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Introdution: Variation in shape, position and treatment response of both tumor and organs at risk are major challenges for accurate dose delivery in radiotherapy. Adaptive radiotherapy (ART) has been proposed to customize the treatment to these motion/response patterns of the individual patients, but increases workload and thereby challenges clinical implementation. This paper reviews strategies and workflows for clinical and in silico implemented ART for prostate, bladder, gynecological (gyne) and ano-rectal cancers.Material and methods: Initial identification of papers was based on searches in PubMed. For each tumor site, the identified papers were screened independently by two researches for selection of studies describing all processes of an ART workflow: treatment monitoring and evaluation, decision and execution of adaptations. Both brachytherapy and external beam studies were eligible for review.Results: The review consisted of 43 clinical studies and 51 in silico studies. For prostate, 1219 patients were treated with offline re-planning, mainly to adapt prostate motion relative to bony anatomy. For gyne 1155 patients were treated with online brachytherapy re-planning while 25 ano-rectal cancer patients were treated with offline re-planning, all to account for tumor regression detected by magnetic resonance imaging (MRI)/computed tomography (CT). For bladder and gyne, 161 and 64 patients, respectively, were treated with library-based online plan selection to account for target volume and shape variations. The studies reported sparing of rectum (prostate and bladder cancer), bladder (ano-rectal cancer) and bowel cavity (gyne and bladder cancer) as compared to non-ART.Conclusion: Implementations of ART were dominated by offline re-planning and online brachytherapy re-planning strategies, although recently online plan selection workflows have increased with the availability of cone-beam CT. Advantageous dosimetric and outcome patterns using ART was documented by the studies of this review. Despite this, clinical implementations were scarce due to challenges in target/organ re-contouring and suboptimal patient selection in the ART workflows. [ABSTRACT FROM AUTHOR]

Background. Radical prostatectomy (RP) is worldwide probably the most common procedure to treat localized prostate cancer (PC). Due to a more widespread use of Prostate-Specific Antigen (PSA) testing, patients operated today are often younger and have organ confined disease justifying a more preservative surgery. At the same time, surgical technique has improved resulting in lower risk of permanent side-effects. This paper aims to give an overview of results from modern surgery regarding cancer control and side-effects. A brief overview of the history is given. Material and Methods. A literature research identified recently published papers focusing on outcome and side-effects after RP. Results. One large randomized study (SPCG-4) compared RP and watchful waiting (WW). The study showed that RP was superior to WW in preventing local progression (RR 0.36), distant metastasis (RR 0.65) and death from PC (RR 0.65). Observational studies also show a better outcome for men treated with RP compared to WW. Peri-operative mortality after RP is low in most material around 0.1%. The risk of stricture of the vesico-urethral anastomosis has decreased with improved technique from historically 10-20% to a low incidence of around 2-9% today. Also the risk of incontinence has declined with improved technique. However, while the rates of severe incontinence is usually very low, as many as 30% still report light incontinence after long-term follow-up. Erectile dysfunction (ED) is still a frequent side-effect after RP. This risk is dependent on age, pre-operative sexual function, surgical technique and other risk factors for ED such as smoking, diabetes, etc. In selected subgroups the risk of ED is low. Inguinal hernia is a more recently described complication after open retropubic RP with a post-operative incidence of 15-20% within three years of surgery. Conclusion. RP is an effective method to achieve cancer control in selected patients. With modern technique it is a safe procedure with a low risk of permanent side-effects except for ED. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Radiotherapy (RT) always requires a compromise between tumor control and normal tissue side-effects. Technical innova- tion in radiation therapy (RT), such as three dimensional RT, is now established. Concerning prostate cancer (PC), it is reasonable to assume that RT of PC will increase in the future. The combination of small margins, a movable target (prostate), few fractions and high doses will probably demand dynamically positioning systems and in real time. This is called four dimensional radiotherapy (4DRT). Moreover, biological factors must be included in new treatments such as hypofractionation schedules. This new era is called five dimensional radiotherapy, 5DRT. In this paper we discuss new concepts in RT in respect to PC. [ABSTRACT FROM AUTHOR]

Radiotherapy (RT) always requires a compromise between tumor control and normal tissue side-effects. Technical innovation in radiation therapy (RT), such as three dimensional RT, is now established. Concerning prostate cancer (PC), it is reasonable to assume that RT of PC will increase in the future. The combination of small margins, a movable target (prostate), few fractions and high doses will probably demand dynamically positioning systems and in real time. This is called four dimensional radiotherapy (4DRT). Moreover, biological factors must be included in new treatments such as hypofractionation schedules. This new era is called five dimensional radiotherapy, 5DRT. In this paper we discuss new concepts in RT in respect to PC. [ABSTRACT FROM AUTHOR]

Background: Secondary lymphedema is a known side effect to radiotherapy (RT), but limited information regarding prevalence and risk factors for lower limb edema (LLE) after curative radiotherapy in patients with prostate cancer (PCa) is available. This study provides a descriptive analysis of patientreported LLE with analysis of risk factors in a cohort of patients with PCa treated with curative RT. Material and methods: A total of 302 patients with PCa with prospective registration of patientreported LLE (EORTC QLQ-PR25 (Question 46)) were included. Analysis of LLE was done with the calculation of prevalence rates and Kaplan-Meier statistics. Risk factors for LLE were analyzed multivariate with Cox regression analysis. Results: At a median follow-up of 15 (3-51) months, the overall crude incidence of patients reporting 'quite a bit' or 'a lot' of LLE was 49 (16.2%) and 21 (7.0%), respectively. The baseline prevalence rate of 'quite a bit' and 'a lot' of LLE was 5.0% and 0.8%, respectively. During follow-up the prevalence rate for 'quite a bit' or 'a lot' of LLE increased significantly and remained constant from 6 months where 11.5% (±1.7%) reported 'quite a bit' and 2.9% (±0.5%) reported 'very much' LLE (p<0.001), respectively. Results: Significant risk factors (p<0.10) for LLE in univariate analysis included lymph node irradiation (HR:2.325), baseline Body Mass Index (BMI) (HR:1.100), Charlson Comorbidity Index (HR:1.227), Androgen Deprivation Therapy (HR:2,979), and Performance Status (HR:0.594). Only high BMI (HR:1.091) remained significant in multivariate analysis with a three-fold increase in LLE in patients with BMI = 30 compared to normal weight patients. Conclusion: Severe patient-reported LLE after curative RT for PCa is rare. Significantly more patients with a high BMI report 'quite a bit' or 'very much' LLE compared to patients with a normal BMI. Obese PCa patients could be offered a rehabilitation program for early detection and management of LLE. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses various reports within the issue on topics including benefits of proton therapy for prostate cancer, stereotactic body radiation therapy (SBRT) in radiotherapy (RT) and volumetric arc therapy (VMAT) of the prostate metastases.

