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BACKGROUND: Adjuvant chemotherapy for patients with early breast cancer improves outcomes but its toxicity affects patients' quality of life (QOL). The UK TACT2 trial investigated whether accelerated epirubicin improves time to recurrence and if oral capecitabine is non-inferior to cyclophosphamide, methotrexate, and fluorouracil (CMF) for efficacy with less toxicity. Results showed no benefit for accelerated epirubicin and capecitabine was non-inferior. As part of the QOL substudy, we aimed to assess the effect of chemotherapies on psychological distress, physical symptoms, and functional domains. METHODS: TACT2 was a multicentre, phase 3, open-label, parallel-group, randomised, controlled trial done in 129 UK centres. Participants were aged 18 years or older with histologically confirmed node-positive or high-risk node-negative invasive primary breast cancer, who had undergone complete excision, and due to receive adjuvant chemotherapy. Patients were randomly assigned (1:1:1:1) to four cycles of 100 mg/m2 epirubicin either every 3 weeks (standard epirubicin) or every 2 weeks with 6 mg pegfilgrastim on day 2 of each cycle (accelerated epirubicin), followed by four 4-week cycles of either CMF (600 mg/m2 cyclophosphamide intravenously on days 1 and 8 or 100 mg/m2 orally on days 1-14; 40 mg/m2 methotrexate intravenously on days 1 and 8; and 600 mg/m2 fluorouracil intravenously on days 1 and 8 of each cycle) or four 3-week cycles of 2500 mg/m2 capecitabine (1250 mg/m2 given twice daily on days 1-14 of each cycle). The randomisation schedule was computer generated in random permuted blocks, stratified by centre, number of nodes involved (none vs 1-3 vs ≥4), age (≤50 years vs >50 years), and planned endocrine treatment (yes vs no). QOL was one of the secondary outcomes and is reported here. All patients from a subset of 44 centres were invited to complete QOL questionnaires (Hospital Anxiety and Depression Scale [HADS] and European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire 30-item core module [QLQ-C30] and Quality of Life Questionnaire breast module [QLQ-BR23]) at baseline, end of standard or accelerated epirubicin, end of CMF or capecitabine, and at 12 and 24 months after randomisation. The QOL substudy prespecified two coprimary QOL outcomes assessed in the intention-to-treat population: overall QOL (reported elsewhere) and HADS total score. Prespecified secondary QOL outcomes were EORTC QLQ-C30 subscales of physical function, role function, and fatigue and EORTC QLQ-BR23 subscales of sexual function and systemic therapy side-effects. This trial is registered with ISRCTN, ISRCTN68068041, and ClinicalTrials.gov, NCT00301925. FINDINGS: From Dec 16, 2005, to Dec 5, 2008, 4391 patients (20 [0·5%] of whom were male) were enrolled in TACT2; 1281 (85·8%) of 1493 eligible patients were included in the QOL substudy. Eight (0·6%) participants in the QOL substudy were male and 1273 (99·4%) were female. Median follow-up was 85·6 months (IQR 80·6-95·9). Analysis was performed on the complete QOL dataset (as of Sept 15, 2011) when all participants had passed the 24-month timepoint. Prerandomisation questionnaires were completed by 1172 (91·5%) patients and 1179 (92·0%) completed at least one postrandomisation questionnaire. End-of-treatment HADS depression score (p=0·0048) and HADS total change score (p=0·0093) were worse for CMF versus capecitabine. Accelerated epirubicin led to worse physical function (p=0·0065), role function (p<0·0001), fatigue (p=0·0002), and systemic side-effects (p=0·0001), but not sexual function (p=0·36), compared with standard epirubicin during treatment, but the effect did not persist. Worse physical function (p=0·0048), sexual function (p=0·0053), fatigue (p<0·0001), and systemic side-effects (p<0·0001), but not role functioning (p=0·013), were seen for CMF versus capecitabine at end of treatment; these differences persisted at 12 months and 24 months. INTERPRETATION: Accelerated epirubicin was associated with worse QOL than was standard epirubicin but only during treatment. These findings will help patients and clinicians make an informed choice about accelerated chemotherapy. CMF had worse QOL effects than did capecitabine, which were persistent for 24 months. The favourable capecitabine QOL compared with CMF supports its use as an adjuvant option after neoadjuvant chemotherapy in patients with triple-negative breast cancer. FUNDING: Cancer Research UK, Amgen, Pfizer, and Roche.
