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Abstract: The GYN GEC-ESTRO working group issued three parts of recommendations and highlighted the pivotal role of MRI for the successful implementation of 3D image-based cervical cancer brachytherapy (BT). The main advantage of MRI as an imaging modality is its superior soft tissue depiction quality. To exploit the full potential of MRI for the better ability of the radiation oncologist to make the appropriate choice for the BT application technique and to accurately define the target volumes and the organs at risk, certain MR imaging criteria have to be fulfilled. Technical requirements, patient preparation, as well as image acquisition protocols have to be tailored to the needs of 3D image-based BT. The present recommendation is focused on the general principles of MR imaging for 3D image-based BT. Methods and parameters have been developed and progressively validated from clinical experience from different institutions (IGR, Universities of Vienna, Leuven, Aarhus and Ljubljana) and successfully applied during expert meetings, contouring workshops, as well as within clinical and interobserver studies. It is useful to perform pelvic MRI scanning prior to radiotherapy (“Pre-RT-MRI examination”) and at the time of BT (“BT MRI examination”) with one MR imager. Both low and high-field imagers, as well as both open and close magnet configurations conform to the requirements of 3D image-based cervical cancer BT. Multiplanar (transversal, sagittal, coronal and oblique image orientation) T2-weighted images obtained with pelvic surface coils are considered as the golden standard for visualisation of the tumour and the critical organs. The use of complementary MRI sequences (e.g. contrast-enhanced T1-weighted or 3D isotropic MRI sequences) is optional. Patient preparation has to be adapted to the needs of BT intervention and MR imaging. It is recommended to visualise and interpret the MR images on dedicated DICOM-viewer workstations, which should also assist the contouring procedure. Choice of imaging parameters and BT equipment is made after taking into account aspects of interaction between imaging and applicator reconstruction, as well as those between imaging, geometry and dose calculation. In a prospective clinical context, to implement 3D image-based cervical cancer brachytherapy and to take advantage of its full potential, it is essential to successfully meet the MR imaging criteria described in the present recommendations of the GYN GEC-ESTRO working group. [Copyright &y& Elsevier]

Background. The aim of this pilot study was to assess tumour hypoxia in patients with cervical cancer before, during and after combined radio-chemotherapy and Magnetic Resonance Imaging (MRI) guided brachytherapy (BT) by use of the hypoxia Positron Emission Tomography (PET) tracer 18F-fluoroazomycin-arabinoside (18FAZA ). Material and methods. Fifteen consecutive patients with locally advanced cervical cancer referred for definitive radiotherapy (RT) were included in an approved clinical protocol. Stage distribution was 3 IB1, 1 IB2, 10 IIB, 1 IIIB, tumour volume was 55 cm3 (+/− 67, SD). Dynamic and static 18FAZA -PET scans were performed before, during and after external beam therapy (EBRT) and image guided BT +/− concomitant cisplatin. Dose was prescribed to the individual High Risk Clinical Target Volume (HR CTV) taking into account the dose volume constraints for adjacent organs at risk. Results. Five patients had visually identifiable tumours on 18FAZA -PET scans performed prior to radio-chemotherapy and four patients before brachytherapy. One of five 18FAZA PET positive patients had incomplete remission three months after RT, one had regional recurrence. Four of ten 18FAZA-PET negative patients developed distant metastases. The one patient with incomplete remission received 69 Gy (D90) in the HR CTV, whereas all other patients received mean 99 Gy (+/−12, SD). Conclusion. PET imaging with 18FAZA is feasible in patients with cancer of the uterine cervix. However, its predictive and prognostic value remains to be clarified. This applies in particular for the additional value of 18FAZA-PET compared to morphologic repetitive MRI within the setting of image guided high dose radiotherapy which may contribute to overcome hypoxia related radioresistance. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To introduce and test a direct reconstruction concept for intracavitary tandem ring applicators in MR image-based brachytherapy treatment planning. Materials and methods: Optical measurements of transparent ring-phantoms provided the geometric relation between source path and the Vienna ring applicator as visible on MRI. For the manual direct reconstruction method (PLATO), the geometry plotted on a transparency was placed on the screen and rotated to fit with visible ring holes. With the software-integrated reconstruction method (OncentraGYN), the applicator geometry was directly used when placing the visible parts of the applicator in the 3D dataset. Clinical feasibility was tested in 10 clinical insertions. Reconstruction and dose calculation were performed independently on two treatment planning systems (PLATO and OncentraGYN) using MRI alone. DVH parameters for targets and organs at risk were analysed and compared to the clinically used radiograph/MRI registration-based method. Results: The direct reconstruction concept for both methods was feasible and reduced treatment planning time. Evaluated DVH parameters for plans using direct reconstruction methods differed from clinically used plans (traditional reconstruction) in mean differences ⩽0.2Gy for plans with 7Gy prescribed dose. Conclusion: If the relation between applicator shape visible on MRI and the source path is defined once, the reconstruction process can be performed by directly placing the applicator in the MRI dataset. [Copyright &y& Elsevier]

