Primoz Petric

Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group (IV): Basic principles and parameters for MR imaging within the frame of image based adaptive cervix cancer brachytherapy.

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.

Image guided brachytherapy in locally advanced cervical cancer: Improved pelvic control and survival in RetroEMBRACE, a multicenter cohort study

PURPOSE Image guided brachytherapy (IGBT) for locally advanced cervical cancer allows dose escalation to the high-risk clinical target volume (HRCTV) while sparing organs at risk (OAR). This is the first comprehensive report on clinical outcome in a large multi-institutional cohort. PATIENTS AND METHODS From twelve centres 731 patients, treated with definitive EBRT±concurrent chemotherapy followed by IGBT, were analysed. Kaplan-Meier estimates at 3/5years were calculated for local control (LC, primary endpoint), pelvic control (PC), overall survival (OS), cancer specific survival (CSS). In 610 patients, G3-4 late toxicity (CTCAEv3.0) was reported. RESULTS Median follow up was 43months, percent of patients per FIGO stage IA/IB/IIA 22.8%, IIB 50.4%, IIIA-IVB 26.8%. 84.8% had squamous cell carcinomas; 40.5% lymph node involvement. Mean EBRT dose was 46±2.5Gy; 77.4% received concurrent chemotherapy. Mean D90 HRCTV was 87±15Gy (EQD210), mean D2cc was: bladder 81±22Gy, rectum 64±9Gy, sigmoid 66±10Gy and bowel 64±9Gy (all EQD23). The 3/5-year actuarial LC, PC, CSS, OS were 91%/89%, 87%/84%, 79%/73%, 74%/65%. Actuarial LC at 3/5years for IB, IIB, IIIB was 98%/98%, 93%/91%, 79%/75%. Actuarial PC at 3/5years for IB, IIB, IIIB was 96%/96%, 89%/87%, 73%/67%. Actuarial 5-year G3-G5 morbidity was 5%, 7%, 5% for bladder, gastrointestinal tract, vagina. CONCLUSION IGBT combined with radio-chemotherapy leads to excellent LC (91%), PC (87%), OS (74%), CSS (79%) with limited severe morbidity.

Effect of tumor dose, volume and overall treatment time on local control after radiochemotherapy including MRI guided brachytherapy of locally advanced cervical cancer.

BACKGROUND AND PURPOSE Currently, there is no consensus on dose prescription in image guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer. The purpose of this study was to provide evidence based recommendations for tumor dose prescription based on results from a multi-center patient series (retroEMBRACE). MATERIALS AND METHODS This study analyzed 488 locally advanced cervical cancer patients treated with external beam radiotherapy±chemotherapy combined with IGABT. Brachytherapy contouring and reporting was according to ICRU/GEC-ESTRO recommendations. The Cox Proportional Hazards model was applied to analyze the effect on local control of dose-volume metrics as well as overall treatment time (OTT), dose rate, chemotherapy, and tumor histology. RESULTS With a median follow up of 46months, 43 local failures were observed. Dose (D90) to the High Risk Clinical Target Volume (CTVHR) (p=0.022, HR=0.967 per Gy) was significant for local control, whereas increasing CTVHR volume (p=0.004, HR=1.017 per cm3), and longer OTT (p=0.004, HR=1.023 per day) were associated with worse local control. Histology (p=0.084), chemotherapy (p=0.49) and dose rate (p=1.00) did not have significant impact on local control. Separate analyses according to stage of disease showed that dose to CTVHR, residual gross tumor volume (GTVres), and Intermediate Risk CTV (CTVIR) has significant impact on local control. CONCLUSION CTVHR dose of ⩾85Gy (D90) delivered in 7weeks provides 3-year local control rates of >94% in limited size CTVHR (20cm3), >93% in intermediate size (30cm3) and >86% in large size (70cm3) CTVHR. CTVIR and GTVres dose of ⩾60Gy and ⩾95Gy (D98) leads to similar local control. A dose of 5Gy (CTVHR) is required to compensate an increase of OTT by one week. Increased CTVHR volume by 10cm3 requires additional 5Gy for equivalent local control.