To evaluate differences between MR-guided daily-adaptive RT (MRgRT) and image-guided RT (IGRT) with or without fiducial markers in prostate cancer (PCa) stereotactic body radiotherapy (SBRT) in terms of dose distribution on critical structures. Two hundred treatment sessions in 40 patients affected by low and intermediate PCa were evaluated. The prescribed dose was 35 Gy in 5 fractions delivered on alternate days. MRgRT patients (10) were daily recontoured, re-planned, and treated with IMRT technique. IGRT patients without (20) and with (10) fiducials were matched on soft tissues or fiducials and treated with VMAT technique. Respective CBCTs were retrospectively delineated and the prescribed plan was overlaid for dosimetric analysis. The daily dose for rectum, bladder, and prostate was registered. MRgRT resulted in a significantly lower rate of constraints violation as compared to IGRT without fiducials, especially for rectum V28Gy, rectum V32Gy, rectum V35Gy, rectum Dmax, and bladder Dmax. IGRT with fiducials reported high accuracy levels, comparable to MRgRT. MRgRT and IGRT with fiducials reported no significant prostate CTV underdosage, while IGRT without fiducials was associated with occasional cases of prostate CTV under dosage. MR-guided daily-adaptive SBRT seems a feasible and accurate strategy for treating prostate cancer with ablative doses. IGRT with the use of fiducials provides a comparable level of accuracy and acceptable real-dose distribution over treatment fractions. Future study will provide additional data regarding the tolerability and the clinical outcome of this new technological approach. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this work was to determine how the spatial pattern of dose in the ano-rectal wall is related to late gastro-intestinal toxicity for prostate cancer patients treated with mainly IMRT. Patients and methods: Patients from the DUE-01 multicentre study with patient-reported (prospective) follow-up and available dosimetric data were included. Conventionally fractionated patients received 74–80 Gy and hypofractionated patients received 65–75.2 Gy. A large majority of the patients were treated with intensity-modulated radiotherapy (IMRT). Dose-surface maps (DSMs) for the anal canal and rectum as a single structure, and for the anal canal and the rectum separately, were co-registered rigidly in two dimensions and, for the patients with and without toxicity, respectively, the mean value of the dose in each pixel was calculated. A pixel-wise t-test was used to highlight the anatomical areas where there was a significant difference between the 'mean dose maps' of each group. Univariate models were also fitted to a range of spatial parameters. The endpoints considered were a mean grade ≥1 late fecal incontinence and a maximum grade ≥2 late rectal bleeding. Results: Twenty-six out of 213 patients had fecal incontinence, while 21/225 patients had rectal bleeding. Incontinence was associated with a higher dose in the caudal region of the anal canal; the most relevant spatial parameter was the lateral extent of the low and medium isodoses (5–49 Gy in EQD2). Bleeding was associated with high isodoses reaching the posterior rectal wall. The spatial dose parameters with the highest AUC value (.69) were the lateral extent of the 60–70 Gy isodoses. Conclusions: To avoid fecal incontinence it is important to limit the portion of the anal canal irradiated. Our analysis confirms that rectal bleeding is a function of similar spatial dose parameters for patients treated with IMRT, compared to previous studies on patients treated with three-dimensional conformal radiotherapy. [ABSTRACT FROM AUTHOR]

Background: For conventional radiotherapy treatment units, automated planning can significantly improve plan quality. For robotic radiosurgery, systems for automatic generation of clinically deliverable plans do not yet exist. For prostate stereotactic body radiation therapy (SBRT), few studies have systematically compared VMAT with robotic treatment. Material and methods: The multi-criteria autoplanning optimizer, developed at our institute, was coupled to the commercial treatment planning system of our robotic treatment unit, for fully automated generation of clinically deliverable plans (autoROBOT). The system was then validated by comparing autoROBOT plans with manually generated plans. Next, the autoROBOT system was used for systematic comparisons between autoROBOT plans and VMAT plans, that were also automatically generated (autoVMAT). CTV-PTV margins of 3mm were used for autoROBOT (clinical routine) and autoVMAT plan generation. For autoVMAT, an extra plan was generated with 5mm margin (often applied for VMAT). Plans were generated for a 4 x 9.5 Gy fractionation scheme. Results: Compared to manual planning, autoROBOT improved rectum D1cm3 (16%), V60GyEq (75%) and Dmean (41%), and bladder Dmean (37%) (all p ≤ .002), with equal PTV coverage. In the autoROBOT and autoVMAT comparison, both with 3mm margin, rectum doses were lower for autoROBOT by 5% for rectum D1cm3 (p=.002), 33% for V60GyEq (p=.001) and 4% for Dmean (p=.05), with comparable PTV coverage and other OAR sparing. With 5mm margin for VMAT, 18/20 plans had a PTV coverage lower than requested (<95%) and all plans had higher rectum doses than autoROBOT (mean percentage differences of 13% for D1cm3, 69% for V60GyEq and 32% for Dmean (all p<.001)). Conclusions: The first system for fully automated generation of clinically deliverable robotic plans was built. Autoplanning did largely enhance robotic plan quality, compared to manual planning. Using autoplanning for both the robotic system and VMAT, superiority of non-coplanar robotic treatment compared to coplanar VMAT for prostate SBRT was demonstrated. [ABSTRACT FROM AUTHOR]

Background: The α/β values for prostate cancer (PCa) are usually assumed to be low (1.0-1.8 Gy). This study estimated the α/β values of PCa from phase III randomized trials of conventional (CRT) versus hypofractionated (HRT) external beam radiotherapy (RT), reported as isoeffective in terms of their 5-year biochemical (BF) or biochemical and/or clinical failure (BCF) rates. Material and methods: The α/β for each trial was estimated from the equivalent biological effective doses using the linear-quadratic model for each of their HRT and CRT schedules. The cumulative outcomes of these trials were evaluated by meta-analysis for odds ratio (OR), risk ratio (RR) and risk difference (RD). Results: Eight trials from seven studies, randomized 6993 patients between CRT (n¼2941) and HRT (n¼4052). RT treatment varied between the two treatment groups in terms of dose/fraction, total dose, overall treatment time and %patients on androgen deprivation therapy (ADT). Differences in OR, RR, and RD for both BF and BCF were nonsignificant. The computed α/β ranged from 1.3 to 11.1 Gy (4.9± 3.9 Gy; 95% CI: 1.6-8.2). On multivariate regression, %ADT was the sole determinant of computed α/β (model R2: 0.98, p<.001). Conclusions: Clinically estimated α/β for PCa from isoeffective randomized trials using known variables in the linear-quadratic expression ranged between 1.3 and 11.1 Gy. The estimated α/β values were inversely related to %ADT usage, which should be considered when planning future RT dose-fractionation schedules. [ABSTRACT FROM AUTHOR]

The article discusses a study focusing on the treatment outcome in prostate cancer when treated with magnetic resonance imaging-guided high-dose-rate brachytherapy (MRI-guided BT) which is combined with external beam radiotherapy. Topics discussed include the clinical target volume, quality of life data assessed in the study, and the toxicity observed in the patients.

Background:To evaluate the outcome of patients affected by a single isolated body metastasis treated with stereotactic body radiotherapy (SBRT). Material and methods:Seven-eight patients were treated with SBRT for isolated body metastasis. The most frequent primary tumor was prostate cancer (28.2%), followed by colorectal cancer (23.1%) and lung cancer (20.5%). Median age at diagnosis of oligometastatic disease was 70 years (range 47–88). Median Karnofsky Performance Status (KPS) was 90 (range 70–100). The most common SBRT fractionation scheme was 5 × 7 Gy (total dose 35 Gy). Response to radiotherapy was determined according to RECIST criteria v1.1. Toxicity was registered according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0. The survival analysis was performed with the Kaplan–Meier method. The correlation between time actuarial incidence and clinical parameters was studied, and the Kaplan–Meier method of log-rank test was applied. Results:With a median follow-up of 22.68 months, local control was achieved in 89.7% of the cases. The two-year overall survival (OS) and progression-free survival (PFS) were 68% and 42%, respectively. On univariate analysis, KPS ≥80 is predictive for improved OS (p = .001) and PFS (p = .001). Acute toxicity of grade ≥2 occurred in eight (10.2%) patients and late grade ≥2 toxicity in five (6.4%) patients. Conclusions:Ablative radiotherapy in ‘early oligometastatic state’ is a safe, effective and minimally invasive treatment modality. A good performance status (KPS ≥80) seems to influence the clinical outcome. [ABSTRACT FROM AUTHOR]

Aim:Anterior-oblique (AO) proton beams can form an attractive option for prostate patients receiving external beam radiotherapy (EBRT) as they avoid the femoral heads. For a cohort with hydrogel prostate-rectum spacers, we asked whether it was possible to generate AO proton plans robust to end-of-range elevations in linear energy transfer (LET) and modeled relative biological effectiveness (RBE). Additionally we considered how rectal spacers influenced planned dose distributions for AO and standard bilateral (SB) proton beams versus intensity-modulated radiotherapy (IMRT). Material and methods:We studied three treatment strategies for 10 patients with rectal spacers: (A) AO proton beams, (B) SB proton beams and (C) IMRT. For strategy (A) dose and LET distributions were simulated (using the TOPAS Monte Carlo platform) and the McNamara model was used to calculate proton RBE as a function of LET, dose per fraction, and photon α/β. All calculations were performed on pretreatment scans: inter- and intra-fractional changes in anatomy/set-up were not considered. Results:For 9/10 patients, rectal spacers enabled generation of AO proton plans robust to modeled RBE elevations: rectal dose constraints were fulfilled even when the variable RBE model was applied with a conservative α/β = 2 Gy. Amongst a subset of patients the proton rectal doses for the planning target volume plans were remarkably low: for 2/10 SB plans and 4/10 AO plans, ≤10% of the rectum received ≥20 Gy. AO proton plans delivered integral doses a factor of approximately three lower than IMRT and spared the femoral heads almost entirely. Conclusion:Typically, rectal spacers enabled the generation of anterior beam proton plans that appeared robust to modeled variation in RBE. However, further analysis of day-to-day robustness would be required prior to a clinical implementation of AO proton beams. Such beams offer almost complete femoral head sparing, but their broader value relative to IMRT and SB protons remains unclear. [ABSTRACT FROM PUBLISHER]

