RESUMO
Lymphovascular space invasion (LVSI) occurs in a minority of endometrial cancer (EC) cases, and the extent of LVSI is an important risk factor for recurrence and/or metastases. Our aim was to improve the reproducibility of measuring clinically meaningful LVSI by performing a quantitative analysis of the correlation between LVSI and the risk of pelvic lymph node recurrence in EC. EC samples from PORTEC-1 and PORTEC-2 trials were retrieved and used to collect quantitative data, including the number of LVSI-positive vessels per H&E-stained slide. Using a predefined threshold for clinical relevance, the risk of pelvic lymph node recurrence risk was calculated (Kaplan-Meier method, with Cox regression) using a stepwise adjustment for the number of LVSI-positive vessels. This analysis was then repeated in the Danish Gynecological Cancer Database (DGCD) cohort. Among patients in PORTEC-1 and PORTEC-2 trials who did not receive external beam radiotherapy, the 5-yr pelvic lymph node recurrence risk was 3.3%, 6.7% (P=0.51), and 26.3% (P<0.001), respectively when 0, 1 to 3, or ≥4 vessels had LVSI involvement; similar results were obtained for the DGCD cohort. Furthermore, both the average number of tumor cells in the largest embolus and the number of LVSI-positive H&E slides differed significantly between focal LVSI and substantial LVSI. On the basis of these results, we propose a numeric threshold (≥4 LVSI-involved vessels in at least one H&E slide) for defining clinically relevant LVSI in EC, thereby adding supportive data to the semiquantitative approach. This will help guide gynecologic pathologists to differentiate between focal and substantial LVSI, especially in borderline cases.
Assuntos
Neoplasias do Endométrio , Vasos Linfáticos , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/patologia , Feminino , Humanos , Linfonodos/patologia , Metástase Linfática/patologia , Vasos Linfáticos/patologia , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Prognóstico , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
BACKGROUND: Vaginal brachytherapy is currently recommended as adjuvant treatment in patients with high-intermediate risk endometrial cancer to maximize local control and has only mild side effects and no or limited impact on quality of life. However, there is still considerable overtreatment and also some undertreatment, which may be reduced by tailoring adjuvant treatment to the patients' risk of recurrence based on molecular tumor characteristics. PRIMARY OBJECTIVES: To compare the rates of vaginal recurrence in women with high-intermediate risk endometrial cancer, treated after surgery with molecular-integrated risk profile-based recommendations for either observation, vaginal brachytherapy or external pelvic beam radiotherapy or with standard adjuvant vaginal brachytherapy STUDY HYPOTHESIS: Adjuvant treatment based on a molecular-integrated risk profile provides similar local control and recurrence-free survival as current standard adjuvant brachytherapy in patients with high-intermediate risk endometrial cancer, while sparing many patients the morbidity of adjuvant treatment and reducing healthcare costs. TRIAL DESIGN: A multicenter, international phase III randomized trial (2:1) of molecular-integrated risk profile-based adjuvant treatment (experimental arm) or adjuvant vaginal brachytherapy (standard arm). MAJOR INCLUSION/EXCLUSION CRITERIA: Women aged 18 years and over with a histological diagnosis of high-intermediate risk endometrioid endometrial cancer after total abdominal or laparoscopic hysterectomy and bilateral salpingo-oophorectomy. High-intermediate risk factors are defined as: (i) International Federation of Gynecology and Obstetrics stage IA (with invasion) and grade 3; (ii) stage IB grade 1 or 2 with age ≥60 and/or lymph-vascular space invasion; (iii) stage IB, grade 3 without lymph-vascular space invasion; or (iv) stage II (microscopic and grade 1). ENDPOINTS: The primary endpoint is vaginal recurrence. Secondary endpoints are recurrence-free and overall survival; pelvic and distant recurrence; 5-year vaginal control (including treatment for relapse); adverse events and patient-reported symptoms and quality of life; and endometrial cancer-related healthcare costs. SAMPLE SIZE: 500 eligible and evaluable patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Estimated date for completing accrual will be late 2021. Estimated date for presentation of (first) results is expected in 2023. TRIAL REGISTRATION: The trial is registered at clinicaltrials.gov (NCT03469674) and ISRCTN (11659025).
