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Background: Inter-fractional anatomical changes challenge robust delivery of whole-pelvic proton therapy for high-risk prostate cancer. Pre-treatment robust evaluation (PRE) takes uncertainties in isocenter shifts and distal beam edge in treatment plans into account. Using weekly control computed tomography scans (cCTs), the aim of this study was to evaluate the PRE strategy by comparing to an off-line during-treatment robust evaluation (DRE) while also assessing plan robustness with respect to protocol planning constraints., Material and Methods: Treatment plans and cCTs from ten patients included in the pilot phase of the PROstate PROTON Trial 1 were analysed. Treatment planning followed protocol guidelines with 78 Gy to the primary clinical target volume (CTVp) and 56 Gy to the elective target (CTVe) in 39 fractions. Recalculations of the treatment plans were performed for a total of 64 cCTs and dose/volume measures corresponding to clinical constraints were evaluated for this DRE against the simulated scenario interval from the PRE., Results: Of the 64 cCTs, 59 showed DRE CTVp measures within the robustness range from the PRE; this was also the case for 39 of the cCTs for the CTVe measures. However, DRE CTVe coverage was still within constraints for 57 of the 64 cCTs. DRE dose/volume measures for CTVp fulfilled target coverage constraints in 59 of 64 cCTs. All DRE measures for the rectum, bladder, and bowel were inside the PRE range in 63, 39, and 31 cCTs, respectively., Conclusion: The PRE strategy predicted the DRE scenarios for CTVp and rectum. CTVe, bladder, and bowel showed more complex anatomical variations than simulated by the PRE isocenter shift. Both original and recalculated nominal treatment plans showed robust treatment delivery in terms of target coverage.

Background: The aim of this study was to assess acute and late morbidity measured by the physician and patient-reported outcomes (PROs) in high-risk prostate cancer (PC) patients receiving whole pelvic intensity-modulated radiotherapy (IMRT) in the setting of a national clinical trial., Material and Methods: A total of 88 patients with adenocarcinoma of the prostate and high-risk parameters were enrolled from 2011 to 2013. All patients received 78 Gy in 39 fractions of IMRT delivering simultaneous 78 Gy to the prostate and 56 Gy to the seminal vesicles and lymph nodes. Physician-reported morbidity was assessed by CTCAE v.4.0. PROs were registered for gastro-intestinal (GI) by the RT-ARD score, genito-urinary (GU) by DAN-PSS, sexual and hormonal by EPIC-26, and quality of life (QoL) by EORTC QLQ-C30., Results: Median follow-up (FU) time was 4.6 years. No persistent late CTCAE grade 3+ morbidity was observed. Prevalence of CTCAE grade 2+ GI morbidities varied from 0 to 6% at baseline throughout FU time, except for diarrhea, which was reported in 19% of the patients post-RT. PROs revealed increased GI morbidity (≥1 monthly episode) for "rectal urgency", "use of pads", "incomplete evacuation", "mucus in stool" and "bowel function impact on QoL" all remained significantly different ( p  < .05) at 60 months compared to baseline. CTCAE grade 2+ GU and sexual morbidity were unchanged. GU PROs on obstructive and irritative GU items (≥daily episode) increased during RT and normalized at 24 months. No clinically significant differences were found in sexual, hormonal, and QoL scores compared to baseline., Conclusions: Whole pelvic RT resulted in a mild to the moderate burden of late GI morbidities demonstrated by a relatively high prevalence of PROs. Whereas, physician-assessed morbidity revealed a low prevalence of late GI morbidity scores. This emphasizes the importance of using both PROs and physician-reported scoring scales when reporting late morbidity in clinical trials.

