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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]

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]

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: 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 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]