Pretrial Quality Assurance for Hypofractionated Salvage Radiation Therapy After Prostatectomy in the Multi-Institutional PERYTON-trial.

Purpose: The PERYTON trial is a multicenter randomized controlled trial that will investigate whether the treatment outcome of salvage external beam radiation therapy (sEBRT) will be improved with hypofractionated radiation therapy. A pretrial quality assurance (QA) program was undertaken to ensure protocol compliance within the PERYTON trial and to assess variation in sEBRT treatment protocols between the participating centers. Methods and Materials: Completion of the QA program was mandatory for each participating center (N = 8) to start patient inclusion. The pretrial QA program included (1) a questionnaire on the center-specific sEBRT protocol, (2) a delineation exercise of the clinical target volume (CTV) and organs at risk, and (3) a treatment planning exercise. All contours were analyzed using the pairwise dice similarity coefficient (DSC) and the 50th and 95th percentile Hausdorff distance (HD50 and HD95, respectively). The submitted treatment plans were reviewed for protocol compliance. Results: The results of the questionnaire showed that high-quality, state-of-the-art radiation therapy techniques were used in the participating centers and identified variations of the sEBRT protocols used concerning the position verification and preparation techniques. The submitted CTVs showed significant variation, with a range in volume of 29 cm3 to 167 cm3, a mean pairwise DSC of 0.52, and a mean HD50 and HD95 of 2.3 mm and 24.4 mm, respectively. Only in 1 center the treatment plan required adaptation before meeting all constraints of the PERYTON protocol. Conclusions: The pretrial QA of the PERYTON trial demonstrated that high-quality, but variable, radiation techniques were used in the 8 participating centers. The treatment planning exercise confirmed that the dose constraints of the PERYTON protocol were feasible for all participating centers. The observed variation in CTV delineation led to agreement on a new (image-based) delineation guideline to be used by all participating centers within the PERYTON trial.

Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography-Based Clinical Target Volume Delineation Guideline for Postprostatectomy Salvage Radiation Therapy: The PERYTON Guideline.

PURPOSE: Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) scan is the standard imaging procedure for biochemical recurrent prostate cancer postprostatectomy because of its high detection rate at low serum prostate-specific antigen levels. However, existing guidelines for clinical target volume (CTV) in prostate bed salvage external beam radiation therapy (sEBRT) are primarily based on experience-based clinical consensus and have been validated using conventional imaging modalities. Therefore, this study aimed to optimize CTV definition in sEBRT by using PSMA PET/CT-detected local recurrences (LRs). METHODS AND MATERIALS: Patients with suspected LR on PSMA PET/CT postprostatectomy were retrospectively enrolled in 9 Dutch centers. Anonymized scans were centrally reviewed by an expert nuclear medicine physician. Each boundary of the CTV guideline from the Groupe Francophone de Radiothérapie en Urologie (GFRU) was evaluated and adapted to improve the accuracy and coverage of the area at risk of LR (CTV) on PSMA PET/CT. The proposed CTV adaptation was discussed with the radiation oncologists of the participating centers, and final consensus was reached. To assess reproducibility, the participating centers were asked to delineate 3 new cases according to the new PERYTON-CTV, and the submitted contours were evaluated using the Dice similarity coefficient (DSC). RESULTS: After central review, 93 LRs were identified on 83 PSMA PET/CTs. The proposed CTV definition improved the coverage of PSMA PET/CT-detected LRs from 67% to 96% compared with the GFRU-CTV, while reducing the GFRU-CTV by 25%. The new CTV was highly reproducible, with a mean DSC of 0.82 (range, 0.81-0.83). CONCLUSIONS: This study contributes to the optimization of CTV definition in postprostatectomy sEBRT by using the pattern of LR detected on PSMA PET/CT. The PERYTON-CTV is highly reproducible across the participating centers and ensures coverage of 96% LRs while reducing the GFRU-CTV by 25%.

Dexamethasone for the Prevention of a Pain Flare After Palliative Radiation Therapy for Painful Bone Metastases: The Multicenter Double-Blind Placebo-Controlled 3-Armed Randomized Dutch DEXA Study.

