Publications by authors named "Kari Tanderup"

160 Publications

3D dose reconstruction based on in vivo dosimetry for determining the dosimetric impact of geometric variations in high-dose-rate prostate brachytherapy.

Radiother Oncol 2022 Jan 13. Epub 2022 Jan 13.

Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

Introduction: In vivo dosimetry (IVD) can be used for source tracking (ST), i.e., estimating source positions, during brachytherapy. The aim of this study was to exploit IVD-based ST to perform 3D dose reconstruction for high-dose-rate prostate brachytherapy and to evaluate the robustness of the treatments against observed geometric variations.

Materials And Methods: Twenty-three fractions of high-dose-rate prostate brachytherapy were analysed. The treatment planning was based on MRI. Time-resolved IVD was performed using a fibre-coupled scintillator. ST was retrospectively performed using the IVD measurements. The ST identified 2D positional shifts of each treatment catheter and thereby inferred updated source positions. For each fraction, the dose was recalculated based on the source-tracked catheter positions and compared with the original plan dose using differences in dose volume histogram indices.

Results: Of 352 treatment catheters, 344 had shifts of less than 5 mm. Shifts between 5 and 10 mm were observed for 3 catheters, and shifts greater than 10 mm for 2 catheters. The ST failed for 3 catheters. The maximum relative difference in clinical target volume (prostate + 3 mm isotropic margin) D was 5%. In one fraction, the bladder D dose increased by 18% (1.4Gy) due to a single source position being inside the bladder rather than nearby as planned. The max increase in urethra dose was 1.5Gy (15%).

Conclusion: IVD-based 3D dose reconstruction for high-dose-rate prostate brachytherapy is feasible. The dosimetric impact of the observed catheter shifts was limited. Dose reconstruction can therefore aid in determining the dosimetric impact of geometric variations and errors in brachytherapy.
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http://dx.doi.org/10.1016/j.radonc.2022.01.006DOI Listing
January 2022

Risk Factors for Late Persistent Fatigue After Chemoradiotherapy in Patients With Locally Advanced Cervical Cancer: An Analysis From the EMBRACE-I Study.

Int J Radiat Oncol Biol Phys 2021 Nov 25. Epub 2021 Nov 25.

Department of Radiation Oncology, Comprehensive Cancer Center, Medical University Hospital of Vienna, Vienna, Austria. Electronic address:

Purpose: This study aimed to evaluate patient- and treatment-related risk factors for late persistent fatigue within the prospective, multicenter EMBRACE-I study.

Methods And Materials: Fatigue was prospectively assessed (Common Terminology Criteria for Adverse Events, version 3) at baseline and during regular follow up in 993 patients with locally advanced cervical cancer after treatment with chemoradiotherapy and magnetic resonance imaging-guided brachytherapy. Risk factors for baseline and late persistent fatigue were evaluated with multivariable logistic regression. Late persistent fatigue was defined when either grade ≥1 or ≥2 was scored in at least half of the follow ups.

Results: The median follow-up time was 57 months. Baseline fatigue grade ≥1/≥2 (35.8%/6.3%, respectively) was associated with preexisting comorbidities, World Health Organization performance status, being underweight, severe pain, and tumor volume. Late persistent grade ≥1/≥2 fatigue (36.3%/5.8%, respectively) was associated with patient-related factors (baseline fatigue, younger age, obesity) along with the size of irradiated volumes and the level of radiation doses from external beam radiation therapy (EBRT) and brachytherapy (EBRT: V43Gy, V57Gy; EBRT + brachytherapy: V60Gy equivalent dose in 2-Gy fractions). Large-volume lymph node (LN) boost increased the risk for late persistent fatigue grade ≥2 by 18% and 5% in patients with and without baseline fatigue, respectively, compared with no LN boost. The risk for late persistent fatigue grade ≥1 increased by 7% and 4% with V43Gy <2000 cm³ versus >3000 cm³ in patients with and without baseline fatigue, respectively. Late persistent grade ≥1 fatigue occurred in 13% of patients without late persistent organ-related symptoms (gastrointestinal, genitourinary, and vaginal) versus 34% to 43%, 50% to 58%, and 73% in patients suffering from persistent symptoms involving 1, 2, or 3 organs, respectively.

Conclusions: Late persistent fatigue occurs in a considerable number of patients after chemoradiotherapy, and is associated with patient-related factors, the size of volumes irradiated to intermediate and high EBRT and brachytherapy doses, and other persistent organ-related morbidity. These findings support the importance of ongoing efforts to better tailor the target dose and reduce irradiation of healthy tissue without compromising target coverage, using highly conformal EBRT and brachytherapy techniques.
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http://dx.doi.org/10.1016/j.ijrobp.2021.11.022DOI Listing
November 2021

Severity and Persistency of Late Gastrointestinal Morbidity in Locally Advanced Cervical Cancer: Lessons Learned From EMBRACE-I and Implications for the Future.

Int J Radiat Oncol Biol Phys 2021 Oct 20. Epub 2021 Oct 20.

Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.

Purpose: The purpose was to evaluate patient- and treatment-related risk factors for physician-assessed and patient-reported gastrointestinal (GI) symptoms after radio(chemo)therapy and image guided adaptive brachytherapy in locally advanced cervical cancer.

Methods And Materials: Of 1416 patients from the EMBRACE-I study, 1199 and 1002 were prospectively evaluated using physician-assessed (Common Terminology Criteria for Adverse Events [CTCAE]) and patient-reported (European Organization for Research and Treatment of Cancer [EORTC]) GI symptoms, respectively. CTCAE severe grade (grade [G] ≥3) events were pooled according to the location in the GI tract (anus/rectum, sigmoid, and colon/small bowel). CTCAE G ≥2 and EORTC "very much" and "quite a bit" plus "very much" scores (≥ "quite a bit") were analyzed for individual symptoms with Cox regression. Logistic regression was used for persistent G ≥1 and EORTC ≥ "quite a bit" symptoms, defined if present in at least half of follow-ups.

Results: The incidence of G ≥3 events was 2.8%, 1.8%, and 2.3% for G ≥3 anus/rectum, sigmoid, and colon/small bowel events, respectively. Among G ≥2 symptoms, diarrhea and flatulence were the most prevalent (8.5% and 9.9%, respectively). Among patient-related factors, baseline morbidity, increasing age, smoking status, and low body mass index were associated with GI symptoms to varying degrees. Among treatment-related factors, rectum D and the International Commission on Radiation Units and Measurements recto-vaginal reference point (ICRU RV-RP) correlated with G ≥3 anus/rectum events and moderate/persistent diarrhea, proctitis, bleeding, abdominal cramps, and difficulty in bowel control. Bowel D correlated with G ≥3 sigmoid and colon/small bowel events and moderate/persistent diarrhea and flatulence. For external beam radiation therapy (EBRT), prescription dose correlated with G ≥3 anus/rectum, diarrhea, and difficulty in bowel control. Patients with large lymph-node boost (V57Gy) were at higher risk for G ≥3 sigmoid events, moderate/persistent diarrhea, proctitis, and cramps.

Conclusions: The analysis showed that both EBRT and image guided adaptive brachytherapy contribute to GI symptoms after locally advanced cervical cancer treatment. Rectum D, ICRU RV-RP , and bowel D are risk factors for GI morbidity. The risk for various symptoms was lower with an EBRT prescription of 45 Gy than 50 Gy and increased with larger V57Gy.
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http://dx.doi.org/10.1016/j.ijrobp.2021.09.055DOI Listing
October 2021

A high-Z inorganic scintillator-based detector for time-resolved in vivo dosimetry during brachytherapy.

