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Major improvements in radiotherapy over the past two decades in the definitive treatment of locally advanced cervical cancer have significantly improved loco-regional control and survival, whereas little progress has been made with chemotherapy since the implementation of concomitant cisplatin 25 years ago. However, the randomized study INTERLACE (A phase III multicenter trial of weekly induction chemotherapy followed by standard chemoradiation versus standard chemoradiation alone in patients with locally advanced cervical cancer) of neoadjuvant chemotherapy presented recently, has shown significant improvement in survival with the use of six cycles of weekly carboplatin and paclitaxel. Although INTERLACE is yet to be published, neoadjuvant chemotherapy is already being advocated as the new standard, and studies are being designed with neoadjuvant chemotherapy followed by chemoradiation and brachytherapy as the standard arm. It is noteworthy that INTERLACE was initiated before the improvements in radiotherapy mentioned above were broadly implemented. The survival rate in the standard arm of INTERLACE was therefore inferior to the results obtained with the latest state-of-the-art external beam radiotherapy and image guided adaptive brachytherapy (EMBRACE, Magnetic Resonance Imaging (MRI)-Guided Brachytherapy in Locally Advanced Cervical Cancer). Moreover, patient selection impedes the comparison of INTERLACE with other studies as the patients included in INTERLACE were younger, had better performance status, and had less advanced disease than in other studies. Notably patients with involved para-aortic nodes were excluded. In this review, we discuss neoadjuvant chemotherapy in the frame of the EMBRACE studies and show how the impact of modern radiotherapy and patient selection affects the interpretation of the results of INTERLACE. This has led us to conclude that neoadjuvant chemotherapy is not needed for the majority of patients with cervical cancer treated with definitive modern radiotherapy, and may cause harm. However, it is possible that short course neoadjuvant chemotherapy may benefit a minor subgroup of patients who need to be identified. Comprehensive understanding, including cost utility analyses, are needed to draw conclusions regarding the potential benefit of neoadjuvant chemotherapy in low and middle income countries with limited access to modern radiotherapy.
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BACKGROUND: The multicentre randomised SPARC trial evaluated the efficacy of a nurse-led sexual rehabilitation intervention on sexual functioning, distress, dilator use, and vaginal symptoms after radiotherapy for gynaecological cancers. METHODS: Eligible women were randomised to the rehabilitation intervention or care-as-usual. Four intervention sessions were scheduled over 12 months, with concurrent validated questionnaires and clinical assessments. Primary outcome was the Female Sexual Function Index (FSFI). A generalised-mixed-effects model compared groups over time. RESULTS: In total, 229 women were included (n = 112 intervention; n = 117 care-as-usual). No differences in FSFI total scores were found between groups at any timepoint (P = 0.37), with 12-month scores of 22.57 (intervention) versus 21.76 (care-as-usual). The intervention did not significantly improve dilator use, reduce sexual distress or vaginal symptoms compared to care-as-usual. At 12 months, both groups had minimal physician-reported vaginal stenosis; 70% of women were sexually active and reported no or mild vaginal symptoms. After radiotherapy and brachytherapy, 85% (intervention) versus 75% (care-as-usual) of participants reported dilation twice weekly. DISCUSSION: Sexual rehabilitation for women treated with combined (chemo)radiotherapy and brachytherapy improved before and during the SPARC trial, which likely contributed to comparable study groups. Best practice involves a sexual rehabilitation appointment 1 month post-radiotherapy, including patient information, with dilator guidance, preferably by a trained nurse, and follow-up during the first year after treatment. CLINICAL TRIAL REGISTRATION: NCT03611517.
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BACKGROUND: Numerous studies have shown that older women with endometrial cancer have a higher risk of recurrence and cancer-related death. However, it remains unclear whether older age is a causal prognostic factor, or whether other risk factors become increasingly common with age. We aimed to address this question with a unique multimethod study design using state-of-the-art statistical and causal inference techniques on datasets of three large, randomised trials. METHODS: In this multimethod analysis, data from 1801 women participating in the randomised PORTEC-1, PORTEC-2, and PORTEC-3 trials were used for statistical analyses and causal inference. The cohort included 714 patients with intermediate-risk endometrial cancer, 427 patients with high-intermediate risk endometrial cancer, and 660 patients with high-risk endometrial cancer. Associations of age with clinicopathological and molecular features were analysed using non-parametric tests. Multivariable competing risk analyses were performed to determine the independent prognostic value of age. To analyse age as a causal prognostic variable, a deep learning causal inference model called AutoCI was used. FINDINGS: Median follow-up as estimated using the reversed Kaplan-Meier method was 12·3 years (95% CI 11·9-12·6) for PORTEC-1, 10·5 years (10·2-10·7) for PORTEC-2, and 6·1 years (5·9-6·3) for PORTEC-3. Both overall recurrence and endometrial cancer-specific death significantly increased with age. Moreover, older women had a higher frequency of deep myometrial invasion, serous tumour histology, and p53-abnormal tumours. Age was an independent risk factor for both overall recurrence (hazard ratio [HR] 1·02 per year, 95% CI 1·01-1·04; p=0·0012) and endometrial cancer-specific death (HR 1·03 per year, 1·01-1·05; p=0·0012) and was identified as a significant causal variable. INTERPRETATION: This study showed that advanced age was associated with more aggressive tumour features in women with endometrial cancer, and was independently and causally related to worse oncological outcomes. Therefore, our findings suggest that older women with endometrial cancer should not be excluded from diagnostic assessments, molecular testing, and adjuvant therapy based on their age alone. FUNDING: None.