PURPOSE: After radiation therapy for painful bone metastases, up to 44% of patients report a pain flare (PF). Our study compared 2 dose schedules of dexamethasone versus placebo to prevent PF. METHODS AND MATERIALS: This double-blind, randomized, placebo-controlled trial allocated patients with painful bone metastases from solid tumors randomly to receive 8 mg dexamethasone before radiation therapy followed by 3 daily doses (group A), 8 mg dexamethasone followed by 3 doses of placebo (group B), or 4 doses of placebo (group C). Patients reported worst pain scores, study medication side effects, and opioid intake before treatment and thereafter daily for 14 days and on day 28. PF was defined as at least a 2-point increase on a 0 to 10 pain scale with no decrease in opioid intake or a 25% or greater increase in opioid intake with no decrease in pain score, followed by a return to baseline or lower. The primary analysis was by intention to treat with patients who had missing data classified as having a PF. RESULTS: From January 2012 to April 2016, 295 patients were randomized. PF incidence was 38% for group A, 27% for group B, and 39% for group C (P = .07). Although patients in group B had the lowest PF incidence, a relatively high percentage did not return to baseline pain levels, indicating pain progression. The mean duration of PF was 2.1 days for group A, 4.5 days for group B, and 3.3 days for group C (P = .0567). Dexamethasone postponed PF occurrence; in group A 52% occurred on days 2 to 5 versus 73% in group B and 99% in group C (P = .02). Patients in group A reported lower mean pain scores on days 2 to 5 than those in group B or C (P < .001). Side effects were similar. CONCLUSIONS: There was insufficient evidence that dexamethasone reduced the incidence of radiation-induced PF. However, dexamethasone postponed the occurrence of PF and led to lower mean pain scores on days 2 to 5.

Timed Get Up and Go Test and Geriatric 8 Scores and the Association With (Chemo-)Radiation Therapy Noncompliance and Acute Toxicity in Elderly Cancer Patients.

PURPOSE: To investigate whether the Geriatric 8 (G8) and the Timed Get Up and Go Test (TGUGT) and clinical and demographic patient characteristics were associated with acute toxicity of radiation therapy and noncompliance in elderly cancer patients being irradiated with curative intent. METHODS AND MATERIALS: Patients were eligible if aged ≥65 years and diagnosed with breast, non-small cell lung, prostate, head and neck, rectal, or esophageal cancer, and were referred for curative radiation therapy. We recorded acute toxicity and noncompliance and identified potential predictors, including the G8 and TGUGT. RESULTS: We investigated 402 patients with a median age of 72 years (range, 65-96 years). According to the G8, 44.4% of the patients were frail. Toxicity grade ≥3 was observed in 22% of patients who were frail according to the G8 and 9.1% of patients who were not frail. The difference was 13% (confidence interval 5.2%-20%; P=.0006). According to the TGUGT 18.8% of the patients were frail; 21% of the frail according to the TGUGT developed toxicity grade ≥3, compared with 13% who were not frail. The difference was 7.3% (confidence interval -2.7% to 17%; P=.11). Overall compliance was 95%. Toxicity was most strongly associated with type of primary tumor, chemotherapy, age, and World Health Organization performance status. Compliance was associated with type of primary tumor and age. CONCLUSIONS: The usefulness of the TGUGT and G8 score in daily practice seems to be limited. Type of primary tumor, chemoradiotherapy, age, and World Health Organization performance status were more strongly associated with acute toxicity. Only chemoradiotherapy and age were associated with noncompliance. Overall the compliance was very high. To allow better-informed treatment decisions, a more accurate prediction of toxicity is desirable.

Final analysis of a prospective trial on functional imaging for nodal staging in patients with prostate cancer at high risk for lymph node involvement.