Med Phys 2021 Nov 20;48(11):7382-7398. Epub 2021 Oct 20.

Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Purpose: High-dose rate (HDR) and pulsed-dose rate (PDR) brachytherapy would benefit from an independent treatment verification system to monitor treatment delivery and to detect errors in real time. This paper characterizes and provides an uncertainty budget for a detector based on a fiber-coupled high-Z inorganic scintillator capable of performing time-resolved in vivo dosimetry during HDR and PDR brachytherapy.

Method: The detector was composed of a detector probe and an optical reader. The detector probe consisted of either a 0.5 × 0.4 × 0.4 mm (HDR) or a 1.0 × 0.4 × 0.4 mm (PDR) cuboid ZnSe:O crystal glued onto an optical-fiber cable. The outer diameter of the detector probes was 1 mm, and fit inside standard brachytherapy catheters. The signal from the detector probe was read out at 20 Hz by a photodiode and a data acquisition device inside the optical reader. In order to construct an uncertainty budget for the detector, six characteristics were determined: (1) temperature dependence of the detector probe, (2) energy dependence as a function of the probe-to-source position in 2D (determined with 2 mm resolution using a robotic arm), (3) the signal-to-noise ratio (SNR), (4) short-term stability over 8 h, and (5) long-term stability of three optical readers and four probes used for in vivo monitoring in HDR and PDR treatments over 21 months (196 treatments and 189 detector calibrations, and (6) dose-rate dependence.

Results: The total uncertainty of the detector at a 20 mm probe-to-source distance was < 5.1% and < 5.8% for the HDR and PDR versions, respectively. Regarding the above characteristics, (1) the sensitivity of the detector decreased by an average of 1.4%/°C for detector probe temperatures varying from 22 to 37°C; (2) the energy dependence of the detector was nonlinear and depended on both probe-to-source distance and the angle between the probe and the brachytherapy source; (3) the median SNRs were 187 and 34 at a 20 mm probe-to-source distance for the HDR and PDR versions, respectively (corresponding median source activities of 4.8 and 0.56 Ci, respectively); (4) the detector response varied by 0.6% in 11 identical irradiations over 8 h; (5) the sensitivity of the four detector probes decreased systematically by 0-1.2%/100 Gy of dose delivered to the probes, and random fluctuations of 4.8% in the sensitivity were observed for the three probes used in PDR and 1.9% for the probe used in HDR; and (6) the detector response was linear with dose rate.

Conclusion: ZnSe:O detectors can be used effectively for in vivo dosimetry and with high accuracy for HDR and PDR brachytherapy applications.
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http://dx.doi.org/10.1002/mp.15257DOI Listing
November 2021

Risk factors for nodal failure after radiochemotherapy and image guided brachytherapy in locally advanced cervical cancer: An EMBRACE analysis.

Radiother Oncol 2021 10 2;163:150-158. Epub 2021 Sep 2.

University Medical Center Utrecht, Department of Radiation Oncology, Utrecht, The Netherlands.

Objective: To assess risk factors for nodal failure (NF) after definitive (chemo)radiotherapy and image-guided brachytherapy for locally advanced cervical cancer (LACC) for patients treated in the EMBRACE I study.

Materials And Methods: Data for pelvic NF and para-aortic (PAO) NF (NF) were analysed. After multiple imputation, univariable and multivariable Cox-regression was performed for clinical and treatment-related variables. For patients with affected pelvic nodes but no PAO nodes at diagnosis, additional analyses were performed for two subgroups: 1. 'small pelvis' nodes in internal and external iliac, obturator, parametrial, presacral and/or common iliac (CI) region and 2. any CI nodes (subgroup of 1).

Results: 1338 patients with 152 NF and 104 NF events were analysed with a median follow-up of 34.2 months (IQR 16.4-52.7). For the entire group, larger tumour width, nodal risk groups (in particular any CI nodes without PAO nodes), local failure, and lower Hb-nadir increased the risk of NF. Elective PAO-irradiation was independently associated with a decreased risk of NF (HR 0.53, 95%-CI 0.28-1.00, p = 0.05). For subgroup 1, having 'any CI nodes without PAO nodes' and local failure significantly increased NF risk. Additionally, elective PAO-irradiation was associated with less risk of NF (HR 0.38, 95%-CI 0.17-0.86, p = 0.02). For subgroup 2 only local failure was associated with higher risk of NF.

Conclusion: In this patient cohort, nodal disease and tumour width at diagnosis, as well as local failure, are risk factors for NF after definitive treatment. Having either 'any PAO nodes' (with or without pelvic nodes) or 'any CI nodes' (without PAO nodes) are stronger risk factors than involvement of nodes in the small pelvis alone. Elective PAO-irradiation was associated with significantly less NF, particularly in patients with nodal disease in the 'small pelvis' and/or CI region at time of diagnosis.
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http://dx.doi.org/10.1016/j.radonc.2021.08.020DOI Listing
October 2021

Impact of Vaginal Symptoms and Hormonal Replacement Therapy on Sexual Outcomes After Definitive Chemoradiotherapy in Patients With Locally Advanced Cervical Cancer: Results from the EMBRACE-I Study.

Int J Radiat Oncol Biol Phys 2022 Feb 1;112(2):400-413. Epub 2021 Sep 1.

Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands; Department of Radiotherapy, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands.

Purpose: To evaluate patient-reported sexual outcomes after chemoradiation therapy and image-guided adaptive brachytherapy for locally advanced cervical cancer in the observational, prospective, multicenter EMBRACE-I study.

Methods And Materials: Sexual outcomes were assessed prospectively with the European Organization for Research and Treatment of Cancer Qualify of Life Questionnaire (EORTC-QLQ-CX24) at baseline and follow-up. Crude incidence and prevalence rates of sexual activity, vaginal functioning problems (dryness, shortening, tightening, pain during intercourse), and sexual enjoyment were evaluated. Associations between pain during intercourse and vaginal functioning problems or sexual enjoyment were calculated, pooling observations over all follow-ups (Spearman correlation coefficient). In patients who were frequently sexually active (≥50% of follow-ups), the effects of regular hormonal replacement therapy (HRT) on vaginal functioning problems were evaluated (Pearson χ).

Results: The analysis involved 1045 patients with a median follow-up of 50 months. Sexual activity was reported by 22% of patients at baseline and by 40% to 47% of patients during follow-up (prevalence rates). Vaginal functioning problems in follow-up were dryness (18%-21%), shortening (15%-22%), tightening (16%-22%), pain during intercourse (9%-21%), and compromised enjoyment (37%-47%). Pain during intercourse was significantly associated with vaginal tightening (r = 0.544), shortening (r = 0.532), and dryness (r = 0.408) and negatively correlated with sexual enjoyment (r = -0.407). Regular HRT was associated with significantly less vaginal dryness (P = .015), shortening (P = .024), pain during intercourse (P = .003), and borderline higher sexual enjoyment (P = .062).

Conclusions: Vaginal functioning problems are associated with pain and compromised sexual enjoyment. Further effort is required for the primary prevention of vaginal morbidity with dose optimization and adaptation. Secondary prevention strategies, including HRT for vaginal and sexual health after radiation therapy in locally advanced cervical cancer, should be considered and sexual rehabilitation programs should be developed further.
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http://dx.doi.org/10.1016/j.ijrobp.2021.08.036DOI Listing
February 2022

Dosimetric impact of edema on inguinal lymph node boost in locally advanced vulvar cancer.

J Appl Clin Med Phys 2021 Oct 25;22(10):315-319. Epub 2021 Aug 25.

Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.

