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Background and purpose Recently, a vaginal dose reporting method for combined EBRT and BT in cervical cancer patients was proposed. The current study was to evaluate vaginal doses with this method in a multicentre setting, wherein different applicators, dose rates and protocols were used. Material and methods In a subset of patients from the EMBRACE study, vaginal doses were evaluated. Doses at the applicator surface left/right and anterior/posterior and at 5 mm depth were measured. In addition, the dose at the Posterior–Inferior Border of Symphysis (PIBS) vaginal dose point and PIBS±2 cm, corresponding to the mid and lower vagina, was measured. Results 153 patients from seven institutions were included. Large dose variations expressed in EQD2 with α/β = 3 Gy were seen between patients, in particular at the top left and right vaginal wall (median 195 (range 61–947) Gy/178 (61–980) Gy, respectively). At 5 mm depth, doses were 98 (55–212) Gy/91 (54–227) Gy left/right, and 71 (51–145) Gy/67 (49–189) Gy anterior/posterior, respectively. The dose at PIBS and PIBS±2 cm was 41 (3–81) Gy, 54 (32–109) Gy and 5 (1–51) Gy, respectively. At PIBS+2 cm (mid vagina) dose variation was coming from BT. The variation at PIBS−2 cm (lower vagina) was mainly dependent on EBRT field border location. Conclusions This novel method for reporting vaginal doses coming from EBRT and BT through well-defined dose points gives a robust representation of the dose along the vaginal axis. In addition, it allows comparison of vaginal dose between patients from different centres. The doses at the PIBS points represent the doses at the mid and lower parts of the vagina. Large variations in dose throughout the vagina were observed between patients and centres. [ABSTRACT FROM AUTHOR]

Dosimetric intra-fraction uncertainties in MRI-guided brachytherapy were analysed for HR-CTV and OARs. While dose differences were generally small, individual outliers occurred. In contrast to HDR, patients treated with PDR show increased mean rectal dose over time. Re-imaging prior to dose delivery helps to detect unfavorable anatomical changes, and allows for intervention. [ABSTRACT FROM AUTHOR]

Purpose: The goal of this study was to determine the dose contributions from image guided adaptive brachytherapy (IGABT) to individual suspicious pelvic lymph nodes (pLNN) in cervical cancer patients. Data were collected in two cancer centers, University of Pittsburgh Cancer Institute (UPCI) and University Medical Center Utrecht (UMCU). Material and methods: 27 and 15 patients with node positive cervical cancer treated with HDR (high dose rate) or PDR (pulsed dose rate)-IGABT were analyzed. HDR-IGABT (UPCI) was delivered with CT/MRI compatible tandem-ring applicators with 5.0-6.0 Gy x five fractions. PDR-IGABT (UMCU) dose was delivered with Utrecht tandem-ovoid applicators with 32 x 0.6 Gy x two fractions. Pelvic lymph nodes with short axis diameter of ≥ 5 mm on pre-treatment MRI or PET-CT were contoured for all BT-plans. Dose contributions to individual pLNN expressed as D90 (dose to 90% of the volume) were calculated from dose-volume histograms as absolute and relative physical dose (% of the reference dose) for each fraction. For each node, the total dose from all fractions was calculated, expressed in EQD2 (equivalent total dose in 2 Gy fractions). Results: Fifty-seven (UPCI) and 40 (UMCU) individual pLNN were contoured. The mean D90 pLNN was 10.8% (range 5.7-25.1%) and 20.5% (range 6.8-93.3%), respectively, and therefore different in the two centers. These values translate into 2.7 Gy (1.3-6.6 Gy) EQD2 and 7.1 Gy (2.2-36.7 Gy) EQD2, respectively. Differences are caused by the location of the individual nodes in relation to the spatial dose distribution of IGABT, differences in total dose administered and radiobiology (HDR versus PDR). Conclusions: The IGABT dose contribution to individual pelvic nodes depends on patient and treatment related factors, and varies considerably. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: To compare MRI-guided treatment planning approaches between four centres that use tandem-ovoid applicators. Material and methods: Four centres generated three treatment plans for four patients: standard, optimised intracavitary, and optimised intracavitary/interstitial. Prescribed D90 High-Risk CTV (HR-CTV) was 85Gy EQD2 (external-beam radiotherapy and brachytherapy), while the D2cc OAR limit was 90Gy EQD2 for bladder and 75Gy EQD2 for rectum, sigmoid, and bowel, respectively. DVH-parameters, source loading patterns and spatial dose distributions of the three treatment plans were compared. Results: The standard plans of the different centres were comparable with respect to the D90 HR-CTV, but differed in OAR doses. MRI-guided intracavitary optimisation resulted in organ sparing and smaller variation in DVH parameters between the centres. Adding interstitial needles led to target dose escalation while respecting the OAR constraints. However, substantial differences in relative weights of the applicator parts resulted in an increased variation in DVH parameters and locations of high dose regions. Conclusions: MRI-guided brachytherapy treatment planning optimisation provides the possibility to increase the dose to the HR-CTV and spare the OARs. Depending on the degree of conformity the centres make different choices in relative weighting of applicator parts, leading to different dose distributions. [Copyright &y& Elsevier]