Context: Different nonsurgical therapeutic strategies can be adopted for intraprostatic relapse of prostate cancer after primary radiotherapy, including re-irradiation (with brachytherapy [BT] or external beam radiotherapy [EBRT]), high-intensity focused ultrasound (HIFU), and cryotherapy. The main issues to consider when choosing nonsurgical salvage local therapies are local tumor control and significant genitourinary toxicity., Objective: To conduct a systematic review and meta-analysis of the role of nonsurgical salvage modalities in patients with radiorecurrent prostate cancer and associated clinical outcomes and toxicity profiles., Evidence Acquisition: We performed a critical review of the Medline, Scopus, and ClinicalKey databases from January 1, 2000 through February 1, 2018 according to the Preferred Reporting Items and Meta-Analyses statement. To assess the overall quality of the literature reviewed, we used a modified Delphi tool for case-series studies., Evidence Synthesis: A total of 64 case-series studies were included, corresponding to a cohort of 5585 patients. The modified Delphi checklist evidenced high methodological quality overall (mean quality score of 80.6%). Biochemical control rates were lowest for patients treated with HIFU (58%, 95% confidence interval [CI] 47-68%) and highest for patients treated with BT (69%, 95% CI 62-76%) and EBRT (69%, 95% CI 53-83%). The lowest prevalence of incontinence was for patients treated with BT (3%, 95% CI 0-6%; I 2 =63.4%) and the highest was among patients treated with HIFU (28%, 95% CI 19-38%; I 2 =89.7%)., Conclusions: Nonsurgical therapeutic options, especially BT, showed good outcomes in terms of biochemical control and tolerability in the local recurrence setting., Patient Summary: The current analysis demonstrated that nonsurgical salvage local therapies offer a chance of a curative local approach in radiorecurrent prostate cancer. However, high-quality data from prospective trials are needed to validate long-term outcomes from nonsurgical strategies for the treatment of intraprostatic recurrence after previous radiotherapy., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: To investigate whether inter-institutional cohort analysis uncovers more reliable dose-response relationships exemplified for late rectal bleeding (LRB) following prostate radiotherapy., Material and Methods: Data from five institutions were used. Rectal dose-volume histograms (DVHs) for 989 patients treated with 3DCRT or IMRT to 70-86.4 Gy@1.8-2.0 Gy/fraction were obtained, and corrected for fractionation effects (α/β = 3 Gy). Cohorts with best-fit Lyman-Kutcher-Burman volume-effect parameter a were pooled after calibration adjustments of the available LRB definitions. In the pooled cohort, dose-response modeling (incorporating rectal dose and geometry, and patient characteristics) was conducted on a training cohort (70%) followed by final testing on the remaining 30%. Multivariate logistic regression was performed to build models with bootstrap stability., Results: Two cohorts with low bleeding rates (2%) were judged to be inconsistent with the remaining data, and were excluded. In the remaining pooled cohorts (n = 690; LRB rate = 12%), an optimal model was generated for 3DCRT using the minimum rectal dose and the absolute rectal volume receiving less than 55 Gy (AUC = 0.67; p = 0.0002; Hosmer-Lemeshow p-value, p HL  = 0.59). The model performed nearly as well in the hold-out testing data (AUC = 0.71; p < 0.0001; p HL  = 0.63), indicating a logistically shaped dose-response., Conclusion: We have demonstrated the importance of integrating datasets from multiple institutions, thereby reducing the impact of intra-institutional dose-volume parameters explicitly correlated with prescription dose levels. This uncovered an unexpected emphasis on sparing of the low to intermediate rectal dose range in the etiology of late rectal bleeding following prostate radiotherapy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: Lower urinary tract symptoms (LUTS) are common following radical prostatectomy (RP) or intended curative radiotherapy in prostate cancer patients. One-quarter of those treated with RP experience biochemical failure and are subsequently offered salvage radiotherapy (SRT) to the prostatic bed. The aim of this study was to elucidate long-term LUTS after surgery and SRT., Materials and Methods: Urodynamic parameters from 16 patients treated with RP and subsequent SRT in the period 2000-2010 were evaluated with uroflowmetry, filling cystometry, pressure-flow and urethral pressure profile (UPP). In conjunction with the urodynamic examination, all patients completed the Danish Prostatic Symptom Score (DAN-PSS) questionnaire, which evaluates the grade of LUTS., Results: Median time from SRT to urodynamic examination was 7.7 years (range 5.8-10.0 years). The following urodynamic parameters were affected: bladder volume at maximal cystometric capacity, bladder compliance, bladder function, bladder outlet obstruction and UPP. The total DAN-PSS index combining all symptoms and their corresponding impact on patients was mild in six patients (≤ 7 points), moderate in seven patients (8-19 points) and severe in three patients (≥ 20 points)., Conclusions: This urodynamic study is one of the first to evaluate long-term urodynamic characteristics in patients treated with SRT. Several urodynamic parameters were affected. This indicates that SRT primarily affects bladder compliance, maximal cystometric capacity and bladder outlet obstruction. LUTS were proven to be strongly related to urodynamic parameters.

Objective: There is a paucity of knowledge of long-term urinary morbidity in patients treated for prostate cancer (PCa) with radical prostatectomy (RP) and salvage radiotherapy (SRT). Improved long-term survival calls for heightened awareness of late effects from radiotherapy after RP. The purpose of this study was to assess late urinary morbidity and its potential impact on quality of life (QoL) in patients treated with RP plus SRT compared with patients treated with RP alone., Materials and Methods: Long-term morbidity and QoL were evaluated using a cross-sectional design with validated questionnaires in urinary morbidity [Danish Prostatic Symptom Score (DAN-PSS)] and QoL [European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)]. Included were a total of 227 patients treated with SRT and 192 treated with RP in the periods 2006-2010 and 2005-2007, respectively., Results: Weak stream, straining, frequency and nocturia were significantly more prevalent in patients treated with RP + SRT than in patients treated with RP alone. Patients treated with RP + SRT generally suffered from more severe urinary symptoms. The QoL scores of the two treatment groups were not statistically significantly different, but a high level of urinary morbidity was significantly related to decreased QoL (p = 0.000)., Conclusions: Patients treated with SRT have a higher rate of urinary morbidity than do patients treated with RP alone. Severe urinary morbidity was significantly related to decreased QoL, but did not differ between the two treatment groups.

Background: Gastro-intestinal (GI) toxicity after radiotherapy (RT) for prostate cancer reduces patient's quality of life. In this study, we explored associations between spatial rectal dose/volume metrics and patient-reported GI symptoms after RT for localized prostate cancer, and compared these with those of dose-surface/volume histogram (DSH/DVH) metrics., Material and Methods: Dose distributions and six GI symptoms (defecation urgency/emptying difficulties/fecal leakage, ≥Grade 2, median follow-up: 3.6 y) were extracted for 200 patients treated with image-guided RT in 2005-2007. Three hundred and nine metrics assessed from 2D rectal dose maps or DSHs/DVHs were subject to 50-times iterated five-fold cross-validated univariate and multivariate logistic regression analysis (UVA, MVA). Performance of the most frequently selected MVA models was evaluated by the area under the receiving-operating characteristics curve (AUC)., Results: The AUC increased for dose-map compared to DSH/DVH-based models (mean SD: 0.64 ± 0.03 vs. 0.61 ± 0.01), and significant relations were found for six versus four symptoms. Defecation urgency and faecal leakage were explained by high doses at the central/upper and central areas, respectively; while emptying difficulties were explained by longitudinal extensions of intermediate doses., Conclusions: Predictability of patient-reported GI toxicity increased using spatial metrics compared to DSH/DVH metrics. Novel associations were particularly identified for emptying difficulties using both approaches in which intermediate doses were emphasized.

