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Purpose: The aim of this study was to investigate the influence of brachytherapy technique and applicator type on target dose, isodose surface volumes, and organ-at-risk (OAR) dose., Methods and Materials: Nine hundred two patients treated with tandem/ovoids (T&O) (n = 299) and tandem/ring (T&R) (n = 603) applicators from 16 EMBRACE centers were analyzed. Patients received external beam radiation therapy and magnetic resonance imaging guided brachytherapy with dose prescription according to departmental practice. Centers were divided into 4 groups, according to applicator/technique: Ovoids and ring centers treating mainly with the intracavitary (IC) technique and ovoids and ring centers treating routinely with the intracavitary/interstitial (IC/IS) technique. V85Gy EQD2 10 , CTV HR D 90% (EQD2 10 ), and bladder, rectum, sigmoid, and vaginal 5-mm lateral-point doses (EQD2 3 ) were evaluated among center groups. Differences between T&O and T&R were tested with multivariable analysis., Results: For similar point A doses, mean CTV HR D 90% was 3.3 Gy higher and V85Gy was 23% lower for ring-IC compared with ovoids-IC centers (at median target volumes). Mean bladder/rectum doses (D 2cm3 and ICRU-point) were 3.2 to 7.7 Gy smaller and vaginal 5-mm lateral-point was 19.6 Gy higher for ring-IC centers. Routine use of IC/IS technique resulted in increased target dose, whereas V85Gy was stable (T&R) or decreased (T&O); reduced bladder and rectum D 2cm3 and bladder ICRU-point by 3.5 to 5.0 Gy for ovoids centers; and similar OAR doses for ring centers. CTV HR D 90% was 2.8 Gy higher, bladder D 2cm3 4.3 Gy lower, rectovaginal ICRU-point 4.8 Gy lower, and vagina 5-mm lateral-point 22.4 Gy higher for ring-IC/IS versus ovoids-IC/IS centers. The P values were <.002 for all comparisons. Equivalently, significant differences were derived from the multivariable analysis., Conclusions: T&R-IC applicators have better target dose and dose conformity than T&O-IC in this representative patient cohort. IC applicators fail to cover large target volumes, whereas routine application of IC/IS improves target and OAR dose considerably. Patients treated with T&R show a more favorable therapeutic ratio when evaluating target, bladder/rectum doses, and V85Gy. A comprehensive view on technique/applicators should furthermore include practical considerations and clinical outcome., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Deformable image registration (DIR) can be used to accumulate the absorbed dose distribution of daily image-guided adaptive external beam radiation treatment (EBRT) and brachytherapy (BT). Since dose-volume parameter addition assumes a uniform delivered EBRT dose around the planned BT boost, the added value of DIR over direct addition was investigated for dose accumulation in bladder and rectum., Material and Methods: For 10 patients (EBRT 46/46.2 Gy EQD2 , EBRT + BT: D 90 85-90 Gy EQD2 , in equivalent dose in 2 Gy fractions), the actually delivered dose from adaptive volumetric-modulated arc therapy (VMAT)/intensity-modulated radiotherapy (IMRT) EBRT was calculated using the daily anatomy from the cone-beam computed tomography (CBCT) scans acquired prior to irradiation. The CBCT of the first EBRT fraction and the BT planning MRI were registered using DIR. The cumulative dose to the 2 cm 3 with the highest dose (D 2cm3 ) from EBRT and BT to the bladder and rectum was calculated and compared to direct addition assuming a uniform EBRT dose (UD)., Results: Differences (DIR-UD) in the total EBRT + BT dose ranged between -0.2-3.9 Gy EQD2 (bladder) and -1.0-3.7 Gy EQD2 (rectum). The total EBRT + BT dose calculated with DIR was at most 104% of the dose calculated with the UD method., Conclusions: Differences between UD and DIR were small (< 3.9 Gy EQD2 ). The dose delivered with adaptive VMAT/IMRT EBRT to bladder and rectum near the planned BT boost can be considered uniform for the evaluation of bladder/rectum D 2cm3 ., Competing Interests: This work was funded by Elekta Brachytherapy. The department has a research collaboration with Elekta and Bel received grants from Elekta/Elekta Brachytherapy. Elekta Brachytherapy was not involved in the study design as well as in analysis, interpretation, and writing of the manuscript.

