Publications by authors named "Lars Fokdal"

75 Publications

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

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

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

Image-Guided Adaptive Brachytherapy (IGABT) for Primary Vaginal Cancer: Results of the International Multicenter RetroEMBRAVE Cohort Study.

Cancers (Basel) 2021 Mar 23;13(6). Epub 2021 Mar 23.

Department of Oncology, Aarhus University Hospital, 8200 Aarhus, Denmark.

Purpose: This study assessed outcomes following the nowadays standing treatment for primary vaginal cancer with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT) in a multicenter patient cohort.

Methods: Patients treated with computer tomography (CT)-MRI-assisted-based IGABT were included. Retrospective data collection included patient, tumor and treatment characteristics. Late morbidity was assessed by using the CTCAE 3.0 scale.

Results: Five European centers included 148 consecutive patients, with a median age of 63 years. At a median follow-up of 29 months (IQR 25-57), two- and five-year local control were 86% and 83%; disease-free survival (DFS) was 73% and 66%, and overall survival (OS) was 79% and 68%, respectively. Crude incidences of ≥ grade-three urogenital, gastro-intestinal and vaginal morbidity was 8%, 3% and 8%, respectively. Lymph node metastasis was an independent prognostic factor for disease-free survival (DFS). Univariate analysis showed improved local control in patients with T2-T4 tumors if >80 Gy EQD2 was delivered to the clinical target volume (CTV) at the time of brachytherapy.

Conclusions: In this large retrospective multicenter study, IGABT for primary vaginal cancer resulted in a high local control with acceptable morbidity. These results compared favorably with two-dimensional (2D) radiograph-based brachytherapy and illustrate that IGABT plays an important role in the treatment of vaginal cancer.
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http://dx.doi.org/10.3390/cancers13061459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004779PMC
March 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

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

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

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

Olaparib treatment in older patients with ovarian cancer: need for 'real-world' data beyond clinical trials.

Ecancermedicalscience 2020 15;14:1104. Epub 2020 Sep 15.

Department of Oncology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Indgang D3, Plan 2, Krydspunkt D203, 8200 Aarhus N, Denmark.

Background: Ageing is a risk factor for cancer. Worldwide, the number and proportion of adults aged ≥65 will increase, along with the incidence of ovarian cancer. Older adults are under-represented in randomised clinical trials (RCTs), and those who are enrolled have a good performance status and no major health issues. These patients are not representative of older patients seen in everyday clinical practice; therefore, age-specific data on efficacy and toxicity of olaparib in the 'real-world' setting are lacking.

Methods: This observational study was conducted in the Central Jutland Region in Denmark. Data in unselected older (≥65) patients with known BRCA mutation receiving olaparib maintenance treatment for platinum-sensitive relapsed ovarian cancer were registered between 2015 and 2019. Toxicity and progression-free survival (PFS) were registered. No geriatric assessment has been performed.

Results: In total, 20 consecutive patients ≥65 years were included with a median age of 75 years (range: 65-85). Most of the patients (18/20) had ECOG PS: 0-1. Treatment interruption and dose reduction occurred in 65% of the patients. Toxicities of any grade occurred in 18 (90%), whereas grade 3/4 toxicities occurred in 6 patients (30%). Treatment was terminated due to disease progression or unacceptable toxicity in 13 (65%) patients. The median PFS was 6 months (range: 2-31), and the median follow-up was 15 months (range: 3-30).

Discussion: Our 'real-world' experience shows that unselected older patients represent a significant larger proportion in real life than in RCTs; furthermore, older patients in a real-world setting may experience more side effects possibly affecting the quality of life. The median PFS data suggest that older patients may not derive the same clinical benefit than their fit and younger counterparts.There is a need to enrol vulnerable/frail older patients into RCTs, ensuring that data will also be applicable in standard clinical settings. Incorporating geriatric assessment into these trials should be encouraged.
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http://dx.doi.org/10.3332/ecancer.2020.1104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532029PMC
September 2020

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

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

Definitive radiotherapy with image-guided adaptive brachytherapy for primary vaginal cancer.

Lancet Oncol 2020 03;21(3):e157-e167

Department of Radiation Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands.