Abstract: Purpose: To evaluate dosimetric parameters and clinical outcome for cervical cancer patients treated with chemo-radiation and MR-image guided adaptive brachytherapy (MR-IGABT) using tandem-ovoid applicators for intracavitary or combined intracavitary/interstitial approaches. Method: This retrospective analysis includes 46 patients treated between 2006 and 2008. Dose–volume parameters D90 HR-CTV (high-risk clinical target volume) and D2cc OARs (organs at risk) were determined and converted into biologically equivalent doses in 2Gy fractions (EQD2). Clinical outcome parameters (local control (LC), progression free survival (PFS) and overall survival (OS)) were analysed actuarially and late morbidity crude rates were scored using CTCAEv3.0. Results: Mean D90 HR-CTV was 84 (SD9) Gy EQD2 for HR-CTV volumes of mean 57 (SD37) cm3 at time of first brachytherapy (BT). Median follow-up was 41 (range, 4–67)months. Three year LC, PFS, and OS rates were 93, 71, and 65%, respectively. Node negative patients had significantly higher 3-year survival rates compared to node positive ones (PFS 85 versus 53% (p =0.013), OS 77 versus 50% (p =0.032), respectively) with an even larger difference for patients with FIGO stages IB-IIB (PFS 87 versus 42% (p =0.002), OS 83 versus 46% (p =0.007), respectively). Late grade 3–4 mainly gastrointestinal or vaginal morbidity was observed in 4 patients (9.5%). No correlations were seen between morbidity and D2cc OAR values. Conclusion: (Chemo-) radiation and MR-IGABT with tandem-ovoid applicators result in high LC and promising survival rates with reasonable morbidity. [Copyright &y& Elsevier]

