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1.
Br J Cancer ; 116(3): 287-292, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-28006819

RESUMEN

BACKGROUND: The current literature indicates that a considerable number of patients in ovarian carcinoma clinical trials have histopathological diagnoses in conflict with inclusion criteria. It has been suggested that specialised pathology review prior to randomisation should become the standard procedure in study protocols. We hypothesised that our new, internet-based high-throughput infrastructure would be capable of providing specialised pathology review within 10 working days (w.d.). METHODS: Patients scheduled for the AGO OVAR17 ovarian carcinoma chemotherapy trial were registered for expert pathologic case review using a new internet-based central pathology review platform prior to randomisation. All original slides were requested from local pathologists. Slides were scanned and uploaded to a secured internet server. A network of experienced gynaecological pathologists was connected to the server through a custom-designed software platform. If deemed necessary by the expert pathologists, immunohistochemistry was available through a collaborating pathology lab. RESULTS: A total of 880 patients with an original diagnosis of ovarian epithelial carcinoma were registered for expert pathology review from October 2011 to July 2013. For case review, five gynaecopathologists from Austria, Switzerland and Germany were available online. Median number of w.d. required to complete the whole process from patient registration to transmission of final review diagnoses was 4 (range 2-31) (w.d.), and in 848 out of 880 (97.5%) cases, it amounted to ⩽10 w.d. In 2.5% (n=22) of cases, a major diagnostic discrepancy of potential clinical relevance was found leading to exclusion from the chemotherapy trial. CONCLUSIONS: Our results show that the use of a new internet-based infrastructure makes timely specialised case review, prior to patient randomisation feasible within ⩽10 w.d. Our new approach helped to protect against overtreatment with chemotherapy of patients with ovarian borderline tumours and inadequate treatment of patients with ovarian metastases, as a result of their inappropriate entry into a clinical trial designed for patients with primary ovarian carcinoma.


Asunto(s)
Recursos en Salud/estadística & datos numéricos , Internet , Estadificación de Neoplasias/normas , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Patología Clínica/métodos , Calidad de la Atención de Salud , Femenino , Recursos en Salud/organización & administración , Humanos , Estadificación de Neoplasias/métodos , Patología Clínica/organización & administración , Selección de Paciente , Ensayos Clínicos Controlados Aleatorios como Asunto/normas , Proyectos de Investigación
2.
Ann Oncol ; 28(4): 711-717, 2017 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-28327917

RESUMEN

The consensus statements regarding first-line therapies in women with ovarian cancer, reached at the Fifth Ovarian Cancer Consensus Conference held in Tokyo, Japan, in November 2015 are reported. Three topics were reviewed and the following statements are recommended: (i) Surgery: the subgroups that should be considered in first-line ovarian cancer clinical trials should be (a) patients undergoing primary debulking surgery and (b) patients receiving neo-adjuvant chemotherapy. The amount of residual disease following surgery should further stratify patients into those with absent gross residual disease and others. (ii) Control arms for chemotherapy: for advanced stage ovarian cancer the standard is intravenous 3-weekly carboplatin and paclitaxel. Acceptable alternatives, which should be stratified variables in trials when more than one regimen is offered, include weekly paclitaxel plus 3-weekly carboplatin, the addition of bevacizumab to 3-weekly carboplatin and paclitaxel, and intraperitoneal therapy. (iii) Trial Endpoints: overall survival is the preferred primary endpoint for first-line clinical trials with or without a maintenance component. Progression-free survival (PFS) is an alternative primary endpoint, but if PFS is chosen overall survival must be measured as a secondary endpoint and PFS must be supported by additional endpoints, including predefined patient reported outcomes and time to first or second subsequent therapy. For neoadjuvant therapy, additional 'window of opportunity' endpoints should be included.


Asunto(s)
Neoplasias Glandulares y Epiteliales/terapia , Neoplasias Ováricas/terapia , Proyectos de Investigación , Carcinoma Epitelial de Ovario , Femenino , Humanos
3.
Ann Oncol ; 27 Suppl 1: i30-i32, 2016 04.
Artículo en Inglés | MEDLINE | ID: mdl-27141067