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Neoplasias de la Mama , Humanos , Masculino , Femenino , Neoplasias de la Mama/patología , Capecitabina , Epirrubicina/efectos adversos , Metotrexato/efectos adversos , Calidad de Vida , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Fluorouracilo , Ciclofosfamida , Quimioterapia Adyuvante/métodos , Fatiga/inducido químicamente , Reino UnidoRESUMEN
PURPOSE: The development of oestrogen resistance is a major challenge in managing hormone-sensitive metastatic breast cancer. Saracatinib (AZD0530), an oral Src kinase inhibitor, prevents oestrogen resistance in animal models and reduces osteoclast activity. We aimed to evaluate the efficacy of saracatinib addition to aromatase inhibitors (AI) in patients with hormone receptor-positive metastatic breast cancer. METHODS: This phase II multicentre double-blinded randomised trial allocated post-menopausal women to AI with either saracatinib or placebo (1:1 ratio). Patients were stratified into an "AI-sensitive/naïve" group who received anastrozole and "prior-AI" group who received exemestane. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR) and toxicity. RESULTS: 140 patients were randomised from 20 UK centres to saracatinib/AI (n = 69) or placebo/AI (n = 71). Saracatinib was not associated with an improved PFS (3.7 months v. 5.6 months placebo/AI) and did not reduce likelihood of bony progression. There was no benefit in OS or ORR. Effects were consistent in "AI-sensitive/naive" and "prior-AI" sub-groups. Saracatinib was well tolerated with dose reductions in 16% and the main side effects were gastrointestinal, hypophosphatemia and rash. CONCLUSION: Saracatinib did not improve outcomes in post-menopausal women with metastatic breast cancer. There was no observed beneficial effect on bone metastases. CRUKE/11/023, ISRCTN23804370.
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Neoplasias de la Mama , Femenino , Humanos , Neoplasias de la Mama/patología , Inhibidores de la Aromatasa/efectos adversos , Aromatasa , Estrógenos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Clinical pathways are used to guide clinicians to provide a standardised delivery of care. Because of their standardisation, the aim of clinical pathways is to reduce variation in both care process and patient outcomes. When learning clinical pathways from data through data mining, it is common practice to represent each patient pathway as a string corresponding to their movements through activities. Clustering techniques are popular methods for pathway mining, and therefore this paper focuses on distance metrics applied to string data for k-medoids clustering. The two main aims are to firstly, develop a technique that seamlessly integrates expert information with data and secondly, to develop a string distance metric for the purpose of process data. The overall goal was to allow for more meaningful clustering results to be found by adding context into the string similarity calculation. Eight common distance metrics and their applicability are discussed. These distance metrics prove to give an arbitrary distance, without consideration for context, and each produce different results. As a result, this paper describes the development of a new distance metric, the modified Needleman-Wunsch algorithm, that allows for expert interaction with the calculation by assigning groupings and rankings to activities, which provide context to the strings. This algorithm has been developed in partnership with UK's National Health Service (NHS) with the focus on a lung cancer pathway, however the handling of the data and algorithm allows for application to any disease type. This method is contained within Sim.Pro.Flow, a publicly available decision support tool.
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Vías Clínicas , Medicina Estatal , Algoritmos , Análisis por Conglomerados , Minería de Datos , HumanosRESUMEN
PURPOSE: Previous studies of hypofractionated adjuvant whole-breast radiotherapy for early breast cancer established a 15- or 16-fraction (fr) regimen as standard. The FAST Trial (CRUKE/04/015) evaluated normal tissue effects (NTE) and disease outcomes after 5-fr regimens. Ten-year results are presented. METHODS: Women ≥ 50 years of age with low-risk invasive breast carcinoma (pT1-2 pN0) were randomly assigned to 50 Gy/25 fr (5 weeks) or 30 or 28.5 Gy in 5 once-weekly fr of 6.0 or 5.7 Gy. The primary end point was change in photographic breast appearance at 2 and 5 years; secondary end points were physician assessments of NTE and local tumor control. Odds ratios (ORs) from longitudinal analyses compared regimens. RESULTS: A total of 915 women were recruited from 18 UK centers (2004-2007). Five-year photographs were available for 615/862 (71%) eligible patients. ORs for change in photographic breast appearance were 1.64 (95% CI, 1.08 to 2.49; P = .019) for 30 Gy and 1.10 (95% CI, 0.70 to 1.71; P = .686) for 28.5 Gy versus 50 Gy. α/ß estimate for photographic end point was 2.7 Gy (95% CI, 1.5 to 3.9 Gy), giving a 5-fr schedule of 28 Gy (95% CI, 26 to 30 Gy) estimated to be isoeffective with 50 Gy/25 fr. ORs for any moderate/marked physician-assessed breast NTE (shrinkage, induration, telangiectasia, edema) were 2.12 (95% CI, 1.55 to 2.89; P < .001) for 30 Gy and 1.22 (95% CI, 0.87 to 1.72; P = .248) for 28.5 Gy versus 50 Gy. With 9.9 years median follow-up, 11 ipsilateral breast cancer events (50 Gy: 3; 30 Gy: 4; 28.5 Gy: 4) and 96 deaths (50 Gy: 30; 30 Gy: 33; 28.5 Gy: 33) have occurred. CONCLUSION: At 10 years, there was no significant difference in NTE rates after 28.5 Gy/5 fr compared with 50 Gy/25 fr, but NTE were higher after 30 Gy/5 fr. Results confirm the published 3-year findings that a once-weekly 5-fr schedule of whole-breast radiotherapy can be identified that appears to be radiobiologically comparable for NTE to a conventionally fractionated regimen.
