Publications by authors named "Jacob C Lindegaard"

42 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

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

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

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

Implementing an online radiotherapy quality assurance programme with supporting continuous medical education - report from the EMBRACE-II evaluation of cervix cancer IMRT contouring.

Radiother Oncol 2020 06 30;147:22-29. Epub 2020 Mar 30.

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

Background And Purpose: EMBRACE-II is an international prospective study of IMRT and MRI-guided adaptive brachytherapy (IGABT) in locally advanced cervix cancer. An online radiotherapy quality assurance (RTQA) programme with minimal data transfer and supporting continuing medical education (CME) was implemented for IMRT contouring.

Materials And Methods: Participant contours for six volumes-of-interest (VOIs) on one benchmark case were scored (2 = excellent, 1 = fair, 0 = revision required) against a consensus reference contour. For contours receiving a 0 or 1 score, additional qualitative comments were provided. The Jaccard conformity index (JCI) was retrospectively calculated. User interaction with CME content (pre-accreditation questionnaire, contouring atlas, practice cases, quizzes, internal target volume (ITV-T) guide) was analysed.

Results: 78 clinicians submitted contours for evaluation. 41% passed at the first attempt, 44% after one revision and 6% after two or more revisions. 9% did not re-submit after failing. The lowest mean scores were for the elective nodal CTV (CTV-E) (1.01/2) and ITV-T (1.06/2). 60 different errors across the six VOIs were identified; five potentially had high impact on loco-regional control. A JCI cut-off of 0.7 would have identified 87% contours that failed expert assessment, but also excluded 54% of passing contours. 39 clinicians responded to the pre-accreditation questionnaire - 36% anticipated difficulties with the ITV-T and 13% with the CTV-E. 35% clinicians contoured on the practice cases, 17% answered a quiz, 96% used the atlas and 38% the ITV-T guide.

Conclusion: Expert evaluation with qualitative feedback improved contouring compliance. The JCI is not a reliable alternative to expert assessment. Moderate uptake of optional CME content limited evaluation.
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http://dx.doi.org/10.1016/j.radonc.2020.02.017DOI Listing
June 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

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

Nodal failure after chemo-radiation and MRI guided brachytherapy in cervical cancer: Patterns of failure in the EMBRACE study cohort.

Radiother Oncol 2019 05 26;134:185-190. Epub 2019 Feb 26.

Department of Radiation Oncology, University Medical Center Utrecht, the Netherlands. Electronic address:

Purpose/objective(s): To investigate the patterns of nodal failure in patients enrolled in the international multicentre EMBRACE study.

Materials/methods: Nodal disease at diagnosis (N-, N+) and nodal failure were analysed per region (NF) (pelvic (parametrial, common iliac, internal/external iliac), inguinal and para-aortic (PAO)) in 1338 patients. Treatment consisted of chemo-radiation and MRI guided brachytherapy. PAO radiotherapy and/or nodal boost was left to the treating centre. At time of diagnosis 52% of patients had pathologic nodes. Frequency analyses were performed in relation to patient, primary tumour and nodal disease characteristics, and treatment related factors.

Results: Median follow up was 34 months and 83% of NF occurred within 24 months. At diagnosis 99% of the N+ patients had pathologic nodes in the pelvis and 14% in the PAO. NF and NF were reported in 55% and 68% of patients with NF, respectively. Overall NF was reported in 152 patients (11%); 7 and 16% for N- and N+ patients. Of the patients with NF, 41% were located outside the elective target (39% PAO), 40% inside and 35% inside the nodal boost target. Twelve percent of N+ patients that received a nodal boost had a NF inside the nodal boost target.

Conclusion: Within the EMBRACE study cohort the overall number of patients developing nodal failure is low, significantly lower for N- compared to N+ patients. Pathological nodes at diagnosis are mainly located in the pelvis, whereas nodal failures are more often reported in the PAO region. About 40% of all nodal failures were reported outside the treatment targets.
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http://dx.doi.org/10.1016/j.radonc.2019.02.007DOI Listing
May 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

Physician assessed and patient reported lower limb edema after definitive radio(chemo)therapy and image-guided adaptive brachytherapy for locally advanced cervical cancer: A report from the EMBRACE study.