RESUMEN

Despite the recent publication of two randomized controlled phase III trials addressing neoadjuvant chemotherapy in advanced ovarian cancer, the optimal timing of multimodal management in primary therapy is still under debate. As both studies met their primary end point by demonstrating non-inferiority, neoadjuvant chemotherapy followed by interval debulking surgery has been proposed to be an alternative standard for primary ovarian cancer treatment. Nevertheless, significant questions remain unanswered in both trials. Especially, the radicality of surgical therapy was below expectation with the median operating times of <3 h and complete gross resection in <20% of the patients. Consecutively, survival rates of patients undergoing primary debulking surgery were low. Since the primarily surgical question of 'primary versus interval-surgery' can only be answered if the key criteria 'complete gross resection' are present in a considerable percentage of patients, additional studies are needed and neoadjuvant chemotherapy should not be used to reduce surgical radicality for ovarian cancer treatment.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Antineoplásicos/farmacología , Quimioterapia Adyuvante , Ensayos Clínicos Fase III como Asunto , Femenino , Humanos , Terapia Neoadyuvante , Neoplasias Ováricas/mortalidad , Análisis de Supervivencia
4.
Phys Chem Chem Phys ; 18(30): 20433-42, 2016 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-27402290

RESUMEN

The adsorption of thymine, a pyrimidine based nucleobase, was studied on the (110) termination of rutile titanium dioxide in order to understand the thermal stability and gross structural parameters of the interaction between a strongly polar adsorbate and a highly corrugated transition metal oxide surface. Near-edge X-ray absorption fine structure (NEXAFS), X-ray photoelectron spectroscopy (XPS), temperature programmed XPS and temperature programmed desorption indicated the growth of a room temperature stable bilayer, which could only be removed by annealing to 450 K. The remaining first layer was remarkably robust, surviving annealing up to 550 K before undergoing N-H bond scission. The comparison to XPS of a sub-monolayer exposure of 1-methyluracil shows that the origin of the room temperature stable bilayer is not intermolecular interactions. This discovery, alongside the deprotonation of one of the first layer's pyrimidinic nitrogen atoms at room temperature, suggests that the thymine molecules in the first layer bind to the undercoordinated surface Ti atoms, and the second layer thymine molecules coordinate with the bridging oxygen atoms which protrude above the Ti surface plane on the (110) surface. The NEXAFS results indicate an almost upright orientation of the molecules in both layers, with a 30 ± 10° tilt away from the surface normal.

5.
Br J Cancer ; 112(4): 660-6, 2015 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-25562434

RESUMEN

BACKGROUND: Incomplete surgical staging is a negative prognostic factor for patients with borderline ovarian tumours (BOT). However, little is known about the prognostic impact of each individual staging procedure. METHODS: Clinical parameters of 950 patients with BOT (confirmed by central reference pathology) treated between 1998 and 2008 at 24 German AGO centres were analysed. In 559 patients with serous BOT and adequate ovarian surgery, further recommended staging procedures (omentectomy, peritoneal biopsies, cytology) were evaluated applying Cox regression models with respect to progression-free survival (PFS). RESULTS: For patients with one missing staging procedure, the hazard ratio (HR) for recurrence was 1.25 (95%-CI 0.66-2.39; P=0.497). This risk increased with each additional procedure skipped reaching statistical significance in case of two (HR 1.95; 95%-CI 1.06-3.58; P=0.031) and three missing steps (HR 2.37; 95%-CI 1.22-4.64; P=0.011). The most crucial procedure was omentectomy which retained a statistically significant impact on PFS in multiple analysis (HR 1.91; 95%-CI 1.15-3.19; P=0.013) adjusting for previously established prognostic factors as FIGO stage, tumour residuals, and fertility preservation. CONCLUSION: Individual surgical staging procedures contribute to the prognosis for patients with serous BOT. In this analysis, recurrence risk increased with each skipped surgical step. This should be considered when re-staging procedures following incomplete primary surgery are discussed.


Asunto(s)
Cistadenoma Seroso/diagnóstico , Cistadenoma Seroso/patología , Procedimientos Quirúrgicos Ginecológicos , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Cistadenoma Seroso/epidemiología , Cistadenoma Seroso/cirugía , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/cirugía , Pronóstico , Adulto Joven
6.
Ann Oncol ; 25(7): 1320-1327, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24618151