Abstract: Background and purpose: To analyse dose–response relationships for local control of cervical cancer after MR image-guided brachytherapy (IGBT) based on dose–volume histogram parameters. Methods and materials: The analysis includes 141 patients with cervix cancer (stages IB–IVA) treated with 45–50.4Gy EBRT±cisplatin plus 4×7Gy IGBT. Gross tumour volume (GTV), high risk clinical target volume (HR CTV) and intermediate risk CTV (IR CTV) were delineated and DVH parameters (D90, D100) were assessed. Doses were converted to the equivalent dose in 2Gy (EQD2) using linear-quadratic model (α/β =10Gy). Groups of patients were formed according to tumour size at diagnosis (GTVD) of 2–5cm (group 1) or >5cm (2), with subgroups of the latter for HR CTV size at first IGBT 2–5cm (2a) or >5cm (2b). Dose–response dependence for local recurrence was evaluated by logit analysis. Results: Eighteen local recurrences in the true pelvis were observed. Dose–response analyses revealed a significant effect of HR CTV D100 (p =0.02) and D90 (p =0.005). The ED50-values for tumour control were 33±15Gy (D100) and 45±19Gy (D90). ED90-values were 67Gy (95% confidence interval [50;104]) and 86Gy [77;113], respectively. Conclusions: A significant dependence of local control on D100 and D90 for HR CTV was found. Tumour control rates of >90% can be expected at doses >67Gy and 86Gy, respectively. [Copyright &y& Elsevier]

Purpose: To investigate the value of dose–volume histogram (DVH) parameters for predicting local control in magnetic resonance (MR) image-guided brachytherapy (IGBT) for patients with cervical cancer. Methods and Materials: Our study population consists of 141 patients with cervical cancer (Stages IB–IVA) treated with 45–50 Gy external beam radiotherapy plus four times 7 Gy IGBT with or without cisplatin. Gross tumor volume (GTV), high-risk clinical target volume (HRCTV), and intermediate-risk clinical target volume (IRCTV) were contoured, and DVH parameters (minimum dose delivered to 90% of the volume of interest [D90] and D100) were assessed. Doses were converted to the equivalent dose in 2 Gy (EQD2) by applying the linear quadratic model (α/β = 10 Gy). Groups were defined for patients with or without local recurrence (LR) in the true pelvis for tumor size at diagnosis (GTV at diagnosis [GTVD] of 2–5 cm (Group 1) or greater than 5 cm (Group 2) and for tumor size response at IGBT (HRCTV) of 2–5 cm (Group 2a) or greater than 5 cm (Group 2b). Results: Eighteen LRs were observed. The most important DVH parameters correlated with LR were the D90 and D100 for HRCTV. Mean D90 and D100 values for HRCTV were 86 ± 16 and 65 ± 10 Gy, respectively. The D90 for HRCTV greater than 87 Gy resulted in an LR incidence of 4% (3 of 68) compared with 20% (15 of 73) for D90 less than 87 Gy. The effect was most pronounced in the tumor group (Group 2b). Conclusions: We showed an increase in local control in IGBT in patients with cervical cancer with the dose delivered, which can be expressed by the D90 and D100 for HRCTV. Local control rates greater than 95% can be achieved if the D90 (EQD2) for HRCTV is 87 Gy or greater. [Copyright &y& Elsevier]

Abstract: Background and purpose: To investigate the inter-observer variation of target contouring when using the GYN GEC-ESTRO recommendations for MR image-guided brachytherapy (IGBT) for cervical cancer. Materials and methods: Nineteen cervical cancer patients, treated by radiotherapy at the Institut Gustave Roussy (IGR) in France (n =9) or at the Medical University of Vienna (AKH) in Austria (n =10) were included in this study. IGBT was used for all patients. Two radiation oncologists, one from IGR and the other from AKH, outlined the target volumes on MRI at the time of brachytherapy according to the GYN GEC-ESTRO recommendations. The absolute, common and encompassing volumes and their conformity indices (CIs) were assessed for the GTV, HR CTV and IR CTV. D90 and D100 for each volume were assessed. Visual evaluation was made to assess the reasons for the most frequent inter-observer differences. Results: The mean volumes of GTV and HR CTV did not differ significantly between the observers, p >0.05. Significant differences were observed only for the mean volumes of the IR CTV of both centres, p <0.05. CIs ranged from 0.5 to 0.7. DVH-parameter analyses did not reveal any statistical differences, except for the D100 for the GTV at AKH, and the D90 for the IR CTV at IGR, p <0.05. Underlying reasons for inter-observer differences included image contrast adjustment and neglecting to consider anatomical borders. Conclusions: The results of this inter-observer study show that the application of the GYN GEC-ESTRO recommendations for IGBT contouring at two different institutions with two different traditions for applicators, CTV assessment, MR image acquisition and dose prescription is feasible, and it produces acceptable inter-observer variability. [Copyright &y& Elsevier]

Brachytherapy (BT) represents and essential aspect of radical radiotherapy of cervical cancer. Within the last decade, 3D MRI-based BT was introduced into clinical practice at some institutions and it was shown that this advanced approach could successfully replace the traditional 2D x-ray-based methods of treatment planning. MRI has general advantages in the depiction of soft tissue and, in particular, in discrimination of cervical cancer from normal uterine and adjacent tissue. Accurate representation of pelvic anatomy and topography, together with detailed information regarding tumor extent and regression during the course of treatment, makes MRI essential for cervical cancer radiotherapy, particularly for BT. The process of implementation of 3D MRI-based BT is described in detail. The first reported single institutional retrospective analysis with systematic utilization of this novel treatment approach in a large consecutive patient series (n = 145) demonstrated the increase in local tumor control up to almost 100% for limited size tumors (2-5 cm) and 90% for tumors over 5 cm in diameter with a low rate of severe morbidity (<5%). [ABSTRACT FROM AUTHOR]

