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1.
Breast Cancer Res Treat ; 168(1): 169-178, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29177605

RESUMEN

BACKGROUND: Intergroup Exemestane Study (IES) was a randomised study that showed a survival benefit of switching adjuvant endocrine therapy after 2-3 years from tamoxifen to exemestane. This PathIES aimed to assess the role of immunohistochemical (IHC)4 score in determining the relative sensitivity to either tamoxifen or sequential treatment with tamoxifen and exemestane. PATIENTS AND METHODS: Primary tumour samples were available for 1274 patients (27% of IES population). Only patients for whom the IHC4 score could be calculated (based on oestrogen receptor, progesterone receptor, HER2 and Ki67) were included in this analysis (N = 430 patients). The clinical score (C) was based on age, grade, tumour size and nodal status. The association of clinicopathological parameters, IHC4(+C) scores and treatment effect with time to distant recurrence-free survival (TTDR) was assessed in univariable and multivariable Cox regression analyses. A modified clinical score (PathIEscore) (N = 350) was also estimated. RESULTS: Our results confirm the prognostic importance of the original IHC4, alone and in conjunction with clinical scores, but no significant difference with treatment effects was observed. The combined IHC4 + Clinical PathIES score was prognostic for TTDR (P < 0.001) with a hazard ratio (HR) of 5.54 (95% CI 1.29-23.70) for a change from 1st quartile (Q1) to Q1-Q3 and HR of 15.54 (95% CI 3.70-65.24) for a change from Q1 to Q4. CONCLUSION: In the PathIES population, the IHC4 score is useful in predicting long-term relapse in patients who remain disease-free after 2-3 years. This is a first trial to suggest the extending use of IHC4+C score for prognostic indication for patients who have switched endocrine therapies at 2-3 years and who remain disease-free after 2-3 years.


Asunto(s)
Androstadienos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/terapia , Recurrencia Local de Neoplasia/epidemiología , Tamoxifeno/uso terapéutico , Anciano , Androstadienos/farmacología , Antineoplásicos Hormonales/farmacología , Mama/patología , Mama/cirugía , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Quimioterapia Adyuvante/métodos , Supervivencia sin Enfermedad , Método Doble Ciego , Resistencia a Antineoplásicos , Femenino , Humanos , Inmunohistoquímica , Mastectomía , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/prevención & control , Pronóstico , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Tamoxifeno/farmacología , Factores de Tiempo
3.
Stat Methods Med Res ; 26(2): 724-751, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-25416688

RESUMEN

Estimates of the overall survival benefit of new cancer treatments are often confounded by treatment switching in randomised controlled trials (RCTs) - whereby patients randomised to the control group are permitted to switch onto the experimental treatment upon disease progression. In health technology assessment, estimates of the unconfounded overall survival benefit associated with the new treatment are needed. Several switching adjustment methods have been advocated in the literature, some of which have been used in health technology assessment. However, it is unclear which methods are likely to produce least bias in realistic RCT-based scenarios. We simulated RCTs in which switching, associated with patient prognosis, was permitted. Treatment effect size and time dependency, switching proportions and disease severity were varied across scenarios. We assessed the performance of alternative adjustment methods based upon bias, coverage and mean squared error, related to the estimation of true restricted mean survival in the absence of switching in the control group. We found that when the treatment effect was not time-dependent, rank preserving structural failure time models (RPSFTM) and iterative parameter estimation methods produced low levels of bias. However, in the presence of a time-dependent treatment effect, these methods produced higher levels of bias, similar to those produced by an inverse probability of censoring weights method. The inverse probability of censoring weights and structural nested models produced high levels of bias when switching proportions exceeded 85%. A simplified two-stage Weibull method produced low bias across all scenarios and provided the treatment switching mechanism is suitable, represents an appropriate adjustment method.