Long term outcome after combined modality treatment for anal cancer

Long term outcome after combined modality treatment for anal cancer Background. The aim of the retrospective study was to evaluate the effectiveness and toxicity of radiochemotherapy in patients with squamous cell carcinoma of the anal canal treated at a single institution. Patients and methods. Between 1/2003 and 9/2010, 84 patients were treated with radical radiochemotherapy at the Institute of Oncology Ljubljana, Slovenia. The treatment consisted of 3-dimensional conformal external beam radiotherapy with concurrent chemotherapy (5-fluorouracil and mytomycin C), followed by brachytherapy or external beam boost. The toxicity of therapy and its effectiveness were assessed. Results. The treatment was completed according to the protocol in 79.8% of patients. The median follow-up time of 55 survivors was 53 months (range: 16-105 months). The 5-year locoregional control (LRC), disease-free survival (DFS), disease-specific survival (DSS), overall survival (OS) and colostomy-free survival (CFS) rates were 71%, 68%, 81%, 67% and 85%, respectively. No treatment-related mortality was observed. The most frequent acute side-effect of the treatment was radiodermatitis (grade 3-4 in 58.2% of patients). LENT-SOMA grade 3-4 late radiation side effects were observed in 15 (18%) patients. In patients with brachytherapy boost a trend of less late side effects was observed compared to patients with external beam boost (P=0.066). On multivariate analysis, complete clinical disease response was identified as an independent prognostic factor for LRC, DFS and DSS, the salvage surgery for LRC and DFS, whereas Hb below 120 g/l retained its independent prognostic value for OS. Conclusions. Radiochemotherapy provides an excellent disease control and the survival with preserving anal sphincter function in majority of patients. Surgical salvage with abdominoperineal resection for persistent or recurrent disease has curative potential.

Comparison of 3D MRI with high sampling efficiency and 2D multiplanar MRI for contouring in cervix cancer brachytherapy

Comparison of 3D MRI with high sampling efficiency and 2D multiplanar MRI for contouring in cervix cancer brachytherapy Background. MRI sequences with short scanning times may improve accessibility of image guided adaptive brachytherapy (IGABT) of cervix cancer. We assessed the value of 3D MRI for contouring by comparing it to 2D multi-planar MRI. Patients and methods. In 14 patients, 2D and 3D pelvic MRI were obtained at IGABT. High risk clinical target volume (HR CTV) was delineated by 2 experienced radiation oncologists, using the conventional (2D MRI-based) and test (3D MRI-based) approach. The value of 3D MRI for contouring was evaluated by using the inter-approach and inter-observer analysis of volumetric and topographic contouring uncertainties. To assess the magnitude of deviation from the conventional approach when using the test approach, the inter-approach analysis of contouring uncertainties was carried out for both observers. In addition, to assess reliability of 3D MRI for contouring, the impact of contouring approach on the magnitude of inter-observer delineation uncertainties was analysed. Results. No approach- or observer - specific differences in HR CTV sizes, volume overlap, or distances between contours were identified. When averaged over all delineated slices, the distances between contours in the inter-approach analysis were 2.6 (Standard deviation (SD) 0.4) mm and 2.8 (0.7) mm for observers 1 and 2, respectively. The magnitude of topographic and volumetric inter-observer contouring uncertainties, as obtained on the conventional approach, was maintained on the test approach. This variation was comparable to the inter-approach uncertainties with distances between contours of 3.1 (SD 0.8) and 3.0 (SD 0.7) mm on conventional and test approach, respectively. Variation was most pronounced at caudal HR CTV levels in both approaches and observers. Conclusions. 3D MRI could potentially replace multiplanar 2D MRI in cervix cancer IGABT, shortening the overall MRI scanning time and facilitating the contouring process, thus making this treatment method more widely employed.