Background:The present study investigates the impact of scatter dose radiation to the testis on ejaculate and sperm counts from treatment of prostate cancer with passive-scatter proton therapy. Material and methods:From March 2010 to November 2014, 20 men with low- or intermediate-risk prostate cancer enrolled in an IRB-approved protocol and provided a semen sample prior to passive-scatter proton therapy and 6–12 months following treatment. Men were excluded if they had high-risk prostate cancer, received androgen deprivation therapy, were on alpha blockers (due to retrograde ejaculation) prior to treatment, had baseline sperm count <1 million, or were unable to produce a pre-treatment sample or could not provide a follow-up specimen. Sperm counts of 0 were considered azoospermia and <15 million/ml were classified as oligospermia. Results:Four patients were unable to provide a sufficient quantity of semen for analysis. Among the 16 remaining patients, only one was found to have oligospermia (7 million/ml). There was a statistically significant reduction in semen volume (median, 0.5 ml) and increase in pH (median 0.5). Although not statistically significant, there appeared to be a decline in sperm concentration (median, 16 million/ml), total sperm count (median, 98.5 million), normal morphology (median, 9%), and rapid progressive motility (median, 9.5%). Discussion:Men did not have azoospermia 6–12 months following passive-scatter proton therapy indicating minimal scatter radiation to the testis during treatment. Changes in semen quantity and consistency may occur due to prostate irradiation, which could impact future fertility and/or sexual activity. [ABSTRACT FROM PUBLISHER]

BackgroundChronic gastrointestinal (GI) morbidity occurs in ≥50% of patients after external beam radiotherapy (EBRT) for carcinoma of prostate (CaP). This prospective, longitudinal study examines which baseline measurements of: 1) homocysteine and micronutrients in plasma; 2) chromosome damage/misrepair biomarkers; and 3) anal and rectal dose volume metrics predict GI morbidity after EBRT. Patients and methodsIn total, 106 patients with CaP had evaluations of GI symptoms (modified LENT-SOMA questionnaires) before EBRT and at one month, one, two and three years after its completion. Other variables measured before EBRT were: 1) plasma concentrations of homocysteine and micronutrients including caroteinoids and selenium; 2) chromosome damage/DNA misrepair (micronuclei/nucleoplasmic bridge) indices; and 3) mean anal and rectal wall doses and volumes of anal and rectal walls receiving ≥40 Gy and ≥60 Gy. Univariate and multivariate analyzes examined the relationships among: 1) plasma levels of homocysteine and micronutrients; 2) indices of chromosome damage/DNA misrepair; and 3) mean anal and rectal wall doses and volumes of anal and rectal walls receiving ≥40 Gy and ≥60 Gy and total GI symptom scores from one month to three years after EBRT. ResultsIncreased frequency and urgency of defecation, rectal mucous discharge and bleeding after EBRT resulted in sustained rises in total GI symptom scores above baseline at three years. On univariate analysis, total GI symptom scores were significantly associated with: 1) plasma selenium and α tocopherol; 2) micronuclei indices of DNA damage; 3) mean anal and rectal wall doses; and 4) volumes of anal and rectal wall receiving ≥40 Gy and ≥60 Gy (p = 0.08–<0.001). On multivariate analysis, only volume of anal wall receiving ≥40 Gy was significant for increased GI symptoms after EBRT (p < 0.001). ConclusionThe volume of anal wall receiving ≥40 Gy predicts chronic GI morbidity after EBRT for CaP. [ABSTRACT FROM PUBLISHER]

Purpose. To report results from the five-year follow-up on a previously reported study using image-guided radiotherapy (IGRT) of localized or locally advanced prostate cancer (PC) and a removable prostate stent as fiducial. Material and methods. Patients with local or locally advanced PC were treated using five-field 3D conformal radiotherapy (3DRT). The clinical target volumes (CTV) were treated to 78 Gy in 39 fractions using daily on-line image guidance (IG). Late genito-urinary (GU) and gastro-intestinal (GI) toxicities were scored using the radiotherapy oncology group (RTOG) score and the common toxicity score of adverse events (CTC) score. Urinary symptoms were also scored using the international prostate symptom score (IPSS). Results. Median observation time was 5.4 year. Sixty-two of the 90 patients from the original study cohort were eligible for toxicity assessment. Overall survival, cancer-specific survival and biochemical freedom from failure were 85%, 96% and 80%, respectively at five years after radiotherapy. Late toxicity GU and GI RTOG scores ≥ 2 were 5% and 0%. Comparing pre- and post-radiotherapy IPSS scores indicate that development in urinary symptoms after radiotherapy may be complex. Conclusions. Prostate image-guided radiotherapy using a prostate stent demonstrated survival data comparable with recently published data. GU and GI toxicities at five-year follow-up were low and comparable to the lowest toxicity rates reported. These findings support that the precision of the prostate stent technique is at least as good as other techniques. IPSS revealed a complex development in urinary symptoms after radiotherapy. [ABSTRACT FROM AUTHOR]

Background. Treatment of localized prostate cancer (PC) is controversial. This is the first randomized study comparing an open surgery procedure (radical prostatectomy) with a combination of high-dose rate brachytherapy (2 × 10 Gy) and external beam radiotherapy (25 × 2 Gy) in PC patients in Sweden 1996-2001. The two randomization arms were compared regarding differences in patients-reported outcomes, such as complications and health-related quality of life (HRQoL). Material and methods. The patients had localized/locally advanced PC, clinical category T1b-T3a, N0, M0 and PSA ≤ 50 ng/ml. All underwent total androgen blockade (six months). Self-reported HRQoL and symptoms including urinary, bowel, and sexual side effects were investigated prospectively before randomization and 12 and 24 months after randomization. A total of 89 patients were randomized and completed the EORTC QLQ C-33 and EORTC PR-25 questionnaires. Results. Over the study period, there were no discernible differences in HRQoL, or complications between the two groups. Emotional functioning, however, improved statistically significantly over time, whereas Social functioning decreased, and financial difficulties increased. No statistically significant differences in group-by-time interactions were found. The survival rate was 76%. Only eight patients (9%) died of PC. Conclusion. Open radical prostatectomy and the combined high-dose rate brachytherapy with external beam radiation appeared to be comparable in the measured outcomes. It was not possible to draw any conclusion on the efficacy of the two treatments due to insufficient power of the study. [ABSTRACT FROM AUTHOR]

Background. Prostate cancer (PCa) patients with metastatic disease often suffer from skeletal pain and urinary retention impairing their quality of life. Prophylactic radiotherapy to bone metastases planned concomitantly with primary PCa radiotherapy could enable more precise control of combined dose in healthy tissues when compared to sequential palliative treatment. Materials and methods. Volumetric modulated arc therapy (VMAT) was planned for 14 PCa patients with primary bone metastases. The bone planning target volume (PTVbone) was contoured together with the PTVs of prostate (pr), pelvic lymph nodes (ln) and seminal vesicles (sv). Another virtual plan was calculated excluding PTVbone for dose volume histogram (DVH) comparison. DVHs were additionally compared to a set of actual VMAT treatment plans of a control cohort of 13 high risk PCa patients treated with PTVpr, PTVsv and PTVln. The prescribed doses varied between 42 and 76 Gy for PTVbone. Results. Recommended healthy tissue tolerances (Quantec) were not exceeded except for one patient's rectum V50Gy value. Rectum doses did not increase significantly due to the inclusion of PTVbone. For bladder, there was a slight increase for V65Gy and V50Gy (2.7% and 7.4%). The DVHs of metastatic and non-metastatic patients were comparable. There were no differences in the PTVpr DVH parameters, while mean PTVln dose increased by 3.7 Gy-4.4 Gy due to the increased treatment volume related to PTVbone. All side effects were < grade 3 during the mean follow-up duration of 25 months. Conclusions. VMAT offers a good optimization tool for adding extra PTVs to the radiotherapy plan. Radiotherapy of bone metastases concomitantly with irradiation of the primary prostate tumor is a safe and well-tolerated approach and deserves to be studied in a randomized setting. [ABSTRACT FROM AUTHOR]