Asunto(s)
Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Algoritmos , Bioestadística/métodos , Simulación por Computador , Estudios Cruzados , Progresión de la Enfermedad , Humanos , Modelos Estadísticos , Análisis de Supervivencia , Evaluación de la Tecnología Biomédica/estadística & datos numéricos
4.
Clin Oncol (R Coll Radiol) ; 28(9): e69-e76, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-26994893

RESUMEN

AIMS: To establish whether there is a difference in recovery of salivary function with bilateral superficial lobe parotid-sparing intensity-modulated radiotherapy (BSLPS-IMRT) versus contralateral parotid-sparing IMRT (CLPS-IMRT) in patients with locally advanced head and neck squamous cell cancers. MATERIALS AND METHODS: A dosimetric analysis was carried out on data from two studies in which patients received BSLPS-IMRT (PARSPORT II) or CLPS-IMRT (PARSPORT). Acute (National Cancer Institute, Common Terminology Criteria for adverse events - NCI CTCAEv3.0) and late (Late Effects of Normal Tissue- subjective, objective, management analytical - LENTSOMA and Radiation Therapy Oncology Group) xerostomia scores were dichotomised: recovery (grade 0-1) versus no recovery (≥grade 2). Incidence of recovery of salivary function was compared between the two techniques and dose-response relationships were determined by fitting dose-response curves to the data using non-linear logistic regression analysis. RESULTS: Seventy-one patients received BSLPS-IMRT and 35 received CLPS-IMRT. Patients received 65 Gy in 30 fractions to the primary site and involved nodal levels and 54 Gy in 30 fractions to elective nodal levels. There were significant differences in mean doses to contralateral parotid gland (29.4 Gy versus 24.9 Gy, P < 0.005) and superficial lobes (26.8 Gy versus 30.5 Gy, P = 0.02) for BSLPS and CLPS-IMRT, respectively. Lower risk of long-term ≥grade 2 subjective xerostomia (LENTSOMA) was reported with BSLPS-IMRT (odds ratio 0.50; 95% confidence interval 0.29-0.86; P = 0.012). The percentage of patients who reported recovery of parotid saliva flow at 1 year was higher with BSLPS-IMRT compared with CLPS-IMRT techniques (67.1% versus 52.8%), but the difference was not statistically significant (P = 0.12). For the whole parotid gland, the tolerance doses, D50, were 25.6 Gy (95% confidence interval 20.6-30.5), k = 2.7 (0.9-4.5) (CLPS-IMRT) and 28.9 Gy (26.1-31.9), k = 2.4 (1.4-3.4) (BSLPS-IMRT). For the superficial lobe, D50 were similar: BSLPS-IMRT 23.5 Gy (19.3-27.6), k = 1.9 (0.5-3.8); CLPS-IMRT 24.0 Gy (17.7-30.1), k = 2.1 (0.1-4.1). CONCLUSION: BSLPS-IMRT reduces the risk of developing high-grade subjective xerostomia compared with CLPS-IMRT. The D50 of the superficial lobe may be a more reliable predictor of recovery of parotid function than the whole gland mean dose.


Asunto(s)
Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeza y Cuello/radioterapia , Glándula Parótida/efectos de la radiación , Radioterapia de Intensidad Modulada/efectos adversos , Radioterapia de Intensidad Modulada/métodos , Xerostomía/epidemiología , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Carcinoma de Células Escamosas de Cabeza y Cuello , Xerostomía/etiología
5.
Br J Cancer ; 114(3): 243-7, 2016 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-26766739

RESUMEN

BACKGROUND: Micrometastases in bone marrow of women with early breast cancer were first identified immunocytochemically in the 1980s. We report on the original cohort of women with a median follow-up of 30 years. PATIENTS AND METHODS: In total, 350 women with primary breast cancer had eight bone marrow aspirates examined with antibody to epithelial membrane antigen. Data on long-term mortality were obtained via record linkage to death certification. RESULTS: At a 30-year median follow-up, 79 out of 89 (89%) patients with micrometastases have died compared with 202 out of 261 (77%) without (hazard ratio=1.46 (95% CI 1.12-1.90), P=0.0043). Most marked effect of micrometastases on overall survival (OS) was seen in patients aged ⩽ 50 at surgery (N=97, P=0.012), and on all patients within 10 years of diagnosis. In multivariable analyses, the presence of micrometastases was no longer a statistically significant prognostic factor. CONCLUSIONS: Bone marrow micrometastases are predictive for OS, particularly in the first decade and in younger patients.