Magnetic resonance imaging for assessment of parametrial tumour spread and regression patterns in adaptive cervix cancer radiotherapy

Abstract Purpose. To investigate the impact of magnetic resonance imaging (MRI)-morphologic differences in parametrial infiltration on tumour response during primary radiochemotherapy in cervical cancer. Material and methods. Eighty-five consecutive cervical cancer patients with FIGO stages IIB (n = 59) and IIIB (n = 26), treated by external beam radiotherapy (± chemotherapy) and image-guided adaptive brachytherapy, underwent T2-weighted MRI at the time of diagnosis and at the time of brachytherapy. MRI patterns of parametrial tumour infiltration at the time of diagnosis were assessed with regard to predominant morphology and maximum extent of parametrial tumour infiltration and were stratified into five tumour groups (TG): 1) expansive with spiculae; 2) expansive with spiculae and infiltrating parts; 3) infiltrative into the inner third of the parametrial space (PM); 4) infiltrative into the middle third of the PM; and 5) infiltrative into the outer third of the PM. MRI at the time of brachytherapy was used for identifying presence (residual vs. no residual disease) and signal intensity (high vs. intermediate) of residual disease within the PM. Left and right PM of each patient were evaluated separately at both time points. The impact of the TG on tumour remission status within the PM was analysed using χ2-test and logistic regression analysis. Results. In total, 170 PM were analysed. The TG 1, 2, 3, 4, 5 were present in 12%, 11%, 35%, 25% and 12% of the cases, respectively. Five percent of the PM were tumour-free. Residual tumour in the PM was identified in 19%, 68%, 88%, 90% and 85% of the PM for the TG 1, 2, 3, 4, and 5, respectively. The TG 3–5 had significantly higher rates of residual tumour in the PM in comparison to TG 1 + 2 (88% vs. 43%, p < 0.01). Conclusion. MRI-morphologic features of PM infiltration appear to allow for prediction of tumour response during external beam radiotherapy and chemotherapy. A predominantly infiltrative tumour spread at the time of diagnosis resulted in a significantly higher rate of residual tumour in the PM at the time of brachytherapy in comparison to a predominantly expansive tumour spread.

Uterine perforation – 5-year experience in 3-D image guided gynaecological brachytherapy at Institute of Oncology Ljubljana

Background. Accurate applicator placement is a precondition for the success of gynaecological brachytherapy (BT). Unrecognized uterine perforation can lead to bleeding, infection, high doses to pelvic organs and underdosage of the target volume, resulting in acute morbidity, long-term complications and reduced chance of cure. We aimed to assess the incidence and clinical characteristics of our cases with uterine perforation, review their management and impact on the treatment course. Patients and methods. In all patients, treated with utero-vaginal image guided BT for gynaecological cancer between January 2006 and December 2011, the CT/MR images with the applicator in place were reviewed. The incidence of uterine perforations was recorded. Clinical factors that may have predisposed to increased risk of perforation were recorded. Management of perforations and their impact on treatment course was assessed. Results. 219 patients (428 applications) were suitable for analysis. Uterine perforation was found in 13 (3.0%) applications in 10 (4.6%) patients. The most frequent perforation site was posterior uterine wall (n = 9), followed by anterior wall (n = 2) and fundus (n = 2). All cases were managed conservatively, without complications. Prophylactic antibiotics were administered in 8 cases. In 4 patients, abdominal and/or transrectal ultrasound (US) guidance was used on subsequent applications for applicator insertion; adequate applicator placement was achieved and treatment completed as planned in all cases. Conclusions. 3D imaging for BT planning enables accurate identification of uterine perforations. The incidence of perforations at our department is one of the lowest reported in the literature. US guidance of applicator insertion is useful and feasible, allowing to complete the planned treatment even in challenging cases.