Introduction: Normal tissue morbidity sets the dose limit for radiotherapy (RT) in cancer treatment and has importance for quality of life for cancer survivors. A previous study of prostate cancer patients treated with RT generated clinical data for radiation-induced morbidity measured by anorectal physiological methods and validated questionnaires. Other studies have identified genetic predictors associated with late radiation-induced morbidity outcome. We have expanded biobank material aiming to validate single nucleotide polymorphisms (SNPs) and a gene expression classifier with endpoints on patient-reported outcomes and biomechanical properties of the anorectum from our cohort matching originally published endpoints., Materials and Methods: The present cohort of prostate cancer patients was treated with RT curative intent in 1999-2007. Nine SNPs associated with late radiation-induced morbidity were tested in 96 patients (rs2788612, rs1800629, rs264663, rs2682585, rs2268363, rs1801516, rs13035033, rs7120482 and rs17779457). A validated gene expression profile predictive of resistance to radiation-induced skin fibrosis was tested in 42 patients. An RT-induced anorectal dysfunction score (RT-ARD) served as a fibrosis-surrogate and a measure of overall radiation-induced morbidity., Results: The lowest p-value found in the genotype analyses was for SNP rs2682585 minor allele (A) in the FSHR gene and the RT-ARD score with odds ratios (OR) = 1.76; 95% CI (0.98-3.17) p = .06, which was out of concordance with original data showing a protective effect of the minor allele. The gene expression profile in patients classified as fibrosis-resistant was associated with high RT-ARD scores OR 4.18; 95% CI (1.1-16.6), p = .04 conflicting with the hypothesis that fibrosis-resistant patients would experience lower RT-ARD scores., Conclusions: We aimed to validate nine SNPs and a gene expression classifier in a cohort of prostate cancer patients with unique scoring of radiation-induced morbidity. One significant association was found, pointing to the opposite direction of originally published data. We conclude that the material was not able to validate previously published genetic predictors of radiation-induced morbidity.

Background: The purpose of this observational cohort study was to evaluate the outcome and prognostic factors following salvage radiotherapy (SRT) in a consecutive national cohort., Material and Methods: Between 2006 and 2010, 259 patients received SRT in Denmark. Patient- and cancer-related characteristics were retrospectively retrieved from patient charts. The primary end point was biochemical progression-free survival (b-PFS)., Results: At the end of follow-up, 51% of the patients displayed a prostate-specific antigen (PSA) level <0.1 ng/ml. The three-year b-PFS rate for the total cohort was 57.0%. Nearly half of the patients (44%) received androgen deprivation therapy (ADT) in combination with SRT. Positive surgical tumour margins (p = 0.025) and ADT (p = 0.001) were the only markers independently correlated with b-PFS. In patients who received SRT without ADT, both a pre-SRT PSA level ≤0.5 ng/ml (p = 0.003) and pathological tumour stage T1-T2 (p = 0.036) independently correlated with b-PFS. Moreover, a duration between radical prostatectomy (RP) and SRT ≤29 months (p = 0.035) independently correlated with b-PFS in patients treated with ADT in combination with RT., Conclusions: In patients treated for biochemical failure after RP, positive surgical tumour margins and PSA levels ≤0.5 ng/mL at the time of SRT were associated with a favourable outcome. Despite less favourable tumour characteristics, patients receiving SRT and ADT demonstrated improved b-PFS, and in particular, patients with PSA levels >0.2 ng/ml benefitted from additional ADT.

Background and Purpose: Radiotherapy (RT) induced genitourinary (GU) morbidity is typically assessed by physicians as single symptoms or aggregated scores including symptoms from various domains. Here we apply a method to group patient-reported GU symptoms after RT for localized prostate cancer based on their interplay, and study how these relate to urinary bladder dose., Materials and Methods: Data were taken from two Scandinavian studies (N=207/276) including men treated with external-beam RT (EBRT) to 78/70Gy (2Gy/fraction; median time-to-follow-up: 3.6-6.4y). Within and across cohorts, bladder dose-volume parameters were tested as predictors for GU symptom domains identified from two study-specific questionnaires (35 questions on frequency, incontinence, obstruction, pain, urgency, and sensory symptoms) using univariate and multivariate logistic regression analysis (MVA) with 10-fold cross-validation. Performance was evaluated using Area Under the Receiver Operating Characteristic Curve (Az)., Results: For the identified Incontinence (2-5 symptoms), Obstruction (3-5 symptoms), and Urgency (2-7 symptoms) domains, MVA demonstrated that bladder doses close to the prescription doses were the strongest predictors for Obstruction (Az: 0.53-0.57) and Urgency (Az: 0.60). For Obstruction, performance increased for the across cohort analysis (Az: 0.61-0.64)., Conclusions: Our identified patient-reported GU symptom domains suggest that high urinary bladder doses, and increased focus on both obstruction and urgency is likely to further add to the understanding of GU tract RT responses., (Published by Elsevier Ireland Ltd.)