Purpose: To compare the contours and dose–volume histograms (DVH) of the tumor and organs at risk (OAR) with computed tomography (CT) vs. magnetic resonance imaging (MRI) in cervical cancer brachytherapy. Methods and Materials: Ten patients underwent both MRI and CT after applicator insertion. The dose received by at least 90% of the volume (D90), the minimal target dose (D100), the volume treated to the prescription dose or greater for tumor for the high-risk (HR) and intermediate-risk (IR) clinical target volume (CTV) and the dose to 0.1 cm3, 1 cm3, and 2 cm3 for the OARs were evaluated. A standardized approach to contouring on CT (CTStd) was developed, implemented (HR- and IR-CTVCTStd), and compared with the MRI contours. Results: Tumor height, thickness, and total volume measurements, as determined by either CT or CTStd were not significantly different compared with the MRI volumes. In contrast, the width measurements differed in HR-CTVCTStd (p = 0.05) and IR-CTVCTStd (p = 0.01). For the HR-CTVCTStd, this resulted in statistically significant differences in the volume treated to the prescription dose or greater (MRI, 96% vs. CTStd, 86%, p = 0.01), D100 (MRI, 5.4 vs. CTStd, 3.4, p <0.01), and D90 (MRI, 8.7 vs. CTStd, 6.7, p <0.01). Correspondingly, the IR-CTV DVH values on MRI vs. CTStd, differed in the D100 (MRI, 3.0 vs. CTStd, 2.2, p = 0.01) and D90 (MRI, 5.6 vs. CTStd, 4.6, p = 0.02). The MRI and CT DVH values of the dose to 0.1 cm3, 1 cm3, and 2 cm3 for the OARs were similar. Conclusion: Computed tomography-based or MRI-based scans at brachytherapy are adequate for OAR DVH analysis. However, CT tumor contours can significantly overestimate the tumor width, resulting in significant differences in the D90, D100, and volume treated to the prescription dose or greater for the HR-CTV compared with that using MRI. MRI remains the standard for CTV definition. [Copyright &y& Elsevier]

Abstract: Background: To investigate the clinical impact of MRI based cervix cancer brachytherapy combined with external beam radiochemotherapy applying dose volume adaptation and dose escalation in a consecutive group of patients with locally advanced cervix cancer. Methods: In the period 1998–2003, 145 patients with cervix cancer stages IB–IVA were treated with definitive radiotherapy +/− cisplatin chemotherapy. Median age was 60 years. In 67 patients, the tumour size was 2–5cm, in 78 patients it was >5cm. In 29 cases the standard intracavitary technique was combined with interstitial brachytherapy. Total prescribed dose was 80–85Gy (total biologically equivalent dose in 2Gy fractions). Since 2001, MRI based treatment planning integrated systematic concepts for High Risk Clinical Target Volume (HR CTV) and organs at risk (OAR), biological modelling, Dose–Volume–Histogram analysis, dose–volume–adaptation (D90, D 2cm3), and dose escalation, if appropriate and feasible. Findings: Dose volume adaptation was performed in 130/145 patients. The mean D90 during the whole period was 86Gy, with a mean D90 of 81Gy and 90Gy during the first and second period, respectively (p ≪0.01). Median follow-up was 51 months. Complete remission at 3 months was achieved in 138/145 patients (95%). Actuarial continuous complete remission for true pelvis (CCRtp) was 88% at 3 years. For tumours 2–5cm, CCRtp was 96% both in 1998–2000 and 2001–2003. For tumours >5cm it was 71% in 1998–2000 and 90% in 2001–2003 (p =0.05). Progression free survival (PFS) for true pelvis (local control) was 85%, PFS for distant metastases was 80%, both at 3 years. Local control for tumours >5cm was 64% in 1998–2000 and 82% in 2001–2003 (p =0.09) and 100% and 96%, respectively, for tumours 2–5cm. PFS for distant metastases remained the same during the two treatment periods with 79% and 80%. Overall survival (OS) was 58%, and cancer-specific survival (CSS) was 68% at 3 years. In the two different periods improvement in OS was from 53% to 64% (p =0.03) and in CSS from 62% to 74% (p =0.13). Improvement occurred only in tumours >5cm: OS 28% versus 58% (p =0.003); CSS 40% versus 62% (p =0.07). Actuarial late morbidity rate (LENT SOMA, grades 3 and 4) at 3 years was gastrointestinal 4%, urinary 4% and vaginal 5% (stage IIA/IIIA). Gastrointestinal and urinary late morbidity (G3,G4) was 10% in 1998–2000 and 2% in 2001–2003. Interpretation: In locally advanced extensive cervix cancer, local control of ⩾85% can be achieved with low treatment related morbidity (G3/G4), when exploiting the potential of MRI based 3D treatment planning including dose volume adaptation and dose escalation and a combined intracavitary/interstitial brachytherapy, if appropriate. A significant impact of this improvement of local control on survival is to be expected. For locally advanced limited disease the MRI based approach will likely result in assuring excellent local control (⩾95%) and in minimizing treatment related morbidity. [Copyright &y& Elsevier]