Purpose: To investigate the isodose surface volumes (ISVs) for 85, 75 and 60 Gy EQD2 for locally advanced cervix cancer patients., Materials and Methods: 1201 patients accrued in the EMBRACE I study were analysed. External beam radiotherapy (EBRT) with concomitant chemotherapy was followed by MR based image-guided adaptive brachytherapy (MR-IGABT). ISVs were calculated using a predictive model based on Total Reference Air Kerma and compared to Point A-standard loading systems. Influence of fractionation schemes and dose rates was evaluated through comparison of ISVs for α/β 10 Gy and 3 Gy., Results: Median V85 Gy , V75 Gy and V60 Gy EQD2 10 were 72 cm 3 , 100 cm 3 and 233 cm 3 , respectively. Median V85 Gy EQD2 10 was 23% smaller than in standard 85 Gy prescription to Point A. For small (<25 cm 3 ), intermediate (25-35 cm 3 ) and large (>35 cm 3 ) CTV HR volumes, the V85 Gy was 57 cm 3 , 70 cm 3 and 89 cm 3 , respectively. In 38% of EMBRACE patients the V85 Gy was similar to standard plans with 75-85 Gy to Point A. 41% of patients had V85 Gy smaller than standard plans receiving 75 Gy at Point A, while 21% of patients had V85 Gy larger than standard plans receiving 85 Gy at Point A., Conclusions: MR-IGABT and individualized dose prescription during EMBRACE I resulted in improved target dose coverage and decreased ISVs compared to standard plans used with classical Point A based brachytherapy. The ISVs depended strongly on CTV HR volume which demonstrates that dose adaptation was performed per individual tumour size and response during EBRT., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: Structure-based deformable image registration (DIR) can be used to calculate accumulated dose volume histogram parameters for cervical cancer brachytherapy (BT). The purpose of this study is to investigate dose warping uncertainties for the accumulated dose to the 2 cm 3 receiving the highest dose [Formula: see text] in the rectal wall, using a physically realistic model (PRM) describing rectal wall deformation., Methods and Materials: For 10 patients, treated with MRI-guided pulsed dose rate BT (two times 24 × 0.75 Gy, given in two applications BT1 and BT2), the planning images were registered with structure-based DIR. The resulting transformation vectors were used to accumulate the total rectum dose from BT. To investigate the dose warping uncertainty, a PRM describing rectal deformation was used. For point pairs on rectum BT1 and rectum BT2 that were at the same location according to the PRM, the dose for BT1 and BT2 was added (D PRM ) and compared to the DIR-accumulated dose (D DIR ) in the BT2 point. The remaining distance after DIR between corresponding point pairs, defined as the residual distance, was calculated., Results: For points within the [Formula: see text] volume, more than 75% was part of the [Formula: see text] volume according to both PRM and DIR. The absolute dose difference was <7.3 Gy EQD2 , and the median (95th percentile) of the residual distance was 8.7 (22) mm., Conclusions: DIR corresponded with the PRM for on average 75% of the [Formula: see text] volume. Local absolute dose differences and residual distances were large. Care should therefore be taken with DIR for dose-warping purposes in BT., (Copyright © 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To quantify magnetic resonance imaging (MRI) distortions on a plastic intracavitary/interstitial applicator with plastic needles at a field strength of 3 T and to determine the dosimetric impact, using patient data., Methods and Materials: For 11 cervical cancer patients, our clinical MRI protocol was extended with 3 scans. From the first scan, a multi-echo acquisition, a map of the magnetic field (B 0 ) was calculated and used to quantify the field inhomogeneity. The expected displacements of the applicator were quantified for the clinical sequence using the measured field inhomogeneity and the clinical sequence's bandwidth. The second and third scan were our routine clinical sequence (duration: <5 minutes each), acquired consecutively using opposing readout directions. The displacement of the applicator between these scans is approximately twice the displacement due to B 0 inhomogeneity. The impact of the displacement on the dose was determined by reconstructing the applicator on both scans. The applicator was then shifted and rotated the same distance as the observed displacement to create a worst-case scenario (ie, twice the actual displacement due to B 0 inhomogeneity). Next, the dose to 98%/90% (D 98 /D 90 ) of the clinical target volume at high risk, as well as the dose to the most irradiated 2 cm 3 for bladder and rectum, were calculated for the original plan as well as the shifted plan., Results: For a volume of interest containing the intrauterine device and the ovoids the 95th percentile of the absolute displacement ranged between 0.2 and 0.75 mm, over all patients. For all patients, the difference in D 98 /D 90 in the opposing readout scans with the original plan was at most 4.7%/4.3%. For the dose to the most irradiated 2 cm 3 of bladder/rectum, the difference was at most 6.0%/6.3%., Conclusions: The dosimetric impact of distortions on this plastic applicator with plastic needles is limited. Applicator reconstruction for brachytherapy planning purposes is feasible at 3 T MRI., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background and Purpose: Structure-based deformable image registration (DIR) can be used to calculate accumulated brachytherapy (BT) and external-beam radiation therapy (EBRT) dose-volume histogram (DVH) parameters in cervical cancer. Since direct parameter addition does not take dose non-uniformity into account, the added value of DIR over addition methods was investigated for bladder and rectum., Materials and Methods: For twelve patients (EBRT: 46Gy, EBRT+BT: D 90 85-90Gy EQD2 in equivalent dose in 2Gy fractions) the EBRT planning CT and BT planning MRI were registered using DIR. Affected lymph nodes, located far from the BT boost region, received an EBRT boost (9.2Gy) not contributing to the BT boost dose. Cumulative bladder/rectum D 2cm3 /D 1cm3 were calculated and compared to direct addition methods, assuming uniform EBRT doses (UD), or overlapping high dose volumes (OHD)., Results: Between the three methods, the maximum differences in the cumulative DVH parameters were 3.2Gy EQD2 (bladder) and 3.3Gy EQD2 (rectum). The difference between DIR and UD was <1.8Gy EQD2 for both organs., Conclusions: The UD method provides a better estimate of D 2cm3 /D 1cm3 than the OHD method. There is no added value of DIR since differences with direct addition methods are clinically insignificant. EBRT dose distributions can be considered uniform in bladder and rectum for the evaluated dose parameters., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: Graphical optimization (GrO) is a common method for high-dose-rate/pulsed-dose-rate (PDR) prostate brachytherapy treatment planning. New methods performing inverse optimization of the dose distribution have been developed over the past years. The purpose is to compare GrO and two established inverse methods, inverse planning simulated annealing (IPSA) and hybrid inverse treatment planning and optimization (HIPO), and one new method, enhanced geometric optimization-interactive inverse planning (EGO-IIP), in terms of speed and dose-volume histogram (DVH) parameters., Methods and Materials: For 26 prostate cancer patients treated with a PDR brachytherapy boost, an experienced treatment planner optimized the dose distributions using four different methods: GrO, IPSA, HIPO, and EGO-IIP. Relevant DVH parameters (prostate-V100%, D90%, V150%; urethra-D(0.1cm3) and D(1.0cm3); rectum-D(0.1cm3) and D(2.0cm3); bladder-D(2.0cm3)) were evaluated and their compliance to the constraints. Treatment planning time was also recorded., Results: All inverse methods resulted in shorter planning time (mean, 4-6.7 min), as compared with GrO (mean, 7.6 min). In terms of DVH parameters, none of the inverse methods outperformed the others. However, all inverse methods improved on compliance to the planning constraints as compared with GrO. On average, EGO-IIP and GrO resulted in highest D90%, and the IPSA plans resulted in lowest bladder D2.0cm3 and urethra D(1.0cm3)., Conclusions: Inverse planning methods decrease planning time as compared with GrO for PDR/high-dose-rate prostate brachytherapy. DVH parameters are comparable for all methods., (Copyright © 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: Dose optimization for stepping source brachytherapy can nowadays be performed using automated inverse algorithms. Although much quicker than graphical optimization, an experienced treatment planner is required for both methods. With automated inverse algorithms, the procedure to achieve the desired dose distribution is often based on trial-and-error., Methods: A new approach for stepping source prostate brachytherapy treatment planning was developed as a quick and user-friendly alternative. This approach consists of the combined use of two novel tools: Enhanced geometrical optimization (EGO) and interactive inverse planning (IIP). EGO is an extended version of the common geometrical optimization method and is applied to create a dose distribution as homogeneous as possible. With the second tool, IIP, this dose distribution is tailored to a specific patient anatomy by interactively changing the highest and lowest dose on the contours., Results: The combined use of EGO-IIP was evaluated on 24 prostate cancer patients, by having an inexperienced user create treatment plans, compliant to clinical dose objectives. This user was able to create dose plans of 24 patients in an average time of 4.4 min/patient. An experienced treatment planner without extensive training in EGO-IIP also created 24 plans. The resulting dose-volume histogram parameters were comparable to the clinical plans and showed high conformance to clinical standards., Conclusions: Even for an inexperienced user, treatment planning with EGO-IIP for stepping source prostate brachytherapy is feasible as an alternative to current optimization algorithms, offering speed, simplicity for the user, and local control of the dose levels.