Background and Purpose: A 15-gene hypoxia profile has previously demonstrated to have both prognostic and predictive impact for hypoxic modification in squamous cell carcinoma of the head and neck. This gene expression profile may also have a prognostic value in other histological cancer types, and could potentially have a function as a universal hypoxia profile. The hypoxia induced upregulation of the included genes, and the validity of the previously used reference genes was established in this study, in a range of different cell lines representing carcinomas of the prostate, colon, and esophagus., Materials and Methods: Eleven adenocarcinoma and one squamous cell lines: Six colon carcinomas (HTC8, HT29, LS174T, SW116, SW948 and T48), 3 prostate carcinomas (LNCaP, DU-145 and PC-3) and 3 esophagus carcinoma cell lines (OE19, OE21 and OE33) were cultured under normoxic or hypoxic conditions (0% O2) for 24hours. Total RNA was extracted and gene expression levels measured by qPCR. For each tissue type, individual reference genes were selected and applied in the normalization of the relative expression levels., Results: In all three tissue types, individual, optimal, reference genes were selected. In the analysis of the hypoxia induced genes, both the original reference genes and the new selected reference genes were used. There was no significant difference in the obtained data. The gene expression analysis demonstrated cell line specific differences in the hypoxia response of the 15 genes, with BNIP3 not being upregulated at hypoxic conditions in 3 out of 6 colon cancer cell lines, and ALDOA in OE21 and FAM162A and SLC2A1 in SW116 only showing limited hypoxia induction. Furthermore, in the esophagus cell lines, the normoxic and hypoxic expression levels of LOX and BNIP3 were below the detection limit in OE19 and OE33, respectively. However, a combined analysis of the 15 genes in both adenocarcinoma cell lines and squamous carcinoma cell lines demonstrated a very consistent expression pattern in hypoxic induced gene expression across all cell lines., Conclusion: This study addressed the tissue type dependency of hypoxia induced genes included in a 15-gene hypoxic profile in carcinoma cell lines from prostate, colon, and esophagus cancer, and demonstrated that in vitro, with minor fluctuations, the genes in the hypoxic profile are hypoxia inducible, and the hypoxia profile may be applicable in other sites than HNSCC., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Gastrointestinal (GI) morbidity after radiotherapy (RT) for prostate cancer is typically addressed by studying specific single symptoms. The aim of this study was to explore the interplay between domains of patient- reported outcomes (PROs) on GI morbidity, and to what extent these are explained by RT dose to the GI tract., Material and Methods: The study included men from two Scandinavian studies (N = 211/277) who had undergone primary external beam radiotherapy (EBRT) for localized prostate cancer to 70-78 Gy (2 Gy/fraction). Factor analysis was applied to previously identified PRO-based symptom domains from two study-specific questionnaires. Number of questions: 43; median time to follow-up: 3.6-6.4 years) and dose-response outcome variables were defined from these domains. Dose/volume parameters of the anal sphincter (AS) or the rectum were tested as predictors for each outcome variable using logistic regression with 10-fold cross-validation. Performance was assessed using area under the receiver operating characteristic curve (Az) and model frequency., Results: Outcome variables from Defecation urgency (number of symptoms: 2-3), Fecal leakage (4-6), Mucous (4), and Pain (3-6) were defined. In both cohorts, intermediate rectal doses predicted Defecation urgency (mean Az: 0.53-0.54; Frequency: 70-75%), and near minimum and low AS doses predicted Fecal leakage (mean Az: 0.63-0.67; Frequency: 83-99%). In one cohort, high AS doses predicted Mucous (mean Az: 0.54; Frequency: 96%), whereas in the other, low AS doses and intermediate rectal doses predicted Pain (mean Az: 0.69; Frequency: 28-82%)., Conclusion: We have demonstrated that Defecation urgency, Fecal leakage, Mucous, and Pain following primary EBRT for localized prostate cancer primarily are predicted by intermediate rectal doses, low AS doses, high AS doses, or a combination of low AS and intermediate rectal doses, respectively. This suggests that there is a domain-specific dose-response for the GI tract. To reduce risk of GI morbidity, dose distributions of both the AS region and the rectum should, therefore, be considered when prescribing prostate cancer RT.

Background: Gastrointestinal morbidity after radiotherapy (RT) for prostate cancer may be related to the biomechanical properties of the rectum. In this study we present a magnetic resonance imaging (MRI)-based method to quantitate the thickness and elasticity of the rectal wall in prostate cancer patients treated with RT., Material and Methods: Four patients previously treated with RT for prostate cancer underwent an MRI session with stepwise rectal bag deflation (from a maximum tolerable volume to 0 ml, in 50 ml steps), with a probe inserted inside the bag to monitor the internal rectal pressure. MRIs were acquired using Dixon sequences (4 mm axial slice thickness) at each deflation step. Rectal walls were defined from the recto-sigmoid junction to 3 cm above the anal canal as the space between the inner and outer wall surfaces. The wall thickness was determined and biomechanical properties (strain and stress) were calculated from the pressure measurements and the MRI-segmented rectal walls., Results: The integral rectal pressure varied for the maximum tolerable volume (range 150-250 ml) across patients and ranged from 1.3 to 4.0 kPa (SD = 1.2 kPa). Wall thickness was found to vary between patients and also across different rectum segments, with a mean (SD) thickness for the different segments at the 50 ml distension volume of 1.8-4.0 (0.6) mm. Stress showed larger variation than strain, with mean (SD) values for the different segments ranging between 1.5 and 7.0 (1.5) kPa., Conclusion: We have developed a method to quantify biomechanical properties of the rectal wall. The resulting rectal wall thickness, strain and stress differed between patients, as well as across different rectal wall sections. These findings could provide guidance in future predictive outcome modelling in order to better understand the rectal dose-volume response relationship.

Background: Patients treated with external beam radiotherapy (EBRT) may suffer from long-term anorectal adverse effects. The purpose of the present study was to assess long-term functional and structural anorectal changes in patients previously treated with EBRT for prostate cancer and to suggest the mechanism behind the development of the adverse effects., Material and Methods: Our previously proposed RT-induced anorectal dysfunction (RT-ARD) score, developed with the intention to survey anorectal dysfunction was used to identify patients with and without anorectal symptoms. Among 309 patients surveyed with the questionnaire, we chose 23 patients with the highest RT-ARD score and 19 patients with the lowest RT-ARD score. They were investigated by multimodal rectal sensory stimulation, standard anal physiological tests. Changes of the rectal mucosa were assessed by flexible sigmoidoscopy and graded by the Vienna Rectoscopy Score (VRS)., Results: The mean follow-up time was 3.8 (range, 2.8; 8.6) years in patients with high RT-ARD and 3.8 (range, 2.6; 5.9) in patients with low RT-ARD. Endoscopic evaluation revealed higher VRS scores in patients with high RT-ARD compared to patients with low RT-ARD (p = 0.002). Patients with high RT-ARD had increased rectal sensory response to distension manifested both as volume (p = 0.006) and cross-sectional area (p = 0.04), and they had reduced maximum anal resting pressure assessed by anal manometri (p = 0.02)., Conclusions: Long-term anorectal symptoms correlate to changes in anorectal biomechanical properties and rectal mucosal injury. Our data suggests that RT-induced long-term anorectal dysfunction is multifactorial caused by injury of the rectal mucosa and the internal anal sphincter combined with increased rectal sensitivity and reduced rectal functional capacity.