PURPOSE: Accurate staging modalities to diagnose lymph node involvement in patients with prostate cancer (PCa) are lacking. We wanted to prospectively assess sensitivity, specificity, and positive predictive value (PPV) and negative predictive value of (11)C-choline positron emission tomography (PET)-computed tomography (CT) and diffusion-weighted (DW) magnetic resonance imaging (MRI) for nodal staging in patients with PCa at high risk for lymph node involvement. MATERIAL AND METHODS: In total, 75 patients with a risk≥10% but<35% for lymph node (LN) metastases (Partin tables) who had N0 lesions based on the findings of contrast-enhanced CT scans were included. Patients underwent (11)C-choline PET-CT and DW MRI before surgery, which consisted of a superextended lymph node dissection followed by radical prostatectomy. LNs were serially sectioned and histopathologically examined after pankeratin staining. These results were used as the gold standard to compare with the imaging results. RESULTS: Of 1,665 resected LNs (median = 21, range: 7-49), 106 affected LNs (median = 2, range: 1-10) were found in 37 of 75 patients (49%). On a region-based analysis, we found a low sensitivity of 8.2% and 9.5% and a PPV of 50.0% and 40.0% for (11)C-choline PET-CT and DW MRI, respectively. The patient-based analysis showed a sensitivity of 18.9% and 36.1% for and a PPV of 63.6% and 86.7% (11)C-choline PET-CT and DW MRI, respectively. Even when both imaging modalities were combined, sensitivity values remained too low to be clinically useful. CONCLUSIONS: Because of the low sensitivity, there is no indication for routine clinical use of either (11)C-choline PET-CT or DW MRI for LN staging in patients with PCa, in whom CT scan findings were normal.

Mapping of pelvic lymph node metastases in prostate cancer.

BACKGROUND: Opinions about the optimal lymph node dissection (LND) template in prostate cancer differ. Drainage and dissemination patterns are not necessarily identical. OBJECTIVE: To present a precise overview of the lymphatic drainage pattern and to correlate those findings with dissemination patterns. We also investigated the relationship between the number of positive lymph nodes (LN+) and resected lymph nodes (LNs) per region. DESIGN, SETTING, AND PARTICIPANTS: Seventy-four patients with localized prostate adenocarcinoma were prospectively enrolled. Patients did not show suspect LNs on computed tomography scan and had an LN involvement risk of ≥ 10% but ≤ 35% (Partin tables) or a cT3 tumor. INTERVENTION: After intraprostatic technetium-99m nanocolloid injection, patients underwent planar scintigraphy and single-photon emission computed tomography imaging. Then surgery was performed, starting with a sentinel node (SN) procedure and a superextended lymphadenectomy followed by radical prostatectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Distribution of scintigraphically detected SNs and removed SNs per region were registered. The number of LN+, as well as the percentage LN+ of the total number of removed LNs per region, was demonstrated in combining data of all patients. The impact of the extent of LND on N-staging and on the number of LN+ removed was calculated. RESULTS AND LIMITATIONS: A total of 470 SNs were scintigraphically detected (median: 6; interquartile range [IQR]: 3-9), of which 371 SNs were removed (median: 4; IQR: 2.25-6). In total, 91 LN+ (median: 2; IQR: 1-3) were found in 34 of 74 patients. The predominant site for LN+ was the internal iliac region. An extended LND (eLND) would have correctly staged 32 of 34 patients but would have adequately removed all LN+ in only 26 of 34 patients. When adding the presacral region, these numbers increased to 33 of 34 and 30 of 34 patients, respectively. CONCLUSIONS: Standard eLND would have correctly staged the majority of LN+ patients, but 13% of the LN+ would have been missed. Adding the presacral LNs to the template should be considered to obtain a minimal template with maximal gain. NOTE: This manuscript was invited based on the 2011 European Association of Urology meeting in Vienna.

Multiparametric MRI for prostate cancer localization in correlation to whole-mount histopathology.

PURPOSE: To prospectively evaluate multiparametric magnetic resonance imaging (MRI) for accurate localization of intraprostatic tumor nodules, with whole-mount histopathology as the gold standard. MATERIALS AND METHODS: Seventy-five patients with biopsy-proven, intermediate, and high-risk prostate cancer underwent preoperative T2-weighted (T2w), dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) MRI at 1.5T. Localization of suspicious lesions was recorded for each of 24 standardized regions of interest on the different MR images and correlated with the pathologic findings. Generalized estimating equations (GEE) were used to estimate the sensitivity, specificity, accuracy, positive, and negative predictive value for every MRI modality, as well as to evaluate the influence of Gleason score and pT-stage. Tumor volume measurements on histopathological specimens were correlated with those on the different MR modalities (Pearson correlation). RESULTS: DW MRI had the highest sensitivity for tumor localization (31.1% vs. 27.4% vs. 44.5% for T2w, DCE, and DW MRI, respectively; P < 0.005), with more aggressive or more advanced tumors being more easily detected with this imaging modality. Significantly higher sensitivity values were obtained for the combination of T2w, DCE, and DW MRI (58.8%) as compared to each modality alone or any combination of two modalities (P < 0.0001). Tumor volume can most accurately be assessed by means of DW MRI (r = 0.75; P < 0.0001). CONCLUSION: Combining T2w, DCE, and DW imaging significantly improves prostate cancer localization.