Purpose: The aims of this study were to investigate the benefit of the Utrecht interstitial CT/MR applicator for combined intracavitary/interstitial (IC/IS) approach, using magnetic resonance imaging—guided brachytherapy, over the intracavitary approach alone in patients with locally advanced cervical cancer and to analyze the clinical use of needles. Methods and Materials: This study includes the first 20 patients treated with the new applicator. Brachytherapy consisted of two pulsed dose rate applications, and the second application was performed with the IC/IS approach. The number of needles, chosen guiding holes through the ovoids, and insertion depths were based on the dose distribution and dosimetric shortcomings of the first application (IC alone). We investigated the dosimetric gain by comparing the clinical interstitial optimized plan (IC/ISclinical) with an additionally generated optimized plan without needle use (ICstudy). Furthermore, we studied the relation of the inserted needles and their source loading patterns with the high-risk clinical target volume (HR-CTV). Results: A total of 54 needles (range, 1–6 per application) were applied with an average depth of 25 mm. The chosen needle positions corresponded with the location of the HR-CTV extensions. The total and individual needle treatment times per application were on average 19% (range, 4–35%) and 7% (range, 2–14%) of the implant treatment time, respectively. The total (external-beam radiotherapy + brachytherapy) D90 HR-CTV for the ICstudy and the IC/ISclinical were on average 79.5 (SD 7.4) Gyα/β10 and 83.9 (SD 6.7) Gyα/β10, respectively, with an average gain of 4.4 (SD 2.3) Gyα/β10 for the second application. Conclusions: Needle placement was feasible in all patients and resulted in a gain in dose and better coverage of HR-CTV. Defining the location of HR-CTV protrusions and analyzing the associated needles has given us deeper understanding of the possibilities in magnetic resonance imaging—guided (pre)treatment planning with the IC/IS Utrecht applicator. [Copyright &y& Elsevier]

Abstract: Purpose: To evaluate the effect of different α/β and half-time of repair T ½ on the assessment of clinical treatment plans for patients with cervical cancer. Materials and methods: We used EBRT and BT treatment plans of five patients, planned with MRI guided BT. We computed 3D EQD2 dose distributions of combined EBRT and BT treatments and calculated D90 of high-risk clinical target volume (HR-CTV) and D2cc for bladder and rectum, and the ratio D2cc(bladder)/D90(HR-CTV). BT was modelled as PDR (two applications of 32×60cGy) and HDR (two applications of 2×7Gy). We assumed a low, standard and high value for the biological parameters: HR-CTV α/β =5/10/15Gy and T ½ =0.5/1.5/2.5h; OAR α/β =2/3/4Gy; T ½ =0.5/1.5/4.5h. Results: The chosen variation in modelling parameters had a much larger effect on PDR treatments than on HDR treatments, especially for OAR, thus creating larger uncertainties. The relative mean range of the ratio D2cc(bladder)/D90(HR-CTV) is 72% for PDR and 25% for HDR. Out of the 125 modelled combinations 48 PDR plans and 23 HDR plans comply with clinical objectives. Conclusion: For HDR brachytherapy, only α/β has a significant impact on reported EQD2 values, whereas for PDR both α/β and T 1/2 are important. Generally, the ratio D2cc(bladder)/D90(HR-CTV) is more favourable for PDR, even considering the larger uncertainties in EQD2. [Copyright &y& Elsevier]

Abstract: Purpose: To evaluate the methods of applicator reconstruction in 3D MR-based planning for brachytherapy of cervical cancer, and to investigate applicator shifts and changes in DVH parameters during PDR treatment. Methods: For each application MR scans with applicator in situ were made: three T2-weighted (4.5mm slices) Turbo Spin Echo (TSE) scans and a balanced Steady State Free Precession scan (1.5mm). Three observers tested two applicator reconstruction methods: (A) directly on the bSSFP scan and (B) on a resampled combination of the three T2-weighted scans. For 10 patients MR imaging was repeated on the second day of each PDR fraction to determine applicator shifts and changes in DVH parameters. Results: For both applicator reconstruction methods the interobserver variation for the DVH parameters was comparable (average <1.5% in dose). Differences between the two methods were larger (up to 6.4% for target) and were related to position differences during MR scanning. The average applicator shift relative to the pelvic structures was 5–6mm into the ventral direction and 3–4mm cranially. For a single PDR fraction, the average D90 (HR-CTV) on ‘day 2’ was 0.2 (SD 2.0)Gy lower than that for day 1. The average increase in D2cc (bladder) was 1.0 (SD 3.0)Gyαβ3 for a single PDR fraction. If the effect of both fractions was combined, for 1 patient a total decrease of D90 of 7Gyαβ10 was found, whereas for another patient the total increase in bladder dose was 12Gyαβ3. Conclusions: Applicator reconstruction on MR data is feasible. In the overall accuracy during PDR brachytherapy the reconstruction uncertainty is of minor importance. Applicator and/or organ movement during the course of the PDR fraction produce larger uncertainties. [Copyright &y& Elsevier]