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Neoplasias do Endométrio , Humanos , Feminino , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/mortalidade , Fatores Etários , Idoso , Pessoa de Meia-Idade , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/epidemiologia , Idoso de 80 Anos ou maisRESUMO
STUDY OBJECTIVES: Pelvic lymph node dissection (PLND) is part of the primary treatment for early-stage cervical cancer and high-intermediate risk or high-risk endometrial cancer. Pelvic lymphocele is a postoperative complication of PLND, and when symptomatic, lymphoceles necessitate treatment. The aim of this study was to investigate the incidence and risk factors of symptomatic lymphocele after robot-assisted laparoscopic PLND in cervical and endometrial cancer. DESIGN: Retrospective cohort study. SETTING: Single-center academic hospital. PATIENTS: Two hundred and fifty-eight patients with cervical cancer and 129 patients with endometrial cancer. INTERVENTIONS: Pelvic lymphadenectomy by robot-assisted laparoscopic surgery. MEASUREMENTS AND MAIN RESULTS: The authors retrospectively included all patients with early-stage cervical cancer and high-intermediate risk or high-risk endometrial cancer who underwent pelvic lymphadenectomy by robot-assisted laparoscopic surgery between 2008 and 2022. Medical records were reviewed for the occurrence of a symptomatic lymphocele. Univariate and multivariate logistic regression analyses were conducted to identify risk factors for developing a symptomatic lymphocele. In total, 387 patients, 258 with cervical cancer and 129 with endometrial cancer, were included in the study. The overall incidence of symptomatic lymphoceles was 9.6% with a median follow-up of 47 months [interquartile range 23-61]. For the entire cohort, smoking was the only significant risk factor for symptomatic lymphoceles identified in univariate (OR 2.47, 95% CI 1.19-5.11) and multivariate analysis (OR 2.42, 95% CI 1.16-5.07). For cervical cancer, body mass index (BMI) (OR 1.09, 95% CI 1.00-1.17) and prior abdominal surgery (OR 2.75, 95% CI 1.22-6.17) were also identified as significant independent risk factors. For endometrial cancer, age was identified as a significant independent risk factor (OR 0.90, 95% CI 0.83-0.97). CONCLUSION: This single-center cohort study demonstrated an incidence of almost 10% of symptomatic lymphoceles after robot-assisted laparoscopic PLND for cervical cancer and endometrial cancer, with a higher risk observed among patients who smoke at the time of diagnosis. Furthermore, risk factors differ between the 2 populations, necessitating further studies to establish risk models.
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Neoplasias do Endométrio , Linfocele , Robótica , Neoplasias do Colo do Útero , Feminino , Humanos , Estudos Retrospectivos , Linfocele/epidemiologia , Linfocele/etiologia , Neoplasias do Colo do Útero/cirurgia , Neoplasias do Colo do Útero/complicações , Estudos de Coortes , Excisão de Linfonodo/efeitos adversos , Neoplasias do Endométrio/cirurgia , Neoplasias do Endométrio/complicações , Pelve/cirurgiaRESUMO
Universal tumor screening in endometrial carcinoma (EC) is increasingly adopted to identify individuals at risk of Lynch syndrome (LS). These cases involve mismatch repair-deficient (MMRd) EC without MLH1 promoter hypermethylation (PHM). LS is confirmed through the identification of germline MMR pathogenic variants (PV). In cases where these are not detected, emerging evidence highlights the significance of double-somatic MMR gene alterations as a sporadic cause of MMRd, alongside POLE/POLD1 exonuclease domain (EDM) PV leading to secondary MMR PV. Our understanding of the incidence of different MMRd EC origins not related to MLH1-PHM, their associations with clinicopathologic characteristics, and the prognostic implications remains limited. In a combined analysis of the PORTEC-1, -2, and -3 trials (n = 1254), 84 MMRd EC not related to MLH1-PHM were identified that successfully underwent paired tumor-normal tissue next-generation sequencing of the MMR and POLE/POLD1 genes. Among these, 37% were LS associated (LS-MMRd EC), 38% were due to double-somatic hits (DS-MMRd EC), and 25% remained unexplained. LS-MMRd EC exhibited higher rates of MSH6 (52% vs 19%) or PMS2 loss (29% vs 3%) than DS-MMRd EC, and exclusively showed MMR-deficient gland foci. DS-MMRd EC had higher rates of combined MSH2/MSH6 loss (47% vs 16%), loss of >2 MMR proteins (16% vs 3%), and somatic POLE-EDM PV (25% vs 3%) than LS-MMRd EC. Clinicopathologic characteristics, including age at tumor onset and prognosis, did not differ among the various groups. Our study validates the use of paired tumor-normal next-generation sequencing to identify definitive sporadic causes in MMRd EC unrelated to MLH1-PHM. MMR immunohistochemistry and POLE-EDM mutation status can aid in the differentiation between LS-MMRd EC and DS-MMRd EC. These findings emphasize the need for integrating tumor sequencing into LS diagnostics, along with clear interpretation guidelines, to improve clinical management. Although not impacting prognosis, confirmation of DS-MMRd EC may release patients and relatives from burdensome LS surveillance.