Patient positioning based on a radioactive tracer implanted in patients with localized prostate cancer: a performance and safety evaluation.

PURPOSE: To evaluate the performance and safety of a radiation therapy positioning system (RealEye) based on tracking a radioactive marker (Tracer) implanted in patients with localized prostate cancer. METHODS AND MATERIALS: We performed a single-arm multi-institutional trial in 20 patients. The iridium-192 ((192)Ir)-containing Tracer was implanted in the patient together with 4 standard gold seed fiducials. Patient prostate-related symptoms were evaluated with the International Prostate Symptom Score (IPSS) questionnaire. Computed tomography (CT) was performed for treatment planning, during treatment, and after treatment to evaluate the migration stability of the Tracer. At 5 treatment sessions, cone beam CT was performed to test the positioning accuracy of the RealEye. RESULTS: The Tracer was successfully implanted in all patients. No device or procedure-related adverse events occurred. Changes in IPSS scores were limited. The difference between the mean change in Tracer-fiducial distance and the mean change in fiducial-fiducial distance was -0.39 mm (95% confidence interval [CI] upper boundary, -0.22 mm). The adjusted mean difference between Tracer position according to RealEye and the Tracer position on the CBCT for all patients was 1.34 mm (95% CI upper boundary, 1.41 mm). CONCLUSIONS: Implantation of the Tracer is feasible and safe. Migration stability of the Tracer is good. Prostate patients can be positioned and monitored accurately by using RealEye.

Early salvage radiation therapy does not compromise cancer control in patients with pT3N0 prostate cancer after radical prostatectomy: results of a match-controlled multi-institutional analysis.

BACKGROUND: Previous randomised trials demonstrated that adjuvant radiation therapy (aRT) improves cancer control in patients with pT3 prostate cancer (PCa). However, there is currently no evidence supporting early salvage radiation therapy (eSRT) as equivalent to aRT in improving freedom from biochemical recurrence (BCR) after radical prostatectomy (RP). OBJECTIVE: To evaluate BCR-free survival for aRT versus observation followed by eSRT in cases of relapse in patients undergoing RP for pT3pN0, R0-R1 PCa. DESIGN, SETTING, AND PARTICIPANTS: Using a European multi-institutional cohort, 890 men with pT3pN0, R0-R1 PCa were identified. INTERVENTION: All patients underwent RP. Subsequently, patients were stratified into two groups: aRT versus initial observation followed by eSRT in cases of relapse. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Propensity-matched analysis was employed, and patients were stratified into two groups: aRT versus observation and eventual eSRT, defined as RT given at a postoperative serum prostate-specific antigen (PSA) ≤ 0.5 ng/ml at least 6 mo after RP. BCR, defined as PSA >0.20 ng/ml and rising after administration of RT, was compared between aRT and initial observation followed by eSRT in cases of relapse using Kaplan-Meier and Cox regression methods. RESULTS AND LIMITATIONS: Overall, 390 (43.8%) and 500 (56.2%) patients were treated with aRT and initial observation, respectively. Within the latter group, 225 (45.0%) patients experienced BCR and underwent eSRT. In the postpropensity-matched cohort, the 2- and 5-yr BCR-free survival rates were 91.4% and 78.4% in aRT versus 92.8% and 81.8% in patients who underwent initial observation and eSRT in cases of relapse, respectively (p=0.9). No differences in the 2- and 5-yr BCR-free survival rates were found, even when patients were stratified according to pT3 substage and surgical margin status (all p ≥ 0.4). These findings were also confirmed in multivariable analyses (p=0.6). Similar results were achieved when the cut-off to define eSRT was set at 0.3 ng/ml (all p ≥ 0.5). CONCLUSIONS: The current study suggests that timely administration of eSRT is comparable to aRT in improving BCR-free survival in the majority of pT3pN0 PCa patients. Therefore, eSRT may not compromise cancer control but significantly reduces overtreatment associated with aRT.

Is there an additional value of ¹¹C-choline PET-CT to T2-weighted MRI images in the localization of intraprostatic tumor nodules?