Background. The precise etiology of fecal incontinence (FI), which occurs frequently following external beam radiotherapy (EBRT) for prostate carcinoma is unknown. It is possibly related to pelvic nerve injury. The aim of this study was to assess the incidence of pudendal nerve dysfunction in men with FI after EBRT for prostate cancer compared to men with FI but no history of EBRT. Material and methods. Data were evaluated from 74 men with intact anal sphincters on endo-anal ultrasound (17 post-EBRT) who had been investigated for FI at a tertiary center. Wexner incontinence scores, pudendal nerve function, anorectal manometry, and rectal sensitivity were compared between the two patient groups. Results. Post-radiotherapy patients were older (77 ± 6 vs. 62 ± 17 years, p < 0.005) and had worse incontinence than those with no history of radiotherapy (Wexner score; 13 ± 3 vs. 8 ± 4; p < 0.005). Bilateral pudendal nerve terminal motor latency (PNTML) was abnormal in 87% of radiotherapy versus 22% of non-radiotherapy patients (p < 0.001) and the significant difference persisted even after correction for age differences. Anal sphincter pressures and rectal sensitivity for both groups were similar. Conclusion. There is a markedly higher incidence of pudendal nerve dysfunction in men with FI after EBRT for prostate cancer compared with men with FI from other etiologies. The increased severity of incontinence in radiotherapy patients is not matched by alterations in either anal sphincter pressures or rectal sensitivity compared to FI in non-ERBT patients. [ABSTRACT FROM AUTHOR]

Background. External beam radiotherapy is an excellent treatment for patients with prostate cancer (PC). Assessing long-term radiotherapy-induced toxicity is important. We evaluated the impact of implementing different rectal dose volume constraints (DVC) on late rectal and urinary toxicity. Material and methods. Six hundred and thirty-seven PC patients were treated with high-dose intensity-modulated radiotherapy (IMRT) in the primary (median dose of 78 Gy to the prostate) or postoperative setting [median dose of 74 (adjuvant) and 76 Gy (salvage) to the prostatic bed]. Three groups were defined according to different DVC applied over time. The incidence of late rectal and urinary toxicity was evaluated. Three-year actuarial risk estimations of grade 2-3 rectal and urinary toxicity were calculated (Kaplan-Meier statistics). Results. Median follow-up was five years. Overall, the incidence of late grade 3 and 2 rectal toxicity was 1% and 11%. The calculated three-year actuarial risk of developing late grade ≥ 2 rectal toxicity decreased from 16% to 7% and 5% for patients in Group 1, Group 2 and Group 3, respectively (p < 0.001). Respectively, 17 (4%) and 98 (24%) patients developed grade 3 and 2 late urinary toxicity in the primary setting. In the postoperative setting, 15 (6%) and 62 (26%) patients developed grade 3 and 2 urinary toxicity, respectively. The three-year actuarial risk of developing late ≥ grade 2 urinary toxicity in primary- and postoperative-treated patients was 22% and 23%, respectively. This was not significantly different between the three groups. Conclusion. The majority of patients developed no or only moderate rectal toxicity after high-dose IMRT for PC. Implementing different rectal DVC resulted in a significant decrease of late rectal toxicity without affecting urinary toxicity. [ABSTRACT FROM AUTHOR]

Background. We compared target and normal tissue dosimetric indices between ultra-hypofractionated passively scattered proton radiotherapy and stereotactic body radiotherapy (SBRT) in the definitive treatment of localized prostate cancer. Material and methods. Ten patients were treated definitively for localized prostate cancer with SBRT to a dose of 36.25 Gy in 5 fractions prescribed to a volume encompassing the prostate only. Dose-volume constraints were applied to the rectum, bladder, penile bulb, femoral heads, and prostatic and membranous urethra. Three-field passively scattered proton plans were retrospectively generated using target volumes from the same patients. Dosimetric indices were compared between the SBRT and proton plans using the Wilcoxon signed rank test. Results. All dose constraints were achieved using both ultra-hypofractionated passively scattered proton and SBRT planning. Proton plans demonstrated significant improvement over SBRT in mean dose delivered to the penile bulb (5.2 CGE vs. 11.4 Gy; p = 0.002), rectum (6.7 CGE vs. 10.6 Gy; p = 0.002), and membranous urethra (32.2 CGE vs. 34.4 Gy; p = 0.006) with improved target homogeneity resulting in a significant reduction in hot spots and volumes of tissue exposed to low doses of radiation. Compared to proton planning, SBRT planning resulted in significant improvement in target conformality with a mean index of 1.17 versus 1.72 (p = 0.002), resulting in a dose reduction to the volume of bladder receiving more than 90% of the PD (V32.6, 7.5% vs. 15.9%; p = 0.01) and mean dose to the left (7.1 Gy vs. 10.4 CGE; p = 0.004) and right (4.0 Gy vs. 10.9 CGE; p = 0.01) femoral heads. Conclusion. Target and normal tissue dose constraints for ultra-hypofractionated definitive radiotherapy of localized prostate cancer are readily achieved using both CK SBRT and passively scattered proton-based therapy suggesting feasibility of either modality. [ABSTRACT FROM AUTHOR]

To compare adverse effects and toxicity in men with high-risk or locally advanced prostate cancer when adding intensity-modulated radiotherapy (IMRT) technique to the pelvis. Patients and methods. In this prospective follow-up study 180 patients treated with conformal radiotherapy (RAD) to the prostate and vesiculae seminales (boost volumes; PV) and long-term androgen deprivation therapy (LADT), were compared to 90 patients managed by LADT, RAD to the PV and additionally pelvic IMRT. Adverse effects were self-reported at baseline, at 3- and 12-month follow-up. At each time point, the patients rated a questionnaire covering urinary, bowel, and sexual function and bother, quality of life, fatigue, and mental distress. Results. At 3-month follow-up urinary and bowel functions were significantly decreased among IMRT compared to RAD. At 12-month follow-up both groups showed the same reductions within the urinary, bowel and sexual domains. RAD patients had more mental distress than IMRT patients. The scores on quality of life, fatigue and mental distress hardly influenced function or bother within the urinary, bowel or sexual domains. Conclusions. Men treated for high-risk or locally advanced prostate cancer with a combination of LADT, RAD and IMRT including PV and pelvic structures had considerably more acute side effects at 3 months than men treated with LADT and RAD to the PV only. However, at 12-month follow-up, the observed genitourinary and gastrointestinal function and bother were similar in both groups. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background. This work evaluates influences of susceptibility-induced bone outline shift and perturbations, and bone segmentation errors on external radiotherapy dose calculation accuracy in magnetic resonance imaging (MRI)-based pseudo-computed tomography (CT) images of the male pelvis. Material and methods. T1/T2*-weighted fast gradient echo, T1-weighted spin echo and T2-weighted fast spin echo images were used in bone detection investigation. Bone edge location and bone diameter in MRI were evaluated by comparing those in the images with actual physical measurements of fresh deer bones positioned in a gelatine phantom. Dose calculation accuracy in pseudo-CT images was investigated for 15 prostate cancer patients. Bone outlines in T1/T2*-weighted images were contoured and additional segmentation errors were simulated by expanding and contracting the bone contours with 1 mm spacing. Heterogeneous pseudo-CT images were constructed by adopting a technique transforming the MRI intensity values into Hounsfield units with separate conversion models within and outside of bone segment. Results. Bone edges and diameter in the phantom were illustrated correctly within a 1 mm-pixel size in MRI. Each 1 mm-sized systematic error in bone segment resulted in roughly 0.4% change to the prostate dose level in the pseudo-CT images. The prostate average (range) dose levels in pseudo-CT images with additional systematic bone segmentation errors of −2 mm, 0 mm and 2 mm were 0.5% (−0.5-1.4%), −0.2% (−1.0-0.7%), and −0.9% (−1.8-0.0%) compared to those in CT images, respectively, in volumetric modulated arc therapy treatment plans calculated by Monte Carlo algorithm. Conclusions. Susceptibility-induced bone outline shift and perturbations do not result in substantial uncertainty for MRI-based dose calculation. Dose consistency of 2% can be achieved reliably for the prostate if heterogeneous pseudo-CT images are constructed with ≤± 2 mm systematic error in bone segment. [ABSTRACT FROM AUTHOR]