Pulsed dose rate (PDR) brachytherapy is a treatment modality that combines physical advantages of high dose rate (HDR) brachytherapy with the radiobiological advantages of low dose rate brachytherapy. The aim of this review was to describe the effective clinical use of PDR brachytherapy worldwide in different tumour locations. We found 66 articles reporting on clinical PDR brachytherapy including the treatment procedure and outcome. Moreover, PDR brachytherapy has been applied in almost all tumour sites for which brachytherapy is indicated and with good local control and low toxicity. The main advantage of PDR is, because of the small pulse sizes used, the ability to spare normal tissue. In certain cases, HDR resembles PDR brachytherapy by the use of multifractionated low-fraction dose.

Background: In pulsed-dose rate prostate brachytherapy the dose is delivered during 48 hours after implantation, making the treatment sensitive to oedematic effects possibly affecting dose delivery. The aim was to study changes in prostate volume during treatment by analysing catheter configurations on three subsequent scans., Methods: Prostate expansion was determined for 19 patients from the change in spatial distribution of the implanted catheters, using three CT-scans: a planning CT (CT1) and two CTs after 24 and 48 hours (CT2, CT3). An additional 4 patients only received one repeat CT (after 24 hours). The mean radial distance (MRD) of all dwell positions to the geometric centre of all dwell positions used was calculated to evaluate volume changes. From three implanted markers changes in inter-marker distances were assessed. The relative shifts of all dwell positions were determined using catheter- and marker-based registrations. Wilcoxon signed-rank tests were performed to compare the results from the different time points., Results: The MRDs measured on the two repeat CTs were significantly different from CT1. The mean prostate volume change derived from the difference in MRD was +4.3% (range -9.3% to +15.6%) for CT1-CT2 (p < .05) and +4.4% (range -7.5% to +16.3%) for CT1-CT3 (p < .05). These values represented a mean increase of 1.2 cm(3) in the first 24 hours and 1.5 cm(3) in the subsequent 24 hours. There was no clear sign of prostate expansion from the change in inter-marker distance (CT1-CT2: 0.2 ± 1.8 mm; CT1-CT3: 0.6 ± 2.2 mm). Catheter configuration remained stable; shifts in catheter positions were largest in the C-C direction: 0 ± 1.8 mm for CT1-CT2 and 0 ± 1.4 mm for CT2-CT3., Conclusions: The volume changes derived from catheter displacements were small and therefore considered clinically insignificant. Implant configuration remains stable during 2 days of treatment, confirming the safety of this technique.

Background: Due to improved visibility on MRI, contouring of the prostate is improved compared to CT. The aim of this study was to quantify the benefits of using MRI for treatment planning as compared to CT-based planning for temporary implant prostate brachytherapy., Material and Methods: CT and MRI image data of 13 patients were used to delineate the prostate and organs at risk (OARs) and to reconstruct the implanted catheters (typically 12). An experienced treatment planner created plans on the CT-based structure sets (CT-plan) and on the MRI-based structure sets (MRI-plan). Then, active dwell-positions and weights of the CT-plans were transferred to the MRI-based structure sets (CT-plan(MRI-contours)) and resulting dosimetric parameters and tumour control probabilities (TCPs) were studied., Results: For the CT-plan(MRI-contours) a statistically significant lower target coverage was detected: mean V100 was 95.1% as opposed to 98.3% for the original plans (p < 0.01). Planning on CT caused cold-spots that influence the TCP. MRI-based planning improved the TCPs by 6-10%, depending on the parameters of the radiobiological model used for TCP calculation. Basing the treatment plan on either CT- or MRI-delineations does not influence plan quality., Conclusion: Evaluation of CT-based treatment planning by transferring the plan to MRI reveals underdosage of the prostate, especially at the base side. Planning on MRI can prevent cold-spots in the tumour and improves the TCP.