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Neoplasias de la Mama/radioterapia , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Estudios Transversales , Fraccionamiento de la Dosis de Radiación , Femenino , Humanos , Estudios Longitudinales , Persona de Mediana Edad , Radioterapia Adyuvante , Tasa de SupervivenciaRESUMEN
INTRODUCTION: Endocrine therapy has played an important role in the management of ER positive breast cancer over recent decades. Despite this, not all patients respond equally to endocrine intervention, which can lead to resistance, associated disease relapse and progression. Previous reports suggest that endocrine agents themselves may induce an invasive phenotype in ER positive breast cancers with low/aberrant expression of E-cadherin. Here we investigate this phenomenon further and provide data supporting a role for the ER co-receptor, PELP-1, in mediating an adverse response to endocrine agents. MATERIALS AND METHODS: The effects of tamoxifen, fulvestrant and estrogen withdrawal (as a model for aromatase inhibitor therapy) on the invasive and migratory capacity of endocrine-sensitive MCF-7 and T47D cells, in the presence or absence of functional E-cadherin and/or PELP-1 (using siRNA knockdown), was assessed via Matrigel invasion and Boyden chamber migration assays. The effects of these endocrine therapies alongside E-cadherin/PELP-1 modulation on cell proliferation were further assessed by MTT assay. Western blotting using phospho-specific antibodies was performed to investigate signalling pathway changes associated with endocrine-induced changes in invasion and migration. RESULTS: Both tamoxifen and fulvestrant induced a pro-invasive and pro-migratory phenotype in ER positive breast cancer cells displaying a high basal expression of PELP-1, which was augmented in the context of poor cell-cell contact. This process occurred in a Src-dependent manner with Src inhibition reversing endocrine induced invasion/migration. While this adverse response was observed using both tamoxifen and fulvestrant therapy, it was not observed under conditions of estrogen withdrawal. CONCLUSIONS: Our data confirms previous reports that anti-estrogens induce an adverse cell phenotype in ER+ breast cancer, particularly in the absence of homotypic cell contact. These results implicate E-cadherin and PELP-1 as potential biomarkers when deciding upon optimum adjuvant endocrine therapy, whereby tumours with high PELP-1/low E-cadherin expression may benefit from estrogen withdrawal therapy via aromatase inhibition, as opposed to ER modulation/antagonism.
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The association between breast cancer and benign thyroid disorders, in particular thyroid autoimmunity, has been debated for decades. Autoantibodies to thyroid peroxidase, the hallmark of thyroid autoimmunity, have a higher prevalence among patients with breast cancer compared with the general population. Furthermore a correlation between their positivity and a better prognosis of breast cancer was found in several independent small-scale studies, even if such observation was not confirmed in a subsequent retrospective study conducted on the largest patient cohort to date. The thyroid and mammary glands present several biological similarities, therefore the hypothesis of an immune response to shared thyroid/breast antigens could in part explain the association between thyroid autoimmunity and breast cancer. The sodium iodide symporter is expressed in both glands, however it seems unlikely to be the key common antigen, considering that autoantibodies targeting it are rare. Instead thyroid peroxidase, one of the major thyroid autoantigens, is also expressed in breast tissue and therefore represents the main antigenic link between thyroid autoimmunity and breast cancer. Furthermore lactoperoxidase, an enzyme of the same family that shares structural similarities with thyroid peroxidase, is expressed in neoplastic breast cells and is responsible for the cross-reactivity with some autoantibodies to thyroid peroxidase. Novel strategies for the diagnosis and treatment of breast cancer might take advantage of the antigenic link between thyroid and breast tissues.