Radiother Oncol 2018 06 6;127(3):449-455. Epub 2018 Apr 6.

Department of Radiation Oncology, Medical University of Vienna, Austria. Electronic address:

Background/purpose: To evaluate the pattern of manifestation and risk factors for lower limb edema (LLE) within the prospective, observational, multi-center EMBRACE study on radiochemotherapy and MRI-guided brachytherapy in locally advanced cervical cancer (LACC).

Material/methods: LLE was prospectively assessed according to the physician-reported CTCAE v.3 and patient-reported EORTC QLQ-CX24 questionnaire at baseline and regular follow-up.

Results: In total, 1176 patients were evaluated with a median follow-up of 27 months. Actuarial analyses revealed 3/5-year estimates of 27%/31% of CTCAE G ≥ 1, 6.1%/6.6% of G ≥ 2 and 0.5%/0.5% for G ≥ 3. Prevalence rates for G ≥ 1 LLE at 3 months, 1, 3 and 5 years after end of treatment were 7%, 12%, 12%, 15% for physician-assessed and 25%, 30%, 30%, 34% for any patient-reported symptoms and showed a steady increase over time. Invasive lymph node staging and obesity at diagnosis are independent significant risk factors for G ≥ 1 LLE, whereas nodal boost has no impact. Extended radiation fields including para-aortic and/or inguinal nodes show a tendency to increase the risk.

Conclusion: Severe LLE after definitive radiochemotherapy in LACC is rare. However, the risk for mild LLE is considerable, and related to patient-, diagnostic- and treatment characteristics. Less invasive diagnostic surgical procedures or non-invasive assessment, less invasive radiotherapy management and active rehabilitation are important pathways for future developments.
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http://dx.doi.org/10.1016/j.radonc.2018.03.026DOI Listing
June 2018

Fatigue, insomnia and hot flashes after definitive radiochemotherapy and image-guided adaptive brachytherapy for locally advanced cervical cancer: An analysis from the EMBRACE study.

Radiother Oncol 2018 06 5;127(3):440-448. Epub 2018 Apr 5.

Department of Radiation Oncology, University Hospitals Leuven, Belgium. Electronic address:

Objective: To evaluate the pattern of manifestation of fatigue, insomnia and hot flashes within the prospective, observational, multi-center EMBRACE study.

Methods: Morbidity was prospectively assessed according to CTCAE v.3 and patient-reported outcome with EORTC QLQ-C30/CX24 at baseline and regular follow-up. Analyses of crude incidence, prevalence rates and actuarial estimates were performed.

Results: A total of 1176 patients were analyzed with a median follow-up of 27 months. At baseline, CTCAE G1/G2 prevalence rates for fatigue were 29%/6.2%, for insomnia 18%/3.1% and for hot flashes 7.9%/1.6% with respective 3-year prevalence rates of 29%/6.8%, 17%/4.4% and 19%/5.9%. Similar patterns of manifestation were seen in patient-reported EORTC outcomes. The 3-year actuarial estimates for G ≥ 3 CTCAE fatigue, insomnia and hot flashes were 5.5%, 4.7% and 1.9%. Younger age was associated with significantly higher risk for fatigue, insomnia and hot flashes.

Conclusion: Fatigue, insomnia and hot flashes occurred mainly in the mild to moderate range. Fatigue and insomnia were already present before treatment and showed minor fluctuations or recovery during follow-up, whereas hot flashes showed a considerable increase after treatment. More research is needed to evaluate contributing risk factors in order to define intervention strategies.
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http://dx.doi.org/10.1016/j.radonc.2018.03.009DOI Listing
June 2018

Can reduction of uncertainties in cervix cancer brachytherapy potentially improve clinical outcome?

Radiother Oncol 2016 09 21;120(3):390-396. Epub 2016 Jul 21.

Department of Radiation Therapy, Comprehensive Cancer Center, Medical University of Vienna, Austria; Christian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical University of Vienna, Austria.

Aim: The aim of this study was to quantify the impact of different types and magnitudes of dosimetric uncertainties in cervix cancer brachytherapy (BT) on tumour control probability (TCP) and normal tissue complication probability (NTCP) curves.