Purpose Vaginal stenosis is a major problem following radiotherapy in cervical cancer. We investigated a new dose planning strategy for vaginal dose de-escalation (VDD). Materials and methods Fifty consecutive locally advanced cervical cancer patients without lower or middle vaginal involvement at diagnosis from 3 institutions were analysed. External beam radiotherapy was combined with MRI-guided brachytherapy. VDD was obtained by decreasing dwell times in ovoid/ring and increasing dwell times in tandem/needles. The aim was to maintain the target dose (D90 of HR-CTV ⩾ 85 Gy EQD2) while reducing the dose to the surface of the vagina to <140% of the physical fractional brachytherapy dose corresponding to a total EQD2 of 85 Gy. Results The mean vaginal loading (ovoid/ring) was reduced from 51% to 33% of the total loading with VDD, which significantly reduced the dose to the vaginal dose points ( p < 0.001) without compromising the target dose. The dose to the ICRU recto-vaginal point was reduced by a mean of 4 ± 4 Gy EQD2 ( p < 0.001), while doses to bladder and rectum (D 2cm 3 ) were reduced by 2 ± 2 Gy and 3 ± 2 Gy, respectively ( p < 0.001). Conclusions VDD significantly reduces dose to the upper vagina which is expected to result in reduction of vaginal stenosis. [ABSTRACT FROM AUTHOR]

Highlights • MR-IGABT in cervix cancer improved target coverage and reduced irradiated volumes. • ISVs correlated with CTV HR volumes showing dose adaptation with tumour size. • From the perspective of normal tissue complications PDR was more sparing than HDR. • Larger EBRT doses of 50 Gy increased the irradiated volumes at doses of 60 Gy. Abstract 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 cm3, 100 cm3 and 233 cm3, respectively. Median V85 Gy EQD2 10 was 23% smaller than in standard 85 Gy prescription to Point A. For small (<25 cm3), intermediate (25–35 cm3) and large (>35 cm3) CTV HR volumes, the V85 Gy was 57 cm3, 70 cm3 and 89 cm3, 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. [ABSTRACT FROM AUTHOR]

Purpose To demonstrate that V 60 Gy, V 75 Gy, and V 85 Gy isodose surface volumes can be accurately estimated from total reference air kerma (TRAK) in cervix cancer MRI-guided brachytherapy (BT). Methods and Materials 60 Gy, 75 Gy, and 85 Gy isodose surface volumes levels were obtained from treatment planning systems (V TPS ) for 239 EMBRACE study patients from five institutions treated with various dose rates, fractionation schedules and applicators. An equation for estimating V TPS from TRAK was derived. Furthermore, a surrogate Point A dose (Point A*) was proposed and tested for correlation with V 75 Gy. Results Predicted volumes V pred = 4965 (TRAK/dref) 3/2 + 170 (TRAK/dref) − 1.5 gave the best fit to V TPS . The difference between V TPS and predicted volumes was 0.0% ± 2.3%. All volumes were predicted within 10%. The prediction was valid for ( 1 ) high-dose rate and pulsed dose rate, ( 2 ) intracavitary vs. intracavitary/interstitial applicators, and ( 3 ) tandem-ring, tandem-ovoid, and mold. Point A* = 14 TRAK was converted to total EQD 2 and showed high correlation with V 75 Gy. Conclusions TRAK derived Isodose surface volumes may become a tool for assessment of treatment intensity. Furthermore, surrogate Point A ∗ doses can be applied for both intracavitary and intracavitary/interstitial BT and can be used to compare treatments across fractionation schedules. [ABSTRACT FROM AUTHOR]