Background. Substantial survival may be observed with oligometastatic prostate cancer. Combining androgen deprivation (AD) and high-dose external beam radiotherapy (RT) to isolated regional or distant lesions may be proposed for these patients and the outcome of this strategy is the purpose of the present report. Material and methods. From 2003 to 2010, 50 prostate cancer patients were diagnosed with synchronous (n = 7) or metachronous (n = 43) oligometastases (OM). Among the relapsing patients, the recurrence occurred after radical prostatectomy in 33 patients and curative RT (± AD) in 10 patients. The median age at diagnosis was 63 years (range, 48-82). All patients underwent a bone scan and 18F-choline or 11C-acetate PET-CT at the time of diagnosis or relapse, showing regional and/or distant nodal and bone and/or visceral metastases in 33 and 17 patients, respectively. The median delivered effective dose was 64 Gy. All but one patient received neo-adjuvant and concomitant AD. Results. After a median follow-up of 31 months (range, 9-89) the three-year biochemical relapse-free survival (bRFS), clinical failure-free survival, and overall survival rates were 54.5%, 58.6% and 92%, respectively. No grade 3 toxicity was observed. Improved bRFS was found to be significantly associated with the number of OM. The three-year bRFS was 66.5% versus 36.4% for patients with 1 and > 1 OMs (p = 0.031). A normalised total dose (NTD in 2 Gy/fraction, alpha/beta = 2 Gy) above 64 Gy was also correlated with a better three-year bRFS compared to lower doses: 65% vs. 41.8%, respectively (p = 0.005). On multivariate analysis, only the NTD > 64 Gy retained statistical significance (HR: 0.37, 95% CI 0.15-0.93). Conclusion. Oligometastatic patients may be successfully treated with short AD and high-dose irradiation to the metastatic lesions. High dose improves bRFS. Such a treatment strategy may hypothetically succeed to prolong the failure-free interval between two consecutive AD courses. [ABSTRACT FROM AUTHOR]

Background. To analyze relevant data on carbon ion radiotherapy for different tumor indications and to review current clinical trials. Material and methods. All published data on carbon ion radiotherapy were searched for with specific criteria in PUBMED. The terms for search were ' carbon ion and (radiotherapy OR radiation therapy) and (nirs OR chiba OR japan OR itep OR st. petersburg OR PSI OR dubna OR uppsala OR clatterbridge OR loma linda OR nice OR orsay OR itemba OR mpri OR himac OR triumf OR GSI OR HMI OR NCC OR ibmc OR pmrc OR MGH OR infn-lns OR shizuoka OR werc OR zibo OR md anderson OR fpti OR ncc ilsan OR boston OR heidelberg OR tsukuba) NOT in vitro NOT cell culture NOT review[Publication Type] Filters: Humans, English'. The search delivered 273 hits, of which only articles in English including 20 or more patients were included. Case reports were not considered. We subdivided into disease- and site-specific groups. Results and conclusion. To date, several studies have been performed, however, no randomized trials have been conducted. Therefore, carbon ion radiotherapy must be considered an experimental treatment, and randomized trials comparing modern photon as well as proton treatments are necessary. [ABSTRACT FROM AUTHOR]

Background and purpose. Deformable image registration (DIR) is a key component of image-guided and adaptive strategies in radiotherapy. DIR based on image intensities alone is promising for online applications, but is challenged in regions with low intensity gradients. In this study we have investigated the performance of intensity- based DIR applied to contour propagation of the rectum and bladder, focusing on the consequences in terms of dose/volume parameters. Material and methods. The rectum and bladder volumes were delineated in the planning computed tomography (pCT) scan and in 8-9 repeat CTs (Vmanual) for nine prostate cancer patients. The volumes from the pCT were propagated onto the repeat CTs using intensity-based DIR (Vprop). Dose/volume parameters for Vmanual and Vprop were derived by dose re-calculations following rigid registration on prostate fiducials. Linear regression was used to identify qualitative and quantitative volumetric measures of the DIR performance being associated with the differences in dose/volume parameters. Results. The median differences in dose/volume parameters assessed for Vprop and Vmanual were modest, but individual differences ˜ 7 Gy were seen. The observed differences in dose/volume parameters showed strong correlations to the measures of the DIR performance as well as with the volume variations, most pronounced for the rectum (R2 = 0.63-0.85; p ≤ 0.05). Conclusion. Limitations in the intensity-based DIR algorithm resulted in large individual differences in dose/volume parameters between propagated and manually segmented volumes, which were correlated with volumetric measures of the DIR performance. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Daily treatment plan selection from a plan library is a major adaptive radiotherapy strategy to account for individual internal anatomy variations. This strategy depends on the initial input images being representative for the variations observed later in the treatment course. Focusing on locally advanced prostate cancer, our aim was to evaluate if residual motion of the prostate (CTV-p) and the elective targets (CTV-sv, CTV-ln) can be prospectively accounted for with a statistical deformable model based on images acquired in the initial part of treatment. Methods. Thirteen patients with locally advanced prostate cancer, each with 9-10 repeat CT scans, were included. Displacement vectors fields (DVF) obtained from contour-based deformable registration of delineations in the repeat- and planning CT scans were used to create patient-specific statistical motion models using principal component analysis (PCA). For each patient and CTV, four PCA-models were created: one with all 9-10 DVF as input in addition to models with only four, five or six DVFs as input. Simulations of target shapes from each PCA-model were used to calculate iso-coverage levels, which were converted to contours. The levels were analyzed for sensitivity and precision. Results. A union of the simulated shapes was able to cover at least 97%, 97% and 95% of the volumes of the evaluated CTV shapes for PCA-models using six, five and four DVFs as input, respectively. There was a decrease in sensitivity with higher iso-coverage levels, with a sharper decline for greater target movements. Apart from having the steepest decline in sensitivity, CTV-sv also displayed the greatest influence on the number of geometries used in the PCA-model. Conclusions. PCA-based simulations of residual motion derived from four to six DVFs as input could account for the majority of the target shapes present during the latter part of the treatment. CTV-sv displayed the greatest range in both sensitivity and precision. [ABSTRACT FROM AUTHOR]

Purpose. To determine if high-risk prostate cancer responds differently to hypofractionation. Material and methods. One hundred and fifty-seven men with NCCN high-risk (T3, PSA > 20, or Gleason ≥ 8) clinically localized prostate cancer treated between 1998 and 2010 met the inclusion criteria for the analysis. Eighty-two were treated with conventional WPRT with a conventionally fractionated sequential boost to the prostate (cRT), with the prostate receiving 75-77 Gy in 1.8-2.0 Gy fractions. Seventy-five were treated with pelvic IMRT with a hypofractionated simultaneous boost to the prostate (hRT), with the prostate receiving 70 Gy in 2.5 Gy fractions. The dose to the pelvic lymph nodes was 45 Gy in the cRT group and 50.4 Gy in the hRT group, both at 1.8 Gy per fraction. Ninety-two percent received neoadjuvant hormonal ablation therapy, typically beginning two months prior to the start of RT. Results. Median follow-up was 6.5 years for men receiving cRT and 3.7 years for those receiving hRT. The actuarial rate of biochemical control at four years was 88% for cRT and 94% for hRT (p = 0.82). The rates of early rectal and urinary grade ≥ 2 toxicities were 35% (29 of 82) and 49% (40 of 82) for the cRT group and 36% (27 of 75) and 44% (33 of 75) for the hRT group. The actuarial rate of late grade ≥ 2 rectal toxicity at four years was 25% for the cRT group and 13% for the hRT group (p = 0.037). The rate of late grade 3 rectal complications was 4% (3 of 82) for patients receiving cRT and 1% (1 of 75) for patients receiving hRT. Conclusion. Initial follow-up indicates equivalent biochemical control between regimens. Patients receiving hRT experienced fewer late rectal complications. [ABSTRACT FROM AUTHOR]