Materials And Methods: A dose-response simulation study was based on systematic and random dose uncertainties and TCP/NTCP models for CTV and rectum. Large patient cohorts were simulated assuming different levels of dosimetric uncertainties. TCP and NTCP were computed, based on the planned doses, the simulated dose uncertainty, and an underlying TCP/NTCP model. Systematic uncertainties of 3-20% and random uncertainties with a 5-30% standard deviation per BT fraction were analysed.

Results: Systematic dose uncertainties of 5% lead to a 1% decrease/increase of TCP/NTCP, while random uncertainties of 10% had negligible impact on the dose-response curve at clinically relevant dose levels for target and OAR. Random OAR dose uncertainties of 30% resulted in an NTCP increase of 3-4% for planned doses of 70-80Gy EQD2.

Conclusion: TCP is robust to dosimetric uncertainties when dose prescription is in the more flat region of the dose-response curve at doses >75Gy. For OARs, improved clinical outcome is expected by reduction of uncertainties via sophisticated dose delivery and treatment verification.
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http://dx.doi.org/10.1016/j.radonc.2016.06.008DOI Listing
September 2016

Dose-volume effect relationships for late rectal morbidity in patients treated with chemoradiation and MRI-guided adaptive brachytherapy for locally advanced cervical cancer: Results from the prospective multicenter EMBRACE study.

Radiother Oncol 2016 09 7;120(3):412-419. Epub 2016 Jul 7.

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

Purpose: To establish dose volume-effect relationships predicting late rectal morbidity in cervix cancer patients treated with concomitant chemoradiation and MRI-guided adaptive brachytherapy (IBABT) within the prospective EMBRACE study.

Material And Method: All patients were treated with curative intent according to institutional protocols with chemoradiation and IGABT. Reporting followed the GEC-ESTRO recommendations ( [Formula: see text] , [Formula: see text] ), applying bioeffect modeling (linear quadratic model) with equieffective doses (EQD2). Morbidity was scored according to the CTC-AE 3.0. Dose-effect relationships were assessed using comparisons of mean doses, the probit model and log rank tests on event-free periods.

Results: 960 patients were included. The median follow-up was 25.4months. Twenty point one percent of the patients had grade 1 events, 6.0% grade 2, 1.6% grade 3 and 0.1%, grade 4. The mean D, [Formula: see text] , and [Formula: see text] were respectively: 66.2±9.1Gy, 72.9±11.9Gy, and 62.8±7.6Gy. Increase of dose was associated with increase in severity of single endpoints and overall rectal morbidity (grade 1-4) (p<0.001-0.026), except for stenosis (p=0.24-0.31). The probit model showed significant relationships between the [Formula: see text] , [Formula: see text] , and D and the probability of grade 1-4, 2-4, and 3-4 rectal events. The equieffective [Formula: see text] for a 10% probability for overall rectal grade⩾2 morbidity was 69.5Gy (p<0.0001). After sorting patients according to 6 [Formula: see text] levels, less favorable outcome was observed in the high dose subgroups, for bleeding, proctitis, fistula, and overall rectal morbidity. A [Formula: see text] ⩾75Gy was associated with a 12.5% risk of fistula at 3years versus 0-2.7% for lower doses (p>0.001). A [Formula: see text] <65Gy was associated with a two times lower risk of proctitis than [Formula: see text] ⩾65Gy.

Conclusions: Significant correlations were established between late rectal morbidity, overall and single endpoints, and dose-volume ( [Formula: see text] , [Formula: see text] ) and dose-point (D) parameters. A [Formula: see text] ⩽65Gy is associated with more minor and less frequent rectal morbidity, whereas a [Formula: see text] ⩾75Gy is associated with more major and more frequent rectal morbidity.
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http://dx.doi.org/10.1016/j.radonc.2016.06.006DOI Listing
September 2016

Image guided adaptive brachytherapy with combined intracavitary and interstitial technique improves the therapeutic ratio in locally advanced cervical cancer: Analysis from the retroEMBRACE study.

Radiother Oncol 2016 09 21;120(3):434-440. Epub 2016 Apr 21.