Purpose: The vagina has not been widely recognized as organ at risk in brachytherapy for cervical cancer. No widely accepted dose parameters are available. This study analyzes the uncertainties in dose reporting for the vaginal wall using tandem-ring applicators. Methods and Materials: Organ wall contours were delineated on axial magnetic resonance (MR) slices to perform dose–volume histogram (DVH) analysis. Different DVH parameters were used in a feasibility study based on 40 magnetic resonance imaging (MRI)–based treatment plans of different cervical cancer patients. Dose to the most irradiated, 0.1 cm3, 1 cm3, 2 cm3, and at defined points on the ring surface and at 5-mm tissue depth were reported. Treatment-planning systems allow different methods of dose point definition. Film dosimetry was used to verify the maximum dose at the surface of the ring applicator in an experimental setup. Results: Dose reporting for the vagina is extremely sensitive to geometrical uncertainties with variations of 25% for 1 mm shifts. Accurate delineation of the vaginal wall is limited by the finite pixel size of MRI and available treatment-planning systems. No significant correlation was found between dose–point and dose–volume parameters. The DVH parameters were often related to noncontiguous volumes and were not able to detect very different situations of spatial dose distributions inside the vaginal wall. Deviations between measured and calculated doses were up to 21%. Conclusions: Reporting either point dose values or DVH parameters for the vaginal wall is based on high inaccuracies because of contouring and geometric positioning. Therefore, the use of prospective dose constraints for individual treatment plans is not to be recommended at present. However, for large patient groups treated within one protocol correlation with vaginal morbidity can be evaluated. [Copyright &y& Elsevier]

Purpose: The aims of this study were to investigate the clinical feasibility and to report on preliminary treatment outcomes of combined intracavitary/interstitial brachytherapy, using a novel applicator and magnetic resonance imaging (MRI)–based treatment planning in patients with locally advanced cervical cancer. Methods and Materials: A total of 22 cervical cancer patients with insufficient response and/or unfavorable topography after external-beam irradiation were included in this study. Parametrial extent of the disease in these patients was judged to exceed the coverage limit of intracavitary brachytherapy alone. A modified tandem/ring (T/R) applicator for guidance of parametrial needles (N) was used to perform high-dose-rate-brachytherapy with MRI-based treatment planning. Clinical feasibility and preliminary treatment outcomes were assessed. Results: A total of 44 interstitial needle implants were performed. The spatial relations between the T/R + N applicator, high-risk clinical target volume, and organs at risk were visible clearly in all cases. Accurate and reproducible needle placement could be achieved in the majority of cases. No severe adverse events were caused by the intervention. The mean follow-up period was 20 months (range, 5–35 months). No G3 to G4 early or persistent late side effects were observed. Complete remission was achieved in 21 patients (95%). One local recurrence was observed within the high-risk clinical target volume area during follow-up. Conclusions: Our preliminary clinical experience indicates that combined intracavitary and interstitial MRI-based brachytherapy in patients with significant residual disease after external-beam therapy extending up to the distal third of parametria is feasible and allows excellent local control and a low rate of morbidity. [Copyright &y& Elsevier]

Purpose: To compare magnetic resonance imaging (MRI) findings at different stages of cervix cancer treatment and to define the potential of MRI to delineate the gross tumor volume (GTV), clinical target volume (CTV), pathoanatomic structures, and organs at risk (OAR) in brachytherapy. Methods and Materials: Forty-nine patients underwent MRI at diagnosis and at brachytherapy. The ability to discriminate anatomic structures on MRI was assessed (quality factor: 0 = inability to discriminate; 1 = fair discrimination; 2 = good discrimination; 3 = excellent discrimination). The overall ability to visualize (percentage of patients with quality factors greater than 0) and the overall discrimination quality score (mean quality factors of all patients) were estimated for the applicator, GTV at diagnosis (GTVD), GTV at brachytherapy (GTVBT)/“gray zones,” cervix rim/uterine corpus, OAR, vaginal wall, and parametria. Results: The overall ability to visualize the applicator on MRI at brachytherapy was 100%; for the GTVBT/“gray zones,” cervix rim/uterine corpus, OAR, and vaginal wall, visualization was 98% (overall discrimination quality factors: 1.2, 2.9, 2.1, 1.9, 1.7, and 2.6). Three of 4 borders of parametrial space were defined in more than 98% (discrimination quality factors: 2.9, 2.1, and 1.2). Conclusion: Magnetic resonance imaging provides appropriate information for definition of the applicator, GTV, CTV, pathoanatomic structures, and OAR that enables precise delineation for cervix cancer brachytherapy. [Copyright &y& Elsevier]