Background. The Late Effects Normal Tissue/Subjective Objective Management Analytic (LENT/SOMA) system for grading of side effects after radiotherapy was proposed several years ago. Only a few studies have previously been performed on the validity of the LENT/SOMA. The aim of the present study was to validate the LENT/SOMA scoring system for recto-anal side effects after treatment for prostate cancer in a randomized trial. Material and methods. A total of 875 patients with locally advanced prostate cancer were randomized to either hormonal treatment alone or hormonal treatment plus radiotherapy in the Scandinavian Prostate Cancer Group 7 (SPCG-7) study. At least three years after treatment was started, the 178 patients that were randomized at St. Olavs Hospital were approached. One hundred and three patients of these accepted inclusion. The side effects according to LENT/SOMA were graded by oncologist and nurse. In addition, side effects were graded according to the European Organisation for Research and Treatment of Cancer and the Radiation Therapy Oncology Group (EORTC/RTOG) toxicity scale and patient-reported health-related quality of life (HRQOL) questionnaires. Content/face validity, sensitivity and inter-rater reliability of the LENT/SOMA tables for rectum were analyzed. Results. Content/face analysis of LENT/SOMA revealed serious problems. Significant correlations (Spearman's rho > 0.4) were found between three of 15 LENT/SOMA items and similar HRQOL items. LENT/SOMA score made it possible to detect significant differences between the two groups of patients (p < 0.001), EORTC/RTOG toxicity score did not (p = 0.138). Inter-rater reliability was acceptable. Conclusions. LENT/SOMA scoring system for recto-anal side effects after radiotherapy for prostate cancer displays serious difficulties in the present study. Replacement of LENT/SOMA tables for rectum by a combination of patient-reported HRQOL questionnaires, clinical examination and objective physiological measurements might be called for. [ABSTRACT FROM AUTHOR]

Background. To investigate post-treatment changes in serum testosterone in low- and intermediate-risk prostate cancer patients treated with hypofractionated passively scattered proton radiotherapy. Material and methods. Between April 2008 and October 2011, 228 patients with low- and intermediate-risk prostate cancer were enrolled into an institutional review board-approved prospective protocol. Patients received doses ranging from 70 Cobalt Gray Equivalent (CGE) to 72.5 CGE at 2.5 CGE per fraction using passively scattered protons. Three patients were excluded for receiving androgen deprivation therapy (n = 2) or testosterone supplementation (n = 1) before radiation. Of the remaining 226 patients, pretreatment serum testosterone levels were available for 217. Of these patients, post-treatment serum testosterone levels were available for 207 in the final week of treatment, 165 at the six-month follow-up, and 116 at the 12-month follow-up. The post-treatment testosterone levels were compared with the pretreatment levels using Wilcoxon's signed-rank test for matched pairs. Results. The median pretreatment serum testosterone level was 367.7 ng/dl (12.8 nmol/l). The median changes in post-treatment testosterone value were as follows: +3.0 ng/dl (+0.1 nmol/l) at treatment completion; +6.0 ng/dl (+0.2 nmol/l) at six months after treatment; and +5.0 ng/dl (0.2 nmol/l) at 12 months after treatment. None of these changes were statistically significant. Conclusion. Patients with low- and intermediate-risk prostate cancer treated with hypofractionated passively scattered proton radiotherapy do not experience testosterone suppression. Our findings are consistent with physical measurements demonstrating that proton radiotherapy is associated with less scatter radiation exposure to tissues beyond the beam paths compared with intensity-modulated photon radiotherapy. [ABSTRACT FROM AUTHOR]

Background and purpose. In radiotherapy (RT), target soft tissues are best defined on MR images. In several cases, CT imaging is needed only for dose calculation and generation of digitally reconstructed radiographs (DRRs). Image co-registration errors between MRI and CT can be avoided by using MRI-only based treatment planning, especially in the pelvis. Since electron density information can not be directly derived from the MRI, a method is needed to convert MRI data into CT like data. We investigated whether there is a relationship between MRI intensity and Hounsfield unit (HU) values for the pelvic bones. The aim was to generate a method to convert bone MRI intensity into HU data surrogate for RT treatment planning. Material and methods. The HU conversion model was generated for 10 randomly chosen prostate cancer patients and independent validation was performed in another 10 patients. Data consisted of 800 image voxels chosen within the pelvic bones in both T1/T2*-weighted gradient echo and CT images. Relation between MRI intensity and electron density was derived from calibrated HU-values. The proposed method was tested by constructing five 'pseudo'-CT series. Results. We found that the MRI intensity is related to the HU value within a HU range from 0 to 1400 within the pelvic bones. The mean prediction error of the conversion model was 135 HU. Dose calculation based on the pseudo-CT images was accurate and the generated DRRs were of good quality. Conclusions. The proposed method enables generation of clinically relevant pseudo-CT data for the pelvic bones from one MRI series. It is simpler than previously reported approaches which require either acquisition of several MRI series or T2* maps with special imaging sequences. The method can be applied with commercial clinical image processing software. The application requires segmentation of the bones in the MR images. [ABSTRACT FROM AUTHOR]

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 (D99) and generalized equivalent dose (gEUD) showed substantial inter-patient variations. For 40% of the investigated scenarios, the patient average simulated D99 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 D99 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. [ABSTRACT FROM AUTHOR]

Large prostate size is associated with higher rates of genitourinary and gastrointestinal toxicities after definitive treatment for prostate cancer, and because of this many men will undergo cytoreduction with androgen deprivation therapy (ADT) before definitive therapy, which results in its own unique toxicities and worsens quality of life. This series investigates genitourinary and gastrointestinal toxicity in men with large prostates (> 60 cm3) undergoing definitive proton therapy (PT) for prostate cancer. Material and methods. From 2006 to 2010, 186 men with prostates ≥ 60 cm3 were treated with definitive PT (median dose, 78 CGE) for low- (47%), intermediate- (37%) and high-risk (16%) prostate cancer. Median prostate size was 76 cm3 (range, 60-143 cm3) and pretreatment IPSS was > 15 in 27%. At baseline, 51% were managed for obstructive symptoms with transurethral resection of the prostate (TURP) (9.7%) or medical management with α blockers (32%), 5 α-reductase inhibitors (15%), and/or saw palmetto (11%). Fourteen men received ADT for cytoreduction. Results. Median follow-up was two years. Grade 3 genitourinary toxicities occurred in 14 men, including temporary catheterization (n = 7), TURP (n = 6), and balloon dilation for urethral stricture (n = 1). Multivariate analysis demonstrated pretreatment medical management (p = 0.0065) and pretreatment TURP (p = 0.0002) were significantly associated with grade 3 genitourinary toxicity. One man experienced grade 3 gastrointestinal toxicity and 15 men had grade 2 gastrointestinal toxicities. On multivariate analysis, dose > 78 CGE was associated with increased grade 2 + gastrointestinal toxicity (p = 0.0142). Conclusion. Definitive management of men with large prostates without ADT was associated with low rates of genitourinary and gastrointestinal toxicity. [ABSTRACT FROM AUTHOR]

The article reports on research which was conducted to investigate whether the drug gefitinib could delay prostate specific antigen (PSA) progression, increase PSA doubling time (PSADT) and postpone the need for hormonal or radiation salvation therapy in patients with rising PSA. Researchers found that gefitinib appeared to increase the PSA doubling time (PSADT) in most patients.