Assuntos
Carcinoma Endometrioide/genética , Carcinoma Endometrioide/terapia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/terapia , Braquiterapia , Carcinoma Endometrioide/radioterapia , Ensaios Clínicos Fase III como Assunto , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Neoplasias do Endométrio/radioterapia , Feminino , Humanos , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Estudos Multicêntricos como Assunto , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Radioterapia Adjuvante , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Purpose: To determine the quality of life (QoL) of patients with muscle-invasive bladder cancer (MIBC) who underwent bladder-sparing treatment with high-dose-rate brachytherapy, and compare their QoL with an age-matched general Dutch population. Material and methods: We conducted a single-center, prospective, descriptive cross-sectional study. MIBC patients who underwent brachytherapy-based bladder sparing treatment in Arnhem, The Netherlands from January 2016 to June 2021, were requested to complete the following questionnaires: European Organization for Research and Treatment of Cancer (EORTC) generic (QLQ-C30), bladder cancer-specific (QLQ-BLM30), and expanded prostate cancer index composite bowel (EPIC-50). Mean scores were calculated and compared with general Dutch population. Results: The mean global health status/QoL score of the treated patients was 80.6. High scores were noted in the functional scales, including physical (86.8), role (85.6), emotional (88.6), cognitive (88.3), and social functioning (88.9), while the main reported complains were related to fatigue (21.9) and urinary symptoms (25.1). Compared to the general Dutch population, significant differences were visible in global health status/QoL (80.6 vs. 75.7), pain (9.0 vs. 17.8), insomnia (23.3 vs. 15.2), and constipation (13.3 vs. 6.8). However, in no case did the mean score differ by more than ten points, which was considered clinically relevant. Conclusions: With a mean global health status/QoL score of 80.6, the patients after brachytherapy-based bladder sparing treatment have a good QoL. We found no clinically relevant difference in QoL comparing with an age-matched general Dutch population. The outcome strengthens the idea that this treatment option should be discussed with all patients eligible for brachytherapy-based treatment.
RESUMO
Organ preservation for muscle-invasive bladder cancer (MIBC) may use trimodality therapy. This includes transurethral resection followed by radiation therapy. Radiosensitization has become one of the standard of care approaches for MIBC with high rates of local disease control and overall survival. The goal of organ preservation is to treat MIBC while preserving a well-functioning natural bladder. Debate remains over the best way to optimize radiation therapy in bladder cancer. In MIBC the role of partial cystectomy has been utilized in smaller solitary tumors with adequate local control and good urinary function. As radiation therapy techniques improve and modernize, smaller radiation volumes to a partial bladder may play an increasing role as we utilize imaging techniques coupled with adaptive radiation therapy planning and other techniques such as brachytherapy. In this review, we explore the use of brachytherapy and partial bladder fields of external beam radiation therapy in the treatment of MIBC.
Assuntos
Braquiterapia , Neoplasias da Bexiga Urinária , Humanos , Bexiga Urinária/patologia , Bexiga Urinária/cirurgia , Braquiterapia/métodos , Terapia Combinada , Cistectomia/métodos , Neoplasias da Bexiga Urinária/radioterapia , Neoplasias da Bexiga Urinária/cirurgia , Invasividade Neoplásica/patologiaRESUMO
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
OBJECTIVE: To investigate if analysis of genetic alterations in the main pathways involved in endometrioid type carcinogenesis (PI3K-AKT, Wnt/ß-catenin, P53-activation and MSI) improves the current risk assessment based on clinicopathological factors. METHODS: Formalin fixed paraffin embedded (FFPE) primary tumor samples of 65 patients with FIGO-stage I endometrioid type endometrial cancer (EEC) were selected from the randomized PORTEC-2 trial. Tumors were stained by immunohistochemistry for P53, PTEN and ß-catenin. Tumor DNA was isolated for sequence analysis of TP53 (exons 4 to 8), hotspot mutation analysis of KRAS (exon 1) and PI3K (exon 9 and 20) and microsatellite-instability (MSI) analysis including MLH1 promotor-methylation status. Univariate and multivariate analyses for disease-free survival (DFS) using Cox regression models were performed. RESULTS: P53 status (HR 6.7, 95%CI 1.75-26.0, p=0.006) and MSI were the strongest single genetic prognostic factors for decreased DFS, while high PI3K-AKT pathway activation showed a trend and ß-catenin was not prognostic. The combination of multiple activated pathways was the most powerful prognostic factor for decreased DFS (HR 5.0; 95%CI 1.59-15.6 p=0.006). Multiple pathway activation, found in 8% of patients, was strongly associated with aggressive clinical course. In contrast, 40% of patients had no alterations in the investigated pathways and had a very low risk of disease progression. CONCLUSIONS: Activation of multiple oncogenic pathways in EEC was the most powerful prognostic factor for decreased DFS, resulting in an individual risk assessment superior to the current approach based on clinicopathological factors.