PURPOSE: To investigate the additional value of (11)C-choline positron emission tomography (PET)-computed tomography (CT) to T2-weighted (T2w) magnetic resonance imaging (MRI) for localization of intraprostatic tumor nodules. METHODS AND MATERIALS: Forty-nine prostate cancer patients underwent T2w MRI and (11)C-choline PET-CT before radical prostatectomy and extended lymphadenectomy. Tumor regions were outlined on the whole-mount histopathology sections and on the T2w MR images. Tumor localization was recorded in the basal, middle, and apical part of the prostate by means of an octant grid. To analyze (11)C-choline PET-CT images, the same grid was used to calculate the standardized uptake values (SUV) per octant, after rigid registration with the T2w MR images for anatomic reference. RESULTS: In total, 1,176 octants were analyzed. Sensitivity, specificity, and accuracy of T2w MRI were 33.5%, 94.6%, and 70.2%, respectively. For (11)C-choline PET-CT, the mean SUV(max) of malignant octants was significantly higher than the mean SUV(max) of benign octants (3.69 ± 1.29 vs. 3.06 ± 0.97, p < 0.0001) which was also true for mean SUV(mean) values (2.39 ± 0.77 vs. 1.94 ± 0.61, p < 0.0001). A positive correlation was observed between SUV(mean) and absolute tumor volume (Spearman r = 0.3003, p = 0.0362). No correlation was found between SUVs and prostate-specific antigen, T-stage or Gleason score. The highest accuracy (61.1%) was obtained with a SUV(max) cutoff of 2.70, resulting in a sensitivity of 77.4% and a specificity of 44.9%. When both modalities were combined (PET-CT or MRI positive), sensitivity levels increased as a function of SUV(max) but at the cost of specificity. When only considering suspect octants on (11)C-choline PET-CT (SUV(max) ≥ 2.70) and T2w MRI, 84.7% of these segments were in agreement with the gold standard, compared with 80.5% for T2w MRI alone. CONCLUSIONS: The additional value of (11)C-choline PET-CT next to T2w MRI in detecting tumor nodules within the prostate is limited.

Prospective evaluation of 11C-choline positron emission tomography/computed tomography and diffusion-weighted magnetic resonance imaging for the nodal staging of prostate cancer with a high risk of lymph node metastases.

BACKGROUND: Contrast-enhanced computed tomography (CT) and magnetic resonance (MR) imaging for lymph node (LN) staging of prostate cancer (PCa) are largely inadequate. OBJECTIVE: Our aim was to assess prospectively the sensitivity, specificity, and positive and negative predictive values for the LN staging by (11)C-choline positron emission tomography (PET)-CT and MR diffusion-weighted imaging (DWI) of the pelvis before retropubic radical prostatectomy (RRP) with extended pelvic LN dissection (PLND). DESIGN, SETTING, AND PARTICIPANTS: From February 2008 to August 2009, 36 patients with histologically proven PCa and no pelvic LN involvement on contrast-enhanced CT with a risk ≥ 10% but ≤ 35% at LN metastasis according to the Partin tables were enrolled in this study. INTERVENTION: Patients preoperatively underwent (11)C-choline PET-CT and DWI. Subsequently all patients underwent a wide RRP and an extended PLND. MEASUREMENTS: Sensitivity, specificity, and positive and negative predictive values (PPV and NPV) for LN status of (11)C-choline PET-CT and DWI were calculated with the final histopathology of the LNs as comparator. RESULTS AND LIMITATIONS: Seventeen patients (47%) had a pN1 stage, and 38 positive LNs were identified. On a LN region-based analysis, sensitivity, specificity, PPV, NPV, and the number of correctly recognised cases at (11)C-choline PET-CT were 9.4%, 99.7%, 75.0%, 91.0%, and 7.9%, respectively, and at DWI these numbers were 18.8%, 97.6%, 46.2%, 91.7%, and 15.8%, respectively. Twelve LN regions containing macrometastases, of which 2 had capsular penetration, were not detected by (11)C-choline PET-CT; 11 LNs, of which 2 had capsular penetration, were not detected by DWI. This is a small study with 36 patients, but we intend to recruit more patients. CONCLUSIONS: From this prospective histopathology-based evaluation of (11)C-choline PET-CT and DWI for LN staging in high-risk PCa patients, it is concluded that these techniques cannot be recommended at present to detect occult LN metastases before initial treatment.

Intrafractional prostate motion during online image guided intensity-modulated radiotherapy for prostate cancer.