Background. Radiotherapy (RT) for abdominal and pelvic malignancies often causes severe small bowel toxicity. Citrulline concentrations are known to decrease with intestinal failure. We thus evaluated the feasibility of plasma citrulline levels in predicting radiation-induced intestinal toxicity. Material and methods. Fifty-three patients (36 prostate cancer, 17 endometrial cancer) who received 45 Gy pelvic RT using conventional fractionation were prospectively evaluated. Patients with prostate cancer received an additional 25-30.6 Gy conformal boost. Plasma citrulline levels were assessed on day 0, mid- (week 3) and post-RT (week 8), and four months post-RT. Dose-volume histogram, citrulline concentration changes, and weekly intestinal toxicity scores were analyzed. Results. Mean age was 63 years (range: 43-81 years) and mean baseline citrulline concentration was 38.0 ± 10.1 μmol/l. Citrulline concentrations were significantly reduced at week 3 (27.4 ± 5.9 μmol/l; p < 0.0001), treatment end (29.9 ± 8.8 μmol/l; p < 0.0001), and four months post-treatment (34.3 ± 12.1; p == 0.01). The following factor pairs were significantly positively correlated: Citrulline concentration/mean bowel dose during, end of treatment, and four months post-RT; dose-volume parameters/citrulline change groups; cumulative mean radiation dose/intestinal toxicity at end and four months post-RT; citrulline changes/intestinal toxicity during and end of RT. Citrulline concentration changes significantly differed during treatment according to RTOG intestinal toxicity grades (p < 0.0001). Although the citrulline changes differed significantly within RTOG intestinal toxicity grades (p == 0.003), the difference between Grade 0 and Grade 1 did not differ significantly at the end of the treatment. At four months after RT, no significant differences were apparent. Conclusion. Citrulline-based assessment scores are objective and should be considered in measuring radiation-induced intestinal toxicity. [ABSTRACT FROM AUTHOR]

Background. Tumor motion during radiotherapy delivery can substantially deteriorate the target dose distribution. A promising method to overcome this problem is dynamic multi-leaf collimator (DMLC) tracking. The purpose of this phantom study was to integrate a wired electromagnetic (EM) transponder localization system with DMLC tracking and to investigate the geometric accuracy of the integrated system. Material and methods. DMLC tracking experiments were performed on a Trilogy accelerator with a prototype DMLC tracking system. A wired implantable EM transponder was mounted on a motion stage with a 3 mm tungsten sphere used for target visualization in continuous portal images. The three dimensional (3D) transponder position signal was used for DMLC aperture adaption. The motion stage was programmed to reproduce eight representative patient-measured trajectories for prostate and for lung tumors. The tracking system latency was determined and prediction was used for the lung tumor trajectories to account for the latency. For each trajectory, three conformal fields with a 10 cm circular MLC aperture and 72 s treatment duration were delivered: (1) a 358°° arc field; (2) an anterior static field; and (3) a lateral static field. The tracking error was measured as the difference between the marker position and the MLC aperture in the portal images. Results. The tracking system latency was 140 ms. The mean root-mean-square (rms) of the 3D transponder localization error was 0.53/0.54 mm for prostate/lung tumor trajectories. The mean rms of the two dimensional (2D) tracking error was 0.69 mm (prostate) and 0.98 mm (lung tumors) with tracking and 3.4 mm (prostate) and 5.3 mm (lung tumors) without tracking. Conclusions. DMLC tracking was integrated with a wired EM transponder localization system and investigated for arc and static field delivery. The system provides sub-mm geometrical errors for most trajectories. [ABSTRACT FROM AUTHOR]

Background and purpose. Uncorrelated motion of targets and large deformations of organs at risk represent challenges for image-guidance in simultaneous integrated boost (SIB) radiotherapy (RT) of pelvic tumour sites. This study aims to evaluate the robustness towards geometrical uncertainties in prostate cancer using two image-guided RT (IGRT) set-up strategies for two SIB delivery methods. Secondly, we evaluate the ability of geometrical parameters to predict when the applied margins are insufficient, resulting in target underdosage (TUD). Material and methods. The study included nine patients with eight to nine repeat computed tomography (CT)-scans evenly distributed throughout their treatment course. The prostate target (CTV-p) and the lymph node target including seminal vesicles (CTV-ln/sv) were delineated in all scans. SIB treatment plans for intensity-modulated RT and volumetric modulated arc therapy were generated on the planning CT and transferred to the repeat CTs for dose re-calculation using registration based on either anatomy or intra-prostatic fiducial markers. Receiving operator characteristic analysis was used to deduce the ability of the parameters to predict TUD. Results. The dosimetric differences between the two positioning strategies were small for all parameters evaluated and significant only for the dose to rectum. Anatomy based registration resulted in inferior target coverage with a larger number of TUDs, mostly seen in the seminal vesicles. For both targets the highest sensitivity and specificity of predicting TUD was seen for the relative volume and the lowest was found for the displacement vector. Conclusions. Positioning based on fiducials gave the best trade-off between coverage of the targets although resulting in the highest dose to rectum. Target underdosage occurred mostly in the seminal vesicles. For both targets, the best parameter to predict TUD was the relative volume. [ABSTRACT FROM AUTHOR]

Background and purpose. In this study the influence of fiducial markers (FMs) on diffusion-weighted (DW) magnetic resonance images was investigated by measuring the intensity variations due to the artefact from the FM image reconstruction. Material and methods. DW- and reference T1W images were acquired of an Agar-gel phantom containing two fixed cylindrical FMs, with a 1.5- and 3T MR scanner. The center of gravity (CoG) positions of the manually segmented FM artefacts (FMA) and the size of FMAs in x-, y- and z direction were measured in the two corresponding image sets, based on the intensity changes caused by the FM reconstruction. Also, a similarity measure, the Dice similarity coefficient (DSC), of the segmented FMAs in the two image sets was calculated. Results. The mean shift of the CoG of the manually segmented FMAs in the phase encoding (PE) and the two orthogonal directions, respectively, was: 1.5T/3T; 0.3 ±± 0.1/0.5 ±± 0.3 cm and 1.5T/3T; 0.1 ±± 0.1/0.1 ±± 0.1 cm. The largest shift was observed in the 3T DW images for FMs aligned with the long axis orthogonal to the PE direction (0.9 ±± 0.1 cm). The mean size of the FMA in the PE- and the two orthogonal directions, respectively, was: 1.5T/3T; 1.7 ±± 0.5/1.3 ±± 0.1 cm, and 1.5T/3T; 0.9 ±± 0.3/1.0 ±± 0.2 cm. The mean DSC value of the segmented artefact volumes in the DW- vs. T1W images were 21% and 5% for the 1.5- and 3.0T MR scanner, respectively. Conclusions. This study has shown that both the size and displacement of the FMAs increase in the PE direction on DW images. The larger shifts were observed for FMs positioned with the long axis orthogonal to the PE direction. Measurements obtained for different b-values gave consistent results. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

It is very attractive, due to the assumed low alfa/beta ratio of prostate cancer (PC), to construct new treatment schedules for prostate cancer using only a few large fractions of radiation (hypofractionation). This will widen the therapeutic window since the ratio for PC might be lower than that of the organs at risk (OAR). PC is an extremely variable disease and often contains both highly and poorly differentiated cells. It is reasonable to assume that different cells have different patterns of radiosensitivity, i.e. alfa/beta ratios and proliferation. In this study we will simulate the effect on the outcome of the treatment with different fractionations and different ratios. Material and methods. In this simulation we use an extension of the Linear Quadratic (LQ)/Biological Effective Dose (BED) formula called the dose volume inhomogenity corrected BED (DVIC-BED). In the formula the tumour volume is divided in 50 subvolumes (step of 2%) and it is possible to calculate the relative effect of the treatment with different ratios (1.5, 4 and 6.5) in different subvolumes. Results. The simulations demonstrate that only a small portion (5 -10%) of cells with a higher ratio will dramatically change the effect of the treatment. Increasing the total dose can compensate this, but this will on the other hand increase the dose to the OAR and also the risk for severe side effects. Conclusion. These simulations highlight possible reasons for concerns about the use of hypofractionation for pathologically heterogeneous tumours, such as prostate cancer, and also demonstrate the need for testing new treatment schedules using both high and low ratios. [ABSTRACT FROM AUTHOR]

Radiotherapy has experienced an extremely rapid development in recent years. Important improvements such as the introduction of multileaf collimators and computed tomography (CT)-based treatment planning software have enabled three dimensional conformal external beam radiation therapy (3DCRT). The development of treatment planning systems and technology for brachytherapy has been very rapid as well. Development of accelerators with integrated on-board imaging equipment and technology, for example image-guided radiation therapy (IGRT) has further improved the precision with reduced margins to adjacent normal tissues. This has, in turn, led to the possibility to administer even higher doses to the prostate than previously. Although radiotherapy and radical prostatectomy have been used for the last decades as curative treatment modalities, still there are no randomized trials published comparing these two options. Outcome data show that the two treatment modalities are highly comparable when used for low- and intermediate-risk prostate cancer. [ABSTRACT FROM AUTHOR]