Background: Methods to accurately accumulate doses in radiotherapy (RT) are important for tumour and normal tissues being influenced by geometric uncertainties. The purpose of this study was to investigate a pre-release deformable image registration (DIR)-based dose accumulation application, in the setting of prostate RT., Material and Methods: Initially accumulated bladder and prostate doses were assessed (based on 8-9 repeat CT scans/patient) for nine prostate cancer patients using an intensity-based DIR and dose accumulation algorithm as provided by the Dynamic Adaptive Radiation Therapy (DART) software. The accumulated bladder and prostate dose-volume histograms (DVHs) were compared on a range of parameters (paired Wilcoxon signed-rank test, 5% significance level) to DVHs derived using an in-house developed dose accumulation method based on biomechanical, contour-driven DIR (SurfaceRegistration). Finally, both these accumulated dose distributions were compared to the 'static' DVH, assessed from the planning CT., Results: Over the population, doses accumulated with DART were overall lower than those from SurfaceRegistration (p < 0.05: D2%, gEUD and NTCP (bladder); Dmin (prostate)). The magnitude of these differences peaked for the bladder gEUD with a population median of 47 Gy for DART versus 57 Gy for SurfaceRegistration. Across the ten bladder dose/volume parameters investigated, the most pronounced individual differences were observed between the 'accumulated' DVHs and the 'static' DVHs, with deviations in mean dose up to 22 Gy., Conclusion: Substantial and significant differences were observed in the dose distributions between the two investigated DIR-based dose accumulation applications. The most pronounced individual differences were seen for the bladder and relative to the planned dose distribution, encouraging the use of repeat imaging data in RT planning and evaluation for this organ.

When pooling retrospective data from different cohorts, slice thicknesses of acquired computed tomography (CT) images used for treatment planning may vary between cohorts. It is, however, not known if varying slice thickness influences derived dose-response relationships. We investigated this for rectal bleeding using dose-volume histograms (DVHs) of the rectum and rectal wall for dose distributions superimposed on images with varying CT slice thicknesses. We used dose and endpoint data from two prostate cancer cohorts treated with three-dimensional conformal radiotherapy to either 74 Gy (N = 159) or 78 Gy (N = 159) at 2 Gy per fraction. The rectum was defined as the whole organ with content, and the morbidity cut-off was Grade ≥2 late rectal bleeding. Rectal walls were defined as 3 mm inner margins added to the rectum. DVHs for simulated slice thicknesses from 3 to 13 mm were compared to DVHs for the originally acquired slice thicknesses at 3 and 5 mm. Volumes, mean, and maximum doses were assessed from the DVHs, and generalized equivalent uniform dose (gEUD) values were calculated. For each organ and each of the simulated slice thicknesses, we performed predictive modeling of late rectal bleeding using the Lyman-Kutcher-Burman (LKB) model. For the most coarse slice thickness, rectal volumes increased (≤18%), whereas maximum and mean doses decreased (≤0.8 and ≤4.2 Gy, respectively). For all a values, the gEUD for the simulated DVHs were ≤1.9 Gy different than the gEUD for the original DVHs. The best-fitting LKB model parameter values with 95% CIs were consistent between all DVHs. In conclusion, we found that the investigated slice thickness variations had minimal impact on rectal dose-response estimations. From the perspective of predictive modeling, our results suggest that variations within 10 mm in slice thickness between cohorts are unlikely to be a limiting factor when pooling multi-institutional rectal dose data that include slice thickness variations within this range.

Purpose: To develop and validate a scoring system for evaluation of long term anorectal dysfunction following radiotherapy for prostate cancer., Materials and Methods: Patients treated for prostate cancer with radiotherapy filled in questionnaires on anorectal function and quality of life. Items for the condensed anorectal dysfunction score (RT-ARD) were identified and weighted by binomial regression analysis. The score was tested in a separate patient material by receiver operating characteristic (ROC) analysis and correlations to quality of life domains., Results: A total of 309 patients participated in the study. The items selected were "incontinence for solid stool", "ability to defer defecation", "unproductive call to stool", "clustering of stool", and "mucus in stool." Patients were grouped into three categories according to the RT-ARD score; 0-8 (no RT-ARD), 9-23 (minor RT-ARD), 24-45 (major RT-ARD). ROC analyses revealed high sensitivity (91%) and specificity (85%) for major RT-ARD. The prediction model demonstrated a perfect fit in 60%, moderate fit in 36% and no fit in 4%. There was good correlation between the RT-ARD score and quality of life., Conclusions: The RT-ARD score is a validated and simple instrument for evaluation of anorectal dysfunction following radiotherapy for prostate cancer, and the RT-ARD score correlates to the patient's quality of life., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Organ motion during treatment delivery in radiotherapy (RT) may lead to deterioration of the planned dose, but can be mitigated by dynamic multi-leaf collimator (DMLC) tracking. The purpose of this study was to implement and experimentally validate a method for time-resolved motion including dose reconstruction for volumetric modulated arc therapy (VMAT) treatments delivered with and without DMLC tracking., Material and Methods: Tracking experiments were carried out on a linear accelerator (Trilogy, Varian) with a prototype DMLC tracking system. A motion stage carrying a biplanar dosimeter phantom (Delta4PT, Scandidos) reproduced eight representative clinical tumor trajectories (four lung, four prostate). For each trajectory, two single-arc 6 MV VMAT treatments with low and high modulation were delivered to the moving phantom with and without DMLC tracking. An existing in-house developed program that adds target motion to treatment plans was extended with the ability to split an arc plan into any number of sub-arcs, allowing the calculated dose for different parts of the treatment to be examined individually. For each VMAT sub-arc, reconstructed and measured doses were compared using dose differences and 3%/3 mm γ-tests., Results: For VMAT sub-arcs the reconstructed dose distributions had a mean root-mean-square (rms) dose difference of 2.1% and mean γ failure rate of 2.0% when compared with the measured doses. For final accumulated doses the mean rms dose difference was 1.6% and the γ failure rate was 0.7%., Conclusion: The time-resolved motion including dose reconstruction was experimentally validated for complex tracking and non-tracking treatments with patient-measured tumor motion trajectories. The reconstructed dose will be of high value for evaluation of treatment plan robustness facing organ motion and adaptive RT.