INTRODUCTION: Intrafractional motion consists of two components: (1) the movement between the on-line repositioning procedure and the treatment start and (2) the movement during the treatment delivery. The goal of this study is to estimate this intrafractional movement of the prostate during prostate cancer radiotherapy. MATERIAL AND METHODS: Twenty-seven patients with prostate cancer and implanted fiducials underwent a marker match procedure before a five-field IMRT treatment. For all fields, in-treatment images were obtained and then processed to enable automatic marker detection. Combining the subsequent projection images, five positions of each marker were determined using the shortest path approach. The residual set-up error (RSE) after kV-MV based prostate localization, the prostate position as a function of time during a radiotherapy session and the required margins to account for intrafractional motion were determined. RESULTS: The mean RSE and standard deviation in the antero-posterior, cranio-caudal and left-right direction were 2.3±1.5 mm, 0.2±1.1 mm and -0.1±1.1 mm, respectively. Almost all motions occurred in the posterior direction before the first treatment beam as the percentage of excursions>5 mm was reduced significantly when the RSE was not accounted for. The required margins for intrafractional motion increased with prolongation of the treatment. Application of a repositioning protocol after every beam could decrease the 1cm margin from CTV to PTV by 2 mm. CONCLUSIONS: The RSE is the main contributor to intrafractional motion. This RSE after on-line prostate localization and patient repositioning in the posterior direction emphasizes the need to speed up the marker match procedure. Also, a prostate IMRT treatment should be administered as fast as possible, to ensure that the pre-treatment repositioning efforts are not erased by intrafractional prostate motion. This warrants an optimized workflow with the use of faster treatment techniques.

A multi-institutional analysis comparing adjuvant and salvage radiation therapy for high-risk prostate cancer patients with undetectable PSA after prostatectomy.

BACKGROUND AND PURPOSE: In men with adverse pathology at the time of radical prostatectomy (RP), the most appropriate timing to administer radiotherapy (RT) remains a subject for debate. To determine whether salvage radiotherapy (SRT) upon early prostate-specific antigen (PSA) relapse is equivalent to immediate adjuvant radiotherapy (ART) post RP. MATERIAL AND METHODS: 130 patients receiving ART and 89 receiving SRT were identified. All had an undetectable PSA after RP. Homogeneous subgroups were built based on the status (±) of lymphatic invasion (LVI) and surgical margins (SM), to allow a comparison of ART and SRT. Biochemical disease-free survival (bDFS) was calculated from the date of surgery and from the end of RT. The multivariate analysis was performed using the Cox Proportional hazard model. RESULTS: In the SM-/LVI- and SM+/LVI- groups, SRT was a significant predictor of a decreased bDFS from the date of surgery, while in the SM+/LVI+ group, there was a trend towards significance. From the end of RT, SRT was also a significant predictor of a decreased bDFS in three patient groups: SM-/LVI-, SM+/LVI- and SM+/LVI+. Gleason score >7 showed to be another factor on multivariate analysis associated with decreased bDFS in the SM-/LVI- group, from the date of surgery and end of RT. Preoperative PSA was a significant predictor in the SM-/LVI- group from the date of RP only. CONCLUSIONS: Immediate ART post RP for patients with high risk features in the prostatectomy specimen significantly reduces bDFS after RP compared with early SRT upon PSA relapse.

Fast, accurate, and robust automatic marker detection for motion correction based on oblique kV or MV projection image pairs.