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Autoanticuerpos/inmunología , Autoinmunidad/inmunología , Neoplasias de la Mama/inmunología , Enfermedades de la Tiroides/inmunología , Glándula Tiroides/inmunología , Animales , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/patología , Femenino , Humanos , Enfermedades de la Tiroides/complicacionesRESUMEN
PURPOSE: This study aimed to explore the associations between dose-volume parameters of localized breast irradiation, longitudinal interleukin-6 soluble receptor (sIL-6R), and leukocyte counts as markers of an immune-mediated response and fatigue as a centrally-driven behavior. METHODS AND MATERIALS: This prospective cohort study recruited 100 women who were diagnosed with stage 0-IIIa breast cancer, prescribed 40 Gy in 15 fractions over 3 weeks adjuvant radiation therapy, and had no prior or concurrent chemotherapy. Dose-volume parameters were derived from treatment plans and related to serum sIL-6R concentrations, leukocyte counts, and a validated measure of self-reported fatigue at baseline, after 10 and 15 fractions, and 4 weeks after radiation therapy. RESULTS: sIL-6R concertation was significantly higher in patients with a total volume of tissue irradiated within the 50% isodose >2040 cm3 (P = .003). When controlling for body mass index, this result only remained significant after treatment. The volume of liver irradiated within the 10% isodose correlated with the sIL-6R concentration during and after radiation therapy (ρ = .3-.4; P = .03-.007). The 38% of the cohort that was classified as fatigued had a higher mean sIL-6sR concentration at all observation points, but the differences were only statistically significant during radiation therapy: Mean (standard deviation [SD]) after 15 fractions for fatigued patients was 47.6 ng/dL (11.2 SD) versus 41.6 ng/dL (11.4 SD) for nonfatigued patients (P = .01). Cohort leukocyte counts and leukocyte subsets decreased consistently from baseline and the values for the fatigued group were 4% lower at baseline and between 7% and 9% lower during and after treatment compared with those of the nonfatigued group but the differences were not statistically significant. CONCLUSIONS: This is the first study to show that localized irradiation induces increased systemic sIL-6R during treatment in participants who reported elevated levels of fatigue before, during, and after treatment. This behavioral response appears to reflect a variation in innate host immunity, which then mediates the cellular and/or psychological stress of radiation therapy.
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Germline mutations in BRCA1/2 predispose individuals to breast cancer (termed germline-mutated BRCA1/2 breast cancer, gBRCA-BC) by impairing homologous recombination (HR) and causing genomic instability. HR also repairs DNA lesions caused by platinum agents and PARP inhibitors. Triple-negative breast cancers (TNBCs) harbor subpopulations with BRCA1/2 mutations, hypothesized to be especially platinum-sensitive. Cancers in putative 'BRCAness' subgroups-tumors with BRCA1 methylation; low levels of BRCA1 mRNA (BRCA1 mRNA-low); or mutational signatures for HR deficiency and those with basal phenotypes-may also be sensitive to platinum. We assessed the efficacy of carboplatin and another mechanistically distinct therapy, docetaxel, in a phase 3 trial in subjects with unselected advanced TNBC. A prespecified protocol enabled biomarker-treatment interaction analyses in gBRCA-BC and BRCAness subgroups. The primary endpoint was objective response rate (ORR). In the unselected population (376 subjects; 188 carboplatin, 188 docetaxel), carboplatin was not more active than docetaxel (ORR, 31.4% versus 34.0%, respectively; P = 0.66). In contrast, in subjects with gBRCA-BC, carboplatin had double the ORR of docetaxel (68% versus 33%, respectively; biomarker, treatment interaction P = 0.01). Such benefit was not observed for subjects with BRCA1 methylation, BRCA1 mRNA-low tumors or a high score in a Myriad HRD assay. Significant interaction between treatment and the basal-like subtype was driven by high docetaxel response in the nonbasal subgroup. We conclude that patients with advanced TNBC benefit from characterization of BRCA1/2 mutations, but not BRCA1 methylation or Myriad HRD analyses, to inform choices on platinum-based chemotherapy. Additionally, gene expression analysis of basal-like cancers may also influence treatment selection.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Carboplatino/uso terapéutico , Mutación/genética , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Femenino , Recombinación Homóloga/genética , Humanos , Supervivencia sin Progresión , Resultado del TratamientoRESUMEN
Purpose: One third of ER-positive breast cancer patients who initially respond to endocrine therapy become resistant to treatment. Such treatment failure is associated with poor prognosis and remains an area of unmet clinical need. Here, we identify a specific posttranslational modification that occurs during endocrine resistance and which results in tumor susceptibility to the apoptosis-inducer TRAIL. This potentially offers a novel stratified approach to targeting endocrine-resistant breast cancer.Experimental Design: Cell line and primary-derived xenograft models of endocrine resistance were investigated for susceptibility to TRAIL. Tumor viability, cancer stem cell (CSC) viability (tumorspheres), tumor growth kinetics, and metastatic burden were assessed. Western blots for the TRAIL-pathway inhibitor, c-FLIP, and upstream regulators were performed. Results were confirmed in primary culture of 26 endocrine-resistant and endocrine-naïve breast tumors.Results: Breast cancer cell lines with acquired resistance to tamoxifen (TAMR) or faslodex were more sensitive to TRAIL than their endocrine-sensitive controls. Moreover, TRAIL eliminated CSC-like activity in TAMR cells, resulting in prolonged remission of xenografts in vivo In primary culture, TRAIL significantly depleted CSCs in 85% endocrine-resistant, compared with 8% endocrine-naïve, tumors, whereas systemic administration of TRAIL in endocrine-resistant patient-derived xenografts reduced tumor growth, CSC-like activity, and metastases. Acquired TRAIL sensitivity correlated with a reduction in intracellular levels of c-FLIP, and an increase in Jnk-mediated phosphorylation of E3-ligase, ITCH, which degrades c-FLIP.Conclusions: These results identify a novel mechanism of acquired vulnerability to an extrinsic cell death stimulus, in endocrine-resistant breast cancers, which has both therapeutic and prognostic potential. Clin Cancer Res; 24(10); 2452-63. ©2018 AACR.