Primary vaginal cancer is a rare cancer and clinical evidence to support recommendations on its optimal management is insufficient. Because primary vaginal cancer resembles cervical cancer in many aspects, treatment strategies are mainly adopted from evidence in locally advanced cervical cancer. To date, the organ-sparing treatment of choice is definitive radiotherapy, consisting of external beam radiotherapy and brachytherapy, combined with concurrent chemotherapy. Brachytherapy is an important component of the treatment and its steep dose gradient enables the delivery of high doses of radiation to the primary tumour, while simultaneously sparing the surrounding organs at risk. The introduction of volumetric CT or MRI image-guided adaptive brachytherapy in cervical cancer has led to better pelvic control and survival, with decreased morbidity, than brachytherapy based on x-ray radiographs. MRI-based image-guided adaptive brachytherapy with superior soft-tissue contrast has also been adopted sporadically for primary vaginal cancer. This therapy has had promising results and is considered to be the state-of-the-art treatment for primary vaginal cancer in standard practice.
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http://dx.doi.org/10.1016/S1470-2045(19)30855-1DOI Listing
March 2020

MRI-based contouring of functional sub-structures of the lower urinary tract in gynaecological radiotherapy.

Radiother Oncol 2020 04 10;145:117-124. Epub 2020 Jan 10.

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

Introduction: Research in radiation-induced urinary morbidity is limited by lack of guidelines for contouring and dose assessment of the lower urinary tract. Based on literature regarding anatomy, physiology and imaging of the lower urinary tract, this study aimed to provide advice on contouring of relevant sub-structures, reference points and reference dimensions for gynaecological radiotherapy.

Material And Methods: 210 MRIs for Image-Guided Adaptive Brachytherapy (IGABT) were analysed in 105 locally advanced cervical cancer patients treated with radio(chemo)therapy. Sub-structures (trigone, bladder neck and urethra) were contoured and trigone height (TH) and width (TW) were measured. Internal urethral ostium (IUO) and Posterior inferior border of pubic symphysis-urethra (PIBS-U) points were used to identify proximal and middle/low urethra, respectively. Urethra reference length (URL) was defined as IUO and PIBS-U distance. TH, TW and URL were also quantified on 54 MRIs acquired for External Beam Radiotherapy (EBRT).

Results: Median absolute differences in volumes and dimensions between first and second IGABT fraction were 0.7 cm, 4.3 cm, 0.2 cm, 0.3 cm and 0.2 cm for trigone, bladder neck, TH, TW and URL, respectively. Mean(±SD) TH and TW were 2.7(±0.4)cm and 4.4(±0.4)cm, respectively, with no significant difference (p = 0.15 and p = 0.06, respectively) between IGABT and EBRT. URL was significantly shorter in EBRT than in IGABT MRIs (p < 0.001).

Conclusions: This study proposed relevant urinary sub-structures and dose points and showed that standardized contouring is reproducible. Trigone reference dimensions are robust despite different bladder filling and treatment conditions. Standardized contouring and reference points may improve understanding of urinary morbidity.
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http://dx.doi.org/10.1016/j.radonc.2019.12.011DOI Listing
April 2020

Recommendations from gynaecological (GYN) GEC-ESTRO working group - ACROP: Target concept for image guided adaptive brachytherapy in primary vaginal cancer.

Radiother Oncol 2020 04 23;145:36-44. Epub 2019 Dec 23.

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

Background And Aim: External beam radiotherapy (EBRT) combined with brachytherapy has an essential role in the curative treatment of primary vaginal cancer. EBRT is associated with significant tumour shrinkage, making primary vaginal cancer suitable for image guided adaptive brachytherapy (IGABT). The aim of these recommendations is to introduce an adaptive target volume concept for IGABT of primary vaginal cancer.

Methods: In December 2013, a task group was initiated within GYN GEC-ESTRO with the purpose to introduce an IGABT target concept for primary vaginal cancer. All participants have broad experience in IGABT and vaginal cancer brachytherapy. The target concept was elaborated as consensus agreement based on an iterative process including target delineation and dose planning comparison, retrospective analysis of clinical data and expert opinions.

Results: Gynaecological examination and MR imaging are the modalities of choice for local tumour assessment. A specific template for standardised documentation with clinical drawings for vaginal cancer was developed. The adaptive target volume concept comprises different response-related target volumes. For EBRT these are related to the primary tumour and the lymph nodes, while for IGABT these are related to the primary tumour and are consisting of the residual gross tumour volume (GTV-T) and the high-, and intermediate risk clinical target volumes (CTV-T, CTV-T).