Background and Purpose: To determine the uncertainties in planned dose associated with catheter and organ movement during 48 hours of stepping source prostate brachytherapy., Material and Methods: Pulsed-dose rate (PDR) prostate brachytherapy as a boost is given in 24 pulses every 2 hours, making the total treatment last 48 hours. The entire treatment is based on one plan, created on the planning CT (CT1). Two follow-up CTs (CT2 and CT3) were acquired; halfway through the treatment and at the end of treatment. On these repeat scans the catheters were reconstructed and PTV and OARs were delineated. The original treatment plan was calculated on the repeat CTs. Target coverage V(100%), D(90), dose to 2cm(3) (D2cm(3)) of the rectum and bladder and dose to 0.1cm(3) of the urethra were recorded from the recalculated DVHs., Results: On the two repeat CTs the V100% decreased -1.5% and -2.3% as compared to the planning CT. For the rectum D2cm(3), the average increase was 14.8% (CT1-CT2) and 17.3% (CT1-CT3). Increase in bladder D2cm(3) was on average 23.1% (CT1-CT2) and 24.8% (CT1-CT3). For the urethra D0.1cm(3) an average decrease of -2% (CT1-CT2) and -3.2% (CT2-CT3) was observed., Conclusions: Changes in target coverage during treatment were small and considered clinically irrelevant. However, an overall increase in dose to the OARs was found as compared to the planned dose, which should be taken into account during treatment planning., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To investigate whether a longer sagittal view and less movement using a dual sagittal crystal probe (DSCP) for trans rectal ultra sound (TRUS) allow for more accurate online-planning in I-125 permanent implant brachytherapy of the prostate, compared to a single sagittal crystal probe (SSCP)., Material and Methods: Between March 2008 and March 2010, 50 patients with prostate cancer were consecutively included in the study. The first 25 of these patients had both their pre- and online-planning based on a single sagittal crystal probe (SSCP). The treatment-plans of the other 25 patients were based on a DSCP TRUS. Three weeks after implantation a post-planning was made based on CT. TRUS online and CT post-plan dose-volume histogram (DVH) parameters, D(90) and V(100), were compared for both groups. Also, the post-plan DVH parameters of SSCP were compared to DSCP. The possible factors that might influence the post-plan D(90) and V(100) were analysed using Analysis of Variance (ANOVA)., Results: SSCP and DSCP online mean D(90) and V(100) were significantly larger than post-plan mean D(90) and V(100) (P < 0.01). The post-plan mean D(90) and mean V(100) were both non-significantly larger for SSCP based post-plans compared to DSCP based post plans (P = 0.76 and P = 0.68). ANOVA showed significant impact of prostate volume on the post-plan D(90) and V(100)., Conclusions: The advantages of the dual sagittal crystal probe did not lead to more accurate online planning by investigating DVH-parameters. The only factor found to have influence on the DVH-parameters was the prostate volume.

Purpose: To investigate the development of gastrointestinal (GI) toxicity, genitourinary (GU) toxicity, erectile dysfunction, and International Prostate Symptom Score (IPSS) resolution in a cohort of patients treated with external-beam radiotherapy (EBRT) followed by a brachytherapy pulsed dose rate (PDR) boost., Methods and Materials: Between 2002 and 2008, 110 patients were treated with 46-Gy EBRT followed by PDR brachytherapy (24.96-28.80 Gy). The investigated outcome variables, GI toxicity, GU toxicity, erectile dysfunction, and IPSS were prospectively scored at several time points during follow-up. Association between time (as continuous and categorical variable) and the outcome variables was assessed using generalized linear models., Results: No statistically significant association was found between time (continuous) and GI toxicity (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.89-1.06), GU toxicity (OR, 0.97; 95% CI, 0.91-1.03), erectile dysfunction (OR, 1.06; 95% CI, 0.99-1.11), and IPSS (-0.11; 95% CI, -0.41-0.20). Also, no statistically significant association was found between these variables and time as a categorical variable. GU toxicity was associated with IPSS resolution (OR, 1.16; 95% CI, 1.09-1.24). Posttreatment IPSS was associated with pretreatment IPSS (0.52; 95% CI, 0.25-0.79)., Conclusions: No accumulation of high-grade toxicity over time could be established for a group of patients treated with EBRT and PDR brachytherapy for prostate cancer, probably because high-grade late toxicity resolves with time. Also, differences in IPSS values among patients are smaller after treatment than before treatment., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To evaluate treatment outcome of pulsed dose-rate brachytherapy (PDR) combined with external-beam radiotherapy (EBRT) for the treatment of prostate cancer., Methods and Materials: Between 2002 and 2007, 106 patients were treated by EBRT combined with PDR and followed prospectively. Two, 38, and 66 patients were classified as low-, intermediate-, and high-risk disease respectively according to the National Comprehensive Cancer Network criteria. EBRT dose was 46 Gy in 2.0-Gy fractions. PDR dose was increased stepwise from 24.96 to 28.80 Gy. Biochemical disease free survival and overall survival were determined by the Kaplan-Meier method. Cumulative incidence of late gastrointestinal (GI) and genitourinary (GU) toxicity were scored, according to the Common Terminology Criteria for Adverse Events., Results: The 3- and 5-year biochemical nonevidence of disease (bNED) were 92.8% (95% confidence interval [CI], 87.1-98.5) and 89.5% (95% CI, 85.2-93.8), respectively. Overall survival at 3 and 5 years was 99% (95% CI, 96-100) and 96% (95% CI, 90-100), respectively. The 3- and 5-year Grade 2 GI toxicity was 5.3% (95% CI, 0-10.6) and 12.0% (95% CI, 1.4-22.6), respectively. No Grade 3 or higher GI toxicity was observed. The 3- and 5-year Grade 2 or higher GU toxicity was 18.7% (95% CI, 10.3-27.1) and 26.9% (95% CI, 15.1-38.7), respectively., Conclusion: Results on tumor control and late toxicity of EBRT combined with PDR are good and comparable to results obtained with EBRT combined with high-dose-rate brachytherapy for the treatment of prostate cancer., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Introduction: Rhabdomyosarcomas in the orbit form a major challenge in terms of cure without severe side effects in childhood cancer. Our specifically developed approach consists of applying brachytherapy to the tumor area using a mold. Analysis of its results for 20 patients was performed., Methods and Materials: Thirteen patients were referred for brachytherapy if complete remission was not reached after chemotherapy (Group I) and 7 in case of relapse (Group II). In total, 20 patients were treated between 1991 and 2007. Four were female and 16 male; their ages varied from 1.1 to 16.5 years, with an average of 8.5 years. After macroscopically radical tumor resection, molds with holes drilled to hold flexible catheters were placed into the orbit. The dose to the clinical target volume was 40-50 Gy., Results: Three patients of Group I and 1 patient of Group II developed local recurrence and underwent exenteration. The progression-free survival in Group I is 71.9% (95% CI 0.44-1.0), in Group II 85.7% (95% CI 0.60-1.0), the overall 5-year survival rate of the entire group is 92% (95% CI 0.76-1.0). During treatment, no serious side effects were observed. The late complications encountered in this series were cataract in 2 patients, 1 of whom also developed mild retinopathy. Two patients with ptosis needed surgical correction. No facial asymmetries or bone growth anomalies were observed., Conclusions: This entire procedure of brachytherapy with a mold offers a tailor-made treatment for orbital rhabdomyosarcomas with only few signs of late toxicity., (Copyright 2010 Elsevier Inc. All rights reserved.)