RESUMEN

BACKGROUND: Approximately one-third of all borderline ovarian tumours (BOT) are diagnosed in patients with child-bearing potential. Detailed information regarding their specific characteristics and prognostic factors is limited. METHODS: Clinical parameters of BOT patients treated between 1998 and 2008 in 24 German centres were retrospectively investigated. Central pathology review and prospective follow-up were carried out. Patients <40 versus ≥40 years were analysed separately and then compared regarding clinico-pathological variables and prognosis. RESULTS: A total of 950 BOT patients with a median age of 49.1 (14.1-91.5) years were analysed [280 patients <40 years (29.5%), 670 patients ≥40 years (70.5%)]. Fertility-preserving surgery was carried out in 53.2% (149 of 280) of patients <40 years with preservation of the primarily affected ovary in 32 of these 149 cases (21.5%). Recurrence was significantly more frequent in patients <40 years (19.0% versus 10.1% 5-year recurrence rate, P < 0.001), usually in ovarian tissue, whereas disease-specific overall survival did not differ between the subgroups. In case of recurrent disease, malignant transformation was less frequent in younger than in older patients (12.0% versus 66.7%, P < 0.001), mostly presenting as invasive peritoneal carcinomatosis. Multivariate analysis for patients <40 years identified advanced International Federation of Gynecology and Obstetrics (FIGO) stage and fertility-sparing approach as independent prognostic factors negatively affecting progression-free survival (PFS) while, for patients ≥40 years, higher FIGO stage and incomplete staging was associated with impaired PFS. CONCLUSIONS: Despite favourable survival, young BOT patients with child-bearing potential are at higher risk for disease recurrence. However, relapses usually remain BOT in the preserved ovaries as opposed to older patients being at higher risk for malignant transformation in peritoneal or distant localisation. Therefore, fertility-sparing approach can be justified for younger patients after thorough consultation.


Asunto(s)
Factores de Edad , Neoplasias Ováricas/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/cirugía , Estudios Retrospectivos , Resultado del Tratamiento , Adulto Joven
7.
Pathologe ; 35(4): 355-60, 2014 Jul.
Artículo en Alemán | MEDLINE | ID: mdl-24992975

RESUMEN

BACKGROUND: Retrospective studies have shown that a significant number of ovarian borderline tumors, ovarian metastases, and nonepithelial tumors were erroneously diagnosed as ovarian carcinomas. This may lead to unnecessary morbidity, suboptimal therapeutic modalities, and unintended bias in clinical trials. The aim of this study was to investigate the frequency and clinical significance of such diagnostic discrepancies. MATERIAL AND METHODS: Original histological slides from patients with ovarian carcinomas included in phase III chemotherapy trials of the Working Group on Gynecological Oncology (AGO) were reviewed by at least two specialized pathologists. Diagnostic discrepancies were classified as being either clinically relevant (major) or clinically not relevant (minor). RESULTS: A total of 454 out of 533 patients from the AGO OVAR11 (ICON7) trial gave consent to the second opinion on the pathology results. All of the 104 institutes of pathology responsible for the original diagnoses contributed to the study. The first diagnosis and the second opinion pathology review were identical in 295 out of 454 (65%) cases. In 128 cases (28.2%) a minor discrepancy was found and 31 cases (6.8%) were shown to have a major discrepancy. CONCLUSION: The assumption of a significant number or erroneous diagnoses in chemotherapy trials of ovarian carcinomas was confirmed. A pathology review seems therefore desirable and may help to reduce unnecessary morbidity and optimize therapeutic strategies. Moreover, improvement of quality in therapy trials may become possible. In another study a new concept allowing a rapid pathology review before randomization of patients has now been successfully tested and it may well have potential to form the basis for modern networking consultation pathology.


Asunto(s)
Errores Diagnósticos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Ovario/patología , Derivación y Consulta , Adenocarcinoma de Células Claras/tratamiento farmacológico , Adenocarcinoma de Células Claras/patología , Carcinoma Endometrioide/tratamiento farmacológico , Carcinoma Endometrioide/patología , Neoplasias del Colon/patología , Progresión de la Enfermedad , Femenino , Alemania , Humanos , Estadificación de Neoplasias , Neoplasias Ováricas/secundario , Selección de Paciente , Estudios Prospectivos
8.
Pathologe ; 35(5): 497-503, 2014 Sep.
Artículo en Alemán | MEDLINE | ID: mdl-25069848

RESUMEN

Histological grading of ovarian cancer has prognostic relevance and implications for treatment decisions. No standardized grading system has been established so far. Several grading systems are currently being used, including the FIGO, WHO, and Silverberg grading systems which cannot be directly translated into each other. Furthermore, individual grading criteria are not uniformly applicable to different histological subtypes. For serous ovarian cancer a binary grading system is now in use as the distinction between low-grade versus high-grade carcinomas reflects the different pathogenesis of these entities. Uniform guidelines for grading ovarian cancer are necessary and should ideally reflect the prognosis. This article provides an overview of commonly used grading systems and their prognostic value. The article demonstrates that a type-specific grading of ovarian cancer should be performed and recommendations for grading the various histological subtypes are given.