Conclusion: This target concept for IGABT of primary vaginal cancer defines adaptive target volumes for volumetric dose prescription and should improve comparability of different radiotherapy schedules of this rare disease. A prospective evaluation of the target volume concept within a multicentre study is planned.
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http://dx.doi.org/10.1016/j.radonc.2019.11.005DOI Listing
April 2020

Evaluation of a New Prognostic Tumor Score in Locally Advanced Cervical Cancer Integrating Clinical Examination and Magnetic Resonance Imaging.

Int J Radiat Oncol Biol Phys 2020 03 30;106(4):754-763. Epub 2019 Nov 30.

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

Purpose: The integral results of clinical examination and magnetic resonance imaging (MRI) of patients with locally advanced cervical cancer may provide prognostic information that cannot readily be placed in current staging systems, such as proximal versus distal parametrial invasion, unilateral versus bilateral involvement, or organ infiltration on MRI. The aim was to develop and investigate the performance of a simple but comprehensive tumor score for reporting and prognostication.

Methods And Materials: In the present study, 400 consecutive patients with locally advanced cervical cancer treated 2005 to 2018 with chemoradiation and image guided adaptive brachytherapy (IGABT) were analyzed. The diagnostic workup included clinical examination, positron emission tomography/computed tomography, and MRI. International Federation of Gynecology and Obstetrics 2009 stage distribution was IB to IIA 9%, IIB 61%, and III to IV 30%. Involvement of 8 anatomic locations (cervix, left parametrium, right parametrium, vagina, bladder, ureter, rectum, and uterine corpus) was scored according to a ranked ordinal scale with 0 to 3 points. The total sum of points constituted the tumor score (T-score).

Results: The median T-score was 6 (range, 0-20). Based on the frequency distribution of the T-score, 4 equally sized groups were formed: 0 to 4, 5 to 6, 7 to 9, and >9 points. The T-score grouping was highly significant in both univariate and multivariable analysis and outperformed International Federation of Gynecology and Obstetrics stage for both survival and local control enabling also intrastage prognostication. Used as a linear variable, the T-score was correlated with IGABT target volume (high-risk clinical target volume, CTV), use of interstitial needles, dose (D90 of CTV), and total reference air kerma.

Conclusions: The T-score is a simple instrument for combining clinical findings and imaging into a powerful prognostic factor for survival and local control with capabilities surpassing traditional staging. In addition, the T-score may already at diagnosis predict essential IGABT parameters and may be used for audit and comparison of results in multicenter settings.
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http://dx.doi.org/10.1016/j.ijrobp.2019.11.031DOI Listing
March 2020

[Workup, treatment and follow-up of vulva cancer].

Ugeskr Laeger 2019 Aug;181(34)

This review summarises the current guidelines for vulva cancer in Denmark. Vulva cancer is a rare disease. The diagnosis is often delayed, which results in large tumours and regional spread. The most important prognostic factor is inguinal lymph node metastases. Staging and treatment is centralised to two hospitals. Primary treatment is wide local excision combined with removal of either inguinal sentinel nodes or lymphadenectomy. Treatment is associated with considerable morbidity, and supportive care is often necessary. Local curable recurrences are common. Relapses in the groin are associated with a poor prognosis. Thus, long term follow-up is essential. *) On behalf of Dansk Gynækologisk Cancer Gruppe for vulvacancer.
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August 2019

Reporting of Late Morbidity After Radiation Therapy in Large Prospective Studies: A Descriptive Review of the Current Status.

Int J Radiat Oncol Biol Phys 2019 12 27;105(5):957-967. Epub 2019 Aug 27.

Department of Oncology, Aarhus University Hospital, Denmark.

Purpose: The purpose of this review was to evaluate the current status of reporting prospectively assessed late morbidity after curative radiation therapy in large clinical studies.

Methods And Materials: A descriptive review on publications from 10 high-impact journals with a primary or partial focus on radiation therapy published between December 1, 2015, and November 30, 2017, was conducted. Publications were considered eligible if they reported prospectively assessed late morbidity after curative radiation therapy and included ≥200 patients with cancer of any type. Full text publication and supplementary material were analyzed according to items based on extensions to the Consolidated Standards of Reporting Trials (CONSORT) statement regarding reporting of harms and patient reported outcomes.