Asunto(s)
Neoplasias de la Médula Ósea/secundario , Neoplasias de la Mama/patología , Micrometástasis de Neoplasia , Anciano , Neoplasias de la Médula Ósea/metabolismo , Neoplasias de la Médula Ósea/terapia , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/terapia , Quimioterapia Adyuvante , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Mucina-1/metabolismo , Pronóstico , Modelos de Riesgos Proporcionales , Carga Tumoral
6.
Breast Cancer Res Treat ; 148(3): 581-90, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25395314

RESUMEN

Neoadjuvant endocrine therapy is an alternative to chemotherapy for women with oestrogen receptor (ER)-positive early breast cancer (BC). We aimed to assess feasibility of recruiting patients to a study comparing chemotherapy versus endocrine therapy in postmenopausal women with ER-rich primary BC, and response as well as translational endpoints were assessed. Patients requiring neoadjuvant therapy were randomised to chemotherapy: 6 × 3-weekly cycles FE100C or endocrine therapy: letrozole 2.5 mg, daily for 18-23 weeks. Primary endpoints were recruitment feasibility and tissue collection. Secondary endpoints included clinical, radiological and pathological response rates, quality of life and translational endpoints. 63/80 patients approached were eligible, of those 44 (70, 95% CI 57-81) were randomised. 12 (54.5, 95% CI 32.2-75.6) chemotherapy patients showed radiological objective response compared with 13 (59.1, 95% CI 36.4-79.3) letrozole patients. Compared with baseline, mean Ki-67 levels fell in both groups at days 2-4 and at surgery [fold change: 0.24 (95% CI 0.12-0.51) and 0.24; (95% CI 0.15-0.37), respectively]. Plasma total cfDNA levels rose from baseline to week 8 [fold change: chemotherapy 2.10 (95% CI 1.47-3.00), letrozole 1.47(95% CI 0.98-2.20)], and were maintained at surgery in the chemotherapy group [chemotherapy 2.63; 95% CI 1.56-4.41), letrozole 0.95 (95% CI 0.71-1.26)]. An increase in plasma let-7a miRNA was seen at surgery for patients with objective radiological response to chemotherapy. Recruitment and tissue collection endpoints were met; however, a larger trial was deemed unfeasible due to slow accrual. Both regimens were equally efficacious. Dynamic changes were seen in Ki-67 and circulating biomarkers in both groups with increases in cfDNA and let-7a miRNA persisting until surgery for chemotherapy patients.


Asunto(s)
Antineoplásicos Hormonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Inhibidores de la Aromatasa/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Terapia Neoadyuvante , Adulto , Antineoplásicos Hormonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Inhibidores de la Aromatasa/efectos adversos , Neoplasias de la Mama/sangre , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Letrozol , MicroARNs/sangre , Persona de Mediana Edad , Nitrilos/administración & dosificación , Posmenopausia , Calidad de Vida , Receptores de Estrógenos/metabolismo , Triazoles/administración & dosificación
7.
Oral Oncol ; 50(2): 141-6, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24263110

RESUMEN

OBJECTIVES: Induction chemotherapy (IC) followed by chemoradiation (CRT) for locally advanced squamous cell head and neck cancer (SCCHN) remains controversial in the absence of clear evidence to define its role. As part of a prospective, randomised, multicentre study of CRT for stage III/IV laryngeal/hypopharyngeal cancers (ART DECO, CRUK/10/018), we have examined the attitudes of oncologists in the United Kingdom (UK) to IC. MATERIALS AND METHODS: Head and neck oncologists across the UK who expressed an interest in participating in the ART DECO trial were asked to complete a short written questionnaire designed to identify current UK practice of IC for stage III-IVb SCCHN. Completed questionnaires were returned to the clinical trials office prior to patient recruitment. RESULTS: Clinicians from twenty-five/48 centres (52.1%) responded. Twenty centres (80%) elected to use IC in the trial. For stage III disease, 80% of centres did not prescribe IC for T1N1 disease and 60% did not offer IC for T3N0 disease. Patients with bulky primary tumours or extensive nodal disease were more likely to receive IC. Thirteen prescribing centres (65%) use 3 drugs (docetaxel, cisplatin, and 5-fluorouracil) compared to 7 (35%) using 2 drugs (cisplatin and 5-fluorouracil). Fifteen centres (75%) prescribed 2 cycles of IC, and 5 (25%) prescribed 3 cycles. There was variation in the dosage for both the 2- and 3-drug regimens. CONCLUSION: Results suggest that clinical practice in the UK is currently divided between a 2- versus 3-drug regimen for IC for specific subgroups of patients. A consensus regarding the optimal combinations and dosages is required before further optimization of systemic therapy with other cytotoxics and biological agents is attempted.


Asunto(s)
Actitud del Personal de Salud , Neoplasias Hipofaríngeas/tratamiento farmacológico , Quimioterapia de Inducción/estadística & datos numéricos , Neoplasias Laríngeas/tratamiento farmacológico , Oncología Médica/métodos , Humanos , Reino Unido
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