Department of Oncology, Aarhus University Hospital, Denmark.

Background And Purpose: Image guided adaptive brachytherapy (IGABT) using intracavitary applicators (IC) has led to a significant improvement of local control in locally advanced cervical cancer (LACC). Further improvement has been obtained with combined intracavitary/interstitial (IC/IS) applicators. The aim of this analysis was to evaluate the impact on local control and late morbidity of application of combined IS/IC brachytherapy in a large multicentre population.

Material/methods: 610 patients with LACC from the retroEMBRACE study were included. Patients were divided into an IC group (N=310) and an IC/IS group (N=300). The IC/IS group was defined from the time point, when a centre performed IC/IS brachytherapy in more than 20% of cases.

Results: With systematic usage of IC/IS the D90 of CTV increased from 83±14Gy to 92±13Gy (p<0.01). No difference in doses to organs at risk was found. The 3-year local control rate in patients having a CTV volume⩾30cm was 10% higher (p=0.02) in the IC/IS group. No difference was found for CTV<30cm (p=0.50). No significant difference in late morbidity was found between the IC/IS group and IC group.

Conclusion: Combined IC/IS brachytherapy improves the therapeutic ratio in LACC by enabling a tumour specific dose escalation resulting in significantly higher local control in large tumours without adding treatment related late morbidity.
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http://dx.doi.org/10.1016/j.radonc.2016.03.020DOI Listing
September 2016

Health-Related Quality of Life in Locally Advanced Cervical Cancer Patients After Definitive Chemoradiation Therapy Including Image Guided Adaptive Brachytherapy: An Analysis From the EMBRACE Study.

Int J Radiat Oncol Biol Phys 2016 Apr 29;94(5):1088-98. Epub 2015 Dec 29.

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

Purpose: This study analyzed functioning and symptom scores for longitudinal quality of life (QoL) from patients with locally advanced cervical cancer who underwent definitive chemoradiation therapy with image guided adaptive brachytherapy in the EMBRACE study.

Methods And Materials: In total, 744 patients at a median follow-up of 21 months were included. QoL was prospectively assessed using European Organization for Research and Treatment of Cancer Quality of Life core module 30 (EORTC QLQ-C30) and EORTC cervical cancer module 24 (CX24) questionnaires at baseline, then every 3 months during the first year, every 6 months in the second and third years, and finally yearly thereafter in patients with no evidence of disease. Outcomes were evaluated over time and compared to those from an age-matched female reference population.

Results: General QoL and emotional and social functioning were impaired at baseline but improved during the first 6 months after treatment, to reach a level comparable to that of the reference population, whereas cognitive functioning remained impaired. Both social and role functioning showed the lowest scores at baseline but which increased after treatment to reach a plateau at 6 months and then declined slightly at 3 and 4 years. The overall symptom experience was elevated at baseline and decreased to a level within the range of that of the reference population. Similarly, tumor-related symptoms (eg, pain, appetite loss, and constipation), which were present before treatment, decreased substantially at the first follow-up after treatment. Several treatment-related symptoms developed either immediately after and persisted over time (diarrhea, menopausal symptoms, peripheral neuropathy, and sexual functioning problems) or developed gradually after treatment (lymphedema and dyspnea).

Conclusions: This longitudinal prospective QoL analysis showed that patients' general QoL and functioning were impaired before treatment compared to those of reference data. Several tumor-related symptoms resolved after treatment, and functioning and general QoL returned to that of the level of the reference population, indicating a transient impact of diagnosis and treatment. However, several treatment-related symptoms and problems did develop and persist, either immediately or gradually after treatment.
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http://dx.doi.org/10.1016/j.ijrobp.2015.12.363DOI Listing
April 2016

Dose-effect relationship and risk factors for vaginal stenosis after definitive radio(chemo)therapy with image-guided brachytherapy for locally advanced cervical cancer in the EMBRACE study.

Radiother Oncol 2016 Jan 9;118(1):160-6. Epub 2016 Jan 9.

Department of Oncology, Aarhus University Hospital, Denmark.

Background/purpose: To identify risk factors for vaginal stenosis and to establish a dose-effect relationship for image-guided brachytherapy in locally advanced cervical cancer.