Asunto(s)
Neoplasias Glandulares y Epiteliales/patología , Neoplasias Ováricas/patología , Carcinoma Epitelial de Ovario , Transformación Celular Neoplásica/clasificación , Transformación Celular Neoplásica/patología , Femenino , Humanos , Clasificación del Tumor , Neoplasias Glandulares y Epiteliales/clasificación , Neoplasias Glandulares y Epiteliales/terapia , Neoplasias Ováricas/clasificación , Neoplasias Ováricas/terapia , Ovario/patología , Pronóstico
9.
Ann Oncol ; 24(12): 3028-34, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24190964

RESUMEN

BACKGROUND: The majority of women with ovarian cancer develop recurrent disease. For patients with a platinum-free interval of >6 months, platinum-based chemotherapy is a treatment of choice. The benefit of platinum-based combination chemotherapy in randomized trials varies, and a meta-analysis was carried out to gain more secure information on the size of the benefit of this treatment. MATERIALS AND METHODS: We initiated a systematic review and meta-analysis following a pre-specified protocol to determine whether combination chemotherapy is superior to single-agent platinum chemotherapy in women with relapsed platinum-sensitive ovarian cancer. RESULTS: A total of five potentially eligible randomized trials were identified that had used combination-platinum chemotherapy versus single-agent platinum chemotherapy in women with relapsed platinum-sensitive ovarian cancer. For one trial (190 patients), adequate contact with the investigators could not be established. Therefore, four trials that randomly assigned 1300 patients were included, with a median follow-up of 36.1 months. Overall survival (OS) analyses were based on 865 deaths and demonstrated evidence for the benefit of combination-platinum chemotherapy (HR = 0.80; 95% CI, 0.64-1.00; P = 0.05). Progression-free survival (PFS) analyses were based on 1167 events and demonstrated strong evidence for the benefit of combination-platinum chemotherapy (HR = 0.68; 95% CI, 0.57-0.81; P < 0.001). There was no evidence of a difference in the relative effect of combination-platinum chemotherapy on either OS or PFS in patient subgroups defined by previous paclitaxel (Taxol) treatment (OS, P = 0.49; PFS, P = 0.66), duration of treatment-free interval (OS, P = 0.86; PFS, P = 0.48) or the number of previous lines of chemotherapy (OS, P = 0.21; PFS, P = 0.27). CONCLUSIONS: In this individual patient data (IPD) meta-analysis, we have demonstrated that combination-platinum chemotherapy improves OS and PFS across all subgroups. This provides the strongest evidence to date of the benefit of combination-platinum over single-agent platinum.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carboplatino/administración & dosificación , Cisplatino/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Recurrencia Local de Neoplasia/mortalidad , Neoplasias Ováricas/mortalidad , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento
10.
Ann Oncol ; 24(4): 937-43, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23104722

RESUMEN

BACKGROUND: Patients with platinum-sensitive recurrent ovarian cancer have variable prognosis and survival. We extend previous work on prediction of progression-free survival by developing a nomogram to predict overall survival (OS) in these patients treated with platinum-based chemotherapy. PATIENTS AND METHODS: The nomogram was developed using data from the CAELYX in Platinum-Sensitive Ovarian Patients (CALYPSO) trial. Multivariate proportional hazards models were generated based on pre-treatment characteristics to develop a nomogram that classifies patient prognosis based on OS outcome. We also developed two simpler models with fewer variables and conducted model validations in independent datasets from AGO-OVAR Study 2.5 and ICON 4. We compare the performance of the nomogram with the simpler models by examining the differences in the C-statistics and net reclassification index (NRI). RESULTS: The nomogram included six significant predictors: interval from last platinum chemotherapy, performance status, size of the largest tumour, CA-125, haemoglobin and the number of organ sites of metastasis (C-statistic 0.67; 95% confidence interval 0.65-0.69). Among the CALPYSO patients, the median OS for good, intermediate and poor prognosis groups was 56.2, 31.0 and 20.8 months, respectively. When CA-125 was not included in the model, the C-statistics were 0.65 (CALYPSO) and 0.64 (AGO-OVAR 2.5). A simpler model (interval from last platinum chemotherapy, performance status and CA-125) produced a significant decrease of the C-statistic (0.63) and NRI (26.4%, P < 0.0001). CONCLUSIONS: This nomogram with six pre-treatment characteristics improves OS prediction in patients with platinum-sensitive ovarian cancer and is superior to models with fewer prognostic factors or platinum chemotherapy free interval alone. With independent validation, this nomogram could potentially be useful for improved stratification of patients in clinical trials and also for counselling patients.


