evaluations included analyses of isocenter shifts and rotations and overlap index. Dosimetric evaluations included minimum dose and equivalent uniform dose (EUD) for prostate and gEUD for rectum. Results: Average isocenter shift and rotation were (dX,dY,dZ,θ) = (0.0 ± 0.7,−1.1 ± 4.0,−0.1 ± 2.5,0.7° ± 2.0°) mm. Prostate motion in anterior-posterior (AP) direction was significantly higher than superior-inferior and left-right (LR) directions. This observation was confirmed by isocenter shift in perspectives AP (1.8 ± 1.8 mm) and RL (3.7 ± 3.0 mm). Organ motion degrades target coverage and reduces doses to rectum. If 2% dose reduction on prostate D 99 is allowed for 90% patients, then minimum 3 mm margins are necessary with ideal image registration. Conclusions: Significant margin reduction can be achieved through online image guidance. Certain margins are still required for nonrigid and intrafraction motion. To further reduce margin, a strategy that combines online geometric intervention and offline dose replanning is necessary.

Purpose: Kilovoltage cone-beam CT (CBCT) implemented on board a medical accelerator is available for image-guidance applications in our clinic. The objective of this work was to assess the magnitude and stability of the residual setup error associated with CBCT online-guided prostate cancer patient setup. Residual error pertains to the uncertainty in image registration, the limited mechanical accuracy, and the intrafraction motion during imaging and treatment. Methods and Materials: The residual error for CBCT online-guided correction was first determined in a phantom study. After online correction, the phantom residual error was determined by comparing megavoltage portal images acquired every 90° to the corresponding digitally reconstructed radiographs. In the clinical study, 8 prostate cancer patients were implanted with three radiopaque markers made of high-winding coils. After positioning the patient using the skin marks, a CBCT scan was acquired and the setup error determined by fusing the coils on the CBCT and planning CT scans. The patient setup was then corrected by moving the couch accordingly. A second CBCT scan was acquired immediately after the correction to evaluate the residual target setup error. Intrafraction motion was evaluated by tracking the coils and the bony landmarks on kilovoltage radiographs acquired every 30 s between the two CBCT scans. Corrections based on soft-tissue registration were evaluated offline by aligning the prostate contours defined on both planning CT and CBCT images. Results: For ideal rigid phantoms, CBCT image-guided treatment can usually achieve setup accuracy of 1 mm or better. For the patients, after CBCT correction, the target setup error was reduced in almost all cases and was generally within ±1.5 mm. The image guidance process took 23–35 min, dictated by the computer speed and network configuration. The contribution of the intrafraction motion to the residual setup error was small, with a standard deviation of ±0.9 mm. The average difference between the setup corrections obtained with coil and soft-tissue registration was greatest in the superoinferior direction and was equal to −1.1 ± 2.9 mm. Conclusion: On the basis of the residual setup error measurements, the margin required after online CBCT correction for the patients enrolled in this study would be approximatively 3 mm and is considered to be a lower limit owing to the small intrafraction motion observed. The discrepancy between setup corrections derived from registration using coils or soft tissue can be due in part to the lack of complete three-dimensional information with the coils or to the difficulty in prostate delineation and requires further study.

Purpose: To improve the efficacy of dose delivery and dose escalation for external beam radiotherapy of prostate cancer, an off-line strategy for constructing a patient-specific planning target volume is developed in the adaptive radiotherapy process using image feedback of target location and patient setup position. Materials and Methods: We hypothesize that a patient-specific confidence-limited planning target volume (cl-PTV), constructed using an initial sequence of daily measurements of internal target motion and patient setup error, exists and ensures that the clinical target volume (CTV) in the prostate cancer patient receives the prescribed dose within a predefined dose tolerance. A patient-specific bounding volume to correct for target location and compensate for target random motion was first constructed using the convex hull of the first k days of CT measurements. The bounding volume and the initial days of CT measurements were minimized based on a predefined dosimetric criterion. The hypothesis was tested using multiple daily CT images by mimicking the actual treatment of both conventional 4-field-box and intensity-modulated radiotherapy (IMRT) on each of 30 patients with prostate cancer. For each patient, a patient-specific setup margin was also applied to the bounding volume to form the final cl-PTV. This margin was determined using the random setup error predicted from the initial days of portal imaging measurements and the residuals after correcting for the systematic setup error. Results: The bounding volume constructed using daily CT measurements in the first week of treatment are adequate for the conventional beam delivery to achieve maximum dose reduction in the CTV of 2% or less of the prescription dose, for at least 80% of patients ( p = 0.08), and 4.5% or less for 95% of patients ( p = 0.1). However, for IMRT delivery, 2 weeks of daily CT measurements are required to achieve a similar level of the dosimetric criterion, otherwise the maximum dose reduction of 7%, on average, in the CTV is expected. Furthermore, the patient-specific setup margin required for the IMRT treatment is at least twice larger than that for the conventional treatment, to maintain the same dosimetric criterion. As compared to the conventional PTV, the volume of cl-PTV is significantly reduced, while maintaining the same dosimetric criterion. Conclusion: The cl-PTV for prostate treatment can be constructed within the first week of treatment using the feedback of imaging measurements. The cl-PTV has the capability to exclude the systematic variation and compensate for the patient-specific random variation on target location and patient setup position. This implies that in the current off-line image feedback adaptive treatment process, a single plan modification can be performed within the second week of treatment to improve the efficacy of dose delivery and dose escalation for external beam therapy of prostate cancer.

Materials/Methods: From August 1999 to March 2002, 330 prostate cancer patients were treated on our clinic’s adaptive radiotherapy (ART) protocol. This protocol demands analysis of each patient’s setup error, discerned by way of electronic portal images (EPIs) acquired for each treatment field. Therefore, for the i patient in this population we have available both the systematic error i,k and standard deviation i,k of the random error, where the index k 1,2,3 indicates the coordinate direction. The estimate i,k includes a residual i,k, which is an upper bound on the uncorrected systematic error–due either to lack of statistical confidence, or to the uncertainty induced by out-of-plane rotations. A minimal k(N) exists and satisfies i,k Mk(N) for at least N% of our population. Define k(N) and k(N) similarly for the residuals and standard deviations, respectively.