Purpose: A multidisciplinary approach, consisting of consecutive Ablative Surgery, MOld technique with afterloading brachytherapy and immediate surgical REconstruction (AMORE) applied after chemotherapy, was designed for children with rhabdomyosarcoma in the head-and-neck region. Analysis of the first 42 patients was performed., Methods and Materials: After macroscopically radical tumor resection, molds were constructed for each individual to fit into the surgical defect. The molds, made of 5-mm-thick layers of thermoplastic rubber, consisted of different parts. Flexible catheters were positioned between layers. After brachytherapy, the molds were removed. Surgical reconstruction was performed during the same procedure., Results: Dose to the clinical target volume varied from 40 to 50 Gy for the primary treatment (31 patients) and salvage treatment groups (11 patients). There were 18 females and 24 males treated from 1993 until 2007. Twenty-nine tumors were located in the parameningeal region, and 13 were located in the nonparameningeal region. Patient age at the time of AMORE was 1.2-16.9 years (average, 6.5 years). Follow-up was 0.2-14.5 years (average, >5.5 years). Eleven patients died, 3 with local recurrence only, 6 with local and distant disease, 1 died of distant metastases only, and 1 patient died of a second primary tumor. Overall 5-year survival rates were 70% for the primary treatment group and 82% for the salvage group. Treatment was well tolerated, and acute and late toxicity were mild., Conclusions: The AMORE protocol yields good local control and overall survival rates, and side effects are acceptable.

Purpose: To determine the safety of pulsed-dose-rate (PDR) brachytherapy by analyzing errors and technical failures during treatment., Methods and Materials: More than 1,300 patients underwent treatment with PDR brachytherapy, using five PDR remote afterloaders. Most patients were treated with consecutive pulse schemes, also outside regular office hours. Tumors were located in the breast, esophagus, prostate, bladder, gynecology, anus/rectum, orbit, head/neck, with a miscellaneous group of small numbers, such as the lip, nose, and bile duct. Errors and technical failures were analyzed for 1,300 treatment sessions, for which nearly 20,000 pulses were delivered. For each tumor localization, the number and type of occurring errors were determined, as were which localizations were more error prone than others., Results: By routinely using the built-in dummy check source, only 0.2% of all pulses showed an error during the phase of the pulse when the active source was outside the afterloader. Localizations treated using flexible catheters had greater error frequencies than those treated with straight needles or rigid applicators. Disturbed pulse frequencies were in the range of 0.6% for the anus/rectum on a classic version 1 afterloader to 14.9% for orbital tumors using a version 2 afterloader. Exceeding the planned overall treatment time by >10% was observed in only 1% of all treatments. Patients received their dose as originally planned in 98% of all treatments., Conclusions: According to the experience in our institute with 1,300 PDR treatments, we found that PDR is a safe brachytherapy treatment modality, both during and outside of office hours.

Purpose: To evaluate the long-term, local relapse-free, distant metastasis-free, and overall survival rates in patients with a solitary bladder tumor <5 cm in diameter who were treated with external beam radiotherapy, limited surgery, and brachytherapy., Methods and Materials: The results of 122 patients after bladder-saving treatment were analyzed. After EBRT, the patients underwent cystotomy, and catheters were implanted. Of the 122 patients, 99 were treated with a continuous low-dose-rate technique and 23 patients with a pulsed-dose-rate technique. The median follow-up period was 5 years., Results: The 5-year local and distant relapse-free survival rate was 76% and 83%, respectively. The 5 and 10-year relapse-free survival rate was 69% and 66%, respectively. For overall survival, the corresponding rates were 73% and 49%. Toxicity was low. No differences were found between the continuous low-dose-rate and pulsed-dose-rate groups., Conclusion: The results of our study have shown that external beam radiotherapy followed by brachytherapy as a bladder-saving treatment for a selected group of patients with bladder cancer yields excellent local tumor control and low toxicity.