Asunto(s)
Recurrencia Local de Neoplasia/patología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Platino (Metal)/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Ensayos Clínicos como Asunto , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/inducido químicamente , Recurrencia Local de Neoplasia/genética , Estadificación de Neoplasias , Nomogramas , Neoplasias Ováricas/patología , Paclitaxel/administración & dosificación , Platino (Metal)/efectos adversos , Platino (Metal)/toxicidad , Pronóstico , Sensibilidad y Especificidad , Resultado del Tratamiento
11.
Br J Cancer ; 106(4): 633-7, 2012 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-22240800

RESUMEN

BACKGROUND: CA-125 as a tumour progression criterion in relapsing ovarian cancer (ROC) trials remains controversial. CALYPSO is a large randomised trial incorporating CA-125 (GCIG criteria) and symptomatic deterioration in addition to Response Evaluation Criteria in Solid Tumours (RECIST) criteria (radiological) to determine progression. METHODS: In all, 976 patients with platinum-sensitive ROC were randomised to carboplatin-paclitaxel (C-P) or carboplatin-pegylated liposomal doxorubicin (C-PLD). CT-scan and CA-125 were performed every 3 months until progression. RESULTS: In all, 832 patients (85%) progressed, with 60% experiencing a first radiological progression, 10% symptomatic progression, and 28% CA-125 progression without evidence of radiological or symptomatic progression. The benefit of C-PLD vs C-P in progression-free survival was not influenced by type of first progression (hazard ratio 0.85 (95% confidence interval (CI): 0.66-1.10) and 0.84 (95% CI: 0.72-0.98) for CA-125 and RECIST, respectively). In patients with CA-125 first progression who subsequently progressed radiologically, a delay of 2.3 months was observed between the two progression types. After CA-125 first progression, median time to new treatment was 2.0 months. In all, 81%of the patients with CA-125 or radiological first progression and 60% with symptomatic first progression received subsequent treatment. CONCLUSION: CA-125 and radiological tests performed similarly in determining progression with C-PLD or C-P. Additional follow-up with CA-125 measurements was not associated with overtreatment.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno Ca-125/análisis , Neoplasias Ováricas/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Doxorrubicina/efectos adversos , Doxorrubicina/análogos & derivados , Femenino , Humanos , Neoplasias Ováricas/diagnóstico por imagen , Paclitaxel/administración & dosificación , Polietilenglicoles/efectos adversos , Recurrencia , Tomografía Computarizada por Rayos X
12.
Ann Oncol ; 23(10): 2605-2612, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22910840

RESUMEN

BACKGROUND: Despite recent progress in the treatment of ovarian cancer, the majority of patients eventually relapse. There is little information on the effectiveness of chemotherapy in higher treatment lines. PATIENTS AND METHODS: Characterization of the second to sixth line therapy and its effects on survival was carried out, based on data of n = 1620 patients from three large randomized phase III trials investigating primary therapy. RESULTS: Median progression-free survival (PFS) after the first, second, third, fourth and fifth relapse was 10.2 [95% confidence interval (CI) 9.6-10.7], 6.4 (5.9-7.0), 5.6 (4.8-6.2), 4.4 (3.7-4.9) and 4.1 (3.0-5.1) months, respectively. Median overall survival (OS) after the first, second, third, fourth and fifth relapse was 17.6 (95% CI 16.4-18.6), 11.3 (10.4-12.9), 8.9 (7.8-9.9), 6.2 (5.1-7.7) and 5.0 (3.8-10.4) months, respectively. The most frequent second and third line chemotherapy was platinum combination (n = 313, 24.5%) and topotecan (n = 118, 23.6%), respectively. Relapse treatment improved PFS and OS at the second to fourth recurrence, although frequently not performed according to the standard of care. In multivariate analysis, platinum sensitivity and optimal primary tumor debulking were revealed as independent prognostic factors for PFS up to third relapse. CONCLUSION: A maximum of three lines of subsequent relapse treatment seems to be beneficial for patients with recurrent ovarian cancer. Optimal primary tumor debulking and platinum sensitivity remain independent prognostic factors even after more frequent relapses.