We aimed to evaluate the extent of groin edema and its dosimetric effect in boosted inguinal lymph nodes (LN) for vulvar cancer patients. The level of edema was determined in 10 patients treated with radical radiotherapy. A dosimetric evaluation of six LNs in the patient with the maximum level of edema was performed. The accumulated dose across CBCT fractions was acceptable for all six LNs (>94% of prescribed dose) even with the development of up to 13 mm of edema. The major contributor to fractional dose degradation was geographical displacement of the nodes. We suggest evaluation of edema on daily CBCT.
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http://dx.doi.org/10.1002/acm2.13372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8504581PMC
October 2021

Exclusive 3D-brachytherapy as a good option for stage-I inoperable endometrial cancer: a retrospective analysis in the gynaecological cancer GEC-ESTRO Working Group.

Clin Transl Oncol 2021 Jul 16. Epub 2021 Jul 16.

Radiation Oncology Department, University Hospital Leuven, Herestraat 49, 3000, Leuven, Belgium.

Purpose: Analyse outcomes of stage-I inoperable endometrial cancer (EC) patients from seven European centres treated with 3D-image-guided brachytherapy (IGBT) alone.

Materials And Methods: From 2004 to 2018, 62 patients (41 stage-IA and 21 IB) were retrospectively studied, analysing anaesthetic procedure, applicator type, BT-planning imaging, clinical target volume (CTV), BT schedule, overall daily-dose equivalent to 2 Gy (EQD2) to the CTV and D2 cm for organs at risk. Complications were evaluated using CTCAEv4 scores. The 2 and 5 year survival was calculated [cancer-specific survival (CSS), disease-free survival (DFS), local relapse-free survival (LRFS), loco-regional relapse-free survival (LRRFS) and distant metastasis-free survival (DMFS)]. Descriptive analysis and the Kaplan-Meier method were used for survival analysis.

Results: Mean follow-up: 32.8 months (SD 33.7). Spinal anaesthesia (38/62) followed by none (16/62) were the most common. Y-shaped Rotte applicators were used in 74% of patients. High-dose rate brachytherapy was administered in 89%. Median D90 to the CTV was 58.9 Gy (8.66-144 Gy). Eight patients presented relapse: four uterine, four nodal and four distant. The 2 and 5 year CSS was 93.3 and 80.5%, DFS 84.8 and 80.5%, LRFS was 93.1 and 88.7%, LRRFS was 91 and 91% and DMFS was 90.2 and 90.2%, respectively, CSS was better in stage-IA vs. IB (p = 0.043). Late vaginal and bladder G3-complication rates were 2.1%, respectively.

Conclusion: Inoperable EC patients can be safely treated by BT with 2 and 5 year CSS of 93 and 80.5%, respectively, with even better results for IA cases. Prospective studies on 3D-IGBT are necessary to better analyse EC patient outcomes based on dose and treated volumes.
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http://dx.doi.org/10.1007/s12094-021-02680-zDOI Listing
July 2021

IBS-GEC ESTRO-ABS recommendations for CT based contouring in image guided adaptive brachytherapy for cervical cancer.

Radiother Oncol 2021 07 18;160:273-284. Epub 2021 May 18.

Division of Radiation Oncology, Department of Radiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

MR Imaging is regarded asthe gold standardfor Image Gudied Adaptive Brachytherapy (IGABT) for cervical cancer. However, its wide applicability is limited by its availability, logistics and financial implications. Use of alternative imaging like CTand Ultrasound (US) for IGABT has been attempted. In order to arrive at a systematic, uniform and international approach for CT based definition and contouring of target structures, GEC ESTRO, IBS and ABS agreed to jointly develop such recommendations based on the concepts and terms as published in the ICRU Report 89. The minimum requirements are clinical examination & documentation, CT or MR imaging at diagnosis and at a minimum, CT imaging with the applicator in place. The recommendations are based on (i) assessment of the GTV at diagnosis and at brachytherapy, (ii) categorizing the response to external radiation into different clinical remission patterns, (iii) defining various clinico-radiological environments and (iv) definition & delineation of a target on CT imaging at the time of brachytherapy with the applicator in situ. CT based target contouring recommendations based on 4 remission categories within 8 defined environments, aim at improving the contouring accuracy for IGABT using CT, US and MRI as available. For each clinico-radiological environment, there is an attempt to minimize the specific uncertainties in order to arrive at the best possible contouring accuracy. Evaluating feasibility & reproducibility, to achieve a benchmark towards a gold standard MR IGABT and further clinical research including outcomes with CT Based IGABT will become the next steps.
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http://dx.doi.org/10.1016/j.radonc.2021.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8675891PMC
July 2021

Characterization of combined intracavitary/interstitial brachytherapy including oblique needles in locally advanced cervix cancer.

Brachytherapy 2021 Jul-Aug;20(4):796-806. Epub 2021 May 14.

Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.

Purpose: To characterize and report on dosimetric outcomes of image guided adaptive brachytherapy (IGABT) using intracavitary and interstitial (IC/IS) applicators including oblique needles (O-needles) in locally advanced cervical cancer (LACC).

Methods And Materials: Twenty LACC patients treated with radio-chemotherapy and offered IC/IS-IGABT including O-needles were analyzed. An in-house 3D-printed vaginal template was used to steer the needles parallel and obliquely in relation to the tandem, supplemented with free-hand needles if needed. Implant characteristics and loading patterns were analyzed. Using the equivalent dose in 2Gy-fractions (EQD2) concept, cumulative (EBRT+BT) V85, V75, V60Gy, targets/OARs doses and high dose volumes (150%, 200% and 300% (100% = 85 Gy EQD2)) were evaluated.

Results: Median(range) tumor width at diagnosis was 5.5(3.6; 7.5)cm; CTV volume was 45(23; 136)cm with maximum distance from tandem to CTV border of 3.4(2.5; 4.8)cm. T-stage distribution was IIB/III/IVA in 6(30%)/9(45%)/5(25%) of patients. At BT, 13(65%) patients had distal parametrial/pelvic wall infiltration. Median(range) number of needles per patient was 11(8-18). Average distribution of intrauterine, vaginal and interstitial dwell times were 31%, 25% and 44%, respectively. Median(range) dwell-time per dwell position was 11(2-127)% of average point-A based standard loading. Median V/V/V/V were 85(38; 171)/41(21; 93)/22(12; 41)/7(4; 19) cm; CTV D was 93(83; 97)Gy EQD2; bladder/rectum/sigmoid/bowel D were 78(64; 104)/65(52; 76)/59(53; 69)/61(47; 76)Gy EQD2.

Conclusions: The use of O-needles in patients with large and/or unfavorable tumors resulted in excellent target coverage and OARs sparing. Intrauterine and vaginal loadings were reduced compared to standard loading and almost half of the loading was shifted into IS needles. This was achieved with gentle loading in the majority of dwell positions.
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http://dx.doi.org/10.1016/j.brachy.2021.03.019DOI Listing
October 2021

Nomogram Predicting Overall Survival in Patients With Locally Advanced Cervical Cancer Treated With Radiochemotherapy Including Image-Guided Brachytherapy: A Retro-EMBRACE Study.

Int J Radiat Oncol Biol Phys 2021 09 29;111(1):168-177. Epub 2021 Apr 29.

Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.

Purpose: To present a nomogram for prediction of overall survival (OS) in patients with locally advanced cervical cancer (LACC) undergoing definitive radiochemotherapy including image-guided adaptive brachytherapy (IGABT).