Assuntos
Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Instabilidade de Microssatélites , Recidiva Local de Neoplasia/metabolismo , Proteína Supressora de Tumor p53/genética , Via de Sinalização Wnt/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Éxons , Feminino , Humanos , Estimativa de Kaplan-Meier , Metilação , Pessoa de Meia-Idade , Análise Multivariada , Proteína 1 Homóloga a MutL , Mutação , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Regiões Promotoras Genéticas , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas p21(ras) , Medição de Risco , Análise de Sequência de DNA , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/metabolismo , beta Catenina/metabolismo , Proteínas ras/genéticaRESUMO
PURPOSE: The European Organisation for Research and Treatment of Cancer (EORTC) trial 22991 (NCT00021450) showed that 6 months of concomitant and adjuvant androgen suppression (AS) improves event- (EFS, Phoenix) and clinical disease-free survival (DFS) of intermediate- and high-risk localized prostatic carcinoma, treated by external-beam radiotherapy (EBRT) at 70-78 Gy. We report the long-term results in intermediate-risk patients treated with 74 or 78 Gy EBRT, as per current guidelines. PATIENT AND METHODS: Of 819 patients randomly assigned between EBRT or EBRT plus AS started on day 1 of EBRT, 481 entered with intermediate risk (International Union Against Cancer TNM 1997 cT1b-c or T2a with prostate-specific antigen (PSA) ≥ 10 ng/mL or Gleason ≤ 7 and PSA ≤ 20 ng/mL, N0M0) and had EBRT planned at 74 (342 patients, 71.1%) or 78 Gy (139 patients, 28.9%). We report the trial primary end point EFS, DFS, distant metastasis-free survival (DMFS), and overall survival (OS) by intention-to-treat stratified by EBRT dose at two-sided α = 5%. RESULTS: At a median follow-up of 12.2 years, 92 of 245 patients and 132 of 236 had EFS events in the EBRT plus AS and EBRT arm, respectively, mostly PSA relapse (48.7%) or death (45.1%). EBRT plus AS improved EFS and DFS (hazard ratio [HR] = 0.53; CI, 0.41 to 0.70; P < .001 and HR = 0.67; CI, 0.49 to 0.90; P = .008). At 10 years, DMFS was 79.3% (CI, 73.4 to 84.0) with EBRT plus AS and 72.7% (CI, 66.2 to 78.2) with EBRT (HR = 0.74; CI, 0.53 to 1.02; P = .065). With 140 deaths (EBRT plus AS: 64; EBRT: 76), 10-year OS was 80.0% (CI, 74.1 to 84.7) with EBRT plus AS and 74.3% (CI, 67.8 to 79.7) with EBRT, but not statistically significantly different (HR = 0.74; CI, 0.53 to 1.04; P = .082). CONCLUSION: Six months of concomitant and adjuvant AS statistically significantly improves EFS and DFS in intermediate-risk prostatic carcinoma, treated by irradiation at 74 or 78 Gy. The effects on OS and DMFS did not reach statistical significance.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Doses de Radiação , Fatores de Risco , Fatores de TempoRESUMO
UNLABELLED: The aim of this study was to look at the impact of the number of sites with tumour involvement on outcome for patients with stage IIIA endometrioid-type endometrial carcinoma. PATIENTS AND METHODS: 141 patients stage IIIA were included. A central histopathological review was performed. Patients staged solely on the presence of a positive peritoneal washing were excluded. Follow-up ranged from 2 to 217 months with a median of 43 months. Endpoints of the study were locoregional recurrence rates, distant metastasis-free survival (DMFS), disease-free survival (DFS) and disease-specific survival (DSS). RESULTS: In multivariate analyses the number of involved sites showed to be the only independent significant variable for DMFS, DFS, and DSS with a Hazard Ratio of 2.1, 2.2, and 2.2, respectively. The DSS was significantly related to the number of involved sites, with a 5-year DSS of 70.4% for one site, 42.8% for two sites, and 43.9% for three sites, respectively (p=0.001). CONCLUSION: The number of involved sites outside the corpus uterine for stage IIIA seems to be a strong negative prognostic factor for stage IIIA endometrial carcinoma.