Materials/methods: Patients from the ongoing EMBRACE study with prospectively assessed morbidity (CTCAEv3.0) at baseline and at least one follow-up were selected. Patient-, disease- and treatment characteristics were tested as risk factors for vaginal stenosis G ⩾ 2 in univariate and multivariable analyses (Cox proportional hazards model) and a dose-effect curve was deduced from the estimates. The ICRU rectum point was used to derive the recto-vaginal reference point dose.

Results: In 630 patients included (median follow-up 24months), 2-year actuarial estimate for vaginal stenosis G ⩾ 2 was 21%. Recto-vaginal reference point dose (HR=1.025, p=0.029), external beam radiotherapy (EBRT) dose >45 Gy/25 fractions (HR=1.770, p=0.056) and tumor extension in the vagina (HR=2.259, p ⩽ 0.001) were risk factors for vaginal stenosis, adjusted for center reporting effects. Based on the model curve, the risk was 20% at 65 Gy, 27% at 75 Gy and 34% at 85 Gy (recto-vaginal reference point dose).

Conclusion: Keeping the EBRT dose at 45 Gy/25 fractions and decreasing the dose contribution of brachytherapy to the vagina decrease the risk of stenosis. A planning aim of ⩽65 Gy EQD2 (EBRT+brachytherapy dose) to the recto-vaginal reference point is therefore proposed.
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http://dx.doi.org/10.1016/j.radonc.2015.12.025DOI Listing
January 2016

A 30-year experience in using oral methotrexate as initial treatment for gestational trophoblastic neoplasia regardless of risk group.

Acta Oncol 2016 24;55(2):234-9. Epub 2015 Jun 24.

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

Background: Treatment of postmolar gestational trophoblastic neoplasia (GTN) is often stratified according to FIGO score using methotrexate (MTX) for low-risk patients and first-line multi-agent chemotherapy (e.g. EMA-CO) for high-risk patients. In contrast, oral MTX may be given as first-line therapy to all GTN patients regardless of risk group. The aim was to examine the efficacy of oral MTX and a response-adapted treatment policy, which has been used for three decades at Aarhus University Hospital (AUH).

Material And Methods: Seventy-one consecutive postmolar GTN patients treated 1981-2011 were included. Data were obtained from medical records, using histopathology and human choriogonadotropin (hCG) to verify the diagnosis. All patients received oral MTX as first-line chemotherapy. Second- and third-line chemotherapy was given according to response.

Results: Sixty-four (90%) patients were retrospectively categorized as FIGO low-risk disease, whereas seven patients (10%) had high-risk disease. Complete response to first-line oral MTX chemotherapy was observed in 35/71 (49%) patients, while 62/71 (87%) had complete remission on MTX (first-line) and/or MTX plus dactinomycin (second-line), without the use of multi-agent therapy. Nine patients (13%) received third-line multi-agent chemotherapy, six low-risk (67%) and three high-risk (33%) patients. There were no recurrences and no patients died as a consequence of toxicity or disease.

Conclusion: Fifty percent of all patients can be cured on oral MTX alone. By adding dactinomycin, about 90% are cured without use of multi-agent chemotherapy. The use of oral MTX as initial treatment can minimize the number of patients receiving multi-agent chemotherapy.
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http://dx.doi.org/10.3109/0284186X.2015.1059486DOI Listing
January 2017

[Successful treatment of primary small cell neuroendocrine carcinoma of the cervix].

Ugeskr Laeger 2014 Nov;176(47)

Onkologisk Afdeling D, Aarhus Universitetshospital, Nørrebrogade 44, 8000 Aarhus.

Primary small cell neuroendocrine carcinoma of the cervix is a rare disease and associated with poor prognosis. Currently there are no guidelines regarding optimal treatment for this disease. This case report describes a successful approach with chemotherapy traditionally used for small cell lung cancer combined with intensity-modulated radiotherapy with concomitant chemotherapy followed by image-guided adaptive brachytherapy.
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November 2014

Assessment of radiation doses to the para-aortic, pelvic, and inguinal lymph nodes delivered by image-guided adaptive brachytherapy in locally advanced cervical cancer.