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Reparo de Erro de Pareamento de DNA , Neoplasias do Endométrio , Feminino , Humanos , Reparo de Erro de Pareamento de DNA/genética , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Neoplasias do Endométrio/patologia , Mutação em Linhagem Germinativa , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Instabilidade de Microssatélites , Metilação de DNARESUMO
BACKGROUND: State of the art combined radiochemotherapy and image-guided brachytherapy for locally advanced cervical cancer (LACC) has shown improved disease control and survival as well as a significant reduction of organ related morbidity. However, LACC cancer survivors are still experiencing a spectrum of symptoms. The aim of this study was to identify co-occurring symptoms in cervix cancer survivors by using patient-reported outcome and physician assessed morbidity. MATERIALS AND METHOD: EMBRACE I is a multicenter prospective observational study with 1416 LACC patients (2008-2015). Information on physician-assessed morbidity and patient-reported outcome was assessed at baseline and at regular follow-ups up with the CTCAE v.3 and EORTC-C30/CX24, respectively. Patients with at least 2 years of follow-up were included and data from 3 months to 2 years was used in the analysis. Factor analysis was used on both EORTC and CTCAE data with symptoms and follow-ups as observations. The extracted factors represent clusters of symptoms. Subsequently, regression models were built to investigate associations between the symptom clusters and QOL. RESULTS: The analysis included 742 patients. Despite the differences in the definition of physician-assessed and patient-reported symptoms, similar clusters are identified by the two assessment methods. Three main organ-related clusters are recognized for urinary, gastro-intestinal and vaginal morbidity. Furthermore, a general symptoms cluster where fatigue, pain, insomnia, neuropathy, and hot flashes have large weights is found. Lastly, a cluster with nausea, vomit and lack of appetite is also identified. The general, gastrointestinal and nausea clusters show significant associations with general QOL. CONCLUSIONS: This analysis on both PRO and physician-assessed morbidity found a cluster associated with general symptoms and organ-related symptom clusters (urinary, gastrointestinal, vaginal). This shows that LACC survivors experience a variety of co-occurring symptoms. Our analysis also shows that the cluster of general symptoms is associated with a decrease in QOL.
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Neoplasias do Colo do Útero , Feminino , Humanos , Qualidade de Vida , Síndrome , Estudos Prospectivos , Náusea , Quimiorradioterapia/métodos , Análise por ConglomeradosRESUMO
OBJECTIVE: To evaluate the effect on patient outcomes when introducing a novice robotic surgeon, trained in accordance with a structured learning curriculum, to an experienced robotic surgery team treating cervical cancer patients. METHODS: Patients with early-stage cervical cancer who were treated with primary robot-assisted surgery between 2007 and 2019 were retrospectively included. In addition to the 165 patients included in a former analysis, we included a further 61 consecutively treated patients and divided all 226 patients over three groups: early learning phase of 61 procedures without structured training (group 1), experienced phase of 104 procedures (group 2), and the 61 procedures during introduction of a novice with structured training (group 3). Risk-adjusted cumulative sum (RA-CUSUM) analysis was performed to assess the learning curve effect. Patient outcomes between the groups were compared. RESULTS: Based on RA-CUSUM analysis, no learning curve effect was observed for group 3. Regarding surgical outcomes, mean operation time in group 3 was significantly shorter than group 1 (p < 0.001) and similar to group 2 (p = 0.96). Proportions of intraoperative and postoperative adverse events in group 3 were not significantly different from the experienced group (group 2). Regarding oncological outcomes, the 5-year disease-free survival, disease-specific survival, and overall survival in group 3 were not significantly different from the experienced group. CONCLUSIONS: Introducing a novice robotic surgeon, who was trained in accordance with a structured learning curriculum, resulted in similar patient outcomes as by experienced surgeons suggesting novices can progress through a learning phase without compromising outcomes of cervical cancer patients.