Results: Overall, 802 publications were identified in PubMed; of these, 69 met the eligibility criteria. Mild and moderate morbidity were reported in 40% and 57% of publications; aggregated endpoints instead of individual endpoints were reported in 23%. In 43% of publications, crude incidence of worst grade of morbidity was used as the only statistical method for summarizing physician-assessed morbidity. Duration of morbidity or recurrent events were not reported in any of the publications.

Conclusions: Comprehensive, quantitative reporting of late morbidity after radiation therapy is challenging because of the high dimensionality and time evolution of the range of normal tissue effects. The following suggestions and recommendations are proposed: (1) report on individual severity grades, including moderate and mild; (2) use patient reported outcomes in complement to physician-assessed morbidity; (3) report on individual symptoms/endpoints on top of aggregated endpoints; (4) report on duration of morbidity or recurrent events; (5) take steps toward a consensus on severity grading scales/patient questionnaires; (6) use time to event analysis and prevalence rates; (7) report or use statistical methods accounting for pretreatment morbidity when relevant.
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http://dx.doi.org/10.1016/j.ijrobp.2019.08.040DOI Listing
December 2019

Robustness of elective lymph node target coverage with shrinking Planning Target Volume margins in external beam radiotherapy of locally advanced cervical cancer.

Phys Imaging Radiat Oncol 2019 Jul 26;11:9-15. Epub 2019 Jun 26.

Department of Oncology, Aarhus University Hospital, Denmark.

Background And Purpose: Image-Guidance decreases set-up uncertainties, which may allow for Planning Target Volume (PTV) margins reduction. This study evaluates the robustness of the elective lymph node target coverage to translational and rotational set-up errors in combination with shrinking PTV margins and determines the gain for the Organs At Risk (OARs).

Material And Methods: Ten cervix cancer patients who underwent external beam radiotherapy with 45 Gy/25Fx were analysed. Daily Image-Guidance was based on bony registration of Cone Beam CT (CBCT) to planning CT (pCT) and daily couch correction (translation and yaw). On each pCT, four Volumetric Modulated Arc Therapy dose-plans were generated with PTV margins of 0, 3, 5 and 8 mm. The elective clinical target volume (CTV-E) was propagated from daily CBCTs to the pCT to evaluate daily CTV-E dose. Additional systematic translational isocenter shifts of 2 mm were simulated. D98% (dose received by 98% of the volume of interest) and D99.9% were extracted from each CTV-E for all dose-plans and scenarios. Total dose was accumulated by Dose-Volume Histogram addition. The dosimetric impact of PTV margin reduction on the OARs was evaluated through V30Gy (volume included within the 30 Gy isodose), V40Gy and body V43Gy.

Results: When decreasing the PTV margin from 5 to 0 mm, bowel V30Gy was decreased by 13% (from 247 cm to 214 cm), body V43Gy by 19% (from 1462 cm to 1188 cm) and PTV by 39% (from 1416 to 870 cm). The dosimetric impact of combined systematic shifts and residual rotations on the elective target with a 0 mm PTV margin was a decrease of D98% (mean ± SD) from 44.1 Gy ± 0.4 Gy to 43.7 Gy ± 0.8 Gy and a minimum of 42.4 Gy.

Conclusion: PTV margin reduction from 5 to 0 mm induced significant OARs dosimetric gains while elective target coverage remained robust to positioning uncertainties.
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http://dx.doi.org/10.1016/j.phro.2019.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807569PMC
July 2019

Change in Patterns of Failure After Image-Guided Brachytherapy for Cervical Cancer: Analysis From the RetroEMBRACE Study.

Int J Radiat Oncol Biol Phys 2019 07 30;104(4):895-902. Epub 2019 Mar 30.

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

Purpose: Image guided adaptive brachytherapy (IGABT) for cervical cancer improves pelvic control and survival across all stages. Improvement in pelvic control is larger in advanced stages, but improvement in survival is similar across stages. This paper analyzes the patterns of failure in the RetroEMBRACE cohort to investigate this discrepancy.

Methods And Materials: 731 patients from 12 institutions treated with chemoradiation therapy and magnetic resonance imaging or computed tomography-based IGABT were evaluated. The pattern of failure at time of first relapse was analyzed.