Methods And Materials: Seven hundred twenty patients with LACC treated with radiochemotherapy including IGABT in 12 institutions (median follow-up 56 months) were analyzed; 248 deaths occurred. Thirteen candidate predictors for OS were a priori chosen on the basis of the literature and expert knowledge. Missing data (7.2%) were imputed using multiple imputation and predictive mean matching. Univariate analysis with a multivariable Cox regression model for OS stratified by center was performed. Stepwise selection of predictive factors with the Akaike Information Criterion was used to obtain a predictive model and construct a nomogram for OS predictions 60 months from diagnosis; this was internally validated by concordance probability as a measure of discrimination and a calibration plot.

Results: Thirteen potential predictive factors were evaluated; 10 factors reached statistical significance in univariate analysis (age, Hemoglobin, FIGO Stage, tumor width, corpus involvement, lymph node involvement, concurrent chemotherapy, dose to 90% of the high-risk clinical target volume volume of CTV at the first brachytherapy [CTVVolumeBT], overall treatment time [OTT]). Four factors were confirmed significant within the multivariable Cox regression model (FIGO Stage, lymph node involvement, concurrent chemotherapy, CTVVolumeBT). The predictive model and corresponding nomogram were based on 7 Akaike Information Criterion-selected factors (age, corpus involvement, FIGO Stage, lymph node involvement, concurrent chemotherapy, CTVVolumeBT, OTT) and showed promising calibration and discrimination (cross-validated concordance probability c = 0.73).

Conclusions: This is the first nomogram to predict OS in patients with LACC treated with IGABT. In addition to previously reported factors (age, FIGO stage, corpus involvement, chemotherapy delivery, OTT, lymph node involvement), status of primary tumor at the time of brachytherapy seems to be an essential outcome predictor. These results can facilitate individualized tailoring of treatment and patient counseling during the treatment.
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http://dx.doi.org/10.1016/j.ijrobp.2021.04.022DOI Listing
September 2021

Impact of interfractional target motion in locally advanced cervical cancer patients treated with spot scanning proton therapy using an internal target volume strategy.

Phys Imaging Radiat Oncol 2021 Jan 6;17:84-90. Epub 2021 Feb 6.

Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.

Background And Purpose: The more localized dose deposition of proton therapy (PT) compared to photon therapy might allow a reduction in treatment-related side effects but induces additional challenges to address. The aim of this study was to evaluate the impact of interfractional motion on the target and organs at risk (OARs) in cervical cancer patients treated with spot scanning PT using an internal target volume (ITV) strategy.

Methods And Materials: For ten locally advanced cervical cancer patients, empty and full bladder planning computed tomography (pCT) as well as 25 daily cone beam CTs (CBCTs) were available. The Clinical Target Volume (CTV), the High Risk CTV (CTV) (gross tumor volume and whole cervix), the non-involved uterus as well as the OARs (bowel, bladder and rectum) were contoured on the daily CBCTs and transferred to the pCT through rigid bony match. Using synthetic CTs derived from pCTs, four-beam spot scanning PT plans were generated to target the patient-specific ITV with 45 Gy(RBE) in 25 fractions. This structure was defined based on pre-treatment MRI and CT to anticipate potential target motion throughout the treatment. D98% of the targets and V40Gy(RBE) of the OARs were extracted from the daily anatomies, accumulated and analyzed. In addition, the impact of bladder volume deviations from planning values on target and bowel dose was investigated.

Results: The ITV strategy ensured a total accumulated dose >42.75 Gy(RBE) to the CTV for all ten patients. Two patients with large bladder-related uterus motion had accumulated dose to the non-involved uterus of 35.7 Gy(RBE) and 41.1 Gy(RBE). Variations in bowel V40Gy(RBE) were found to be correlated (Pearson r = -0.55; p-value <0.0001) with changes in bladder volume during treatment.

Conclusion: The ITV concept ensured adequate dose to the CTV, but was insufficient for the non-involved uterus of patients subject to large target interfractional motion. CBCT monitoring and occasional replanning is recommended along the same lines as with photon radiotherapy in cervical cancer.
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http://dx.doi.org/10.1016/j.phro.2021.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058016PMC
January 2021

MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study.

Lancet Oncol 2021 04;22(4):538-547

Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.

Background: The concept of the use of MRI for image-guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer was introduced 20 years ago. Here, we report on EMBRACE-I, which aimed to evaluate local tumour control and morbidity after chemoradiotherapy and MRI-based IGABT.

Methods: EMBRACE-I was a prospective, observational, multicentre cohort study. Data from patients from 24 centres in Europe, Asia, and North America were prospectively collected. The inclusion criteria were patients older than 18 years, with biopsy-proven squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix, The International Federation of Gynecology and Obstetrics (FIGO) stage IB-IVA disease or FIGO stage IVB disease restricted to paraaortic lymph metastasis below the L1-L2 interspace, suitable for curative treatment. Treatment consisted of chemoradiotherapy (weekly intravenous cisplatin 40 mg/m, 5-6 cycles, 1 day per cycle, plus 45-50 Gy external-beam radiotherapy delivered in 1·8-2 Gy fractions) followed by MRI-based IGABT. The MRI-based IGABT target volume definition and dose reporting was according to Groupe Européen de Curiethérapie European Society for Radiation Oncology recommendations. IGABT dose prescription was open according to institutional practice. Local control and late morbidity were selected as primary endpoints in all patients available for analysis. The study was registered with ClinicalTrials.gov, NCT00920920.

Findings: Patient accrual began on July 30, 2008, and closed on Dec 29, 2015. A total of 1416 patients were registered in the database. After exclusion for not meeting patient selection criteria before treatment, being registered but not entered in the database, meeting the exclusion criteria, and being falsely excluded, data from 1341 patients were available for analysis of disease and data from 1251 patients were available for assessment of morbidity outcome. MRI-based IGABT including dose optimisation was done in 1317 (98·2%) of 1341 patients. Median high-risk clinical target volume was 28 cm (IQR 20-40) and median minimal dose to 90% of the clinical target volume (D) was 90 Gy (IQR 85-94) equi-effective dose in 2 Gy per fraction. At a median follow-up of 51 months (IQR 20-64), actuarial overall 5-year local control was 92% (95% CI 90-93). Actuarial cumulative 5-year incidence of grade 3-5 morbidity was 6·8% (95% CI 5·4-8·6) for genitourinary events, 8·5% (6·9-10·6) for gastrointestinal events, 5·7% (4·3-7·6) for vaginal events, and 3·2% (2·2-4·5) for fistulae.

Interpretation: Chemoradiotherapy and MRI-based IGABT result in effective and stable long-term local control across all stages of locally advanced cervical cancer, with a limited severe morbidity per organ. These results represent a positive breakthrough in the treatment of locally advanced cervical cancer, which might be used as a benchmark for clinical practice and all future studies.

Funding: Medical University of Vienna, Aarhus University Hospital, Elekta AB, and Varian Medical Systems.
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http://dx.doi.org/10.1016/S1470-2045(20)30753-1DOI Listing
April 2021

Vaginal dose-surface maps in cervical cancer brachytherapy: Methodology and preliminary results on correlation with morbidity.

Brachytherapy 2021 May-Jun;20(3):565-575. Epub 2021 Mar 17.

Department of Radiation Oncology, University Medical Centre Utrecht, the Netherlands.

Purpose: The purpose of the study was to develop a methodology for vaginal dose-surface maps (DSMs) in patients with cervix cancer and to investigate dose-surface histogram metrics as predictors for vaginal stenosis (St) and mucositis (Muc).