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Neoplasias de la Mama/metabolismo , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/metabolismo , Resistencia a Antineoplásicos , Procesamiento Proteico-Postraduccional , Receptores de Estrógenos/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Animales , Antineoplásicos Hormonales/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/genética , Línea Celular Tumoral , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Randomised clinical trials (RCTs) are the gold standard for evaluating new cancer treatments. They are, however, expensive to conduct, particularly where long-term follow-up of participants is required. Tracking participants via routine datasets could provide a cost-effective alternative for ascertaining follow-up information required to evaluate disease outcomes. This project explores the potential for routine data to inform cancer trials, using, the historical National Cancer Data Repository (NCDR) for English NHS sites and, for validation, mature data available from the TACT trial. METHODS: Datasets were matched using patients' NHS number, date of birth (dob) and name/initials. Demographics, clinical characteristics and outcomes were assessed for agreement and completeness. Overall survival was compared between NCDR and TACT. RESULTS: A total of 3151 patients underwent linkage; 3047 (96.7%) of which had matched records. Extensive cleaning was required for some registry data fields, e.g. cause of death, whilst others had large amounts of missing data, e.g. tumour size (22.1%). Other data had high levels of matching such as dob (99.6%) and date of death (89.6%). There was no evidence of differential survival rates (8-year survival: TACT = 75% (95% CI 73, 76); NCDR = 76% (95% CI 74, 77)). CONCLUSIONS: Data quality and completeness requires improvement before routine data could be used for RCTs. Introduction of new routine datasets, including COSD, is welcomed although reporting of disease-recurrence events remains a concern. Prospective validation of such datasets is required before RCTs can confidently switch patient follow-up to utilise routinely collected NHS-based data. TACT TRIAL REGISTRATION: Clinicaltrials.gov NCT00033683 , registered on 9 April 2002; ISRCTN79718493 , registered on 1 July 2001.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Minería de Datos/métodos , Investigación sobre Servicios de Salud/métodos , Registro Médico Coordinado/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Sistema de Registros , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Bases de Datos Factuales , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Reproducibilidad de los Resultados , Estudios Retrospectivos , Factores de Riesgo , Medicina Estatal , Factores de Tiempo , Resultado del Tratamiento , Reino UnidoRESUMEN
BACKGROUND: Small-scale studies correlated the presence of thyroid autoimmunity with both improved or worsened breast cancer outcome. OBJECTIVES: We aimed to clarify this association in a large cohort using the phase III, randomized, controlled Taxotere as Adjuvant Chemotherapy Trial (TACT, CRUK01/001). METHODS: TACT women >18 years old with node-positive or high-risk node-negative early breast cancer (pT1-3a, pN0-1, M0), with stored plasma (n = 1,974), taken 15.5 (median; IQR 7.0-24.0) months after breast surgery were studied. Patients had also received chemotherapy (100%), radiotherapy (1,745/1,974; 88.4%), hormonal therapy (1,378/ 1,974; 69.8%), or trastuzumab (48/1,974; 2.4%). History of thyroid diseases and/or related treatments was not available. The prognostic significance of autoantibodies to thyroid peroxidase (TPOAb; positive ≥6 kIU/L), free-thyroxine and thyrotropin (combined: euthyroid, hypothyroid, hyperthyroid) was evaluated for disease-free survival (DFS), overall-survival (OS), and time-to-recurrence (TTR), with Cox regression models in univariate and multivariable analyses. The extended median follow-up was 97.5 months. RESULTS: No difference in DFS was found by TPOAb status (unadjusted hazard ratio [HR]: 0.97, 95%CI: 0.78-1.19; p = 0.75) and/or thyroid function (unadjusted HR [hypothyroid vs. euthyroid]: 1.15, 95% CI: 0.79-1.68; p = 0.46; unadjusted HR [hyperthyroid vs. euthyroid]: 1.14, 95% CI: 0.82-1.61; p = 0.44). Similar results were obtained for OS, TTR, multivariable analyses, when TPOAb titre by tertiles was considered, and in a subgroup of 123 patients with plasma collected before adjuvant treatments. CONCLUSIONS: No evidence for a prognostic role of TPOAb and/or thyroid function in moderate-to-high-risk early breast cancer was found in the largest and longest observational study to date.