Abstract: Background and purpose: To assess feasibility, safety and effectiveness of CT–based 3D conformal external beam radiotherapy (EBRT) plus concurrent cisplatin and MRI–based 3D conformal HDR-brachytherapy (HDR-BT) in the treatment of advanced cervical cancer. Patients and methods: A total of 48 patients with advanced cervical cancer, treated with CT–based EBRT plus simultaneous cisplatin chemotherapy (40mg/m2 of body surface per week for 5 weeks) and MRI–based HDR-BT, were included for analysis. Results: All patients completed radiotherapy as planned and 90% received at least four cycles chemotherapy. Frequencies of CTC grade 3 anaemia, grade 3–4 leucopenia and grade 3 thrombocytopenia were 4, 23 and 10%, respectively. Two patients developed deep vein thrombosis and one non-fatal pulmonary embolism. Grade 4 genitourinary late side effects (bladder) occurred in 2 patients. No grade 3–4 gastrointestinal side effects were observed. Complete response (CR) was obtained in 45 patients (94%). After a median follow-up of 33 months, 27 patients were disease free. Actuarial overall survival at 3 years was 61%, progression free survival 51% and continuous complete remission for true pelvis 85%. Conclusions: MRI–based 3D HDR-BT and 3D EBRT plus cisplatin appears to be safe and effective, although acute haematological toxicity is increased. Gastrointestinal morbidity is minimal when prospectively applying 3D dose volume constraints and MRI–based 3D dose volume adaptation. [Copyright &y& Elsevier]

The article compares the effectiveness of high-technology external beam therapy (EBT) and high-technology brachytherapy (BT) for cervix carcinoma. Methodology-wise, three different groups were defined ang undergo combined EBT and BT. Based on the results, the researchers concluded that if IMXT plans are limited to similar D2cc and D1cc values as advanced BT, D90 for the HR-PTV and IR-PTV was lower depending on treatment margin and patient specific anatomy.

Abstract: Background: To analyse the overall clinical outcome and benefits by applying protocol based image guided adaptive brachytherapy combined with 3D conformal external beam radiotherapy (EBRT)±chemotherapy (ChT). Methods: Treatment schedule was EBRT with 45–50.4Gy±concomitant cisplatin chemotherapy plus 4×7Gy High Dose Rate (HDR) brachytherapy. Patients were treated in the “protocol period” (2001–2008) with the prospective application of the High Risk CTV concept (D90) and dose volume constraints for organs at risk including biological modelling. Dose volume adaptation was performed with the aim of dose escalation in large tumours (prescribed D90>85Gy), often with inserting additional interstitial needles. Dose volume constraints (D2cc) were 70–75Gy for rectum and sigmoid and 90Gy for bladder. Late morbidity was prospectively scored, using LENT/SOMA Score. Disease outcome and treatment related late morbidity were evaluated and compared using actuarial analysis. Findings: One hundred and fifty-six consecutive patients (median age 58years) with cervix cancer FIGO stages IB–IVA were treated with definitive radiotherapy in curative intent. Histology was squamous cell cancer in 134 patients (86%), tumour size was >5cm in 103 patients (66%), lymph node involvement in 75 patients (48%). Median follow-up was 42months for all patients. Interstitial techniques were used in addition to intracavitary brachytherapy in 69/156 (44%) patients. Total prescribed mean dose (D90) was 93±13Gy, D2cc 86±17Gy for bladder, 65±9Gy for rectum and 64±9Gy for sigmoid. Complete remission was achieved in 151/156 patients (97%). Overall local control at 3years was 95%; 98% for tumours 2–5cm, and 92% for tumours >5cm (p =0.04), 100% for IB, 96% for IIB, 86% for IIIB. Cancer specific survival at 3years was overall 74%, 83% for tumours 2–5cm, 70% for tumours >5cm, 83% for IB, 84% for IIB, 52% for IIIB. Overall survival at 3years was in total 68%, 72% for tumours 2–5cm, 65% for tumours >5cm, 74% for IB, 78% for IIB, 45% for IIIB. In regard to late morbidity in total 188 grade 1+2 and 11 grade 3+4 late events were observed in 143 patients. G1+2/G3+4 events for bladder were n =32/3, for rectum n =14/5, for bowel (including sigmoid) n =3/0, for vagina n =128/2, respectively. Interpretation: 3D conformal radiotherapy±chemotherapy plus image (MRI) guided adaptive intracavitary brachytherapy including needle insertion in advanced disease results in local control rates of 95–100% at 3years in limited/favourable (IB/IIB) and 85–90% in large/poor response (IIB/III/IV) cervix cancer patients associated with a moderate rate of treatment related morbidity. Compared to the historical Vienna series there is relative reduction in pelvic recurrence by 65–70% and reduction in major morbidity. The local control improvement seems to have impact on CSS and OS. Prospective clinical multi-centre studies are mandatory to evaluate these challenging mono-institutional findings. [Copyright &y& Elsevier]

Purpose: To evaluate the predictive value of dose–volume histogram (DVH) parameters for late side effects of the rectum, sigmoid colon, and bladder in image-guided brachytherapy for cervix cancer patients. Methods and Materials: A total of 141 patients received external-beam radiotherapy and image-guided brachytherapy with or without chemotherapy. The DVH parameters for the most exposed 2, 1, and 0.1 cm3 (D2cc, D1cc, and D0.1cc) of the rectum, sigmoid, and bladder, as well as International Commission on Radiation Units and Measurements point doses (DICRU) were computed. Total doses were converted to equivalent doses in 2 Gy by applying the linear-quadratic model (α/β = 3 Gy). Late side effects were prospectively assessed using the Late Effects in Normal Tissues–Subjective, Objective, Management and Analytic score. The following patient groups were defined: Group 1: no side effects (Grade 0); Group 2: side effects (Grade 1–4); Group 3: minor side effects (Grade 0–1); and Group 4: major side effects (Grade 2–4). Results: The median follow-up was 51 months. The overall 5-year actuarial side effect rates were 12% for rectum, 3% for sigmoid, and 23% for bladder. The mean total D2cc were 65 ± 12 Gy for rectum, 62 ± 12 Gy for sigmoid, and 95 ± 22 Gy for bladder. For rectum, statistically significant differences were observed between Groups 1 and 2 in all DVH parameters and DICRU. Between Groups 3 and 4, no difference was observed for D0.1cc. For sigmoid, significant differences were observed for D2cc and D1cc, but not for D0.1cc in all groups. For bladder, significant differences were observed for all DVH parameters only comparing Groups 3 and 4. No differences were observed for DICRU. Conclusions: The parameters D2cc and D1cc have a good predictive value for rectal toxicity. For sigmoid, no prediction could be postulated because of limited data. In bladder, DVH parameters were predictive only for major toxicity. [Copyright &y& Elsevier]