Assuntos
Carcinoma Endometrioide/secundário , Neoplasias do Endométrio/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/radioterapia , Carcinoma Endometrioide/cirurgia , Terapia Combinada , Intervalo Livre de Doença , Neoplasias do Endométrio/radioterapia , Neoplasias do Endométrio/cirurgia , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/patologia , Estadiamento de NeoplasiasRESUMO
Optimum risk stratification in early-stage endometrial cancer combines clinicopathologic factors and the molecular endometrial cancer classification defined by The Cancer Genome Atlas (TCGA). It is unclear whether analysis of intratumoral immune infiltrate improves this. We developed a machine-learning, image-based algorithm to quantify density of CD8+ and CD103+ immune cells in tumor epithelium and stroma in 695 stage I endometrioid endometrial cancers from the PORTEC-1 and -2 trials. The relationship between immune cell density and clinicopathologic/molecular factors was analyzed by hierarchical clustering and multiple regression. The prognostic value of immune infiltrate by cell type and location was analyzed by univariable and multivariable Cox regression, incorporating the molecular endometrial cancer classification. Tumor-infiltrating immune cell density varied substantially between cases, and more modestly by immune cell type and location. Clustering revealed three groups with high, intermediate, and low densities, with highly significant variation in the proportion of molecular endometrial cancer subgroups between them. Univariable analysis revealed intraepithelial CD8+ cell density as the strongest predictor of endometrial cancer recurrence; multivariable analysis confirmed this was independent of pathologic factors and molecular subgroup. Exploratory analysis suggested this association was not uniform across molecular subgroups, but greatest in tumors with mutant p53 and absent in DNA mismatch repair-deficient cancers. Thus, this work identified that quantification of intraepithelial CD8+ cells improved upon the prognostic utility of the molecular endometrial cancer classification in early-stage endometrial cancer.
Assuntos
Antígenos CD/imunologia , Biomarcadores Tumorais , Linfócitos T CD8-Positivos/imunologia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/imunologia , Cadeias alfa de Integrinas/imunologia , Idoso , Idoso de 80 Anos ou mais , Reparo de Erro de Pareamento de DNA , Feminino , Humanos , Modelos Lineares , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Estadiamento de Neoplasias , Prognóstico , Proteína Supressora de Tumor p53/genéticaRESUMO
PURPOSE: To investigate the feasibility of in vivo dosimetry using microMOSFET dosimeters in patients treated with brachytherapy using two types of gynecological applicators. METHODS AND MATERIALS: In this study, a microMOSFET was placed in an empty needle of an Utrecht Interstitial Fletcher applicator or MUPIT (Martinez Universal Perineal Interstitial Template) applicator for independent verification of treatment delivery. Measurements were performed in 10 patients, with one to three microMOSFETs per applicator and repeated for one to four fractions, resulting in 50 in vivo measurements. Phantom measurements were used to determine characteristics of the microMOSFETs. RESULTS: Phantom measurements showed a linear relationship between dose and microMOSFET threshold voltage, and a calibration coefficient (mV/cGy) was determined. Reproducibility of repeated 50 cGy irradiations was 2% (1 standard deviation). Distance and angle dependencies were measured and correction factors were determined. Subsequently, three microMOSFETs were placed in a phantom to measure a validation plan. The difference between predicted and measured dose was less than the measurement uncertainty (±9%, 2 standard deviations). In vivo measurements were corrected for distance and angle dependencies. Differences between predicted and measured dose in the patients were smaller than the measurement uncertainty for the majority of the measurements. CONCLUSIONS: In vivo dosimetry using microMOSFETs in MUPIT and Utrecht Interstitial Fletcher applicators has proved to be feasible. Reimaging should be performed after detection of differences larger than 10% between predicted and measured dose to verify the applicator configuration. Movement of the applicator relative to the target or organs at risk is undetectable with this method.