Distance Deviation Measure of Contouring Variability

Abstract Background. Several methods that are currently used for contouring analysis have problems providing reliable and/ or meaningful results. In this paper a solution to these problems is proposed in a form of a novel measure, which was developed based on requirements defined for contouring studies. Materials and methods. The proposed distance deviation measure can be understood as an extension of the closest point measures in such a way that it does not measure only distances between points on contours but rather analyse deviation of distances to both/all contours from each image point/voxel. The obtained result is information rich, reliable and provided in a form of an image, enabling detailed topographic analysis. In addition to image representation, results can be further processed into angular representation for compact topographic analysis or into overall scalar estimates for quick assessment of contour disagreement. Results. Distance deviation method is demonstrated on a multi observer contouring example with complex contour shapes, i.e., with pronounced extremes and void interior. The results are presented using the three proposed methods. Conclusions. The proposed method can detect and measure contour variation irrespective of contour complexity and number of contour segments, while the obtained results are easy to interpret. It can be used in various situations, regarding the presence of reference contour or multiple test contours.

MRI-assisted cervix cancer brachytherapy pre-planning, based on application in paracervical anaesthesia: final report.

Abstract Background. Optimal applicator insertion is a precondition for the success of cervix cancer brachytherapy (BT). We aimed to assess feasibility and efficacy of MRI-assisted pre-planning, based on applicator insertion in para-cervical anaesthesia (PCA). Patients and methods. Five days prior to BT, the pre-planning procedure was performed in 18 cervix cancer patients: tandem-ring applicator was inserted under PCA, pelvic MRI obtained and applicator removed. Procedure tolerability was assessed. High risk clinical target volume (HR CTV) and organs at risk were delineated on the pre-planning MRI, virtual needles placed at optimal positions, and dose planning performed. At BT, insertion was carried out in subarachnoidal anaesthesia according to pre-planned geometry. Pre-planned and actual treatment parameters were compared. Results. Pre-planning procedure was well tolerated. Median difference between the pre-planned and actual needle insertion depth and position were 2 (0―10) mm and 4 (0―30) degrees, respectively. The differences between the pre-planned and actual geometric and dosimetric parameters were statistically non-significant. All actual needles were positioned inside the HR CTV and outside the organs at risk (OAR). Conclusions. Our pre-planning approach is well tolerated and effective. Pre-planned geometry and dose distribution can be reproduced at BT.

Potential role of TRAns Cervical Endosonography (TRACE) in brachytherapy of cervical cancer: proof of concept

Purpose Magnetic resonance imaging (MRI) is the gold standard for image guided adaptive brachytherapy (BT) of cervical cancer. Ultrasound is an attractive alternative with reasonable costs and high soft tissue depiction quality. This technical note aims to demonstrate the proof of principle for use of TRAns Cervical Endosonography with rotating transducer in the context of brachytherapy (TRACE BT). Material and methods TRACE BT presentation is based on a single stage IIB cervical cancer patient. Prior to second BT implant, rotating US transducer (6.9 mm diameter) was inserted in cervical canal and axial images obtained at 10 MHz, focal range of 30 mm, and axial resolution of 0.4 mm. Size and topography of hypo-echoic areas were assessed and optimal positions of interstitial needles were determined. Finally, intracavitary applicator was placed and needles inserted through vaginal ring-template according to TRACE pre-plan. MRI-based high risk clinical target volume (CTVHR) dimensions were compared with hypoechoic areas on TRACE. Topography of parametrial needles on post-insertion MRI was compared with TRACE pre-plan. Results Insertion of rotating mechanism into cervico-uterine cavity was safe, feasible and fast. The 360° imaging in axial plane enabled real-time assessment of cervix, uterus, and adjacent parametria. Qualitative comparison of TRACE with post-insertion MRI revealed favorable agreement of findings. In-plane size of CTVHR on MRI was comparable to hypoechoic areas on TRACE. Needle positions on post-insertion MRI corresponded to TRACE-based pre-plan. Main limitation of TRACE was gradual deterioration of image quality due to coupling gel removal. Conclusions Present proof of concept demonstrates potential role of TRACE-BT for cervical cancer as an attractive high-tech approach with reasonable costs. Prior to investigation of its clinical role, further development of TRACE methodology is needed. This includes reliable transducer-tissue coupling, applicator reconstruction, imaging range, limitations in extensive tumors, US-based contouring concepts, registration with other imaging methods, organ dose-assessment, real-time dosimetry, etc.