Brachytherapy 2015 Jan-Feb;14(1):56-61. Epub 2014 Aug 28.

Department of Medical Physics, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.

Purpose: This study evaluated the dose delivered to lymph nodes (LNs) by brachytherapy (BT) and the effect of BT image-guided optimization on the LN dose.

Methods And Materials: Twenty-five patients with locally advanced cervical cancer were retrospectively analyzed, 16 patients of them had LN involvement. The patients received whole pelvis intensity-modulated radiation therapy (45-50 Gy/25-30 fx) to whole pelvis and two fractions of MRI pulsed-dose-rate BT. The delineated LN groups were para-aortic, inguinal, common iliac (CI), external iliac, internal iliac, obturator, and presacral. For each LN group, D98%, D50%, and D2% (the dose that covers 98%, 50%, and 2% of the volume, respectively) were evaluated for optimized and standard BT plans. The correlation between total reference air kerma (TRAK) and D50% of the LN groups was evaluated.

Results: BT contributed considerable dose (mean D50% was 3.8-6.2 Gy equivalent total dose in 2-Gy fractions) to the pelvic LN (external iliac, internal iliac, obturator, and presacral) in optimized plans, whereas less-dose contribution to CI, para-aortic, and inguinal (mean D50% was 0.5-1.9 Gy equivalent total dose in 2-Gy fractions) was observed. Optimized plans delivered less dose to the LNs as compared with standard plans, although differences only amounted to a mean of 0.2-0.9 Gy (D50%). TRAK showed a significant correlation with LN D50% for all LN groups except CI, although only 19-38% of the dose variation could be explained by the TRAK.

Conclusions: BT contributes considerable dose to pelvic LNs and should be considered in the evaluation of total LN doses.
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http://dx.doi.org/10.1016/j.brachy.2014.07.005DOI Listing
June 2015

Correction of diffusion-weighted magnetic resonance imaging for brachytherapy of locally advanced cervical cancer.

Acta Oncol 2014 Aug 14;53(8):1073-8. Epub 2014 Jul 14.

Department of Clinical Engineering, Aarhus University Hospital , Aarhus , Denmark.

Background: Geometrical distortion is a major obstacle for the use of echo planar diffusion-weighted magnetic resonance imaging (DW-MRI) in planning of radiotherapy. This study compares geometrical distortion correction methods of DW-MRI at time of brachytherapy (BT) in locally advanced cervical cancer patients.

Material And Methods: In total 21 examinations comprising DW-MRI, dual gradient echo (GRE) for B₀ field map calculation and T2-weighted (T2W) fat-saturated MRI of eight patients with locally advanced cervical cancer were acquired during BT with a plastic tandem and ring applicator in situ. The ability of B0 field map correction (B₀M) and deformable image registration (DIR) to correct DW-MRI geometric image distortion was compared to the non-corrected DW-MRI including evaluation of apparent diffusion coefficient (ADC) for the gross tumor volume (GTV).

Results: Geometrical distortion correction decreased tandem displacement from 3.3 ± 0.9 mm (non-corrected) to 2.9 ± 1.0 mm (B₀M) and 1.9 ± 0.6 mm (DIR), increased mean normalized cross-correlation from 0.69 ± 0.1 (non- corrected) to 0.70 ± 0.10 (B₀M) and 0.77 ± 0.1 (DIR), and increased the Jaccard similarity coefficient from 0.72 ± 0.1 (non-corrected) to 0.73 ± 0.06 (B₀M) and 0.77 ± 0.1 (DIR). For all parameters only DIR corrections were significant (p < 0.05). ADC of the GTV did not change significantly with either correction method.

Conclusion: DIR significantly improved geometrical accuracy of DW-MRI, with remaining residual uncertainties of less than 2 mm, while no significant improvement was seen using B₀ field map correction.
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http://dx.doi.org/10.3109/0284186X.2014.938831DOI Listing
August 2014

Manifestation pattern of early-late vaginal morbidity after definitive radiation (chemo)therapy and image-guided adaptive brachytherapy for locally advanced cervical cancer: an analysis from the EMBRACE study.