PURPOSE: A robust and accurate method that allows the automatic detection of fiducial markers in MV and kV projection image pairs is proposed. The method allows to automatically correct for inter or intrafraction motion. METHODS: Intratreatment MV projection images are acquired during each of five treatment beams of prostate cancer patients with four implanted fiducial markers. The projection images are first preprocessed using a series of marker enhancing filters. 2D candidate marker locations are generated for each of the filtered projection images and 3D candidate marker locations are reconstructed by pairing candidates in subsequent projection images. The correct marker positions are retrieved in 3D by the minimization of a cost function that combines 2D image intensity and 3D geometric or shape information for the entire marker configuration simultaneously. This optimization problem is solved using dynamic programming such that the globally optimal configuration for all markers is always found. Translational interfraction and intrafraction prostate motion and the required patient repositioning is assessed from the position of the centroid of the detected markers in different MV image pairs. The method was validated on a phantom using CT as ground-truth and on clinical data sets of 16 patients using manual marker annotations as ground-truth. RESULTS: The entire setup was confirmed to be accurate to around 1 mm by the phantom measurements. The reproducibility of the manual marker selection was less than 3.5 pixels in the MV images. In patient images, markers were correctly identified in at least 99% of the cases for anterior projection images and 96% of the cases for oblique projection images. The average marker detection accuracy was 1.4 +/- 1.8 pixels in the projection images. The centroid of all four reconstructed marker positions in 3D was positioned within 2 mm of the ground-truth position in 99.73% of all cases. Detecting four markers in a pair of MV images takes a little less than a second where most time is spent on the image preprocessing. CONCLUSIONS: The authors have developed a method to automatically detect multiple markers in a pair of projection images that is robust, accurate, and sufficiently fast for clinical use. It can be used for kV, MV, or mixed image pairs and can cope with limited motion between the projection images.

External beam radiotherapy for prostate cancer.

External beam radiotherapy (EBRT) constitutes an important management option for prostate cancer (PCa). Radiation doses >or=74 Gy are warranted. Dose escalation of EBRT using three-dimensional-conformal radiotherapy (RT) or intensity-modulated RT improves the therapeutic index by minimizing normal tissue complication probability and increasing tumor control probability. Although higher doses are associated with better biochemical disease-free survival, no impact on local recurrence or overall survival has been demonstrated. Hypofractionation for PCa may be an attractive therapeutic option, but toxicity data need to be confirmed in randomized phase III trials. Advances in RT technology, such as volumetric modulated arc therapy and image-guided RT, could facilitate the introduction of dose escalation and hypofractionation into clinical practice. Particle beam irradiation and more specific carbon ion RT are also very promising new techniques that are under investigation. Ultimately, these techniques may lead to focal dose escalation by selective boosting of dominant intraprostatic lesions, which is currently under investigation as a solution to overcome increased toxicity of homogenous dose escalation. This review will give a comprehensive overview of all the recent advances in these new radiation therapy techniques.

IMRT-based optimization approaches for volumetric modulated single arc radiotherapy planning.

This paper reports on an evaluation of 5 RapidArc optimization approaches vs IMRT. This study includes 11 patients with adenocarcinoma of the prostate. Rectal Normal Tissue Complication Probability is used as a constraint in a dose escalation. RapidArc rectal NTCP's are lower than those of IMRT (p = 0.007). This allows a mean dose escalation of 2.1 Gy([0.7 Gy,3.5 Gy]).

A semi-automated 2D/3D marker-based registration algorithm modelling prostate shrinkage during radiotherapy for prostate cancer.

BACKGROUND AND PURPOSE: Currently, most available patient alignment tools based on implanted markers use manual marker matching and rigid registration transformations to measure the needed translational shifts. To quantify the particular effect of prostate gland shrinkage, implanted gold markers were tracked during a course of radiotherapy including an isotropic scaling factor to model prostate shrinkage. MATERIALS AND METHODS: Eight patients with prostate cancer had gold markers implanted transrectally and seven were treated with (neo) adjuvant androgen deprivation therapy. After patient alignment to skin tattoos, orthogonal electronic portal images (EPIs) were taken. A semi-automated 2D/3D marker-based registration was performed to calculate the necessary couch shifts. The registration consists of a rigid transformation combined with an isotropic scaling to model prostate shrinkage. RESULTS: The inclusion of an isotropic shrinkage model in the registration algorithm cancelled the corresponding increase in registration error. The mean scaling factor was 0.89+/-0.09. For all but two patients, a decrease of the isotropic scaling factor during treatment was observed. However, there was almost no difference in the translation offset between the manual matching of the EPIs to the digitally reconstructed radiographs and the semi-automated 2D/3D registration. A decrease in the intermarker distance was found correlating with prostate shrinkage rather than with random marker migration. CONCLUSIONS: Inclusion of shrinkage in the registration process reduces registration errors during a course of radiotherapy. Nevertheless, this did not lead to a clinically significant change in the proposed table translations when compared to translations obtained with manual marker matching without a scaling correction.

Quality assurance in the 22991 EORTC ROG trial in localized prostate cancer: dummy run and individual case review.