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Laparoscopia , Procedimentos Cirúrgicos Robóticos , Cirurgiões , Neoplasias do Colo do Útero , Feminino , Humanos , Procedimentos Cirúrgicos Robóticos/métodos , Estudos Retrospectivos , Neoplasias do Colo do Útero/cirurgia , Neoplasias do Colo do Útero/etiologia , Estudos de Coortes , Curva de Aprendizado , Currículo , Laparoscopia/métodosRESUMO
PURPOSE: The molecular classification of endometrial cancer (EC) has proven to have prognostic value and is predictive of response to adjuvant chemotherapy. Here, we investigate its predictive value for response to external beam radiotherapy (EBRT) and vaginal brachytherapy (VBT) in early-stage endometrioid EC (EEC). METHODS: Data of the randomized PORTEC-1 trial (n = 714) comparing pelvic EBRT with no adjuvant therapy in early-stage intermediate-risk EC and the PORTEC-2 trial (n = 427) comparing VBT with EBRT in early-stage high-intermediate-risk EC were used. Locoregional (including vaginal and pelvic) recurrence-free survival was compared between treatment groups across the four molecular classes using Kaplan-Meier's methodology and log-rank tests. RESULTS: A total of 880 molecularly classified ECs, 484 from PORTEC-1 and 396 from PORTEC-2, were included. The majority were FIGO-2009 stage I EEC (97.2%). The median follow-up was 11.3 years. No locoregional recurrences were observed in EC with a pathogenic mutation of DNA polymerase-ε (POLEmut EC). In mismatch repair-deficient (MMRd) EC, locoregional recurrence-free survival was similar after EBRT (94.2%), VBT (94.2%), and no adjuvant therapy (90.3%; P = .74). In EC with a p53 abnormality (p53abn EC), EBRT (96.9%) had a substantial benefit over VBT (64.3%) and no adjuvant therapy (72.2%; P = .048). In EC with no specific molecular profile (NSMP EC), both EBRT (98.3%) and VBT (96.2%) yielded better locoregional control than no adjuvant therapy (87.7%; P < .0001). CONCLUSION: The molecular classification of EC predicts response to radiotherapy in stage I EEC and may guide adjuvant treatment decisions. Omitting radiotherapy seems to be safe in POLEmut EC. The benefit of radiotherapy seems to be limited in MMRd EC. EBRT yields a significantly better locoregional recurrence-free survival than VBT or no adjuvant therapy in p53abn EC. VBT is the treatment of choice for NSMP EC as it is as effective as EBRT and significantly better than no adjuvant therapy for locoregional tumor control.
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Braquiterapia , Neoplasias do Endométrio , Radioterapia (Especialidade) , Feminino , Humanos , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/radioterapia , Terapia CombinadaRESUMO
PURPOSE: To develop a novel decision-support system for radiation oncology that incorporates clinical, treatment and outcome data, as well as outcome models from a large clinical trial on magnetic resonance image-guided adaptive brachytherapy (MR-IGABT) for locally advanced cervical cancer (LACC). METHODS: A system, called EviGUIDE, was developed that combines dosimetric information from the treatment planning system, patient and treatment characteristics, and established tumor control probability (TCP), and normal tissue complication probability (NTCP) models, to predict clinical outcome of radiotherapy treatment of LACC. Six Cox Proportional Hazards models based on data from 1341 patients of the EMBRACE-I study have been integrated. One TCP model for local tumor control, and five NTCP models for OAR morbidities. RESULTS: EviGUIDE incorporates TCP-NTCP graphs to help users visualize the clinical impact of different treatment plans and provides feedback on achievable doses based on a large reference population. It enables holistic assessment of the interplay between multiple clinical endpoints and tumour and treatment variables. Retrospective analysis of 45 patients treated with MR-IGABT showed that there exists a sub-cohort of patients (20%) with increased risk factors, that could greatly benefit from the quantitative and visual feedback. CONCLUSION: A novel digital concept was developed that can enhance clinical decision- making and facilitate personalized treatment. It serves as a proof of concept for a new generation of decision support systems in radiation oncology, which incorporate outcome models and high-quality reference data, and aids the dissemination of evidence-based knowledge about optimal treatment and serve as a blueprint for other sites in radiation oncology.
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Braquiterapia , Radioterapia Guiada por Imagem , Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/radioterapia , Neoplasias do Colo do Útero/patologia , Estudos Retrospectivos , Radiometria , Tomada de Decisões , Dosagem RadioterapêuticaRESUMO
PURPOSE: To develop and implement a software that enables centers, treating patients with state-of-the-art radiation oncology, to compare their patient, treatment, and outcome data to a reference cohort, and to assess the quality of their treatment approach. MATERIALS AND METHODS: A comprehensive data dashboard was designed, which al- lowed holistic assessment of institutional treatment approaches. The software was tested in the ongoing EMBRACE-II study for locally advanced cervical cancer. The tool created individualized dashboards and automatic analysis scripts, verified pro- tocol compliance and checked data for inconsistencies. Identified quality assurance (QA) events were analysed. A survey among users was conducted to assess usability. RESULTS: The survey indicated favourable feedback to the prototype and highlighted its value for internal monitoring. Overall, 2302 QA events were identified (0.4% of all collected data). 54% were due to missing or incomplete data, and 46% originated from other causes. At least one QA event was found in 519/1001 (52%) of patients. QA events related to primary study endpoints were found in 16% of patients. Sta- tistical methods demonstrated good performance in detecting anomalies, with precisions ranging from 71% to 100%. Most frequent QA event categories were Treatment Technique (27%), Patient Characteristics (22%), Dose Reporting (17%), Outcome 156 (15%), Outliers (12%), and RT Structures (8%). CONCLUSION: A software tool was developed and tested within a clinical trial in radia- tion oncology. It enabled the quantitative and qualitative comparison of institutional patient and treatment parameters with a large multi-center reference cohort. We demonstrated the value of using statistical methods to automatically detect implau- sible data points and highlighted common pitfalls and uncertainties in radiotherapy for cervical cancer.