Unlabelled: Internal target and organ motion during treatment is a challenge in radiotherapy (RT) of the prostate and the involved elective targets, with residual motion being present also following image-guidance strategies. The aim of this study was to investigate organ motion-induced dose degradations for the prostate, seminal vesicle and the pelvic lymph node when treating these targets with proton therapy, using different image-guidance and delivery strategies., Material and Methods: Four patients were selected from a larger series as they displayed large inter-fractional variation in bladder and rectum volume. Intensity-modulated proton therapy plans were generated using both simultaneous integrated and sequential boost delivery. For each technique, three isotropic margin expansions (in the range of 4-10 mm) were evaluated for the clinical target volume of prostate (CTV-p), seminal vesicles (CTV-sv) and lymph nodes (CTV-ln). Simulation of the dose degradations for all treatment plans were based on dose re-calculations for the 8-9 repeat CTs available for each patient, after applying rigid registrations to reproduce set-up based on either intra-prostatic fiducials or bony anatomy., Results: The simulated dose received by 99% of the target volume (D(99)) and generalized equivalent dose (gEUD) showed substantial inter-patient variations. For 40% of the investigated scenarios, the patient average simulated D(99) for all targets were within 2 GyE from the planned dose. The largest difference between simulated and planned dose was seen for the CTV-sv when using SIB delivery, with an average relative reduction in D(99) of 13% and 15% for the largest margin expansion, when positioned using fiducials and bony anatomy, respectively., Conclusions: The most severe dose degradations were found for CTV-sv, but they were also evident for CTV-ln. The degradations could not be completely resolved, neither by using the largest margin expansion nor with the choice of set-up. With fiducial set-up CTV-p was robust against the inter-fraction changes.

Variations in bladder position, shape and volume cause uncertainties in the doses delivered to this organ during a course of radiotherapy for pelvic tumors. The purpose of this study was to evaluate the potential of dose accumulation based on repeat imaging and deformable image registration (DIR) to improve the accuracy of bladder dose assessment. For each of nine prostate cancer patients, the initial treatment plan was re-calculated on eight to nine repeat computed tomography (CT) scans. The planned bladder dose-volume histogram (DVH) parameters were compared to corresponding parameters derived from DIR-based accumulations as well as DVH summation based on dose re-calculations. It was found that the deviations between the DIR-based accumulations and the planned treatment were substantial and ranged (-0.5-2.3) Gy and (-9.4-13.5) Gy for D(2%) and D(mean), respectively, whereas the deviations between DIR-based accumulations and DVH summation were small and well within 1 Gy. For the investigated treatment scenario, DIR-based bladder dose accumulation did not result in substantial improvement of dose estimation as compared to the straightforward DVH summation. Large variations were found in individual patients between the doses from the initial treatment plan and the accumulated bladder doses. Hence, the use of repeat imaging has a potential for improved accuracy in treatment dose reporting.

Background and Purpose: Daily organ motion occurring during the course of radiotherapy in the pelvic region leads to uncertainties in the doses delivered to the tumour and the organs at risk. Motion patterns include both volume and shape changes, calling for deformable image registration (DIR), in approaches involving dose accumulation and adaptation. In this study, we tested the performance of a DIR application for contour propagation from the treatment planning computed tomography (pCT) to repeat cone-beam CTs (CBCTs) for a set of prostate cancer patients., Material and Methods: The prostate, rectum and bladder were delineated in the pCT and in six to eight repeat CBCTs for each of five patients. The pCT contours were propagated onto the corresponding CBCT using the Multi-modality Image Registration and Segmentation application, resulting in 36 registrations. Prior to the DIR, a rigid registration was performed. The algorithm used for the DIR was based on a 'demons' algorithm and the performance of it was examined quantitatively using the Dice similarity coefficient (DSC) and qualitatively as visual slice-by-slice scoring by a radiation oncologist grading the deviations in shape and/or distance relative to the anatomy., Results: The average DSC (range) for the DIR over all scans and patients was 0.80 (0.65-0.87) for prostate, 0.77 (0.63-0.87) for rectum and 0.73 (0.34-0.91) for bladder, while the corresponding DSCs for the rigid registrations were 0.77 (0.65-0.86), 0.71 (0.55-0.82) and 0.64 (0.33-0.87). The percentage of propagated contours of good/acceptable quality was 45% for prostate; 20% for rectum and 33% for bladder. For the bladder, there was an association between the average DSC and the different scores of the qualitative evaluation., Conclusions: DIR improved the performance of pelvic organ contour propagation from the pCT to CBCTs as compared to rigid registration only. Still, a large fraction of the propagated rectum and bladder contours were unacceptable. The image quality of the CBCTs was sub-optimal and the usability of CBCTs for dose accumulation and adaptation purposes is therefore likely to benefit from improved image quality and improvements of the DIR algorithm.

Background: Faecal incontinence (FI) after radiotherapy is a known phenomenon, but has received little attention to date. This article aimed to review current knowledge on faecal incontinence related to radiotherapy for prostate cancer., Methods: PubMed was searched for English-language articles published from January 1966 to December 2009 using the primary keywords 'faecal incontinence', 'prostate cancer' and 'radiotherapy'. Prospective, retrospective and controlled trials reporting FI as a complication of radiotherapy for prostate cancer were included. The retrieved titles and abstracts were screened permissively and evaluated as to whether they satisfied the predefined inclusion and exclusion criteria., Results: Nine hundred and ninety four articles were identified from the search. After step-wise review, 213 papers were selected for full article review of which 40 were selected for this review. The incidence of faecal incontinence following radiotherapy for prostate cancer varied from 1.6% to 58%. The mechanism of faecal incontinence was not entirely clear but it is most likely due to injury to the nerve plexus of the rectal muscular layer. Correlation between rectal dose-volume parameters and incidence is equivocal, although some studies suggest parameters confined to the lower rectum and/or anal canal may be of value to predict the extent of the injury and could be used as constraints in the dose planning process., Conclusions: Interpretation of data is limited due to lack of large cohort studies with data on pre-treatment continence status and because variable instruments have been used to assess the severity of the condition. Well-designed prospective studies are needed to investigate dosimetric parameters focusing on the anal canal and sphincter apparatus. Considering the spatial distribution of radiation to the rectum may identify a more direct linkage between radiation damage and faecal incontinence., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Successful deformable image registration is an essential component of both dose accumulation and plan adaptation in radiotherapy. The aim of this study was to evaluate the performance of a deformable image registration application for propagation of contours using repeat CT scans of the pelvis, a region where considerable deformations are expected., Material and Methods: The study involved four prostate cancer patients, each with 9-11 repeat CT scans. An oncologist contoured bladder, rectum, clinical target volume of pelvic lymph nodes (CTV-ln) and prostate (CTV-p) in all CT scans. The reference CT was retrospectively registered to the repeat CT scans with both rigid and deformable registration using a recently released commercial clinical software application. Two different diffusion-based 'demons' deformable registration algorithms were applied, differing in the amount of deformations being allowed, with algorithm A being more generous than algorithm B. The evaluation of the propagated structures included both quantitative measures and qualitative scoring., Results: We found the differences between the algorithms to be most evident for bladder and rectum. An increase in mean Dice similarity coefficient relative the rigid registrations of 12% and 13% was obtained with algorithm A for bladder and rectum, compared to 2% with algorithm B. For bladder the mean sensitivity and positive predictive value was 0.92 and 0.87 with algorithm A and 0.82 and 0.83 with algorithm B. Corresponding values for rectum was 0.81 and 0.76 with algorithm A and 0.75 and 0.69 with algorithm B. This translated into 57% and 26% passing the clinical evaluation for bladder and rectum, with algorithm A, compared to 17% and 14% with algorithm B. For CTV-ln and CTV-p both algorithms performed well by all measures, e.g. with 86% of the target structures passing the clinical evaluation., Conclusions: Deformable image registration improved contour propagation in the pelvis for all organs investigated. Differences in the performance of the algorithms were seen which became more pronounced for the highly deformable organs of bladder and rectum.