Int J Radiat Oncol Biol Phys 2014 May;89(1):88-95

Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna/General Hospital of Vienna, Austria; Christian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical University of Vienna, Austria.

Background And Purpose: Brachytherapy in the treatment of locally advanced cervical cancer has changed substantially because of the introduction of combined intracavitary/interstitial applicators and an adaptive target concept, which is the focus of the prospective, multi-institutional EMBRACE study (www.embracestudy.dk) on image-guided adaptive brachytherapy (IGABT). So far, little has been reported about the development of early to late vaginal morbidity in the frame of IGABT. Therefore, the aim of the present EMBRACE analysis was to evaluate the manifestation pattern of vaginal morbidity during the first 2 years of follow-up.

Methods And Materials: In total, 588 patients with a median follow-up time of 15 months and information on vaginal morbidity were included. Morbidity was prospectively assessed at baseline, every 3 months during the first year, and every 6 months in the second year according to the Common Terminology Criteria for Adverse Events, version 3, regarding vaginal stenosis, dryness, mucositis, bleeding, fistula, and other symptoms. Crude incidence rates, actuarial probabilities, and prevalence rates were analyzed.

Results: At 2 years, the actuarial probability of severe vaginal morbidity (grade ≥3) was 3.6%. However, mild and moderate vaginal symptoms were still pronounced (grade ≥1, 89%; grade ≥2, 29%), of which the majority developed within 6 months. Stenosis was most frequently observed, followed by vaginal dryness. Vaginal bleeding and mucositis were mainly mild and infrequently reported.

Conclusion: Severe vaginal morbidity within the first 2 years after definitive radiation (chemo)therapy including IGABT with intracavitary/interstitial techniques for locally advanced cervical cancer is limited and is significantly less than has been reported from earlier studies. Thus, the new adaptive target concept seems to be a safe treatment with regard to the vagina being an organ at risk. However, mild to moderate vaginal morbidity is still pronounced with currently applied IGABT, and it needs further attention.
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http://dx.doi.org/10.1016/j.ijrobp.2014.01.032DOI Listing
May 2014

Proof of principle: Applicator-guided stereotactic IMRT boost in combination with 3D MRI-based brachytherapy in locally advanced cervical cancer.

Brachytherapy 2014 Jul-Aug;13(4):361-8. Epub 2014 Mar 18.

Department of Medical Physics, Aarhus University Hospital, Aarhus, Denmark; Department of Oncology, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.

Purpose: To describe a new technique involving high-precision stereotactic intensity-modulated radiation therapy (IMRT) boost in combination with intracavitary-interstitial (IC-IS) brachytherapy (BT) in cervical tumors that cannot be sufficiently covered by IC-IS-BT due to extensive residual disease and/or difficult topography at the time of BT.

Methods And Materials: Three patients with stage IIIB-IVA cervical cancer had significant residual disease at the time of BT. MRI-guided IC-IS-BT (pulsed-dose rate) was combined with a stereotactic IMRT boost guided according to the BT applicator in situ, using cone beam CT. The planning aim dose (total external beam radiotherapy and BT) for the high-risk clinical target volume (HR-CTV) was D90 >70-85 Gy, whereas constraints for organs at risk were D2cm3 <70 Gy for rectum, sigmoid, and bowel and <90 Gy for bladder in terms of equivalent total dose in 2 Gy fractions. An IMRT boost adapted to the BT dose distribution was optimized to target the regions poorly covered by BT.

Results: HR-CTV doses of D90 >81 Gy were obtained in the central HR-CTV and D90 >69 Gy in the distal regions of HR-CTV. Image-guided set up of the IMRT boost with the applicator in situ was feasible. The dose plans were robust to intra-fraction uncertainties of 3 mm. Local control with acceptable morbidity was obtained at a followup of 3, 2.5, and 1 year, respectively.

Conclusions: The combination of MRI-guided BT with an applicator-guided stereotactic IMRT boost is feasible. This technique seems to be useful in the few cases where HR-CTV coverage cannot be obtained even with IS-IC-BT.
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http://dx.doi.org/10.1016/j.brachy.2014.02.003DOI Listing
September 2014
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