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Radioterapia (Especialidade) , Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/radioterapia , Ciência de Dados , Planejamento da Radioterapia Assistida por Computador , Inquéritos e Questionários , Garantia da Qualidade dos Cuidados de Saúde/métodosRESUMO
BACKGROUND AND PURPOSE: Image-guided adaptive brachytherapy (IGABT) is an important modality in the cervical cancer treatment, and plan quality is sensitive to time pressure in the workflow. Patient anatomy-based quality-assurance (QA) with overlap volume histograms (OVHs) has been demonstrated to detect suboptimal plans (outliers). This analysis quantifies the possible improvement of plans detected as outliers, and investigates its suitability as a clinical QA tool in a multi-center setting. MATERIALS AND METHODS: In previous work OVH-based models were investigated for the use of QA. In this work a total of 160 plans of 68 patients treated in accordance with the current state-of-the-art IGABT protocol from Erasmus MC (EMC) were analyzed, with a model based on 120 plans (60 patients) from UMC Utrecht (UMCU). Machine-learning models were trained to define QA thresholds, and to predict dose D2cm3 to bladder, rectum, sigmoid and small bowel with the help of OVHs of the EMC cohort. Plans out of set thresholds (outliers) were investigated and retrospectively replanned based on predicted D2cm3 values. RESULTS: Analysis of replanned plans demonstrated a median improvement of 0.62 Gy for all Organs At Risk (OARs) combined and an improvement for 96 % of all replanned plans. Outlier status was resolved for 36 % of the replanned plans. The majority of the plans that could not be replanned were reported having implantation complications or insufficient coverage due to tumor geometry. CONCLUSION: OVH-based QA models can detect suboptimal plans, including both unproblematic BT applications and suboptimal planning circumstances in general. OVH-based QA models demonstrate potential for clinical use in terms of performance and user-friendliness, and could be used for knowledge transfer between institutes. Further research is necessary to differentiate between (sub)optimal planning circumstances.
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Braquiterapia , Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/radioterapia , Neoplasias do Colo do Útero/patologia , Braquiterapia/métodos , Estudos Retrospectivos , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador/métodos , Órgãos em Risco/patologiaRESUMO
PURPOSE: To report clinical and treatment characteristics, remission and failure patterns, and risk factors for local failure (LF) from the EMBRACE-I study. MATERIALS AND METHODS: EMBRACE-I was a prospective, observational, multicenter cohort study on magnetic resonance imaging-based image-guided adaptive brachytherapy (MR-IGABT) in locally advanced cervical cancer. Treatment consisted of external beam radiotherapy, concurrent chemotherapy, and MR-IGABT. LF was defined as progressive or recurrent disease in the cervix, uterus, parametria, pelvic wall, or vagina. Competing risk analysis was used to estimate local tumor control (LC) and Cox proportional regression models for multivariable analysis and dose-response analysis. RESULTS: One thousand three hundred eighteen patients with a median follow-up of 52 months were available for this analysis. Eighty-one patients had persistent disease 3 months after end of treatment. Of those, 60 patients achieved LC at 6-9 months without further treatment, whereas 21 patients had progressive disease. In addition, 77 patients developed a local recurrence after complete remission comprising a total number of 98 LFs. LFs were located inside the MR-IGABT target volumes in 90% of patients with LF. In multivariable analysis, histology, minimal dose to 90% of high-risk clinical target volume (CTVHR), maximum tumor dimension, CTVHR > 45 cm3, overall treatment time, tumor necrosis on magnetic resonance imaging at diagnosis, uterine corpus infiltration at diagnosis and at MR-IGABT, and mesorectal infiltration at MR-IGABT had significant impact on LF. Dose-response analysis showed that a minimal dose to 90% of 85 Gy to the CTVHR led to 95% (95% CI, 94 to 97) LC 3 years postintervention for squamous cell in comparison to 86% (95% CI, 81 to 90) for adeno/adenosquamous carcinoma histology. CONCLUSION: The present study demonstrates the safety and validity of the GYN GEC-ESTRO/ICRU-89 target concept and provides large-scale evidence for dose prescription and new risk factors for LF in MR-IGABT in locally advanced cervical cancer.