Background: High-dose radiotherapy is standard treatment for patients with brain cancer. However, in preclinical research external beam radiotherapy is limited to heterotopic murine models- high-dose radiotherapy to the murine head is fatal due to radiation toxicity. Therefore, we developed a stereotactic brachytherapy mouse model for high-dose focal irradiation of experimental intracerebral (orthotopic) brain tumors., Methods: Twenty-one nude mice received a hollow guide-screw implanted in the skull. After three weeks, 5 x 105 U251-NG2 human glioblastoma cells were injected. Five days later, a 2 mCi iodine-125 brachytherapy seed was inserted through the guide-screw in 11 randomly selected mice; 10 mice received a sham seed. Mice were euthanized when severe neurological or physical symptoms occurred. The cumulative irradiation dose 5 mm below the active iodine-125 seeds was 23.0 Gy after 13 weeks (BEDtumor = 30.6 Gy)., Results: In the sham group, 9/10 animals (90%) showed signs of lethal tumor progression within 6 weeks. In the experimental group, 2/11 mice (18%) died of tumor progression within 13 weeks. Acute side effects in terms of weight loss or neurological symptoms were not observed in the irradiated animals., Conclusion: The intracerebral implantation of an iodine-125 brachytherapy seed through a stereotactic guide-screw in the skull of mice with implanted brain tumors resulted in a significantly prolonged survival, caused by high-dose irradiation of the brain tumor that is biologically comparable to high-dose fractionated radiotherapy- without fatal irradiation toxicity. This is an excellent mouse model for testing orthotopic brain tumor therapies in combination with radiation therapy.

Background: Results of high-dose chemo-radiotherapy (CRT), using the treatment schedules of EORTC study 08972/22973 or radiotherapy (RT) alone were analyzed among all patients (pts) with Non Small Cell Lung Cancer (NSCLC) treated with curative intent in our department from 1995-2004., Material: Included are 131 pts with medically inoperable or with irresectable NSCLC (TNM stage I:15 pts, IIB:15 pts, IIIA:57 pts, IIIB:43 pts, X:1 pt)., Treatment: Group I: Concomitant CRT: 66 Gy/2.75 Gy/24 fractions (fx)/33 days combined with daily administration of cisplatin 6 mg/m(2): 56 pts (standard).Group II: Sequential CRT: two courses of a 21-day schedule of chemotherapy (gemcitabin 1250 mg/m(2) d1, cisplatin 75 mg/m2 d2) followed by 66 Gy/2.75 Gy/24 fx/33 days without daily cisplatin: 26 pts.Group III: RT: 66 Gy/2.75 Gy/24 fx/33 days or 60 Gy/3 Gy/20 fx/26 days: 49 pts., Results: The 1, 2, and 5 year actuarial overall survival (OS) were 46%, 24%, and 15%, respectively.At multivariate analysis the only factor with a significantly positive influence on OS was treatment with chemo-radiation (P = 0.024) (1-, 2-, and 5-yr OS 56%, 30% and 22% respectively). The incidence of local recurrence was 36%, the incidence of distant metastases 46%.Late complications grade 3 were seen in 21 pts and grade 4 in 4 patients. One patient had a lethal complication (oesophageal). For 32 patients insufficient data were available to assess late complications., Conclusion: In this study we were able to reproduce the results of EORTC trial 08972/22973 in a non-selected patient population outside of the setting of a randomised trial. Radiotherapy (66 Gy/24 fx/33 days) combined with either concomitant daily low dose cisplatin or with two neo-adjuvant courses of gemcitabin and cisplatin are effective treatments for patients with locally advanced Non-Small Cell Lung Cancer. The concomitant schedule is also suitable for elderly people with co-morbidity.

Catheters were developed that can be fixed in the prostate gland by self-expanding parts for use in PDR brachytherapy. Daily CT-scans were made to investigate the magnitude of catheter displacement. The mean absolute displacement during the 3 day treatment was 1.2 mm. The resulting minor alterations in dose-volume parameters were of no clinical importance.

Purpose: To evaluate the feasibility and efficacy of a concomitant partial bladder boost schedule in radiotherapy for invasive bladder cancer, coupling a limited boost volume with shortening of the overall treatment time., Methods and Materials: Between 1994 and 1999, 50 patients with a T2-T4 N0M0 transitional cell carcinoma of the bladder received radiotherapy delivered in a short overall treatment time with a concomitant boost technique. With this technique a dose of 40 Gy in 2-Gy fractions was administered to the small pelvis with a concomitant boost limited to the bladder tumor area plus margin of 15 Gy in fractions of 0.75 Gy. The total tumor dose was 55 Gy in 20 fractions in 4 weeks. Toxicity was scored according to EORTC/RTOG toxicity criteria., Results: The feasibility of the treatment was good. Severe acute toxicity >/=G3 was observed in seven patients (14%). Severe late toxicity >/=G3 was observed in six patients (13%). Thirty-seven patients (74%) showed a complete and five (10 %) a partial remission after treatment. The actuarial 3-year freedom of local progression was 55%., Conclusion: In external radiotherapy for muscle invasive bladder cancer a concomitant boost technique coupling a partial bladder boost with shortening of the overall treatment time provides a high probability of local control with acceptable toxicity.

Purpose: To assess the spatial variability of a bladder tumor relative to the planning target volume boundaries during radical radiotherapy, and furthermore to develop strategies to reduce spatial variability., Methods and Materials: Seventeen patients with solitary T2-T4N0M0 bladder cancer were treated with a technique delivering 40 Gy/2 Gy in 20 fractions to the whole bladder with a concomitant boost to the bladder tumor of 20 Gy in 1 Gy fractions in an overall time of 4 weeks. CT scans were made weekly, immediately after treatment, and matched with the planning CT scan. Spatial variability of the tumor, as well as bladder volume and rectal diameter, were scored for each patient each week., Results: In 65% of patients, a part of the tumor appeared outside the planning target volume boundaries at least one time during the course of radiotherapy. No consistent relation of this variability with time was found. Bladder volumes and rectal diameters showed marked variability during the course of treatment. A large initial bladder volume and rectal diameter predicted a large volume variation and a large tumor spatial variability., Conclusion: In this study, a margin of 1.5 to 2 cm seemed to be inadequate in 65% of the patients with respect to spatial variability. Bladder volume and rectal diameter were found to be predictive for spatial variability of a bladder tumor during concomitant boost radiotherapy.