Methods And Materials: Thirty-one patients with locally advanced cervix cancer with no vaginal St/Muc (CTCAE-v3) G ≥ 2 at baseline were analyzed. Patients were divided in four morbidity groups: 15 with St/Muc G0/1, 6 with St G ≥ 2, 4 with St/Muc G ≥ 2, and 6 with Muc G ≥ 2. Patients received external beam radiotherapy and 4-fraction intracavitary/interstitial high-dose-rate brachytherapy using tandem and ovoids. DSMs were generated from inner/outer vaginal surfaces. DSMs of external beam radiotherapy and brachytherapy (Gy EQD2) were added based on a system of homologous points, to generate cumulative DSMs. Dose-surface histogram/dose-volume histogram parameters, location of high/intermediate-dose regions, rectovaginal reference point, vaginal lateral 5 mm point doses, and vagina/implant dimensions were investigated for St and Muc prediction. Average/difference DSMs and one-way analysis of variance were used to compare between groups.

Results: Best predictors of stenosis were D and upper-vagina S(%). Cutoffs of ∼90 Gy EQD2 for D and ∼80% for S to top 3 cm inner vaginal surface suitably discriminated for stenosis. Spatial dose location on average/difference DSMs showed significantly higher doses (by > 20 Gy, p < 0.001) over longer parts of the dorsolateral vagina and higher rectovaginal reference point doses for any G ≥ 2 morbidity, over the whole circumference of the upper vagina for G ≥ 2 stenosis. Dose-volume histogram parameters were dependent on vaginal wall thickness. An increase of wall thickness from 2 to 4 mm resulted in an increase of D (D) of 16% (32%).

Conclusions: A novel method was developed to generate vaginal DSMs and spatial-dose metrics. DSMs were found to correlate with vaginal stenosis. The findings of this study are promising and should be further validated on a larger patient cohort, treated with different applicators.
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http://dx.doi.org/10.1016/j.brachy.2021.02.004DOI Listing
October 2021

Accuracy of an in vivo dosimetry-based source tracking method for afterloading brachytherapy - A phantom study.

Med Phys 2021 May 23;48(5):2614-2623. Epub 2021 Mar 23.

Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

Purpose: To report on the accuracy of an in vivo dosimetry (IVD)-based source tracking (ST) method for high dose rate (HDR) prostate brachytherapy (BT).

Methods: The ST was performed on a needle-by-needle basis. A least square fit of the expected to the measured dose rate was performed using the active dwell positions in the given needle. Two fitting parameters were used to determine the position of each needle relative to the IVD detector: radial (away or toward the detector) and longitudinal (along the axis of the treatment needle). The accuracy of the ST was assessed in a phantom where the geometries of five HDR prostate BT treatments previously treated at our clinic were reproduced. For each of the five treatment geometries, one irradiation was performed with the detector placed in the middle of the implant. Furthermore, four additional irradiations were performed for one of the geometries where the detector was retracted caudally in four steps of 10-15 mm and up to 12 mm inferior of the most inferior active dwell position, which represented the prostate apex. The time resolved dose measurements were retrieved at a rate of 20 Hz using a detector based on an Al O :C radioluminescence crystal, which was placed inside a standard BT needle. Individual calibrations of the detector were performed prior to each of the nine irradiations.

Results: Source tracking could be applied in all needles across all nine irradiations. For irradiations with the detector located in the middle region of the implant (a total of 89 needles), the mean ± standard deviation (SD, k = 1) accuracy was -0.01 mm ± 0.38 mm and 0.30 mm ± 0.38 mm in the radial and longitudinal directions, respectively. Caudal retraction of the detector did not lead to reduced accuracy as long as the detector was located superior to the most inferior active dwell positions in all needles. However, reduced accuracy was observed for detector positions inferior to the most inferior active dwell positions which corresponded to detector positions in and inferior to the prostate apex region. Detector positions in the prostate apex and 12 mm inferior to the prostate resulted in mean ± SD (k = 1) ST accuracy of 0.7 mm ± 1 mm and 2.8 mm ± 1.6 mm, respectively, in radial direction, and -1.7 mm ± 1 mm and -2.1 mm ± 1.1 mm, respectively, in longitudinal direction. The largest deviations for the configurations with those detector positions were 2.6 and 5.4 mm, respectively, in the radial direction and -3.5 and -3.8 mm, respectively, in the longitudinal direction.

Conclusion: This phantom study demonstrates that ST based on IVD during prostate BT is adequately accurate for clinical use. The ST yields submillimeter accuracy on needle positions as long as the IVD detector is positioned superior to at least one active dwell position in all needles. Locations of the detector inferior to the prostate apex result in decreased ST accuracy while detector locations in the apex region and above are advantageous for clinical applications.
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http://dx.doi.org/10.1002/mp.14812DOI Listing
May 2021

Risk factors and dose-effects for bladder fistula, bleeding and cystitis after radiotherapy with imaged-guided adaptive brachytherapy for cervical cancer: An EMBRACE analysis.

Radiother Oncol 2021 05 3;158:312-320. Epub 2021 Feb 3.

Department of Oncology, Aarhus University Hospital, Denmark.

Purpose: To identify patient- and treatment-related risk factors for fistula, bleeding, cystitis, pain and difficulty in voiding in locally advanced cervical cancer patients treated with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT).

Material And Methods: Morbidity within the EMBRACE-I study was prospectively reported for physician-assessed (CTCAE) fistula, bleeding and cystitis and patient-reported (EORTC) pain and difficulty in voiding. Analysis of risk factors was performed in patients without bladder infiltration. Risk factors were tested with Cox regression for grade (G) ≥ 3 cystitis, for G ≥ 2 fistula, bleeding and cystitis, and for EORTC "very much" and "quite a bit" or worse.

Results: Of 1416 patients enrolled, 1153 and 884 patients without bladder infiltration were evaluable for the analysis of CTCAE and EORTC items, respectively. Median follow-up was 48[3-120] months. Crude incidence rates for G ≥ 2 fistula, bleeding and cystitis were 0.7%, 2.7% and 8.8%, respectively, and 16% and 14% for "quite a bit" or worse pain and difficulty in voiding, respectively. Baseline urinary morbidity and overweight/obesity were significant risk factors for most endpoints. Bladder D correlated with G ≥ 2 fistula, bleeding and cystitis, while ICRU bladder point dose correlated with EORTC pain "quite a bit" or worse. An increase from 75 Gy to 80 Gy in bladder D resulted in an increase from 8% to 13% for 4-year actuarial estimate of G ≥ 2 cystitis.

Conclusion: Clinical and treatment-related risk factors for bladder fistula, bleeding and cystitis were identified within a prospective and multi-institutional setting. A dose-effect was established with bladder D, reinforcing the importance of continued optimization during individualized IGABT planning.
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http://dx.doi.org/10.1016/j.radonc.2021.01.019DOI Listing
May 2021

Results of image guided brachytherapy for stage IB cervical cancer in the RetroEMBRACE study.

Radiother Oncol 2021 04 19;157:24-31. Epub 2021 Jan 19.

Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna, Austria.

Objective: Multiple treatment options are used in early local-stage cervical cancer, including combinations of surgery with neoadjuvant/adjuvant radiotherapy and chemotherapy. Our aim was to determine the outcome for definitive chemoradiation with image guided brachytherapy (IGBT).

Methods: FIGO staging system was used in our study. We included 123 patients with stage IB cervical cancer, treated at 12 centers with external beam radiotherapy (EBRT) ± Chemotherapy and IGBT. Three- and 5-year actuarial local control (LC), pelvic control (PC), overall survival (OS), cancer-specific survival (CSS) and late morbidity (CTCAE v 3.0) were computed.