Background and purpose Regarding latest developments, the need of a radiotherapy ‘Patterns of Care’ survey was expressed by the Dutch National Platform Radiotherapy for Gynaecological Cancer (LPRGT). Therefore, this study investigated current practice for cervical cancer in all 16 radiation oncology centres in the Netherlands specialised in gynaecological oncology. Material and methods A structured ‘patterns of care’ questionnaire was completed and followed by an in-depth interview with radiation oncologists from all radiotherapy centres specialised in gynaecological oncology. Specific topics addressed were: definition of target volumes, treatment preparation, imaging for treatment planning, treatment planning, and image-guided adaptive radiotherapy for external beam radiotherapy and brachytherapy. Results Current radiotherapy practice in the Netherlands for cervical cancer appears to be in accordance with international standards. However, at the time of the survey some differences were revealed that might have relevant clinical impact. For instance: 1) Half of the centres acquired positron emission tomography combined with CT (PET-CT) for staging and target delineation for every patient, 2) The definition of upper border of the para-aortal lymph node area and dose prescription for external beam radiotherapy varied between the centres, and 3) 12 centres used a single treatment plan for delivering EBRT, and four used a plan-of-the-day strategy with a library of 3–4 treatment plans. Conclusions Most differences were found at the cutting edge of clinical evidence. However, the majority of these uncertainties are topics being addressed in current and planned (inter)national studies. [ABSTRACT FROM AUTHOR]

Background and purpose: To compare the dosimetric impact of organ and target variations relative to the applicator for intracavitary brachytherapy by a multicentre analysis with different application techniques and fractionation schemes. Material and methods: DVH data from 363 image/contour sets (120 patients, 6 institutions) were included for 1–6 fractions per patient, with imaging intervals ranging from several hours to ∼20days. Variations between images acquired within one (intra-application) or between consecutive applicator insertions (inter-application) were evaluated. Dose plans based on a reference MR or CT image series were superimposed onto subsequent image sets and for the bladder, rectum and sigmoid and D 90 for HR CTV were recorded. Results: For the whole sample, the systematic dosimetric variations for all organs at risk, i.e. mean variations of , were found to be minor (<5%), while random variations, i.e. standard deviations were found to be high due to large variations in individual cases. The variations (mean±1SD) were 0.6±19.5%, 4.1±21.7% and 1.6±26.8%, for the bladder, rectum and sigmoid. For HR CTV, the variations of D90 were found to be −1.1±13.1% for the whole sample. Grouping of the results by intra- and inter-application variations showed that random uncertainties for bladder and sigmoid were 3–7% larger when re-implanting the applicator for individual fractions. No statistically significant differences between the two groups were detected in dosimetric variations for the HR CTV. Using 20% uncertainty of physical dose for OAR and 10% for HR CTV, the effects on total treatment dose for a 4 fraction HDR schedule at clinically relevant dose levels were found to be 4–8Gy EQD2 for OAR and 3Gy EQD2 for HR CTV. Conclusions: Substantial variations occur in fractionated cervix cancer BT with higher impact close to clinical threshold levels. The treatment approach has to balance uncertainties for individual cases against the use of repetitive imaging, adaptive planning and dose delivery. [ABSTRACT FROM AUTHOR]