Purpose: To present a combined intracavitary and interstitial dedicated applicator and magnetic resonance imaging (MRI) treatment planning for cervical cancer brachytherapy. Methods and Materials: A modified ring applicator allows interstitial needles to be implanted in parallel to the intrauterine tandem. MRI treatment planning based on a standard loading pattern with stepwise dwell weight adaptation and needle loading is performed to achieve optimal dose coverage and sparing of organs at risk. Dose constraints are applied for dose–volume histogram parameters. Results: The use of additional interstitial needles provides prescription dose up to 15 mm lateral to point A. Twenty-two patients with high-risk clinical target volumes of mean 44 cm3 were treated with a mean prescribed total dose of 85 Gy (biologically equivalent to 2 Gy fractionation, α/β = 10 Gy) and 93% coverage (V100). The dose to organs at risk was within standard limits for intracavitary brachytherapy alone. Conclusions: A combined interstitial-intracavitary applicator results in reproducible implants for cervical cancer brachytherapy. MRI-based treatment planning based on a target concept, dose–volume constraints, and limitations for the relative dwell weight allows for an increase in target coverage, treated volume, and total dose without increasing the dose to critical structures. [Copyright &y& Elsevier]

Image-guided adaptive brachytherapy (IGABT) has been shown to improve local/regional control and survival for cervix cancer patients while reducing morbidity. However, the technique is complex involving several conceptual, methodological, and technical innovations compared to conventional brachytherapy. The delivery of high-quality IGABT which will translate into improved outcomes is therefore critically dependent on effective education and training of all health professionals involved in the brachytherapy treatment process. This paper reviews the (GEC)-ESTRO/EMBRACE initiatives for education and training to promote the dissemination and implementation of IGABT for cervix cancer worldwide. The new skills required in different health professionals for successful implementation of IGABT are described. The achievements and challenges of current educational strategies for disseminating IGABT are discussed. Innovations to improve the effectiveness of current and future educational strategies are explored. [ABSTRACT FROM AUTHOR]

Objective: To evaluate health-related quality of life (HR-QoL) and patient reported symptoms (PRS) before, during and early after treatment with external-beam radiotherapy (EBRT), chemotherapy and image-guided adaptive brachytherapy (IGABT) for locally advanced cervical cancer. Method: In fifty consecutive patients, HR-QoL and PRS were prospectively assessed with the EORTC-QLQ-C30+CX24 questionnaire prior to and during treatment, one week after IGABT and three months thereafter. HR-QoL was compared to an age-matched, female normative reference population. Prevalence rates of individual PRS are presented and defined as "substantial", if reported as "quite a bit" or "very much". Result: Global health status and physical and role functioning show a highly significant decline during treatment (p≤0.001), before returning to near the baseline levels three months after end of treatment. Compared to the reference population, the global health status and emotional and role functioning remain impaired. The most frequently reported substantial PRS during active treatment are: fatigue (78%), diarrhea (68%), urinary frequency (60%) and nausea (54%); these recover to some degree three months after end of treatment. However, fatigue remains increased (50%) and an onset of hot flashes (44%), sexual worries (38%) and limb edema (22%) is observed. Conclusions: Several impairments in HR-QoL and PRS were found during definitive radio(chemo)therapy with IGABT, with different patterns of progress over time and signs of recovery three months thereafter, although some aspects of functional HR-QoL remain impaired. These findings support a comprehensive patients' counseling on what to expect and how to organize professional, social and family life and plan additional support during this period. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the psychological consequences of high-dose-rate brachytherapy with 2 fractions in 1 application under spinal/epidural anesthesia in the treatment of locally advanced cervical cancer. Methods and Materials: In 50 patients with locally advanced cervical cancer, validated questionnaires were used for prospective assessment of acute and posttraumatic stress disorder (ASD/PTSD) (Impact of Event Scale–Revision), anxiety/depression (Hospital Anxiety and Depression Scale), quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30/Cervical Cancer 24), physical functioning (World Health Organization performance status), and pain (visual analogue scale), before and during treatment and 1 week and 3 months after treatment. Qualitative interviews were recorded in open format for content analysis. Results: Symptoms of ASD occurred in 30% of patients 1 week after treatment; and of PTSD in 41% 3 months after treatment in association with this specific brachytherapy procedure. Pretreatment predictive variables explain 82% of the variance of PTSD symptoms. Helpful experiences were the support of the treatment team, psychological support, and a positive attitude. Stressful factors were pain, organizational problems during treatment, and immobility between brachytherapy fractions. Conclusions: The specific brachytherapy procedure, as performed in the investigated mono-institutional setting with 2 fractions in 1 application under spinal/epidural anesthesia, bears a considerable risk of traumatization. The source of stress seems to be not the brachytherapy application itself but the maintenance of the applicator under epidural anesthesia in the time between fractions. Patients at risk may be identified before treatment, to offer targeted psycho-social support. The patients' open reports regarding helpful experiences are an encouraging feedback for the treatment team; the reported stressful factors serve as a basis for improvement of patient management, especially regarding pain control. [Copyright &y& Elsevier]