Results: Median age was 48 (23-82) years. FIGO stage distribution was: IB1 68% and IB2 32%; 41% of the entire cohort had nodal metastases and 73% squamous-cell carcinoma. MRI-based tumor size was >40 mm in 63%. Median EBRT dose was 45 (40-50) Gy; 84% received chemotherapy. At IGBT, mean CTV-HR D90 was 93 ± 17 Gy (EQD2). D2cc for bladder was 76 ± 14 Gy, rectum 66 ± 11 Gy, sigmoid 66 ± 10 Gy, bowel 67 ± 7 Gy (EQD2). At 43-months median follow-up, 9% of patients had systemic, 6% paraaortic, 3% pelvic-nodal and 2% local failure. Five-year LC was 98%, PC 96%, CSS 90%, OS 83%. Intestinal G3--4 morbidity was 8%, urinary 7% and vaginal 0%.

Conclusions: Chemoradiation with IGBT for FIGO stage IB cervical cancer leads to excellent loco-regional control with limited morbidity. In IB node-negative disease, it can be regarded equivalent to surgery in terms of oncologic outcome. In tumors with unfavorable pre-treatment characteristics, chemoradiation is the first choice to avoid combining surgery with adjuvant therapy.
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http://dx.doi.org/10.1016/j.radonc.2021.01.005DOI Listing
April 2021

dosimetry in brachytherapy: Requirements and future directions for research, development, and clinical practice.

Phys Imaging Radiat Oncol 2020 Oct 28;16:1-11. Epub 2020 Sep 28.

Department of Oncology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus, Denmark.

Brachytherapy can deliver high doses to the target while sparing healthy tissues due to its steep dose gradient leading to excellent clinical outcome. Treatment accuracy depends on several manual steps making brachytherapy susceptible to operational mistakes. Currently, treatment delivery verification is not routinely available and has led, in some cases, to systematic errors going unnoticed for years. The brachytherapy community promoted developments in dosimetry (IVD) through research groups and small companies. Although very few of the systems have been used clinically, it was demonstrated that the likelihood of detecting deviations from the treatment plan increases significantly with time-resolved methods. Time-resolved methods could interrupt a treatment avoiding gross errors which is not possible with time-integrated dosimetry. In addition, lower experimental uncertainties can be achieved by using source-tracking instead of direct dose measurements. However, the detector position in relation to the patient anatomy remains a main source of uncertainty. The next steps towards clinical implementation will require clinical trials and systematic reporting of errors and near-misses. It is of utmost importance for each IVD system that its sensitivity to different types of errors is well understood, so that end-users can select the most suitable method for their needs. This report aims to formulate requirements for the stakeholders (clinics, vendors, and researchers) to facilitate increased clinical use of IVD in brachytherapy. The report focuses on high dose-rate IVD in brachytherapy providing an overview and outlining the need for further development and research.
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http://dx.doi.org/10.1016/j.phro.2020.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807583PMC
October 2020

Dosimetric Impact of Intrafraction Motion in Online-Adaptive Intensity Modulated Proton Therapy for Cervical Cancer.

Int J Radiat Oncol Biol Phys 2021 04 20;109(5):1580-1587. Epub 2020 Nov 20.

Erasmus MC Cancer Institute, University Medical Center Rotterdam, Department of Radiotherapy, The Netherlands; Holland PTC, Delft, The Netherlands.

Purpose: A method was recently developed for online-adaptive intensity modulated proton therapy (IMPT) in patients with cervical cancer. The advantage of this approach, relying on the use of tight margins, is challenged by the intrafraction target motion. The purpose of this study was to evaluate the dosimetric effect of intrafraction motion on the target owing to changes in bladder filling in patients with cervical cancer treated with online-adaptive IMPT.

Methods And Materials: In 10 patients selected to have large uterus motion induced by bladder filling, the intrafraction anatomic changes were simulated for several prefraction durations for online (automated) contouring and planning. For each scenario, the coverage of the primary target was evaluated with margins of 2.5 and 5 mm.

Results: Using a 5- mm planning target volume margin, median accumulated D98% was greater than 42.75 Gy (95% of the prescribed dose) in the case of a prefraction duration of 5 and 10 minutes. For a prefraction duration of 15 minutes, this parameter deteriorated to 42.6 Gy. When margins were reduced to 2.5 mm, only a 5-minute duration resulted in median target D98% above 42.75 Gy. In addition, smaller bladders were found to be associated with larger dose degradations compared with larger bladders.

Conclusions: This study indicates that intrafraction anatomic changes can have a substantial dosimetric effect on target coverage in an online-adaptive IMPT scenario for patients subject to large uterus motion. A margin of 5 mm was sufficient to compensate for the intrafraction motion due to bladder filling for up to 10 minutes of prefraction time. However, compensation for the uncertainties that were disregarded in this study, by using margins or robust optimization, is also required. Furthermore, a large bladder volume restrains intrafraction target motion and is recommended for treating patients in this scenario. Assuming that online-adaptive IMPT remains beneficial as long as narrow margins are used (5 mm or below), this study demonstrates its feasibility with regard to intrafraction motion.
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http://dx.doi.org/10.1016/j.ijrobp.2020.11.037DOI Listing
April 2021

3D source tracking and error detection in HDR using two independent scintillator dosimetry systems.

Med Phys 2021 May 28;48(5):2095-2107. Epub 2021 Mar 28.

The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Purpose: The aim of this study is to perform three-dimensional (3D) source position reconstruction by combining in vivo dosimetry measurements from two independent detector systems.

Methods: Time-resolved dosimetry was performed in a water phantom during HDR brachytherapy irradiation with Ir source using two detector systems. The first was based on three plastic scintillator detectors and the second on a single inorganic crystal (CsI:Tl). Brachytherapy treatments were simulated in water under TG-43U1 conditions, including a HDR prostate plan. Treatment needles were placed in distances covering a range of source movement of 120 mm around the detectors. The distance from each dwell position to each scintillator was determined based on the measured dose rates. The three distances given by the mPSD were recalculated to a position along the catheter (z) and a distance radially away from the mPSD (xy) for each dwell position (a circumference around the mPSD). The source x, y, and z coordinates were derived from the intersection of the mPSD's circumference with the sphere around the ISD based on the distance to this detector. We evaluated the accuracy of the source position reconstruction as a function of the distance to the source, the most likely location for detector positioning within a prostate volume, as well as the capacity to detect positioning errors.

Results: Approximately 4000 source dwell positions were tracked for eight different HDR plans. An intersection of the mPSD torus and the ISD sphere was observed in 77.2% of the dwell positions, assuming no uncertainty in the dose rate determined distance. This increased to 100% if 1σ search regions were added. However, only 73(96)% of the expected dwell positions were found within the intersection band for 1(2) σ uncertainties. The agreement between the source's reconstructed and expected positions was within 3 mm for a range of distances to the source up to 50 mm. The experiments on a HDR prostate plan, showed that by having at least one of the detectors located in the middle of the prostate volume, reduces the measurement deviations considerably compared to scenarios where the detectors were located outside of the prostate volume. The analysis showed a detection probability that, in most cases, is far from the random detection threshold. Errors of 1(2) mm can be detected in ranges of 5-25 (25-50) mm from the source, with a true detection probability rate higher than 80%, while the false probability rate is kept below 20%.

Conclusions: By combining two detector responses, we enabled the determination of the absolute source coordinates. The combination of the mPSD and the ISD in vivo dosimetry constitutes a promising alternative for real-time 3D source tracking in HDR brachytherapy.
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http://dx.doi.org/10.1002/mp.14607DOI Listing
May 2021

Management of oligo-metastatic and oligo-recurrent cervical cancer: A pattern of care survey within the EMBRACE research network.