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Braquiterapia , Radioterapia Guiada por Imagem , Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/radioterapia , Braquiterapia/efeitos adversos , Braquiterapia/métodos , Estudos Prospectivos , Estudos de Coortes , Estadiamento de Neoplasias , Imageamento por Ressonância Magnética , Dosagem Radioterapêutica , Fatores de Risco , Radioterapia Guiada por Imagem/efeitos adversosRESUMO
BACKGROUND: Risk-assessment of endometrial cancer (EC) is based on clinicopathological factors and molecular subgroup. It is unclear whether adding hormone receptor expression, L1CAM expression or CTNNB1 status yields prognostic refinement. METHODS: Paraffin-embedded tumour samples of women with high-risk EC (HR-EC) from the PORTEC-3 trial (n = 424), and a Dutch prospective clinical cohort called MST (n = 256), were used. All cases were molecularly classified. Expression of L1CAM, ER and PR were analysed by whole-slide immunohistochemistry and CTNNB1 mutations were assessed with a next-generation sequencing. Kaplan-Meier method, log-rank tests and Cox's proportional hazard models were used for survival analysis. RESULTS: In total, 648 HR-EC were included. No independent prognostic value of ER, PR, L1CAM, and CTNNB1 was found, while age, stage, and adjuvant chemotherapy had an independent impact on risk of recurrence. Subgroup-analysis showed that only in NSMP HR-EC, ER-positivity was independently associated with a reduced risk of recurrence (HR 0.33, 95%CI 0.15-0.75). CONCLUSIONS: We confirmed the prognostic impact of the molecular classification, age, stage, and adjuvant CTRT in a large cohort of high-risk EC. ER-positivity is a strong favourable prognostic factor in NSMP HR-EC and identifies a homogeneous subgroup of NSMP tumours. Assessment of ER status in high-risk NSMP EC is feasible in clinical practice and could improve risk stratification and treatment.
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Neoplasias do Endométrio , Molécula L1 de Adesão de Célula Nervosa , Feminino , Humanos , Prognóstico , Receptores de Estrogênio , Imuno-Histoquímica , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Estudos Prospectivos , Neoplasias do Endométrio/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análiseRESUMO
PURPOSE: To quantify the association of persistent morbidity with different aspects of quality of life (QOL) in locally advanced cervical cancer (LACC) survivors. MATERIAL AND METHODS: Longitudinal outcome from the EMBRACE-I study was evaluated. Patient-reported symptoms and QOL were prospectively scored (EORTC-C30/CX24) at baseline and regular follow-ups. Physician-assessed symptoms were also reported (CTCAEv.3). Persistent symptoms were defined if present in at least half of the follow-ups. QOL items were linearly transformed into a continuous scale. Linear mixed-effects models (LMM) were applied to evaluate and quantify the association of persistent symptoms with QOL. Overall QOL deterioration was evaluated by calculating the integral difference in QOL over time obtained with LMM for patients without and with persistent symptoms. RESULTS: Out of 1416 patients enrolled, 741 with baseline and ≥ 3 late follow-ups were analyzed (median 59 months). Proportions of persistent EORTC symptoms ranged from 21.8 % to 64.9 % (bowel control and tiredness). For CTCAE the range was 11.3-28.6 % (limb edema and fatigue). Presence of any persistent symptom was associated with QOL, although with varying magnitude. Role functioning and Global health/QOL were the most impaired aspects. Fatigue and pain showed large differences, with reductions of around 20 % for most of the QOL aspects. Among organ-related symptoms, abdominal cramps showed the largest effect. CONCLUSION: Persistent symptoms are associated with QOL reductions in LACC survivors. Organ-related symptoms showed smaller differences than general symptoms such as fatigue and pain. In addition to optimizing treatment to minimize organ-related morbidity, effort should be directed towards a more comprehensive and targeted morbidity management.
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Sobreviventes de Câncer , Neoplasias do Colo do Útero , Feminino , Humanos , Qualidade de Vida , Neoplasias do Colo do Útero/terapia , Estudos Prospectivos , Morbidade , Sobreviventes , Inquéritos e QuestionáriosRESUMO
PURPOSE: To evaluate overall severe late morbidity (grade ≥3) in patients with locally advanced cervical cancer treated with chemo-radiation therapy and magnetic resonance image guided adaptive brachytherapy within the prospective EMBRACE-I study, and to compare the results with published literature after standard radiograph based brachytherapy (BT). METHODS AND MATERIALS: From 2008 to 2015 the EMBRACE-I study enrolled 1416 patients. Morbidity was assessed (Common Terminology Criteria for Adverse Events version 3.0) every 3 months the 1st year, every 6 months the second and third year, and yearly thereafter and 1251 patients had available follow-up on late morbidity. Morbidity events (grade 3-5) were summarized as the maximum grade during follow-up (crude incidence rates) and actuarial estimates at 3 and 5 years. To compare with the published literature on standard radiograph based BT, Common Terminology Criteria for Adverse Events scores from the EMBRACE-I study were retrospectively converted into a corresponding score in the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer system. RESULTS: In total, 534 severe events occurred in 270 patients; 429 events were grade 3 and 105 were grade 4 events. Actuarial estimates for grade ≥3 gastrointestinal (GI), genitourinary (GU), vaginal and fistula events at 5 years were 8.5% (95% confidence interval [CI], 6.9%-10.6%), 6.8% (95% CI, 5.4%-8.6%), 5.7% (95% CI, 4.3%-7.6%), and 3.2% (95% CI, 2.2%-4.5%), respectively. The 5-year actuarial estimate for organ-related events (GI, GU, vaginal, or fistula) was 18.4% (95% CI, 16.0%-21.2%). The 5-year actuarial estimate when aggregating all G≥3 endpoints (GI, GU, vaginal, fistulas, and non-GI/GU/vaginal) was 26.6% (95% CI, 23.8%-29.6%). Thirteen patients had a treatment-related death, 8 of which were associated with GI morbidity. CONCLUSIONS: This report assesses severe morbidity from the largest prospective study on chemo-radiation therapy and image guided adaptive brachytherapy for locally advanced cervical cancer to date. Severe late morbidity was limited per endpoint and organ category, but considerable when aggregated across organs and all endpoints. The late morbidity results in the EMBRACE-I study compare favorably with published literature on standard radiograph based BT for GI morbidity, vaginal morbidity, and fistulas.