Background and Purpose: Radiobiological studies suggest equivalent biological effects between continuous low dose rate brachytherapy (CLDR) and pulsed brachytherapy (PB) when pulses are applied without interruption every hour. However, radiation protection and institute-specific demands requested the design of a practical PB protocol substituting the CLDR boost in breast cancer patients. An office hours scheme was designed, considering the CLDR dose rate, the overall treatment time, pulse frequency and tissue repair characteristics. Radiobiological details are presented as well as the logistics and technical feasibility of the scheme after treatment of the first 100 patients., Materials and Methods: Biologically effective doses (BEDs) were calculated according to the linear quadratic model for incomplete repair. Radiobiological parameters included an alpha/beta value of 3 Gy for normal tissue late effects and 10 Gy for early normal tissue or tumour effects. Tissue repair half-time ranged from 0.1 to 6 h. The reference CLDR dose rate of 0.80 Gy/h was obtained retrospectively from analysis of patients' data. The treatment procedure was evaluated with regard to variations in implant characteristics after treatment of 100 patients., Results: A PB protocol was designed consisting of two treatment blocks separated by a night break. Dose delivery in PB was 20 Gy in two 10 Gy blocks and, for application of the 15 Gy boost, one 10 Gy block plus one 5 Gy block. The dose per pulse was 1.67 Gy, applied with a period time of approximately 1.5 h. An inter-patient variation of 30% (1 SD) was observed in the instantaneous source strength. Taking also the spread in implant size into account, the net variation in pulse duration amounted to 38%., Conclusion: An office hours PB boost regimen was designed for substitution of the CLDR boost in breast-conserving therapy on the basis of the BED. First treatment experience shows the office hour regimen to be convenient to the patients and no technical perturbations were encountered.

Background and Purpose: To analyze the treatment results of transperineal (125)Iodine seeds in localized prostate cancer., Patients and Methods: Between 1985 and 1996, 102 patients with T1-T2 N0 prostate cancer were treated with transperineal (125)Iodine seed implants at the Academic Medical Centre in Amsterdam. Tumours were classified as T1c in four patients, T2a in 73 patients and T2b in 25 patients. The mean pre-treatment PSA was 17 ng/ml. The (125)Iodine seeds were implanted transperineally under transrectal ultrasound guidance. The mean prostate volume was 31 ml (range 15-48 ml). An average of 49 seeds (range 29-74) was implanted. The dose to the periphery of the prostate was 160 Gy. Until 1988, 27 patients had additional external pelvic irradiation to a dose of 40 Gy in 20 daily fractions of 2 Gy., Results: The 5- and 7-year actuarial survival rates were 77 and 63%, respectively (median 102 months). Ten patients (9.5%) died from prostate cancer. The 5- and 7-year clinical progression rates were 12 and 17%, respectively. Biochemical failure rates at 5 and 7 years were 39 and 44%, respectively. Age, alkaline phosphatase, creatinine, differentiation grade, additional treatment, staging procedure, number of seeds, prostate volume, treatment period and PSA were analyzed as prognostic factors. Only pre-treatment PSA was a prognosticator of clinical and biochemical outcome but not of survival. Biochemical control at 6 years varied from 30% for pre-treatment PSA values higher than 20 ng/ml to 95% for values < or =8 ng/ml. Forty-one out of 49 patients who were sexually active before brachytherapy maintained sexual function during the follow-up. Complete urinary incontinence occurred in one patient. No rectal complications were seen in patients receiving brachytherapy alone., Conclusions: Transperineal (125)Iodine seeds brachytherapy in localized prostate cancer achieves a good clinical control and overall survival with acceptable late toxicity. Biochemical failure was strongly correlated to the pre-treatment PSA value.

The objective of the dynamic radiotherapy project 'Dynarad' within the European Community has been to compare and grade treatment techniques that are currently applied or being developed at the participating institutions. Cervical cancer was selected as the tumour site on the grounds that the involved organs at risk, mainly the rectum and the bladder, are very close to the tumour and partly located inside the internal target volume. In this work, a solid phantom simulating the pelvic anatomy was used by institutions in Belgium, France, Greece, Holland, Italy, Sweden and the United Kingdom. The results were evaluated using both biological and physical criteria. The main purpose of this parallel evaluation is to test the value of biological and physical evaluations in comparing treatment techniques. It is demonstrated that the biological objective functions allow a much higher conformality and a more clinically relevant scoring of the outcome. Often external beam treatment techniques have to be combined with intracavitary therapy to give clinically acceptable results. However, recent developments can reduce or even eliminate this need by delivering more conformal dose distributions using intensity modulated external dose delivery. In these cases the reliability of the patient set-up procedure becomes critical for the effectiveness of the treatment.