Purpose: The use of marker-based on-line image guided radiotherapy for prostate cancer has considerably reduced the treatment margins to sub-cm. In this study we have quantified the residual set-up errors remaining after isocenter correction, studied their development during beam delivery and estimated their impact on margins., Methods and Materials: After initial on-line patient set-up based on orthogonal kV x-ray images of implanted fiducial markers, continuous electronic portal imaging was performed during treatment delivery in 10 of 39 treatment sessions for 20 prostate cancer patients. The cranio-caudal (CC) position of the centre-of-mass of the three markers was found using a threshold technique on every single image frame for all patients, typically 12-14 images for 5 treatment beams in every fraction. The CC prostate position was determined relative to its initial position at treatment onset and relative to its planned position within the field aperture. These results allowed determination of the CC intrafraction prostate motion and the intrafraction progression of the geometrical CC error, respectively., Results: At treatment onset the standard deviation (SD) of the set-up error was 1.0mm in the lateral direction and 1.5mm in the cranio-caudal (CC) direction. It did not depend significantly on the duration of the set-up procedure (mean: 3.0 min, span 1.2-14.6 min). The distribution of CC prostate positions relative to the position at treatment onset broadened from 0 to 1.4mm during the treatment session, while the corresponding CC setup error distribution broadened from 1.5 to 1.9 mm. This broadening means that the necessary CC setup margin increased by around 1mm during the treatment fraction., Conclusions: Large differences in the intrafraction CC prostate motion patterns were found, however, intrafraction motion only results in a modest additional CC set-up margin of around 1mm relative to the margins needed for the residual set-up error at treatment start.

Background and Purpose: Image-guided on-line correction of the target position allows radiotherapy of prostate cancer with narrow set-up margins. The present study investigated the residual set-up error after on-line prostate localization and its impact on margins., Materials and Methods: Prostate localization based on two orthogonal X-ray images of gold markers implanted in the prostate was performed with an on-board imager at four treatment sessions for 90 patients. The set-up error in the sagittal plane residual after couch adjustment was evaluated on lateral verification portal images., Results: The set-up error was less than 3.0mm in 92% of the cases in the anterior-posterior (AP) direction and in 95% of the cases in the cranio-caudal (CC) direction. The set-up error was dominated by internal prostate motion taking place during the set-up procedure. Set-up margins were calculated using two formalisms: margins designed to ensure a minimum CTV dose of 95% for 90% of the patient population were 3.6mm (AP) and 3.5mm (CC). Patient-independent normal distributed set-up errors would result in margins of 4.3mm (AP) and 4.0mm (CC) to ensure complete CTV inclusion in the PTV with 90% probability., Conclusion: Internal prostate motion during the set-up procedure was the main contributor to residual set-up errors.

The incidence of prostate cancer is increasing sharply in Denmark and an increasing proportion of patients have clinically localised disease at diagnosis. The therapeutic strategy encompasses intended curative therapy: radical prostatectomy with complete removal of the prostate gland and seminal vesicles performed as an open procedure or laparoscopically, external beam radiation therapy, or implantation of radioactive seeds into the prostate (brachytherapy). In older patients with good prognostic factors, active surveillance should be considered. The various therapeutic modalities are reviewed.

Background and Purpose: To examine the accuracy of the BeamCath urethral catheter technique for prostate localization during radiotherapy., Materials and Methods: Sixty-four patients were CT scanned twice with the BeamCath catheter, and once without the catheter. The catheter contains radiopaque fiducial markers for prostate visualization on setup images. It is held in place by a balloon inflated with air in the bladder. The repeated CT scans were co-registered and the relative shifts of the BeamCath isocenter fiducial, the prostate center-of-mass, and external skin markers were evaluated. The displacement of the BeamCath isocenter fiducial relative to its position at the planning CT scan was also determined on setup films for 53 consecutive patients (222 setup films)., Results: The standard deviation (SD) of the prostate movement relative to the BeamCath isocenter fiducial was 0.9 mm in the left-right (LR), 2.8 mm in the cranial-caudal (CC), and 1.6 mm in the anteroposterior (AP) directions, respectively. When the balloon radius differed more than 1mm between the CT scans (14 of 64 cases) the SD in the CC direction increased to 4.5 mm. The SD of the prostate movement relative to the pelvic bone was 0.6 mm (LR), 2.4 mm (CC), and 2.8 mm (AP), while the prostate movement relative to external skin markers was considerably larger. Removal of the catheter resulted in a mean cranial prostate movement of 1.5mm relative to the pelvic bone. Caudal catheter displacements of 7-30 mm were observed in 5% of the setup films. In these cases, recatherization was necessary to obtain reliable prostate localization., Conclusions: The BeamCath catheter technique markedly improved prostate localization in all directions when compared with skin markers. In the AP direction, the BeamCath technique was also superior to the use of bony structures. However, in the CC direction the catheter position was very vulnerable to changes in the balloon volume.