Asunto(s)
Antineoplásicos/uso terapéutico , Compuestos Organoplatinos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Taxoides/uso terapéutico , Femenino , Humanos , Recurrencia , Análisis de Supervivencia
13.
Br J Cancer ; 105(8): 1144-50, 2011 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-21915127

RESUMEN

BACKGROUND: Patients with platinum-sensitive recurrent ovarian cancer are a heterogeneous group, and it is not possible to accurately predict the progression-free survival (PFS) in these patients. We developed and validated a nomogram to help improve prediction of PFS in patients treated with platinum-based chemotherapy. METHODS: The nomogram was developed in a training cohort (n=955) from the CALYPSO trial and validated in the AGO-OVAR 2.5 Study (n=340). The proportional-hazards model (nomogram) was based on pre-treatment characteristics. RESULTS: The nomogram had a concordance index (C-index) of 0.645. Significant predictors were tumour size platinum-chemotherapy-free interval, CA-125, number of organ metastatic sites and white blood count. When the nomogram was applied without CA-125 (CA-125 was not available in validation cohort), the C-indices were 0.624 (training) and 0.594 (validation). When classification was based only on the platinum-chemotherapy-free interval, the indices were 0.571 (training) and 0.560 (validation). The calibration plot in the validation cohort based on four predictors (without CA-125) suggested good agreement between actual and nomogram-predicted 12-month PFS probabilities. CONCLUSION: This nomogram, using five pre-treatment characteristics, improves prediction of PFS in patients with platinum-sensitive ovarian cancer having platinum-based chemotherapy. It will be useful for the design and stratification of patients in clinical trials and also for counselling patients.


Asunto(s)
Antineoplásicos/uso terapéutico , Carboplatino/uso terapéutico , Supervivencia sin Enfermedad , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/patología , Pronóstico , Modelos de Riesgos Proporcionales
14.
Br J Cancer ; 105(7): 890-6, 2011 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-21878937

RESUMEN

BACKGROUND: This study aims to identify prognostic factors and to develop a risk model predicting survival in patients undergoing secondary cytoreductive surgery (SCR) for recurrent epithelial ovarian cancer. METHODS: Individual data of 1100 patients with recurrent ovarian cancer of a progression-free interval at least 6 months who underwent SCR were pooled analysed. A simplified scoring system for each independent prognostic factor was developed according to its coefficient. Internal validation was performed to assess the discrimination of the model. RESULTS: Complete SCR was strongly associated with the improvement of survival, with a median survival of 57.7 months, when compared with 27.0 months in those with residual disease of 0.1-1 cm and 15.6 months in those with residual disease of >1 cm, respectively (P<0.0001). Progression-free interval (≤23.1 months vs >23.1 months, hazard ratio (HR): 1.72; score: 2), ascites at recurrence (present vs absent, HR: 1.27; score: 1), extent of recurrence (multiple vs localised disease, HR: 1.38; score: 1) as well as residual disease after SCR (R1 vs R0, HR: 1.90, score: 2; R2 vs R0, HR: 3.0, score: 4) entered into the risk model. CONCLUSION: This prognostic model may provide evidence to predict survival benefit from secondary cytoreduction in patients with recurrent ovarian cancer.


Asunto(s)
Adenocarcinoma de Células Claras/mortalidad , Adenocarcinoma Mucinoso/mortalidad , Cistadenocarcinoma Seroso/mortalidad , Neoplasias Endometriales/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Neoplasias Ováricas/mortalidad , Ovariectomía , Adenocarcinoma de Células Claras/patología , Adenocarcinoma de Células Claras/cirugía , Adenocarcinoma Mucinoso/patología , Adenocarcinoma Mucinoso/cirugía , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Cistadenocarcinoma Seroso/patología , Cistadenocarcinoma Seroso/cirugía , Neoplasias Endometriales/patología , Neoplasias Endometriales/cirugía , Femenino , Estudios de Seguimiento , Humanos , Agencias Internacionales , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Neoplasias Ováricas/cirugía , Tasa de Supervivencia , Resultado del Tratamiento , Adulto Joven
15.
Gynecol Oncol ; 123(1): 27-32, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21733566

RESUMEN

OBJECTIVE: The aim of this study was to select the best catumaxomab regimen for further investigation in ovarian cancer based on confirmed tumour response. METHODS: Randomised open-label phase IIa study in women with platinum-resistant or -refractory epithelial ovarian cancer. Catumaxomab (6-hour intraperitoneal infusion on days 0, 3, 7 and 10) was administered at a low (10, 10, 10 and 10 µg) or high dose (10, 20, 50 and 100 µg). Responders were patients with either a complete (CR) or partial (PR) response. RESULTS: Forty-five patients were randomised to receive either low dose (23) or high dose (22). There were no responders in the low-dose versus one patient (5%) in the high-dose group with a PR. In the low-dose group, two patients (9%) had stable disease compared with five patients (23%) in the high-dose group. Catumaxomab was well tolerated and there was no difference between the dose groups in the incidence of treatment-induced adverse events, the most common of which were gastrointestinal and injection-site reactions. CONCLUSION: Catumaxomab had modest activity in platinum-resistant ovarian cancer. The high-dose regimen was associated with a slightly better therapeutic index than the low dose regimen.