Radiother Oncol 2021 02 2;155:151-159. Epub 2020 Nov 2.

Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, the Netherlands. Electronic address:

Background: In the metastatic or recurrent cervical cancer, systemic chemotherapy constitutes the main treatment. Though there is an increasing use of high dose external radiation and brachytherapy in the metastatic setting, no consensus exists.

Methods: A 17-item survey was designed with additional case-based questions to explore present management of oligo-metastatic and oligo-recurrent cervix cancer within EMBRACE research group participating sites. The questions were designed to elicit prevailing practices in the management of de-novo oligo-metastasis and oligo-recurrent setting after completing the primary treatment of cervix cancer. The survey was sent electronically with two rounds of email reminders to respond over a 2-week survey period. The online survey was designed such that it was mandatory to complete all questions. The responses were recorded and results were summarized as proportions and summary statistics were generated.

Results: Twenty-two centers responded to this survey. A majority (90%) of respondents reported a low incidence of de-novo oligo-metastatic cervical cancer in their practice (<5%), with a higher proportion of patients with oligo-recurrence after completing primary treatment (5-10%). All responding sites preferred to treat pelvic disease in the de-novo oligo-metastatic setting albeit with different fractionation regimens. While 68.2% of respondents recommended chemo-radiation and brachytherapy, 31.8% considered additional systemic therapy. Overall 77.3% centers recommended the use of stereotactic ablative radiation therapy to oligo-metastasis. For out-of-field nodal recurrences, 63.7% of respondents considered treating with curative intent, while 59% preferred treating in-field recurrence with palliative intent. A vast majority of the participating centers (90%) have stereotactic radiation therapy capacity and would consider a clinical trial addressing oligo-metastatic and oligo-recurrent cervical cancer.

Conclusion: Although contemporary practice is variable, a substantial proportion of EMBRACE centers consider high dose radiation in de-novo metastatic and oligo-recurrence settings. However, there is clear need for a joint clinical protocol and prospective studies to address the role of high dose radiation within oligo-recurrent and oligo-metastatic scenarios.
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http://dx.doi.org/10.1016/j.radonc.2020.10.037DOI Listing
February 2021

Dose-Volume Effects and Risk Factors for Late Diarrhea in Cervix Cancer Patients After Radiochemotherapy With Image Guided Adaptive Brachytherapy in the EMBRACE I Study.

Int J Radiat Oncol Biol Phys 2021 03 14;109(3):688-700. Epub 2020 Oct 14.

Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.

Purpose: To evaluate patient- and treatment-related risk factors associated with incidence and persistence of late diarrhea after radiochemotherapy and image guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer.

Materials And Methods: Of 1416 patients from the EMBRACE I study, 1199 were prospectively evaluated using physician-reported (Common Terminology Criteria for Adverse Events version 3 [CTCAEv3]) assessment for diarrhea; median follow-up 48 months. Patient-reported outcome (EORTC) was available in 900 patients. Incidence of CTCAE G≥2, G≥3, and EORTC "very much" diarrhea was analyzed with Cox proportional hazards regression. Binary logistic regression was used for analysis of persistent G≥1 and EORTC "quite a bit" - "very much" (≥"quite a bit") diarrhea, defined if present in at least half of all follow-ups.

Results: Crude incidences of G≥2 and G≥3 diarrhea were 8.3% and 1.5%, respectively, and 8% of patients reported "very much" diarrhea. Persistent G≥1 and ≥"quite a bit" diarrhea was present in 16% and 7%, respectively. Patient-related risk factors were baseline diarrhea, smoking, and diabetes with hazard ratios of 1.4 to 7.3. Treatment-related risk factors included prescribed dose, V43 Gy, V57 Gy (lymph node boost), and para-aortic irradiation for external beam radiation therapy (EBRT). G≥2 diarrhea at 3 years increased from 9.5% to 19.9% with prescribed dose 45 Gy versus 50 Gy, 8.7% to 14.0% with V43 Gy <2500 cm versus >3000 cm and 9.4% to 19.0% with V57 Gy <165 cm versus ≥165 cm. Brachytherapy-related bowel and rectum D were also associated with diarrhea.

Conclusion: Dose and volume effects have been established for late diarrhea after radiochemotherapy and IGABT in both CTCAE and EORTC reporting. The risk of diarrhea was lower with a pelvic EBRT prescription of 45 Gy, and higher with larger lymph node boosts volumes (ie, ≥165 cm). The importance of EBRT volumes as determinants of late toxicity underline the need for continuous quality assurance of target contouring, dose planning, and conformity. The findings of brachytherapy dosimetric factors related to the intestines may become more important with highly conformal EBRT.
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http://dx.doi.org/10.1016/j.ijrobp.2020.10.006DOI Listing
March 2021

Importance of the ICRU bladder point dose on incidence and persistence of urinary frequency and incontinence in locally advanced cervical cancer: An EMBRACE analysis.

Radiother Oncol 2021 05 14;158:300-308. Epub 2020 Oct 14.

Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.

Purpose: To identify patient- and treatment-related risk factors and dose-effects for urinary frequency and incontinence in locally advanced cervical cancer (LACC) treated with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT).

Material And Methods: Physician-assessed (CTCAE) and patient-reported (EORTC) frequency and incontinence recorded in the EMBRACE-I study were analysed. Risk factors analysis was performed in patients without bladder infiltration and with baseline morbidity available. Cox regression was used for CTCAE grade (G) ≥ 3 and G ≥ 2 and for EORTC "very much" and "quite a bit" or worse. Logistic regression was used for late persistent morbidity defined when CTCAE G ≥ 1 or EORTC ≥ "quite a bit" were scored in at least half of follow-ups.

Results: Longitudinal data on 1153 and 884 patients were available for CTCAE and EORTC analysis, respectively. Median follow-up was 48[3-120] months. Crude incidence rates of G≥2 were 13% and 11% for frequency and incontinence, respectively. Baseline morbidity and overweight-obesity were risk factors for both symptoms. Elderly patients were at higher risk for incontinence. Patients receiving conformal-radiotherapy were at higher risk for frequency. ICRU bladder point (ICRU-BP) dose was a stronger predictor for incontinence than bladder D. The 5-year actuarial estimate of G ≥ 2 incontinence increased from 11% to 20% with ICRU-BP doses > 75 Gy compared to ≤ 65 Gy. Frequency showed weaker associations with dose.

Conclusion: ICRU-BP dose, in addition to clinical parameters, is a risk factor for urinary incontinence and shows a dose-effect after radio(chemo)therapy and IGABT. ICRU-BP dose should be monitored during treatment planning alongside volumetric parameters. Frequency seems associated with larger irradiated volumes.
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http://dx.doi.org/10.1016/j.radonc.2020.10.003DOI Listing
May 2021

Initiatives for education, training, and dissemination of morbidity assessment and reporting in a multiinstitutional international context: Insights from the EMBRACE studies on cervical cancer.

Brachytherapy 2020 Nov - Dec;19(6):837-849. Epub 2020 Sep 22.

Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.