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Braquiterapia , Neoplasias do Colo do Útero , Feminino , Humanos , Braquiterapia/efeitos adversos , Braquiterapia/métodos , Neoplasias do Colo do Útero/terapia , Neoplasias do Colo do Útero/tratamento farmacológico , Estudos Prospectivos , Estudos Retrospectivos , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Morbidade , Vagina , Imageamento por Ressonância Magnética/métodos , Dosagem RadioterapêuticaRESUMO
BACKGROUND: Endometrial cancer can be molecularly classified into POLEmut, mismatch repair deficient (MMRd), p53 abnormal (p53abn), and no specific molecular profile (NSMP) subgroups. We aimed to develop an interpretable deep learning pipeline for whole-slide-image-based prediction of the four molecular classes in endometrial cancer (im4MEC), to identify morpho-molecular correlates, and to refine prognostication. METHODS: This combined analysis included diagnostic haematoxylin and eosin-stained slides and molecular and clinicopathological data from 2028 patients with intermediate-to-high-risk endometrial cancer from the PORTEC-1 (n=466), PORTEC-2 (n=375), and PORTEC-3 (n=393) randomised trials and the TransPORTEC pilot study (n=110), the Medisch Spectrum Twente cohort (n=242), a case series of patients with POLEmut endometrial cancer in the Leiden Endometrial Cancer Repository (n=47), and The Cancer Genome Atlas-Uterine Corpus Endometrial Carcinoma cohort (n=395). PORTEC-3 was held out as an independent test set and a four-fold cross validation was performed. Performance was measured with the macro and class-wise area under the receiver operating characteristic curve (AUROC). Whole-slide images were segmented into tiles of 360 µm resized to 224 × 224 pixels. im4MEC was trained to learn tile-level morphological features with self-supervised learning and to molecularly classify whole-slide images with an attention mechanism. The top 20 tiles with the highest attention scores were reviewed to identify morpho-molecular correlates. Predictions of a nuclear classification deep learning model serve to derive interpretable morphological features. We analysed 5-year recurrence-free survival and explored prognostic refinement by molecular class using the Kaplan-Meier method. FINDINGS: im4MEC attained macro-average AUROCs of 0·874 (95% CI 0·856-0·893) on four-fold cross-validation and 0·876 on the independent test set. The class-wise AUROCs were 0·849 for POLEmut (n=51), 0·844 for MMRd (n=134), 0·883 for NSMP (n=120), and 0·928 for p53abn (n=88). POLEmut and MMRd tiles had a high density of lymphocytes, p53abn tiles had strong nuclear atypia, and the morphology of POLEmut and MMRd endometrial cancer overlapped. im4MEC highlighted a low tumour-to-stroma ratio as a potentially novel characteristic feature of the NSMP class. 5-year recurrence-free survival was significantly different between im4MEC predicted molecular classes in PORTEC-3 (log-rank p<0·0001). The ten patients with aggressive p53abn endometrial cancer that was predicted as MMRd showed inflammatory morphology and appeared to have a better prognosis than patients with correctly predicted p53abn endometrial cancer (p=0·30). The four patients with NSMP endometrial cancer that was predicted as p53abn showed higher nuclear atypia and appeared to have a worse prognosis than patients with correctly predicted NSMP (p=0·13). Patients with MMRd endometrial cancer predicted as POLEmut had an excellent prognosis, as do those with true POLEmut endometrial cancer. INTERPRETATION: We present the first interpretable deep learning model, im4MEC, for haematoxylin and eosin-based prediction of molecular endometrial cancer classification. im4MEC robustly identified morpho-molecular correlates and could enable further prognostic refinement of patients with endometrial cancer. FUNDING: The Hanarth Foundation, the Promedica Foundation, and the Swiss Federal Institutes of Technology.