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Braquiterapia/instrumentação , Neoplasias dos Genitais Femininos/radioterapia , Dosimetria in Vivo , Dosímetros de Radiação , Braquiterapia/métodos , Calibragem , Estudos de Viabilidade , Feminino , Humanos , Imagens de Fantasmas , Dosagem Radioterapêutica , Reprodutibilidade dos TestesRESUMO
PURPOSE: To report experience and early results of laparoscopic implantation for interstitial brachytherapy (BT) of solitary bladder tumors and the feasibility of a high-dose-rate (HDR) schedule. METHODS AND MATERIALS: From December 2009 to April 2015, 57 patients with a T2 solitary bladder tumor were treated in Arnhem with transurethral bladder resection followed by external beam irradiation, applied to the bladder and regional iliac lymph nodes, 40 Gy in 20 fractions, 5 fractions per week, and within 1 week interstitial HDR BT, in selected cases combined with partial cystectomy and lymph node dissection. The BT catheters were placed via a transabdominal approach with robotic assistance from a Da Vinci robot after a successful initial experience with a nonrobotic laparoscopic approach. The fraction schedule for HDR was 10 fractions of 2.5 Gy, 3 fractions per day. This was calculated to be equivalent to a reference low-dose-rate schedule of 30 Gy in 60 hours. Data for oncologic outcomes and toxicity (Common Toxicity Criteria version 4) were prospectively collected. RESULTS: These modifications resulted in an average postoperative hospitalization of 6 days, minimal blood loss, and no wound healing problems. Two patients had severe acute toxicity: 1 pulmonary embolism grade 4 and 1 cardiac death. Late toxicity was mild (n=2 urogenital grade 3 toxicity). The median follow-up was 2 years. Using cumulative incidence competing risk analysis, the 2-year overall, disease-free, and disease-specific survival and local control rates were 59%, 71%, 87%, and 82%, respectively. CONCLUSIONS: The benefits of minimally invasive surgery for implantation of BT catheters and the feasibility of HDR BT in bladder cancer are documented. The patient outcome and adverse events are comparable to the best results published for a bladder-sparing approach.
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Braquiterapia/mortalidade , Cateterismo Periférico/mortalidade , Laparoscopia/mortalidade , Lesões por Radiação/mortalidade , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/radioterapia , Idoso , Braquiterapia/métodos , Cateterismo Periférico/métodos , Estudos de Viabilidade , Feminino , Humanos , Laparoscopia/métodos , Estudos Longitudinais , Masculino , Países Baixos , Prevalência , Implantação de Prótese/métodos , Implantação de Prótese/mortalidade , Hipofracionamento da Dose de Radiação , Lesões por Radiação/patologia , Dosagem Radioterapêutica , Fatores de Risco , Procedimentos Cirúrgicos Robóticos , Taxa de Sobrevida , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologiaRESUMO
PURPOSE: Recommendations for adjuvant treatment for women with early-stage endometrial carcinoma are based on clinicopathologic features. Comprehensive genomic characterization defined four subgroups: p53-mutant, microsatellite instability (MSI), POLE-mutant, and no specific molecular profile (NSMP). We aimed to confirm the prognostic capacity of these subgroups in large randomized trial populations, investigate potential other prognostic classifiers, and integrate these into an integrated molecular risk assessment guiding adjuvant therapy. EXPERIMENTAL DESIGN: Analysis of MSI, hotspot mutations in 14 genes including POLE, protein expression of p53, ARID1a, ß-catenin, L1CAM, PTEN, ER, and PR was undertaken on 947 available early-stage endometrioid endometrial carcinomas from the PORTEC-1 and -2 trials, mostly high-intermediate risk (n = 614). Prognostic value was determined using univariable and multivariable Cox proportional hazard models. AUCs of different risk stratification models were compared. RESULTS: Molecular analyses were feasible in >96% of the patients and confirmed the four molecular subgroups: p53-mutant (9%), MSI (26%), POLE-mutant (6%), and NSMP (59%). Integration of prognostic molecular alterations with established clinicopathologic factors resulted in a stronger model with improved risk prognostication. Approximately 15% of high-intermediate risk patients had unfavorable features (substantial lymphovascular space invasion, p53-mutant, and/or >10% L1CAM), 50% favorable features (POLE-mutant, NSMP being microsatellite stable, and CTNNB1 wild-type), and 35% intermediate features (MSI or CTNNB1-mutant). CONCLUSIONS: Integrating clinicopathologic and molecular factors improves the risk assessment of patients with early-stage endometrial carcinoma. Assessment of this integrated risk profile is feasible in daily practice, and holds promise to reduce both overtreatment and undertreatment. Clin Cancer Res; 22(16); 4215-24. ©2016 AACR.