Asunto(s)
Anticuerpos Biespecíficos/administración & dosificación , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Epitelial de Ovario , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Femenino , Humanos , Infusiones Parenterales , Persona de Mediana Edad , Compuestos Organoplatinos/farmacología
16.
Ann Oncol ; 21(2): 370-375, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19889612

RESUMEN

BACKGROUND: The purpose of the phase I dose-escalation study was to evaluate the maximum tolerated dose (MTD) of BIBF 1120, an oral triple angiokinase inhibitor of vascular endothelial growth factor, platelet derived growth factor and fibroblast growth factor receptors, combined with paclitaxel and carboplatin. PATIENTS AND METHODS: Patients with advanced gynecological malignancies received BIBF 1120 twice-daily (b.i.d.) continuously at 100, 150, 200 or 250 mg, combined with paclitaxel (175 mg/m(2)) and carboplatin (area under the curve 5 min.mg/ml) every 3 weeks. The MTD, safety, pharmacokinetics (PK) and clinical activity were evaluated. RESULTS: Twenty-two patients were treated. Three experienced dose-limiting toxic effects in the first treatment cycle: 1 of 13 at 200 mg b.i.d. BIBF 1120 [diarrhea, common terminology criteria for adverse events (CTCAE) grade 3]; two of two at 250 mg b.i.d. BIBF 1120 (elevated alanine aminotransferase and aspartate aminotransferase, CTCAE grade 3/4). The MTD was defined as 200 mg b.i.d. Principal adverse events were gastrointestinal disorders. No clinically relevant drug-drug interaction was observed after 20 days treatment with 200 mg b.i.d. BIBF 1120 on the PK of paclitaxel or carboplatin and vice versa. CONCLUSIONS: The MTD of BIBF 1120 in a 20-day continuous dosing regimen with standard-dose paclitaxel and carboplatin was 200 mg b.i.d. This combination had an acceptable safety profile and no clinically relevant drug-drug interactions. Further evaluation of this combination is warranted in this indication.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/administración & dosificación , Neoplasias de los Genitales Femeninos/tratamiento farmacológico , Indoles/administración & dosificación , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Paclitaxel/administración & dosificación , Administración Oral , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carboplatino/efectos adversos , Carboplatino/farmacocinética , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Neoplasias de los Genitales Femeninos/metabolismo , Humanos , Indoles/efectos adversos , Indoles/farmacocinética , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias Glandulares y Epiteliales/metabolismo , Paclitaxel/efectos adversos , Paclitaxel/farmacocinética , Resultado del Tratamiento
17.
Gynecol Oncol ; 116(3): 317-22, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19959213

RESUMEN

BACKGROUND: For the adjuvant setting of advanced ovarian cancer (AOC) after primary radical surgery the combination of paclitaxel and platinum in a 3-week schedule has emerged as the current standard. In preclinical studies additional anti-angiogenic effects of low dose paclitaxel infusion were demonstrated. A sequential schedule of carboplatin and paclitaxel has the potential to improve the therapeutic index. METHODS: In this multicenter phase II trial four cycles of carboplatin at a dose of AUC 5 (d1/q21d) followed by 12 cycles of weekly paclitaxel at a dose of 80 mg/m(2) (d1/q7d) were applied after primary radical surgery. Eligible were all optimally or sub-optimally debulked patients with FIGO IA-IV ovarian cancer. All patients with hemoglobin levels <12 mg/dl received erythropoietin additionally. RESULTS: Between July 2003 and May 2005, 105 patients from 27 institutions were enrolled. The median age was 60 years (range: 23-80 years). A median number of 16 courses (range 1-16) were applied. The incidence of non-hematological toxicities was very low. Only 41% of patients experienced alopecia (grade 1-2). Neurotoxicity (grade 3-4) was not observed. Grade 3-4 hematological toxicity (43% of all patients) included thrombocytopenia (17%), anemia (3%), leucopenia (23%), and neutropenic fever (0%). Ninety-seven percent received erythropoietin. Thromboembolic events (4%) were not increased in patients who received erythropoietin. After a median time of 23 months (range: 1-42 months) 32 patients had died, and the median overall survival was not reached. The progression-free survival was 25.4 months (95% CI: 18.8-40+). CONCLUSION: These results suggest that this sequential regimen using weekly paclitaxel represents an efficacious and well-tolerated regimen. A randomized study comparing this new schedule with the conventional 3-week protocol is warranted.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/cirugía , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Tasa de Supervivencia , Resultado del Tratamiento , Adulto Joven
18.
Pathologe ; 29 Suppl 2: 157-9, 2008 Nov.
Artículo en Alemán | MEDLINE | ID: mdl-18726596