Purpose. A clinical feasibility study using a removable prostate stent as fiducial for image-guided radiotherapy (IGRT) of localized prostate cancer (PC). Material and methods. The study included patients with local or locally advanced PC. The clinical target volume (CTV) was outlined on magnetic resonance (MR) images co-registered to planning computer tomography (CT) images. Daily online IGRT was delivered using the stent as fiducial. Risk of migration was estimated using multiple MR. Acute urinary toxicity was scored using the international prostate symptom score (IPSS). Late gastro-intestinal (GI) and genito-urinary (GU) toxicity was scored using the Radio Therapy Oncology Group (RTOG) score, biochemical failure (BF) was defined as an elevation of prostate specific antigen (PSA) above nadir plus 2 ng/ml after radiotherapy. Results. One hundred men were enrolled in the study. Ninety completed radiotherapy with the stent as fiducial. No migration of the stent was seen, but three cases of dislocation of the stent to the bladder were observed. Acute urinary toxicity based on IPSS was comparable to toxicity in patients who had gold markers (GM) as fiducials. Removal of the stent was associated with a high frequency of urinary retention. Late GI and GU toxicity and BF were comparable to those of other studies, but longer observation time is needed. Conclusions. This study reports the first clinical results of using a prostate stent as fiducial. No migration of the stent observed. Dislocation of the stent to the urinary bladder was observed in three cases, requiring removal of the stent and insertion of a new fiducial. Acute toxicity during radiotherapy evaluated from IPSS was comparable to toxicity in patients with GM. Removal of the stent was associated with a high frequency of post procedural urinary retention. Late toxicity and BF were comparable to those of other studies, though longer observation time is needed. [ABSTRACT FROM AUTHOR]

It is very attractive, due to the assumed low alfa/beta ratio of prostate cancer (PC), to construct new treatment schedules for prostate cancer using only a few large fractions of radiation (hypofractionation). This will widen the therapeutic window since the ratio for PC might be lower than that of the organs at risk (OAR). PC is an extremely variable disease and often contains both highly and poorly differentiated cells. It is reasonable to assume that different cells have different patterns of radiosensitivity, i.e. alfa/beta ratios and proliferation. In this study we will simulate the effect on the outcome of the treatment with different fractionations and different ratios. Material and methods. In this simulation we use an extension of the Linear Quadratic (LQ)/Biological Effective Dose (BED) formula called the dose volume inhomogenity corrected BED (DVIC-BED). In the formula the tumour volume is divided in 50 subvolumes (step of 2%) and it is possible to calculate the relative effect of the treatment with different ratios (1.5, 4 and 6.5) in different subvolumes. Results. The simulations demonstrate that only a small portion (5--10%) of cells with a higher ratio will dramatically change the effect of the treatment. Increasing the total dose can compensate this, but this will on the other hand increase the dose to the OAR and also the risk for severe side effects. Conclusion. These simulations highlight possible reasons for concerns about the use of hypofractionation for pathologically heterogeneous tumours, such as prostate cancer, and also demonstrate the need for testing new treatment schedules using both high and low ratios. [ABSTRACT FROM AUTHOR]

Purpose. To investigate inter-/intra-observer variability in defining the prostate by use of planning computed tomography (PCT) and cone beam CT (CBCT) with magnetic resonance image (MRI) as guidance prior to the introduction of an adaptive radiotherapy for prostate cancer. Material and methods. We reviewed PCT and firstly acquired CBCT datasets of each ten patients with prostate cancer. Three physicians independently delineated the prostate based on PCT and CBCT with MRI as guidance, allowing determination of inter-physician variability. Two physicians repeated prostate contouring three times in total to investigate intra-physician variability. We compared delineated prostate volumes in terms of the generalized conformity index (CIgen), maximum variation ratio (MVR), and center of mass (COM). Results. There were no significant inter-/intra-observer differences in the estimation of prostate volume on both PCT and CBCT. For both inter- and intra-observer variability in contouring the prostate gland, there were no significant differences in MVR between PCT and CBCT. The CIgen for inter-observer variability was 0.74 by PCT and 0.69 by CBCT. The CIgen for intra-observer variability on PCT and CBCT was 0.84 and 0.81 for observer 2 and 0.76 and 0.73 for observer 3. COM analyses showed that the greatest inter-/intra-observer variability was in the measurement of the prostate apex and base. With respect to CIgen and COM analysis for the inter-observer variability, more precise delineation of the prostate was possible on PCT than CBCT. More precise contouring in terms of both CIgen and COM was demonstrated by observer 2 than observer 3. Conclusions. Despite some ambiguity in apex and base level, there was a good consistency in delineating the gland on CBCT plus MRI-guided modification both among/within observer(s), without any significant difference from the consistency in defining the prostate on PCT. This study provides a framework for future studies of CBCT imaging of the prostate. [ABSTRACT FROM AUTHOR]

Purpose. To analyze published clinical data and provide a preliminary estimate of tumor repopulation rate and its onset time during radiation therapy for prostate cancer. Methods. Data on prostate cancer treated with external beam radiotherapy (EBRT) by Perez et al. (2004), Amdur et al. (1990) and Lai et al. (1991) were analyzed in this study. The stage-combined pelvic control rate from Perez et al. was calculated to be 0.95±0.01, 0.87±0.02, and 0.72±0.04 for patients treated ≤7 weeks, 7.1-9 weeks, and >9 weeks respectively. Based on the Linear-Quadratic model, extended to account for tumor repopulation, the least χ2 method was used to fit the clinical data and derive the onset time (Tk) and effective doubling time (Td) for prostate cancer. Similar analysis was performed for the other two datasets. Results. Best fit was achieved with onset time Tk=34±7 days and doubling time Td=12±2 days. These parameters were independent of the choice of the α/β values currently published in the literature. Analyses of the other two datasets showed Tk=42±7 days with Td=9 ± 3 days, and Tk=34±6 days with Td=34±5 days, respectively. Tk was found to be dependent on tumor stage. Conclusions. Consistent values for onset time Tk were obtained from different datasets, while the range of doubling time Td was large. Tumor repopulation starts no later than 58 days (at 90% confidence level) in the course of EBRT for prostate cancer. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and purpose. The rectum is a major dose-limiting organ at risk (OR) in radiotherapy (RT) of prostate cancer. Methods to predict adverse effects in the rectum are therefore important but their precision often limited, not the least by the internal motion of this organ. In this study late rectal morbidity is investigated in relation to the internal motion of the rectum by applying the ‘Planning organ at Risk Volume’ (PRV) concept. Materials and methods: Late rectal morbidity was analysed in 242 prostate cancer patients treated to 70 Gy with conformal RT to either the prostate, the prostate and seminal vesicles or the whole pelvis (initial 50 Gy only). Late rectal morbidity was classified by the late gastro-intestinal (GI) RTOG toxicity scoring system. Cumulative dose-volume histograms (DVHs) were derived for the rectum OR and six rectum PRVs i.e. the OR expanded with six different margins (narrow/intermediate/wide in anterior direction or in both anterior and posterior direction). The difference in rectum dose-volume parameters between patients with Grade 0–1 vs. Grade 2 or higher morbidity was investigated by logistic regression and permutation tests. Results: Late Grade 2 or higher morbidity was observed in 25 of 242 (10%) patients. The logistic regression analysis and the permutation tests reached significance (p ≤ 0.05) for only one dose level of the rectum OR (40 Gy). For the PRVs, several dose levels were found to be significant (p-value range: 0.01–0.046), most pronounced for the PRV with narrow margins of 6 mm anterior and 5 mm posterior with five intermediate (38–42 Gy) and ten high (62–71 Gy) dose levels. Conclusions: The statistical methods applied displayed consistently a small though significant difference in DVH parameters between patients with vs. without Grade 2 or higher late rectal morbidity for intermediate and high dose levels. The difference became most evident when using a PRV with narrow margins. [ABSTRACT FROM AUTHOR]