INTRODUCTION: EORTC trial 22991 was designed to evaluate the addition of concomitant and adjuvant short-term hormonal treatments to curative radiotherapy in terms of disease-free survival for patients with intermediate risk localized prostate cancer. In order to assess the compliance to the 3D conformal radiotherapy protocol guidelines, all participating centres were requested to participate in a dummy run procedure. An individual case review was performed for the largest recruiting centres as well. MATERIALS AND METHODS: CT-data of an eligible prostate cancer patient were sent to 30 centres including a description of the clinical case. The investigator was requested to delineate the volumes of interest and to perform treatment planning according to the protocol. Thereafter, the investigators of the 12 most actively recruiting centres were requested to provide data on five randomly selected patients for an individual case review. RESULTS: Volume delineation varied significantly between investigators. Dose constraints for organs at risk (rectum, bladder, hips) were difficult to meet. In the individual case review, no major protocol deviations were observed, but a number of dose reporting problems were documented for centres using IMRT. CONCLUSIONS: Overall, results of this quality assurance program were satisfactory. The efficacy of the combination of a dummy run procedure with an individual case review is confirmed in this study, as none of the evaluated patient files harboured a major protocol deviation. Quality assurance remains a very important tool in radiotherapy to increase the reliability of the trial results. Special attention should be given when designing quality assurance programs for more complex irradiation techniques.

Predictors of the risk of fibrosis at 10 years after breast conserving therapy for early breast cancer: a study based on the EORTC Trial 22881-10882 'boost versus no boost'.

The EORTC 22881-10882 trial in 5178 conservatively treated early breast cancer patients showed that a 16 Gy boost dose significantly improved local control, but increased the risk of breast fibrosis. To investigate predictors for the long-term risk of fibrosis, Cox regression models of the time to moderate or severe fibrosis were developed on a random set of 1797 patients with and 1827 patients without a boost, and validated in the remaining set. The median follow-up was 10.7 years. The risk of fibrosis significantly increased (P<0.01) with increasing maximum whole breast irradiation (WBI) dose and with concomitant chemotherapy, but was independent of age. In the boost arm, the risk further increased (P<0.01) if patients had post-operative breast oedema or haematoma, but it decreased (P<0.01) if WBI was given with >6 MV photons. The c-index was around 0.62. Nomograms with these factors are proposed to forecast the long-term risk of moderate or severe fibrosis.

A phase I radiation dose-escalation study to determine the maximal dose of radiotherapy in combination with weekly gemcitabine in patients with locally advanced pancreatic adenocarcinoma.

BACKGROUND: The primary objective of this study was to determine the maximum tolerated dose (MTD) of escalating doses of radiotherapy (RT) concomitantly with a fixed dose of gemcitabine (300 mg/m2/week) within the same overall treatment time. METHODS: Thirteen patients were included. Gemcitabine 300 mg/m2/week was administered prior to RT. The initial dose of RT was 45 Gy in 1.8 Gy fractions, escalated by adding 5 fractions of 1.8 Gy (one/week) to a dose of 54 Gy with a total duration kept at 5 weeks. All patients received a dynamic MRI to assess the pancreatic respiratory related movements. Toxicity was scored using the RTOG-EORTC toxicity criteria. RESULTS: Three of six patients experienced an acute dose limiting toxicity (DLT) at the 54 Gy dose level. For these patients a grade III gastro-intestinal toxicity (GI) was noted. Patients treated at the 45 Gy dose level tolerated therapy without DLT. The 54 Gy dose level was designated as the MTD and was deemed not suitable for further investigation. Between both dose levels, there was a significant difference in percentage weight loss (p = 0.006) and also in cumulative GI toxicity (p = 0.027). There was no grade 3 toxicity in the 45 Gy cohort versus 4 grade 3 toxicity events in the 54 Gy cohort. The mean dose to the duodenum was significantly higher in the 54 Gy cohort (38.45 Gy vs. 51.82 Gy; p = 0.001). CONCLUSION: Accelerated dose escalation to a total dose of 54 Gy with 300 mg/m2/week gemcitabine was not feasible. GI toxicity was the DLT. Retrospectively, the dose escalation of 9 Gy by accelerated radiotherapy might have been to large. A dose of 45 Gy is recommended. Considering the good patient outcomes, there might be a role for the investigation of a fixed dose of gemcitabine and concurrent RT with small fractions (1.8 Gy/day) in borderline resectable or unresectable non-metastatic locally advanced pancreatic cancer.