Purpose: To establish dose-response relationships for late side effects of the rectum and bladder in cervix cancer patients after magnetic resonance image-guided adaptive brachytherapy (IGABT). Methods and Materials: A cohort of 141 patients was treated with 45 to 50.4 Gy with or without cisplatin plus 4 fractions of 7 Gy IGABT. Doses for the most exposed 2, 1, and 0.1-cm3 (D2cc, D1cc, D0.1cc) volumes of the rectum and bladder were converted into the equivalent dose in 2 Gy fractions (EQD2), using a linear quadratic model (α/β = 3 Gy). Late side effects were prospectively assessed (using late effects in normal tissues subjective, objective, management and analytic [LENT SOMA]) scales. Dose-response relationships were determined by logit analyses. Results: Eleven patients developed rectal side effects, and 23 patients had urinary side effects. A significant dose effect was found for all rectal dose-volume histogram (DVH) parameters for patients with side effect grades of 1 to 4 but was only significant for D2cc and D1cc for grades ≥2. The ED10 values for D2cc were 73 Gy for grades 1 to 4 and 78 Gy for grades 2 to 4 rectal morbidity. For bladder side effects, a significant dose effect was shown for all DVH parameters for complication grades ≥2; the respective ED10 was 101 Gy. Conclusions: Well-defined dose-response curves could be established for D2cc in the rectum and the urinary bladder. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: It has been shown that a cumulative dose of ⩾87Gy (EQD2) of external beam radiotherapy (EBRT) and image guided adaptive brachytherapy (IGABT) to the high risk clinical target volume (HR CTV) confer a local control rate >95% in locally advanced cervical cancer. This study examines the dose distribution within the HR CTV and intermediate (IR) CTV in patients with cervical cancer treated with definitive EBRT +/− concomitant chemotherapy and MRI-based IGABT between patients with local recurrence (LR) and patients in continuous complete local remission (CCLR). Material and methods: From 1998 to 2010, 265 patients were treated with definitive EBRT +/− concomitant chemotherapy and IGABT. Twenty-four LRs were documented. For the statistical analysis all patients with LR were matched to patients in CCLR from our database according to the following criteria: FIGO stage, histology, lymph node status, tumour size and chemotherapy. DVH parameters (D50, D90, D98, D100) were reported for HR CTV and IR CTV. In order to report the minimum dose in the region where the recurrence occurred, the HR CTV/IR CTV were divided into four quadrants on transversal planes. The minimum dose at the HR CTV/IR CTV contour was measured (within the corresponding quadrant closest to the LR) in the treatment planning system. A mean minimum point dose (MPD) was calculated by averaging these measurements on four consecutive slices at the level of the recurrence for each of the 4 brachytherapy fractions. EQD2 doses were calculated by summation of all BT and external beam therapy fractions. For each matched patient in the control group the measurements were performed on the same quadrant and at the same level. Results: Sufficient image data were available for 21 LRs. Eight central failures and 13 non-central failures were observed. The mean D90 and D100 for HR CTV were 77Gy and 61Gy for patients with LR and 95Gy and 71Gy for patients in CCLR, respectively (p <0.01). The MPD for HR CTV was 72Gy for patients in the LR arm and 99Gy for patients in the CCLR arm (p <0.01). In the LR arm seven patients had a D90 for HR CTV ⩾87Gy, however, in only three patients the MPD was ⩾87Gy. Conclusion: This study demonstrated significant differences in local outcome according to the delivered dose. In 85% of the LRs systematic low dose regions with less than 87Gy were found at HR CTV contour. Systematic low dose regions leading to local recurrence could be detected even if a D90 HR CTV ⩾87Gy was applied. In addition to DVH parameters, inspection of the spatial dose distribution remains a key point in dose prescription. [Copyright &y& Elsevier]

Abstract: The study aimed to determine whether post-radiation vaginal side effects in cervical cancer patients can be correlated with DVH parameter D2cc. The result was negative in that no correlation could be demonstrated between D2cc and the presence and grade of side effects in this patients’ subset treated with high brachytherapy doses. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To perform a multicentre intercomparison study of treatment concepts for MRI assisted brachytherapy of cervix cancer based on recommendations of the Gynaecological GEC-ESTRO Working Group. Methods: Each participating centre (IGR Paris, University Hospital Leuven, Medical University of Vienna) contributed data of one patient with comparable clinical features. GTV, High Risk CTV (HR CTV), Intermediate Risk CTV (IR CTV) and organ walls of bladder, rectum and sigmoid colon were delineated at the time of each brachytherapy fraction on axial MR images with the applicator in place. Dose–volume histograms were calculated to evaluate doses to tumour, target volumes and organs at risk. Dose values were biologically normalised to equivalent doses in 2Gy fractions (EQD2, equivalent to 50cGy/h low dose rate) applying the linear-quadratic model. Results: Total doses to point A from external beam therapy plus brachytherapy ranged from 85 to 91Gy and were close to the dose covering 90% of HR CTV (D90=85–87Gy). D90 of IR CTV was within 69–73Gy. Doses to organs at risk were comparable. Conclusions: This study indicates the feasibility of the GEC-ESTRO recommendations. Despite different treatment concepts, biologically normalised total doses to tumour, target volumes and organs at risk were comparable. [Copyright &y& Elsevier]