RESUMEN

Currently histopathological review is not standard practice in clinical studies of ovarian carcinomas. Published retrospective analyses as well as own unpublished observations have indicated that a certain percentage of study patients may have ovarian lesions other than ovarian carcinomas which may be in conflict with study inclusion criteria. In this context, the distinction of ovarian carcinomas from borderline tumors, ovarian metastases, and sex cord tumors has been shown to be a potential pitfall. In cases of incorrect diagnoses, non-beneficial morbidity at unnecessary high cost may occur, in other instances, more adequate therapeutic modalities might be withheld from a patient. At present, the concept of a central histopathology review for patients with ovarian carcinomas is being studied prospectively in a translational research project of the AGO-Ovar termed "HIstologische STandardisierte Zweitbegutachtung in einem Studienkollektiv fortgeschrittener Ovarialkarzinome, OVAR 11t-HISTO" (Histological standardized review in a study collective of advanced ovarian cancer; http://www.mh-hannover.de/institute/pathologie/dgp:Studien).


Asunto(s)
Neoplasias Ováricas/patología , Derivación y Consulta , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab , Carboplatino/administración & dosificación , Quimioterapia Adyuvante , Terapia Combinada , Consenso , Errores Diagnósticos , Femenino , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/secundario , Neoplasias Ováricas/cirugía , Ovariectomía , Ovario/patología , Paclitaxel/administración & dosificación , Lesiones Precancerosas/patología , Estudios Prospectivos , Tumores de los Cordones Sexuales y Estroma de las Gónadas/patología
19.
Gynecol Oncol ; 107(3): 518-25, 2007 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-17910981

RESUMEN

OBJECTIVE: A multicenter non-randomized phase II study was initiated to evaluate tolerability and efficacy of pegylated liposomal doxorubicin (PLD) in combination with carboplatin in gynecologic malignancies. METHODS: One hundred forty women with recurrent or advanced endometrial (n=31), cervical or vaginal cancer (n=31), uterine sarcomas (n=11), or recurrent platinum-sensitive ovarian cancer (n=67) received six courses of PLD 40 mg/m2 and carboplatin (AUC 6) every 28 days. RESULTS: Hematological toxicities with NCI-CTC grade 3/4 were anemia in 8%, thrombocytopenia in 14%, neutropenia in 24%, and febrile neutropenia in 2% of 652 cycles. Grade 3/4 non-hematological toxicities included fatigue (14% of patients), pain (10%), dyspnea (9%), palmar-plantar erythrodysesthesia (7%), and nausea/vomiting (7%). Dose intensity reached 87.2% for PLD and 88.2% for carboplatin. Seventy-four percent of all non-progressive patients received at least 5 cycles. Overall response rates were (116 patients evaluable for response): ovarian cancer (n=54) 68%, endometrial cancer (n=27) 44%, uterine sarcomas (n=9) 33%, and cervical/vaginal cancer (n=26) 12%. Median progression-free survival was 11.6 months (95%CI 9.6-14.1) for ovarian cancer and 9.5 months (95%CI 6.6-12.6) for endometrial cancer. Median overall survival was 23.8 months (95%CI 19.0-30.2) and 21.4 months (95%CI 11.9-), respectively. CONCLUSIONS: The combination of PLD and carboplatin was well tolerated and feasible in patients with gynecologic malignancies. Efficacy was low in cervical/vaginal cancer, but promising in patients with endometrial cancer. Efficacy was within the expected range in recurrent platinum-sensitive ovarian cancer and is currently under further investigation in a prospective randomized phase III trial comparing PLD/carboplatin with paclitaxel/carboplatin (CALYPSO-trial; AGO-OVAR 2.9).


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de los Genitales Femeninos/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Doxorrubicina/análogos & derivados , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Persona de Mediana Edad , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Estudios Prospectivos
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