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BACKGROUND: Adjuvant chemotherapy for early breast cancer has improved outcomes but causes toxicity. The UK TACT2 trial used a 2×2 factorial design to test two hypotheses: whether use of accelerated epirubicin would improve time to tumour recurrence (TTR); and whether use of oral capecitabine instead of cyclophosphamide would be non-inferior in terms of patients' outcomes and would improve toxicity, quality of life, or both. METHODS: In this multicentre, phase 3, randomised, controlled trial, we enrolled patients aged 18 years or older from 129 UK centres who had histologically confirmed node-positive or high-risk node-negative operable breast cancer, had undergone complete excision, and were due to receive adjuvant chemotherapy. Patients were randomly assigned to receive four cycles of 100 mg/m2 epirubicin either every 3 weeks (standard epirubicin) or every 2 weeks with 6 mg pegfilgrastim on day 2 of each cycle (accelerated epirubicin), followed by four 4-week cycles of either classic cyclophosphamide, methotrexate, and fluorouracil (CMF; 600 mg/m2 cyclophosphamide intravenously on days 1 and 8 or 100 mg/m2 orally on days 1-14; 40 mg/m2 methotrexate intravenously on days 1 and 8; and 600 mg/m2 fluorouracil intravenously on days 1 and 8 of each cycle) or four 3-week cycles of 2500 mg/m2 capecitabine (1250 mg/m2 given twice daily on days 1-14 of each cycle). The randomisation schedule was computer generated in random permuted blocks, stratified by centre, number of nodes involved (none vs one to three vs four or more), age (≤50 years vs >50 years), and planned endocrine treatment (yes vs no). The primary endpoint was TTR, defined as time from randomisation to first invasive relapse or breast cancer death, with intention-to-treat analysis of standard versus accelerated epirubicin and per-protocol analysis of CMF versus capecitabine. This trial is registered with ISRCTN, number 68068041, and with ClinicalTrials.gov, number NCT00301925. FINDINGS: From Dec 16, 2005, to Dec 5, 2008, 4391 patients (4371 women and 20 men) were recruited. At a median follow-up of 85·6 months (IQR 80·6-95·9) no significant difference was seen in the proportions of patients free from TTR events between the accelerated and standard epirubicin groups (overall hazard ratio [HR] 0·94, 95% CI 0·81-1·09; stratified p=0·42). At 5 years, 85·9% (95% CI 84·3-87·3) of patients receiving standard epirubicin and 87·1% (85·6-88·4) of those receiving accelerated epirubicin were free from TTR events. 4358 patients were included in the per-protocol analysis, and no difference was seen in the proportions of patients free from TTR events between the CMF and capecitabine groups (HR 0·98, 95% CI 0·85-1.14; stratified p=0·00092 for non-inferiority). Compared with baseline, significantly more patients taking CMF than those taking capecitabine had clinically relevant worsening of quality of life at end of treatment (255 [58%] of 441 vs 235 [50%] of 475; p=0·011) and at 12 months (114 [34%] of 334 vs 89 [22%] of 401; p<0·001 at 12 months) and had worse quality of life over time (p<0·0001). Detailed toxicity and quality-of-life data were collected from 2115 (48%) of treated patients. The most common grade 3 or higher adverse events in cycles 1-4 were neutropenia (175 [16%]) and fatigue (56 [5%]) of the 1070 patients treated with standard epirubicin, and fatigue (63 [6%]) and infection (34 [3%]) of the 1045 patients treated with accelerated epirubicin. In cycles 5-8, the most common grade 3 or higher adverse events were neutropenia (321 [31%]) and fatigue (109 [11%]) in the patients treated with CMF, and hand-foot syndrome (129 [12%]) and diarrhoea (67 [6%]) in the 1044 patients treated with capcitabine. INTERPRETATION: We found no benefit from increasing the dose density of the anthracycline component of chemotherapy. However, capecitabine could be used in place of CMF without significant loss of efficacy and with improved quality of life. FUNDING: Cancer Research UK, Amgen, Pfizer, and Roche.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma/tratamiento farmacológico , Epirrubicina/administración & dosificación , Recurrencia Local de Neoplasia , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Neoplasias de la Mama Masculina/tratamiento farmacológico , Neoplasias de la Mama Masculina/cirugía , Capecitabina/administración & dosificación , Capecitabina/efectos adversos , Carcinoma/secundario , Carcinoma/cirugía , Quimioterapia Adyuvante/métodos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Diarrea/inducido químicamente , Supervivencia sin Enfermedad , Epirrubicina/efectos adversos , Fatiga/inducido químicamente , Femenino , Filgrastim , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Estudios de Seguimiento , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Síndrome Mano-Pie/etiología , Humanos , Infecciones/inducido químicamente , Masculino , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Neutropenia/inducido químicamente , Polietilenglicoles , Calidad de Vida , Proteínas Recombinantes/administración & dosificación , Tasa de Supervivencia , Factores de TiempoRESUMEN