Abstract: The second part of the GYN GEC ESTRO working group recommendations is focused on 3D dose-volume parameters for brachytherapy of cervical carcinoma. Methods and parameters have been developed and validated from dosimetric, imaging and clinical experience from different institutions (University of Vienna, IGR Paris, University of Leuven). Cumulative dose volume histograms (DVH) are recommended for evaluation of the complex dose heterogeneity. DVH parameters for GTV, HR CTV and IR CTV are the minimum dose delivered to 90 and 100% of the respective volume: D90, D100. The volume, which is enclosed by 150 or 200% of the prescribed dose (V150, V200), is recommended for overall assessment of high dose volumes. V100 is recommended for quality assessment only within a given treatment schedule. For Organs at Risk (OAR) the minimum dose in the most irradiated tissue volume is recommended for reporting: 0.1, 1, and 2cm3; optional 5 and 10cm3. Underlying assumptions are: full dose of external beam therapy in the volume of interest, identical location during fractionated brachytherapy, contiguous volumes and contouring of organ walls for >2cm3. Dose values are reported as absorbed dose and also taking into account different dose rates. The linear-quadratic radiobiological model—equivalent dose (EQD2)—is applied for brachytherapy and is also used for calculating dose from external beam therapy. This formalism allows systematic assessment within one patient, one centre and comparison between different centres with analysis of dose volume relations for GTV, CTV, and OAR. Recommendations for the transition period from traditional to 3D image-based cervix cancer brachytherapy are formulated. Supplementary data (available in the electronic version of this paper) deals with aspects of 3D imaging, radiation physics, radiation biology, dose at reference points and dimensions and volumes for the GTV and CTV (adding to [Haie-Meder C, Pötter R, Van Limbergen E et al. Recommendations from Gynaecological (GYN) GEC ESTRO Working Group (I): concepts and terms in 3D image-based 3D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessment of GTV and CTV. Radiother Oncol 2005;74:235–245]). It is expected that the therapeutic ratio including target coverage and sparing of organs at risk can be significantly improved, if radiation dose is prescribed to a 3D image-based CTV taking into account dose volume constraints for OAR. However, prospective use of these recommendations in the clinical context is warranted, to further explore and develop the potential of 3D image-based cervix cancer brachytherapy. [Copyright &y& Elsevier]

Purpose: Magnetic resonance imaging (MRI)-based treatment planning in intracavitary brachytherapy allows optimization of the dose distribution on a patient-by-patient basis. In addition to traditionally used point dose and volume parameters, dose-volume histogram (DVH) analysis enables further possibilities for prescribing and reporting. This study reports the systematic development of our concept applied in clinical routine. Methods and Materials: A group of 22 patients treated with 93 fractions using a tandem-ring applicator and MRI-based individual treatment planning for each application was analyzed in detail. High-risk clinical target volumes and gross tumor volumes were contoured. The dose to bladder, rectum, and sigma was analyzed according to International Commission of Radiation Units and Measurements (ICRU) Report 38 and DVH parameters (e.g., D2cc represents the minimal dose for the most irradiated 2 cm3). Total doses, including external beam radiotherapy and the values for each individual brachytherapy fraction, were biologically normalized to conventional 2-Gy fractions (α/β 10 Gy for target, 3 Gy for organs at risk). Results: The total prescribed dose was about 85 Gyαβ10, which was mainly achieved by 45 Gy external beam radiotherapy plus 4 × 7 Gy brachytherapy (total 84 Gyαβ10). The mean value was 82 Gyαβ10 for the point A dose (left, right) and 84 cm3 for the volume of the prescribed dose. The average dose to the clinical target volume was 66 Gyαβ10 for the minimum target dose, 87 Gyαβ10 for the dose received by at least 90% of the volume, with a mean volume treated with at least the prescribed dose of 89%. The mean D2cc for the bladder was 83 Gyαβ3, the ICRU point dose was 75 Gyαβ3, and the dose at the ICRU point plus 1.5 cm cranially was 100 Gyαβ3. The average dose to the rectum was 64 Gyαβ3 for D2cc and at ICRU point 69 Gyαβ3. The sigma D2cc was 63 Gyαβ3. Conclusion: A standard loading pattern should be used as the starting point for MRI-based optimization. Individual changes of active dwell positions and dwell weights are guided by a concept of DVH constraints for target and organs at risk. In our clinical routine, the dose to point A and dose received by at least 90% of the volume for the clinical target volume are both comparable to the prescribed dose. The DVH constraints for organs at risk allow reproducible treatment plans, helping to detect and avoid severe overdosage. [Copyright &y& Elsevier]