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Biomarcadores Tumorais , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , DNA Polimerase II/genética , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/terapia , Feminino , Genes p53 , Humanos , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Estadiamento de Neoplasias , Proteínas de Ligação a Poli-ADP-Ribose/genética , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Medição de Risco , Análise de SobrevidaRESUMO
BACKGROUND: Chemoradiation (RT-CT) is standard treatment for locally advanced cervical cancer (LACC). This study tried to establish if radiotherapy combined with hyperthermia (RT-HT) should be preferred in bulky and/or FIGO-stage ⩾III. METHODS: In this open-label, multicenter randomized trial, patients with LACC were randomly assigned by a computer-generated, biased coin minimization technique to RT-CT or RT-HT. Central randomization was done with stratification by FIGO-stage, tumour diameter and nodal status. Primary endpoint was event free survival (EFS). Secondary endpoints were pelvic recurrence free survival (PRFS), overall survival (OS) and treatment related toxicity. Analysis was done by intention to treat. RESULTS: The trial was closed prematurely (87 of 376 planned patients enrolled: 43 RT-CT; 44 RT-HT). Median follow-up time was 7.1 years. The cumulative incidence of an event was 33% in the RT-CT group and 35% in the RT-HT group. The corresponding hazard rate (HR) for EFS was 1.15 (CI: 0.56-2.36, p=0.7). Also the hazards for PRFS (0.94; CI 0.36-2.44) and OS (1.04; CI 0.48-2.23) at 5 years were comparable between both treatment arms as was grade ⩾3 radiation related late toxicity (6 RT-CT and 5 RT-HT patients). CONCLUSION: After 25% of intended accrual, data suggest comparable outcome for RT-CT and RT-HT.
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Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Hipertermia Induzida/métodos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/radioterapia , Adulto , Idoso , Braquiterapia , Terapia Combinada/métodos , Intervalo Livre de Doença , Término Precoce de Ensaios Clínicos , Feminino , Seguimentos , Humanos , Incidência , Pessoa de Meia-IdadeRESUMO
PURPOSE: Up to 30% of patients who undergo radiation for intermediate- or high-risk localized prostate cancer relapse biochemically within 5 years. We assessed if biochemical disease-free survival (DFS) is improved by adding 6 months of androgen suppression (AS; two injections of every-3-months depot of luteinizing hormone-releasing hormone agonist) to primary radiotherapy (RT) for intermediate- or high-risk localized prostate cancer. PATIENTS AND METHODS: A total of 819 patients staged: (1) cT1b-c, with prostate-specific antigen (PSA) ≥ 10 ng/mL or Gleason ≥ 7, or (2) cT2a (International Union Against Cancer TNM 1997), with no involvement of pelvic lymph nodes and no clinical evidence of metastatic spread, with PSA ≤ 50 ng/mL, were centrally randomized 1:1 to either RT or RT plus AS started on day 1 of RT. Centers opted for one dose (70, 74, or 78 Gy). Biochemical DFS, the primary end point, was defined from entry until PSA relapse (Phoenix criteria) and clinical relapse by imaging or death of any cause. The trial had 80% power to detect hazard ratio (HR), 0.714 by intent-to-treat analysis stratified by dose of RT at the two-sided α = 5%. RESULTS: The median patient age was 70 years. Among patients, 74.8% were intermediate risk and 24.8% were high risk. In the RT arm, 407 of 409 patients received RT; in the RT plus AS arm, 403 patients received RT plus AS and three patients received RT only. At 7.2 years median follow-up, RT plus AS significantly improved biochemical DFS (HR, 0.52; 95% CI, 0.41 to 0.66; P < .001, with 319 events), as well as clinical progression-free survival (205 events, HR, 0.63; 95% CI, 0.48 to 0.84; P = .001). In exploratory analysis, no statistically significant interaction between treatment effect and dose of RT could be evidenced (heterogeneity P = .79 and P = .66, for biochemical DFS and progression-free survival, respectively). Overall survival data are not mature yet. CONCLUSION: Six months of concomitant and adjuvant AS improves biochemical and clinical DFS of intermediate- and high-risk cT1b-c to cT2a (with no involvement of pelvic lymph nodes and no clinical evidence of metastatic spread) prostatic carcinoma, treated by radiation.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Neoplasias da Próstata/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Humanos , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/mortalidade , Dosagem RadioterapêuticaRESUMO