In 2008, the GEC ESTRO Gyn network launched the first multiinstitutional, observational, and prospective international study on MRI-guided brachytherapy in locally advanced cervical cancer patients (EMBRACE-I). EMBRACE-I was followed by EMBRACE-II from 2016 and ongoing. Among the aims of the EMBRACE studies are to benchmark morbidity outcomes and develop dose-volume effects and predictive models for morbidity. The EMBRACE studies collect both physician (CTCAE v.3) and patient (EORTC QLQ-C30/CX24) reported outcomes, including baseline information, in a regular follow-up schedule. The EMBRACE studies feature high numbers of patients (EMBRACE-I N = 1416, EMBRACE-II N = 1500 expected) enrolled from many institutions worldwide (EMBRACE-I n = 23, EMBRACE-II n = 45). This large-scale multiinstitutional approach offers a unique opportunity to investigate and develop new strategies for improving the quality of assessment and reporting of morbidity. This report presents an overview of the challenges and pitfalls regarding the assessment and reporting of morbidity encountered during more than a decade of development and research activities within the EMBRACE consortium. This includes the recognition and evaluation of inconsistencies in the morbidity assessment, and consequently, the provision of assistance and training in the scoring procedure to reduce systematic assessment bias. In parallel, a variety of methodological approaches were tested to comprehensively summarize morbidity outcomes, and a novel approach was developed to refine dose-effect models and risk factor analyses. The purpose of this report is to present an overview of these findings, describe the learning process, and the strategies that have consequently been implemented regarding educational activities, training, and dissemination.
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http://dx.doi.org/10.1016/j.brachy.2020.08.011DOI Listing
June 2021

Phantom-based quality assurance for multicenter quantitative MRI in locally advanced cervical cancer.

Radiother Oncol 2020 12 12;153:114-121. Epub 2020 Sep 12.

Department of Radiation Oncology, the Netherlands Cancer Institute, Amsterdam, the Netherlands.

Background And Purpose: A wide variation of MRI systems is a challenge in multicenter imaging biomarker studies as it adds variation in quantitative MRI values. The aim of this study was to design and test a quality assurance (QA) framework based on phantom measurements, for the quantitative MRI protocols of a multicenter imaging biomarker trial of locally advanced cervical cancer.

Materials And Methods: Fifteen institutes participated (five 1.5 T and ten 3 T scanners). Each institute optimized protocols for T2, diffusion-weighted imaging, T1, and dynamic contrast-enhanced (DCE-)MRI according to system possibilities, institutional preferences and study-specific constraints. Calibration phantoms with known values were used for validation. Benchmark protocols, similar on all systems, were used to investigate whether differences resulted from variations in institutional protocols or from system variations. Bias, repeatability (%RC), and reproducibility (%RDC) were determined. Ratios were used for T2 and T1 values.

Results: The institutional protocols showed a range in bias of 0.88-0.98 for T2 (median %RC = 1%; %RDC = 12%), -0.007 to 0.029 × 10 mm/s for the apparent diffusion coefficient (median %RC = 3%; %RDC = 18%), and 0.39-1.29 for T1 (median %RC = 1%; %RDC = 33%). For DCE a nonlinear vendor-specific relation was observed between measured and true concentrations with magnitude data, whereas the relation was linear when phase data was used.

Conclusion: We designed a QA framework for quantitative MRI protocols and demonstrated for a multicenter trial for cervical cancer that measurement of consistent T2 and apparent diffusion coefficient values is feasible despite protocol differences. For DCE-MRI and T1 mapping with the variable flip angle method, this was more challenging.
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http://dx.doi.org/10.1016/j.radonc.2020.09.013DOI Listing
December 2020

Persistence of Late Substantial Patient-Reported Symptoms (LAPERS) After Radiochemotherapy Including Image Guided Adaptive Brachytherapy for Locally Advanced Cervical Cancer: A Report From the EMBRACE Study.

Int J Radiat Oncol Biol Phys 2021 01 25;109(1):161-173. Epub 2020 Aug 25.

Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna/General Hospital of Vienna, Vienna, Austria.

Purpose: This report describes the persistence of late substantial treatment-related patient-reported symptoms (LAPERS) in the multi-institutional EMBRACE study on magnetic resonance image guided adaptive brachytherapy in locally advanced cervical cancer (LACC).

Methods And Materials: Patient-reported symptoms (European Organization for Research and Treatment of Cancer [EORTC]-C30/CX24) and physician-assessed morbidity (Common Terminology Criteria for Adverse Events [CTCAE], version 3.0) were assessed at baseline and regular timepoints during follow-up. Patients with sufficient EORTC follow-up (baseline and ≥3 late follow-up visits) were analyzed. LAPERS events were defined as the presence of substantial EORTC symptoms (quite a bit/very much) for at least half of the assessments (persistence) and progression beyond baseline condition (treatment-related). For each EORTC symptom, the ratio between LAPERS rates and crude incidence rates of substantial symptoms was calculated to represent the proportion of symptomatic patients with persisting symptoms. For 9 symptoms with a corresponding EORTC/CTCAE assessment, the overlap of LAPERS and severe morbidity events (grades 3-5) was evaluated.

Results: Of 1047 patients with EORTC available, 741 had sufficient follow-up for the LAPERS analyses. The median follow-up was 59 months (interquartile range, 42-70 months). Across all symptoms, the proportion of patients with LAPERS events (LAPERS rates) was in median 4.6% (range, 0.0% vaginal bleeding to 20.4% tiredness). Urinary frequency, neuropathy, fatigue, insomnia, and menopausal symptoms revealed LAPERS rates of >10%. Vomiting, blood in stool, urinary pain/burning, and abnormal vaginal bleeding displayed LAPERS rates of <1%. A median of 19% of symptomatic patients (interquartile range, 8.0%-28.5%) showed persistent long-term symptoms (LAPERS events). In symptoms with a corresponding EORTC/CTCAE assessment, 12% of LAPERS events were accompanied by a severe CTCAE event.

Conclusions: Within this large cohort of survivors of LACC, a subgroup of patients with persistent symptoms (LAPERS events) was identified. For symptoms with a corresponding EORTC/CTCAE assessment, the vast majority of LAPERS events occurred in patients without corresponding severe physician-assessed morbidity. These findings emphasize the importance of distinguishing between transient and persisting symptoms in the aftercare of LACC survivors.
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http://dx.doi.org/10.1016/j.ijrobp.2020.08.044DOI Listing
January 2021

Evidence-Based Dose Planning Aims and Dose Prescription in Image-Guided Brachytherapy Combined With Radiochemotherapy in Locally Advanced Cervical Cancer.

Semin Radiat Oncol 2020 10;30(4):311-327

Medical University/General Hospital of Vienna, Department of Radiation Oncology-Comprehensive Cancer Center, Vienna, Austria.

The last 2 decades have witnessed the development and broad adoption of image-guided adaptive brachytherapy (IGABT) combined with radiochemotherapy in patients with locally advanced cervical cancer. A variety of brachytherapy techniques and dose/fractionation schedules have been applied, and until recently, there was no strong evidence available for preferring one approach to another. However, large volumes of data have now provided high level clinical evidence for dose-effect relations for both disease and morbidity endpoints. It is therefore now possible to apply evidence based dose planning aims and dose prescription protocols in IGABT for locally advanced cervical cancer. This review gives an overview of targets/organs-at-risk and disease/morbidity endpoints which are relevant in the context of treatment planning and dose prescription in IGABT. The dosimetric and clinical evidence is summarized to support the implementation of dose prescription protocols which include hard and soft constraints for targets and organs at risk.
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http://dx.doi.org/10.1016/j.semradonc.2020.05.008DOI Listing
October 2020

Education and training for image-guided adaptive brachytherapy for cervix cancer-The (GEC)-ESTRO/EMBRACE perspective.

Brachytherapy 2020 Nov - Dec;19(6):827-836. Epub 2020 Aug 16.

Department of Radiation Oncology, Medical University of Vienna, Wien, Austria.

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.
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http://dx.doi.org/10.1016/j.brachy.2020.06.012DOI Listing
June 2021
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