Results: Three hundred twenty-five failures (single and synchronous) occurred in 222 of 731 patients (30%). Among the 325 failures, 9% were local and 6% regional. Pelvic (local or regional) failures made up 13%, paraaortic node (PAN) 9%, systemic 21%, and distant (systemic + PAN) 24%. Of the 222 patients with treatment failure, 21% had pelvic failure alone, 57% had distant failure alone, and 23% had both pelvic and distant failure. Of all failures that occurred, 40% to 50% occurred in the first year, with a further 20% to 30% occurring in the second year. Although local, regional, and PAN failure tended to plateau after year 3, systemic failure continued to occur up to year 10.

Conclusions: Implementation of IGABT has changed the patterns of relapse after chemoradiation therapy for cervical cancer. The predominant failure after IGABT is systemic, whereas the predominant failure with conventional brachytherapy is pelvic. Effective treatments to eradicate micrometastases in PAN and distant organs are needed in addition to IGABT and chemoradiation therapy to maximize local, regional, PAN, and systemic control and improve survival.
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http://dx.doi.org/10.1016/j.ijrobp.2019.03.038DOI Listing
July 2019

Importance of Technique, Target Selection, Contouring, Dose Prescription, and Dose-Planning in External Beam Radiation Therapy for Cervical Cancer: Evolution of Practice From EMBRACE-I to II.

Int J Radiat Oncol Biol Phys 2019 07 21;104(4):885-894. Epub 2019 Mar 21.

Department of Oncology, Aarhus University Hospital, Denmark.

Purpose: To describe the evolution of external beam radiation therapy (EBRT) from EMBRACE-I (general guidelines for EBRT) to the initial phase of the EMBRACE-II study (detailed protocol for EBRT).

Methods And Materials: EMBRACE-I enrolled 1416 locally advanced cervical cancer patients treated with chemoradiation including image-guided adaptive brachytherapy during 2008 to 2015. From March 2016 until March 2018, 153 patients were enrolled in the ongoing EMBRACE-II study, which involves a comprehensive detailed strategy and accreditation procedure for EBRT target contouring, treatment planning, and image guidance. EBRT planning target volumes (PTVs), treated volumes (V43 Gy), and conformity index (CI; V43 Gy/PTV) were evaluated in both studies and compared.

Results: For EMBRACE-I, conformal radiation therapy (60% of patients) or intensity-modulated radiation therapy (IMRT) and volumetric arc therapy (VMAT; 40%) was applied with 45 to 50 Gy over 25 to 30 fractions to the elective clinical target volume (CTV). For pelvic CTVs (82%), median PTV and V43 Gy volumes were 1549 and 2390 mL, respectively, and CI was 1.54. For pelvic plus paraortic nodal (PAN) CTVs (15%), median PTV and V43 Gy volumes were 1921 and 2895 mL, and CI was 1.51. For pelvic CTVs treated with 45 to 46 Gy, the use of conformal radiation therapy was associated with a median V43 Gy volume that was 546 mL larger than with IMRT/VMAT. For pelvic CTVs treated with IMRT, the use of a dose prescription ≥48 Gy was associated with a median V43 Gy volumes that was 428 mL larger than with a dose prescription of 45 to 46 Gy. For EMBRACE-II, all patients were treated with: IMRT/VMAT, daily IGRT, 45 Gy over 25 fractions for the elective CTV, and simultaneously integrated boost for pathologic lymph nodes. For pelvic CTVs (61%), median PTV and V43 Gy volumes were 1388 and 1418 mL, and CI was 1.02. For pelvic plus PAN CTVs (32%), median PTV and V43 Gy volumes were 1720 and 1765 mL, and CI was 1.03. From EMBRACE-I to initial II, median V43 Gy was decreased by 972 mL (41%) and 1130 mL (39%), and median CI decreased from 1.54 to 1.02 and 1.51 to 1.03 for pelvic and pelvic plus PAN irradiation, respectively.

Conclusions: Application of IMRT/VMAT, IGRT, and a 45-Gy dose provides the potential of higher conformality inducing significant reduction of treated volume. Adherence to a detailed protocol including comprehensive accreditation, as in EMBRACE-II, reduces considerably V43 Gy and V50 Gy and improves conformality and interinstitutional consistency.
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http://dx.doi.org/10.1016/j.ijrobp.2019.03.020DOI Listing
July 2019
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