Abstract: Image-guided brachytherapy in cervical cancer is increasingly replacing X-ray based dose planning. In image-guided brachytherapy the geometry of the applicator is extracted from the patient 3D images and introduced into the treatment planning system; a process referred to as applicator reconstruction. Due to the steep brachytherapy dose gradients, reconstruction errors can lead to major dose deviations in target and organs at risk. Appropriate applicator commissioning and reconstruction methods must be implemented in order to minimise uncertainties and to avoid accidental errors. Applicator commissioning verifies the location of source positions in relation to the applicator by using auto-radiography and imaging. Sectional imaging can be utilised in the process, with CT imaging being the optimal modality. The results from the commissioning process can be stored as library applicators. The importance of proper commissioning is underlined by the fact that errors in library files result in systematic errors for clinical treatment plans. While the source channel is well visualised in CT images, applicator reconstruction is more challenging when using MR images. Availability of commercial dummy sources for MRI is limited, and image artifacts may occur with titanium applicators. The choice of MR sequence is essential for optimal visualisation of the applicator. Para-transverse imaging (oriented according to the applicator) with small slice thickness (⩽5mm) is recommended or alternatively 3D MR sequences with isotropic voxel sizes. Preferably, contouring and reconstruction should be performed in the same image series in order to avoid fusion uncertainties. Clear and correct strategies for the applicator reconstruction will ensure that reconstruction uncertainties have limited impact on the delivered dose. Under well-controlled circumstances the reconstruction uncertainties are in general smaller than other brachytherapy uncertainties such as contouring and organ movement. [Copyright &y& Elsevier]

Abstract: Purpose: To perform a qualitative and quantitative comparison of different treatment planning methods used in different centres for MRI-based brachytherapy (BT) of cervical cancer. Materials and methods: Two representative patients with advanced cervical cancer (1 “limited volume case”; 1 “extensive volume case”) were planned for brachytherapy (BT) with a tandem-ring applicator by six different centres. During a workshop all centres produced an institutional standard plan and an MRI-based adaptive treatment plan for each case. Optimisation was based on the fractionation schedule (HDR, PDR) and method according to the institutional protocol. Results: The loading pattern, dwell times, shape of the point A isodose varied considerably between institutional standard plans, as did dose–volume parameters for high risk CTV (HR-CTV) and also for the D2cc for OAR, violating the dose–volume constraints in many situations. During optimisation, the centres stayed as close as possible to the standard loading pattern and dwell times. The dose distributions and dose–volume parameters between the plans from the different centres became much more comparable after optimisation. The prescribed dose to the HR-CTV could be achieved in the limited volume case by all centres, in the extensive case only if additional needles were applied. Conclusion: Treatment planning for gynaecologic brachytherapy based on different traditions shows less variation in regard to target coverage and OAR dose, when 3D image-based optimisation is performed with a uniform prescription protocol. [Copyright &y& Elsevier]

Abstract: Purpose: To study the impact of MRI-guided treatment planning on dose/volume parameters in pulsed dose rate (PDR) brachytherapy (BT) for cervical cancer. Additionally, we investigated the potential benefit of an intracavitary/interstitial (IC/IS) modification of the classical tandem ovoid applicator. Material and methods: For 24 patients we compared Standard PDR BT plans, Scaled Standard plans and MRI-guided Optimised plans. The total EBRT/BT prescribed dose to Manchester point A or to 90% of the HR-CTV (D90 HR-CTV) expressed in EQD2 was 80Gyαβ10 in 17 patients (Period I) and 84Gyαβ10 in 7 patients (Period II). The constraints to 2 cm3 of the OAR were 90Gyαβ3 for bladder and 75Gyαβ3 for rectum, sigmoid and bowel. Most cases were treated with a traditional intracavitary tandem ovoid applicator. In 6 patients we used a newly designed combined IC/IS modification for the second PDR fraction and investigated the benefit of the interstitial part. Results: The average gain of MRI-guided optimisation expressed in D90 HR-CTV was 4±9Gyαβ10 (p <0.001) and 10±7Gyαβ10 (p =0.003) in the two periods. The dose to 2 cm3 of the OAR met the constraints. In the group that was treated with the combined IC/IS approach, we could increase the D90 HR-CTV for the second PDR fraction with 5.4±4.2Gyαβ10 (p =0.005) and the D100 with 4.8±3.1Gyαβ10 (p =0.07). Conclusions: Three-dimensional MRI-guided treatment planning and optimisation improves the DVH parameters compared to conventional planning strategies. Additional improvement can be achieved by using a combined IC/IS approach. [Copyright &y& Elsevier]