BACKGROUND: In a non-inferiority (NI) trial, analysis based on the intention-to-treat (ITT) principle is anti-conservative, so current guidelines recommend analysing on a per-protocol (PP) population in addition. However, PP analysis relies on the often implausible assumption of no confounders. Randomisation-based efficacy estimators (RBEEs) allow for treatment non-adherence while maintaining a comparison of randomised groups. Fischer et al. have developed an approach for estimating RBEEs in randomised trials with two active treatments, a common feature of NI trials. The aim of this paper was to demonstrate the use of RBEEs in NI trials using this approach, and to appraise the feasibility of these estimators as the primary analysis in NI trials. METHODS: Two NI trials were used. One comparing two different dosing regimens for the maintenance of remission in people with ulcerative colitis (CODA), and the other comparing an orally administered treatment to an intravenously administered treatment in preventing skeletal-related events in patients with bone metastases from breast cancer (ZICE). Variables that predicted adherence in each of the trial arms, and were also independent of outcome, were sought in each of the studies. Structural mean models (SMMs) were fitted that conditioned on these variables, and the point estimates and confidence intervals compared to that found in the corresponding ITT and PP analyses. RESULTS: In the CODA study, no variables were found that differentially predicted treatment adherence while remaining independent of outcome. The SMM, using standard methodology, moved the point estimate closer to 0 (no difference between arms) compared to the ITT and PP analyses, but the confidence interval was still within the NI margin, indicating that the conclusions drawn would remain the same. In the ZICE study, cognitive functioning as measured by the corresponding domain of the QLQ-C30, and use of chemotherapy at baseline were both differentially associated with adherence while remaining independent of outcome. However, while the SMM again moved the point estimate closer to 0, the confidence interval was wide, overlapping with any NI margin that could be justified. CONCLUSION: Deriving RBEEs in NI trials with two active treatments can provide a randomisation-respecting estimate of treatment efficacy that accounts for treatment adherence, is straightforward to implement, but requires thorough planning during the design stage of the study to ensure that strong baseline predictors of treatment are captured. Extension of the approach to handle nonlinear outcome variables is also required. TRIAL REGISTRATION: The CODA study: ClinicalTrials.gov, identifier: NCT00708656 . Registered on 8 April 2008. The ZICE study trial: ClinicalTrials.gov, identifier: NCT00326820 . Registered on 16 May 2006.
Asunto(s)
Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Proyectos de Investigación , Administración Intravenosa , Administración Oral , Antiinflamatorios/administración & dosificación , Conservadores de la Densidad Ósea/administración & dosificación , Neoplasias Óseas/prevención & control , Neoplasias Óseas/secundario , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/tratamiento farmacológico , Interpretación Estadística de Datos , Difosfonatos/administración & dosificación , Femenino , Fármacos Gastrointestinales/administración & dosificación , Humanos , Ácido Ibandrónico , Imidazoles/administración & dosificación , Análisis de Intención de Tratar , Masculino , Cumplimiento de la Medicación , Mesalamina/administración & dosificación , Modelos Estadísticos , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Inducción de Remisión , Proyectos de Investigación/estadística & datos numéricos , Resultado del Tratamiento , Ácido ZoledrónicoRESUMEN
While endocrine therapy is the mainstay of ER+ breast cancer, the clinical effectiveness of these agents is limited by the phenomenon of acquired resistance that is associated with disease relapse and poor prognosis. Our previous studies revealed that acquired resistance is accompanied by a gain in cellular invasion and migration and also that CD44 family proteins are overexpressed in the resistant phenotype. Given the association of CD44 with tumor progression, we hypothesized that its overexpression may act to promote the aggressive behavior of endocrine-resistant breast cancers. Here, we have investigated further the role of two specific CD44 isoforms, CD44v3 and CD44v6, in the endocrine-resistant phenotype. Our data revealed that overexpression of CD44v6, but not CD44v3, in endocrine-sensitive MCF-7 cells resulted in a gain in EGFR signaling, enhanced their endogenous invasive capacity, and attenuated their response to endocrine treatment. Suppression of CD44v6 in endocrine-resistant cell models was associated with a reduction in their invasive capacity. Our data suggest that upregulation of CD44v6 in acquired resistant breast cancer may contribute to a gain in the aggressive phenotype of these cells and loss of endocrine response through transactivation of the EGFR pathway. Future therapeutic targeting of CD44v6 may prove to be an effective strategy alongside EGFR-targeted agents in delaying/preventing acquired resistance in breast cancer.