BACKGROUND: Lymph-vascular space invasion (LVSI) is an important adverse prognostic factor in endometrial cancer (EC). However, its role in relation to type of recurrence and adjuvant treatment is not well defined, and there is significant interobserver variation. This study aimed to quantify LVSI and correlate this to risk and type of recurrence. METHODS: In the post operative radiation therapy in endometrial carcinoma (PORTEC)-trials stage I EC patients were randomised to receive external beam radiotherapy (EBRT) versus no additional treatment after surgery (PORTEC-1, n=714), or to EBRT versus vaginal brachytherapy (PORTEC-2, n=427). In tumour samples of 926 (81.2%) patients with endometrioid tumours LVSI was quantified using 2-, 3- and 4-tiered scoring systems. Cox proportional hazard models were used for time-to-event analysis. RESULTS: Any degree of LVSI was identified in 129 cases (13.9%). Substantial LVSI (n=44, 4.8%) using the 3-tiered approach had the strongest impact on the risk of distant metastasis (hazard ratio (HR) 4.5 confidence interval (CI) 2.4-8.5). In multivariate analysis (including: age, depth of myometrial invasion, grade, treatment) substantial LVSI remained the strongest independent prognostic factor for pelvic regional recurrence (HR 6.2 CI 2.4-16), distant metastasis (HR 3.6 CI 1.9-6.8) and overall survival (HR 2.0 CI 1.3-3.1). Only EBRT (HR 0.3 CI 0.1-0.8) reduced the risk of pelvic regional recurrence. CONCLUSIONS: Substantial LVSI, in contrast to focal or no LVSI, was the strongest independent prognostic factor for pelvic regional recurrence, distant metastasis and overall survival. Therapeutic decisions should be based on the presence of substantial, not 'any' LVSI. Adjuvant EBRT and/or chemotherapy should be considered for stage I EC with substantial LVSI.
Assuntos
Vasos Sanguíneos/patologia , Carcinoma Endometrioide/secundário , Carcinoma Endometrioide/terapia , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/terapia , Vasos Linfáticos/patologia , Recidiva Local de Neoplasia , Adulto , Idoso , Idoso de 80 Anos ou mais , Braquiterapia , Carcinoma Endometrioide/metabolismo , Distribuição de Qui-Quadrado , Neoplasias do Endométrio/metabolismo , Feminino , Humanos , Histerectomia , Estimativa de Kaplan-Meier , Excisão de Linfonodo , Metástase Linfática , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Ovariectomia , Modelos de Riscos Proporcionais , Radioterapia Adjuvante , Fatores de Risco , Salpingectomia , Fatores de Tempo , Resultado do TratamentoRESUMO
PURPOSE: To evaluate the long-term health-related quality of life (HRQL) after external beam radiation therapy (EBRT) or vaginal brachytherapy (VBT) among PORTEC-2 trial patients, evaluate long-term bowel and bladder symptoms, and assess the impact of cancer on these endometrial cancer (EC) survivors. PATIENTS AND METHODS: In the PORTEC-2 trial, 427 patients with stage I high-intermediate-risk EC were randomly allocated to EBRT or VBT. The 7- and 10-year HRQL questionnaires consisted of EORTC QLQ-C30; subscales for bowel and bladder symptoms; the Impact of Cancer Questionnaire; and 14 questions on comorbidities, walking aids, and incontinence pads. Analysis was done using linear mixed models for subscales and (ordinal) logistic regression with random effects for single items. A two-sided P value <.01 was considered statistically significant. RESULTS: Longitudinal HRQL analysis showed persisting higher rates of bowel symptoms with EBRT, without significant differences in global health or any of the functioning scales. At 7 years, clinically relevant fecal leakage was reported by 10.6% in the EBRT group, versus 1.8% for VBT (P=.03), diarrhea by 8.4% versus 0.9% (P=.04), limitations due to bowel symptoms by 10.5% versus 1.8% (P=.001), and bowel urgency by 23.3% versus 6.6% (P<.001). Urinary urgency was reported by 39.3% of EBRT patients, 25.5% for VBT, P=.05. No difference in sexual activity was seen between treatment arms. Long-term impact of cancer scores was higher among the patients who had an EC recurrence or second cancer. CONCLUSIONS: More than 7 years after treatment, EBRT patients reported more bowel symptoms with impact on daily activities, and a trend for more urinary symptoms, without impact on overall quality of life or difference in cancer survivorship issues.