In this study we report late bladder, gastrointestinal and sexual dysfunctions in 23 patients following radical radiotherapy (66Gy-70Gy/33-35fx, 5 fx/week) for prostate cancer. We interviewed the subjects by telephone and compared the results with those of 45 healthy population controls. In general, the patients' bladder function was well preserved. However, compared with the population controls, significantly more patients reported dysuria and hematuria. Twenty-six percent of the patients reported moderate distress from the gastrointestinal tract. Fecal urgency, incontinence and the use of sanitary pads, as well as diarrhoea, and blood and mucous were significantly more common among the patients. Thirty-nine percent of the patients reported moderate or worse distress upon sexual activity, and significantly more patients suffered from erectile impotence.

Background and Purpose: To correlate long-term colorectal dysfunctions following radical radiotherapy for bladder or prostate cancer with clinical parameters and dose-volume histogram parameters of the small intestine, rectum, and anal canal volume., Materials and Methods: Seventy-one patients previously treated for bladder or prostate cancer were interviewed following CT-based radiotherapy of 60-70 Gy with questions concerning long-term colorectal dysfunctions. Median follow-up time was 30 months (range 12-109 months). Clinical parameters and parameters from the dose-volume histograms were correlated with colorectal dysfunctions (Spearman's test). Median and quartile values of all parameters were used as cut-off values for statistical analyses. A logistic regression model was used for analysis of urgency and incontinence in relation to median or maximum radiation dose to the anal canal volume., Results: Rectum length, volume and several dose-volume parameters from the anal canal volume and rectal volume were correlated with late organ dysfunctions. In a logistic model, fecal urgency and incontinence were dependent of dose-volume parameters from the anal canal volume. No relation between age or follow-up time and late effects were found. Dose-volume parameters of the small intestine were not related to any late dysfunctions., Conclusions: A relationship between several late anorectal dysfunctions and dose-volume parameters from the rectum and anal canal volume was demonstrated. It is recommended to exclude the anal canal volume from the high dose-volume and to apply rectal shielding whenever possible to prevent late anorectal dysfunctions.

Background: The optimal approach to diagnosis and treatment of localized prostate cancer remains controversial. Deoxyribonucleic acid (DNA) ploidy has been suggested as an important predictor for outcome in prostate cancer. The purpose of this study was to correlate DNA ploidy with disease-specific survival in patients with clinically localized prostate cancer treated with no intent to cure., Methods: DNA ploidy was determined by flow cytometry in archival formalin fixed, paraffin embedded tumor tissue obtained at diagnosis in 120 patients with clinically localized prostate cancer with a nearly complete follow-up., Results: Ninety (75%) of the tumors were diploid, while only 11 (9%) tumors were categorized as tetraploid. Tumor DNA ploidy (diploid versus nondiploid) significantly associated with histopathological grade (P=0.002) and disease-specific survival (P=0.011), while there was no association with tumor stage (P=0.054). In a multivariate Cox analysis, histopathological grade (P=0.005) was the only significant predictor of disease-specific death, while analyzing the 96 low-grade tumors separately, DNA ploidy became significant (P= 0.024)., Conclusions: Flow cytometric determined nondiploidy was associated with disease-specific death in patients with clinically localized prostate cancer, but DNA ploidy provided additional prognostic information in patients with low-grade tumors only.

Large variability in the biological behavior of prostate cancer makes prognostic markers important. The extent of tumor cell proliferation has been suggested as an important predictor of clinical outcome. Fifty-five patients suspected of having or with previously diagnosed prostate cancer were labeled in vivo with IdUrd (a thymidine analogue incorporated into DNA in S-phase cells) by intravenous infusion before transurethral resection. IdUrd-labeled cells and MIB-1-positive cells were detected by immunohistochemistry. We found statistically significant associations between the tumor cell proliferation rates measured by in vivo IdUrd labeling and MIB-1 expression in formalin-fixed paraffin-embedded tumors. Good correlations were also found between S-phase fraction, MIB-1 expression, clinical stage and malignancy grade. These results make larger retrospective studies on archival tissue meaningful.

Cell kinetics were measured in vivo in four experimental rat prostatic adenocarcinomas grown in normal or castrated rats. The aim was to investigate the effect of castration on growth rate and cell kinetics in hormone sensitive and hormone insensitive prostatic carcinomas. We used two anaplastic, hormone insensitive, fast growing tumors (Dunning R-3327-AT1 H and E), as well as two well differentiated, hormone sensitive, slow growing tumors (R-3327-H and R-3327-PAP). DNA ploidy, S-phase transit time (Ts), the labeling index (LI) and potential doubling time (Tpot) was determined by dual parameter flow cytometry, after in-vivo labeling, using bromodeoxyuridine (BUdR) and the tumor doubling time (DT) was determined from growth curves. After castration DT in the hormone sensitive H-subline changed from 21.7 days to 82.0 days, and in the PAP-subline from 22.2 days to 33.2 days. No significant changes in Tpot were observed. In the anaplastic tumors no differences in neither DT nor Tpot were seen. The cell loss factor (CLF) was relatively low in the two anaplastic tumors (0.55-0.59) compared to the well differentiated tumors. The CLF was unaffected by castration in the poorly differentiated tumors, whereas it increased significantly (from 0.75 to 0.92, P = 0.005) after castration in the H-tumor, and showed a non-significant increase in the PAP-tumor. This implies that the decrease in tumor growth in the hormone sensitive tumors is due to an increase in cell death, not a decrease in cell proliferation. These data indicate that CLF is the dominating factor in the reduced growth following androgen ablation in an androgen sensitive tumor. This study suggests that Tpot might be an additional predictor of a tumors proliferating rate and it may provide important information of the human prostatic cancer.