Assuntos
Aprendizado Profundo , Neoplasias do Endométrio , Feminino , Humanos , Amarelo de Eosina-(YS) , Hematoxilina , Projetos Piloto , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologiaRESUMO
We aim to investigate the current state of brachytherapy (BT) training among the radiation oncology trainees in Europe. MATERIAL AND METHODS: A 22-question online survey based on the one by the American Association of Radiation Oncology Residents (2017) with added queries pertinent to training in Europe was sent to 1450 residents in two iterations. These included site-specific training, volume of experience, barriers to training, institutional support, and preferences for further education. Responses to individual statements were given on a 1 to 5 Likert-type scale. The answers were reported by junior (≤3 years of training) and senior years of training (year of training 4/5/6 and junior staff). Descriptive statistics were used to describe frequencies. RESULTS: Residents from 21 European countries participated, 445 (31%) responded. 205 (47%) were senior residents. 60% residents consider that performing BT independently at the end of residency is very or somewhat important. Confidence in joining a brachytherapy practice at the end of residency was high or somewhat high in 34% of senior residents. They reported as barriers to achieving independence in BT to be lack of appropriate didactic/procedural training from supervisors (47%) and decreased case load (31%). 68% reported their program lacks a formal BT curriculum and standardized training assessment. CONCLUSIONS: Residents in Europe, feel independent BT practice is very or somewhat important, but do not feel confident they will achieve this goal. To address this gap, efforts are needed to develop and implement a formal and comprehensive BT curriculum with easy access to trained instructors.
Assuntos
Braquiterapia , Internato e Residência , Radioterapia (Especialidade) , Humanos , Competência Clínica , Currículo , Internato e Residência/organização & administração , Radioterapia (Especialidade)/educação , Inquéritos e Questionários , Europa (Continente)RESUMO
Background and purpose: Online adaptive MR-guided treatment planning workflows facilitate daily contour adaptation to the actual anatomy. Allocating contour adaptation to radiation therapists (RTTs) instead of radiation oncologists (ROs) might allow for increasing workflow efficiency. This study investigates conformity of adapted target contours provided by dedicated RTTs and ROs. Materials and methods: In a simulated online procedure, 6 RTTs and 6 ROs recontoured targets and organs at risk (OAR) in prostate cancer (n = 2), rectal cancer (n = 2) and lymph node-oligometastases (n = 2) cases. RTTs gained contouring competence beforehand by following a specific in-house training program. For all target contours and the reference delineations volumetric differences were determined and Dice similarity coefficient (DSC), conformity index (CI) and generalized CI were calculated. Delineation time and -confidence were registered for targets and OAR. Impact of contour adaptation on treatment plan quality was investigated. Results: Delineation conformity was generally high with DSC, CI and generalized CI values in the range of 0.81-0.94, 0.87-0.95 and 0.63-0.85 for prostate cancer, rectal cancer and LN-oligometastasis, respectively. Target volumes were comparable for both, RTTs and ROs. Time needed and confidence in contour adaptation was comparable as well. Treatment plans derived with adapted contours did not violate dose volume constrains as used in clinical routine. Conclusion: After tumor site specific training, daily contour adaptations as needed in adaptive online radiotherapy workflows can be accurately performed by RTTs. Conformity of the derived contours is high and comparable to contours as provided by ROs.
RESUMO
INTRODUCTION: Nowadays, two predominant methods for detecting sentinel lymph nodes (SLNs) in cervical cancer are in use. The most conventional method is a combination of a radiotracer, technetium-99m (99mTc) and blue dye. More recently, another method for SLN mapping using indocyanine green (ICG) is becoming widely accepted. ICG is a fluorescent dye, visualised intraoperatively with near-infrared (NIR) fluorescence imaging, providing real-time visual navigation. The presumed advantages of ICG over 99mTc, that is, being cheaper, non-radioactive and logistically more attractive, are only valuable if its detection rate proves to be at least non-inferior. Before omitting the well-functioning and evidence-based combined approach of 99mTc and blue dye, we aim to provide prospective evidence on the non-inferiority of ICG with NIR fluorescence imaging. METHODS AND ANALYSIS: We initiated a prospective non-inferiority study with a paired comparison of both SLN methods in a single sample of 101 patients with International Federation of Gynecology and Obstetrics (FIGO) stage IA-IB2 or IIA1 cervical cancer receiving primary surgical treatment. All patients undergo SLN mapping with ICG and NIR fluorescence imaging in adjunct to mapping with 99mTc (including single photon emission computed tomography with X-ray computed tomography (SPECT/CT)) and blue dye. Surgeons start SLN detection with ICG while being blinded for the preoperative outcome of SPECT/CT to avoid biased detection with ICG. Primary endpoint of this study is bilateral SLN detection rate of both methods (ie, detection of at least one SLN in each hemipelvis). Since we compare strategies for SLN mapping that are already applied in current daily practice for different types of cancer, no additional risks or burdens are expected from these study procedures. ETHICS AND DISSEMINATION: The current study is approved by the Medical Ethics Research Committee Utrecht (reference number 21-014). Findings arising from this study will be disseminated in peer-reviewed journals, academic conferences and through patient organisations. TRIAL REGISTRATION NUMBER: NL9011 and EudraCT 2020-005134-15.