Assuntos
Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/radioterapia , Nível de Saúde , Qualidade de Vida , Sobreviventes , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Braquiterapia/efeitos adversos , Braquiterapia/métodos , Diarreia/epidemiologia , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/psicologia , Incontinência Fecal/epidemiologia , Feminino , Humanos , Tampões Absorventes para a Incontinência Urinária , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Radioterapia/efeitos adversos , Radioterapia/métodos , Análise de Regressão , Comportamento Sexual , Inquéritos e Questionários , Fatores de Tempo , Incontinência Urinária de Urgência/epidemiologiaRESUMO
PURPOSE: To analyze and report the treatment results of brachytherapy for solitary bladder cancer in the Arnhem Radiotherapy Institute. METHODS AND MATERIALS: Between January 1983 and October 1998, 63 patients with a solitary bladder tumor were treated with a combination of transurethral resection, external beam radiotherapy (EBRT), and interstitial radiotherapy. The indications for bladder-conserving treatment were tumor < or =5 cm, T1G3 (n = 14), T2G2 (n = 8), T2G3 (n = 37), and T3a (n = 4). The prescribed implant dose was either 55 Gy (range 50-65 Gy) in combination with small pelvis external beam RT, 3-4 fractions of 3.5 Gy (n = 58), or 30 Gy in combination with 20 fractions of 2 Gy external beam radiotherapy (n = 5). Brachytherapy was performed with 2-8 137Cs needles until 1995 (n = 48) and 2-5 afterloading catheters (192Ir) since 1996 (n = 15). Follow-up cystoscopies were performed at 3-month intervals during the first 2 years, then every 6 months for 3 years, and annually after the fifth year. The median follow-up was 4.9 years. RESULTS: Twenty patients developed local recurrences, of which 6 were "true in-implant recurrences," 12 were in second bladder locations, and 2 were urethral recurrences. All recurrences developed within 2.5 years after treatment. Of these 20 patients, 13 underwent cystectomy: 6 stayed disease-free, 1 died of postoperative complications, 2 developed regional metastases, and 4 developed distant metastases. The 5-year disease-specific survival rate was 80% for patients with Stage T1 and 60% for those with Stage T2 disease. The local control rate was 70% in the whole patient population and 80% after salvage cystectomy. Forty-four bladders were saved. Acute complications were seen in 14 patients, and no significant late complications occurred. CONCLUSION: Using this treatment technique, a high cure rate with conservation of the bladder and only minor toxicity can be obtained in a selected patient population having a solitary tumor < or =5 cm.
Assuntos
Braquiterapia/métodos , Neoplasias da Bexiga Urinária/radioterapia , Idoso , Idoso de 80 Anos ou mais , Cistectomia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Dosagem Radioterapêutica , Análise de Sobrevida , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgiaRESUMO
PURPOSE: Patients with bone metastases have a widely varying survival. A reliable estimation of survival is needed for appropriate treatment strategies. Our goal was to assess the value of simple prognostic factors, namely, patient and tumor characteristics, Karnofsky performance status (KPS), and patient-reported scores of pain and quality of life, to predict survival in patients with painful bone metastases. METHODS AND MATERIALS: In the Dutch Bone Metastasis Study, 1157 patients were treated with radiation therapy for painful bone metastases. At randomization, physicians determined the KPS; patients rated general health on a visual analogue scale (VAS-gh), valuation of life on a verbal rating scale (VRS-vl) and pain intensity. To assess the predictive value of the variables, we used multivariate Cox proportional hazard analyses and C-statistics for discriminative value. Of the final model, calibration was assessed. External validation was performed on a dataset of 934 patients who were treated with radiation therapy for vertebral metastases. RESULTS: Patients had mainly breast (39%), prostate (23%), or lung cancer (25%). After a maximum of 142 weeks' follow-up, 74% of patients had died. The best predictive model included sex, primary tumor, visceral metastases, KPS, VAS-gh, and VRS-vl (C-statistic = 0.72, 95% CI = 0.70-0.74). A reduced model, with only KPS and primary tumor, showed comparable discriminative capacity (C-statistic = 0.71, 95% CI = 0.69-0.72). External validation showed a C-statistic of 0.72 (95% CI = 0.70-0.73). Calibration of the derivation and the validation dataset showed underestimation of survival. CONCLUSION: In predicting survival in patients with painful bone metastases, KPS combined with primary tumor was comparable to a more complex model. Considering the amount of variables in complex models and the additional burden on patients, the simple model is preferred for daily use. In addition, a risk table for survival is provided.