Purpose: Investigation of normal tissue sparing in pulsed brachytherapy (PB) relative to continuous low-dose rate irradiation (CLDR) by adjusting pulse frequency based on tissue repair characteristics., Method: Using the linear quadratic model, the relative effectiveness (RE) of a 20 Gy boost was calculated for tissue with an alpha/beta ratio ranging from 2 to 10 Gy and a half-time of sublethal damage repair between 0.1 and 3 h. The boost dose was considered to be delivered either in a number of pulses varying from 2 to 25, or continuously at a dose rate of 0.50, 0.80, or 1.20 Gy/h., Results: The RE of 20 Gy was found to be identical for PB in 25 pulses of 0.80 Gy each h and CLDR delivered at 0.80 Gy/h for any alpha/beta value and for a repair half-time > 0.75 h. When normal tissue repair half-times are assumed to be longer than tumor repair half-times, normal tissue sparing can be obtained, within the restriction of a fixed overall treatment time, with higher dose per pulse and longer period time (time elapsed between start of pulse n and start of pulse n + 1). An optimum relative normal tissue sparing larger than 10% was found with 4 pulses of 5 Gy every 8 h. Hence, a therapeutic gain might be obtained when changing from CLDR to PB by adjusting the physical dose in such a way that the biological dose on the tumor is maintained. The normal tissue-sparing phenomenon can be explained by an increase in RE with longer period time for tissue with high alpha/beta ratio and fast or intermediate repair half-time, and the RE for tissue with low alpha/beta ratio and long repair half-time remains almost constant., Conclusion: Within the benchmark of the LQ model, advantage in normal tissue-sparing is expected when matching the pulse frequency to the repair kinetics of the normal tissue exposed. A period time longer than 1 h may lead to a reduction of late normal tissue complications. This theoretical advantage emphasizes the need for better knowledge of human tissue-repair kinetics.

Purpose: Investigation of the effects of hyperthermia on the radiation response of rat lumbosacral spinal cord with respect to: (a) incidence of paralysis, (b) latency, (c) histopathology, and (d) tumor induction., Methods and Materials: Rat lumbosacral spinal cord with the cauda equina was single-dose irradiated with 15 to 32 Gy of x-rays. Hyperthermia for 30 min at a spinal cord temperature of 41.1, 42.3, and 42.6 +/- 0.4 degrees C was applied 5 to 10 min after irradiation by means of a 434 MHz microwave applicator. Animals were observed for 21 months while recording myelopathy and development of tumors., Results: The latent period for hind leg paralysis decreased with increasing radiation dose from 359 +/- 31 days (n = 9) after 20 Gy to 200 +/- 4 days (n = 5) after 32 Gy. Hyperthermia enhanced the radiation response of the lumbosacral spinal cord as evidenced by shortening of the latent period for paralysis and a decrease in the biological effective dose. After 20 Gy followed by 30 min 41.1 degrees C, latency was diminished to 214 +/- 16 days (n = 7, p < 0.001 vs. 20 Gy alone). The ED50 was 21.1 Gy, which was diminished to values between 16 and 17 Gy if radiation was followed by hyperthermia, giving a thermal enhancement ratio between 1.24 and 1.32. Histopathological examination of the spinal cord after combined treatment of x-rays and hyperthermia showed necrosis of nerve roots. Irradiation with 16, 20, 24, and 28 Gy (n = 77) alone led to tumor induction in 17 +/- 8% of the animals (pooled data). If followed by hyperthermia (n = 96), it was increased to 33 +/- 12% (p < 0.01). Most tumors induced by radiation and hyperthermia were sarcomas., Conclusion: First, the radiation response of rat lumbosacral spinal cord was enhanced by heat. Second, latency for paralysis was shortened in the lower dose range. Third, no difference in pathology between x-rays alone or in combination with hyperthermia. Fourth, hyperthermia did increase radiation carcinogenesis.

Treatment of localized prostate cancer by ultrasonically guided transperineal 125I implantation, in contrast to open 125I implantation, may allow for ideal distribution of the seeds and may therefore lead to better treatment results. 46 patients with localized prostatic carcinoma (T1-T2, G1-G3, N0, M0) have been treated since 1985, using this new technique. The longest follow-up is 64 months (median 30 months). The irradiation implantation dose to the prostate was 160 Gy. Assessed by ultrasonography an average prostate volume reduction of 20% was achieved at 6 months, increasing to 24% at 12 months, 39% at 24 months and 56% at 48 months. To evaluate response of the primary tumor systematic ultrasonically guided needle biopsies from the previous malignant prostate areas were performed in all patients every 6 months during follow-up. Tumor-negative biopsies were obtained in 33% of patients at 12 months, 40% at 24 months, progressively increasing to 50% at 48 months. Three patients developed distant metastases, and 6 died, of whom 1 patient due to prostate cancer. Morbidity from implantation has been low and the erectile function was preserved in all patients at 12 months postimplantation. The high percentage of tumor-positive biopsies during follow-up indicates that this technique fails to cure a significant proportion of patients.

A computer program was developed to calculate both integral absorbed dose in a water phantom and entrance exposure, for the imaging of iodine contrast with x-ray intensifying screens. The effect of filtration of the x-ray beam on integral absorbed dose and entrance exposure was studied for 27 different filter materials and four types of intensifying screens. The dose and exposure were calculated, keeping the image contrast and energy absorption in the screens constant. To check the validity of the calculations, a number of measurements were performed, the results of which agreed well with our calculations. A remarkable result is that dose and exposure reduction can be achieved almost equally well with conventional filters (aluminum and copper) as with a number of K-edge filters. This was found for situations commonly encountered in diagnostic radiology (60-80 kV, 20 cm water). This finding is in contrast to a number of earlier studies, in which K-edge filters were found to be superior to conventional filters.

When the power spectrum of radiographic noise is estimated from scans obtained with a microdensitometer equipped with a rectangular slit, a bias is present due to the finite length of this slit. A method to correct for this bias was developed and was tested on both a simulated and a measured spectrum. No bias remains with our method, in situations where a conventional method shows a significantly biased result. Good agreement was found with the synthesized slit method, described by Sandrik and Wagner.

The energy dependence of the luminance ratio due to scattered and primary radiation has been determined for four types of X-ray intensifying screens. A water phantom of 30 cm X 30 cm X 20 cm was used as the scattering medium. Ten narrow band X-ray spectra were used as incident radiation: the mean energies of these spectra ranged from 28 to 84 keV. Using the monoenergetic data, results were calculated for broad spectra and compared with measured results for broad spectra. For tube voltages up to 50 kV the calculated results agreed well with the measured results: for higher tube voltages a small difference occurred.