RESUMEN
BACKGROUND: The Her2 receptor is overexpressed in up to 25 % of breast cancers and is associated with a poor prognosis. Around half of Her2+ breast cancers also express the estrogen receptor and treatment for such tumours can involve both endocrine and Her2-targeted therapies. However, despite preclinical data supporting the effectiveness of these agents, responses can vary widely in the clinical setting. In light of the increasing evidence pointing to the interplay between the tumour and its extracellular microenvironment as a significant determinant of therapeutic sensitivity and response here we investigated the impact of 3D matrix culture of breast cancer cells on their therapeutic sensitivity. METHODS: A 3D Matrigel-based culture system was established and optimized for the growth of ER+/Her2+ breast cancer cell models. Growth of cells in response to trastuzumab and endocrine agents in 3D culture versus routine monolayer culture were assessed using cell counting and Ki67 staining. Endogenous and trastuzumab-modulated signalling pathway activity in 2D and 3D cultures were assessed using Western blotting. RESULTS: Breast cancer cells in 3D culture displayed an attenuated response to both endocrine agents and trastuzumab compared with cells cultured in traditional 2D monolayers. Underlying this phenomenon was an apparent matrix-induced shift from AKT to MAPK signalling; consequently, suppression of MAPK in 3D cultures restores therapeutic response. CONCLUSION: These data suggest that breast cancer cells in 3D culture display a reduced sensitivity to therapeutic agents which may be mediated by internal MAPK-mediated signalling. Targeting of adaptive pathways that maintain growth in 3D culture may represent an effective strategy to improve therapeutic response clinically.
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Neoplasias de la Mama/metabolismo , Técnicas de Cultivo de Célula/métodos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Antineoplásicos Hormonales/farmacología , Western Blotting , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Matriz Extracelular , Femenino , Humanos , Inmunohistoquímica , Receptor ErbB-2/biosíntesis , Transducción de Señal/fisiología , Trastuzumab/farmacología , Microambiente Tumoral/fisiologíaRESUMEN
BACKGROUND: The role of adjuvant bisphosphonates in early breast cancer is uncertain. We therefore did a large randomised trial to investigate the effect of the adjuvant use of zoledronic acid on disease-free survival (DFS) in high-risk patients with early breast cancer. METHODS: In the AZURE trial, an open-label, international, multicentre, randomised, controlled, parallel-group phase 3 trial, women (age ≥18 years) with stage II or III breast cancer were randomly assigned (1:1) by a central automated 24-h computer-generated telephone minimisation system (balanced for number of involved axillary lymph nodes, tumour stage, oestrogen receptor status, type and timing of systemic therapy, menopausal status, statin use, and treatment centre) to receive standard adjuvant systemic treatment alone (control group) or with 4 mg intravenous zoledronic acid every 3-4 weeks for six doses, then every 3 months for eight doses, followed by every 6 months for five doses, for a total of 5 years of treatment. The primary endpoint was disease-free survival (DFS). Secondary endpoints were invasive DFS (IDFS), overall survival, time to bone metastases, time to distant recurrence, and subgroup analyses of variables included in the randomisation. All patients have completed study treatment. Results from the intention-to-treat final analysis of this fully recruited study are presented after a median follow-up of 84 months (IQR 66-93). This final efficacy analysis was planned to take place after 940 DFS events. This trial is registered with ClinicalTrials.gov, NCT00072020. FINDINGS: 3360 women were recruited from 174 centres in seven countries between Sept 4, 2003, and Feb 16, 2006. The number of DFS events did not differ between groups: 493 in the control group and 473 in the zoledronic acid group (adjusted hazard ratio [HR] 0·94, 95% CI 0·82-1·06; p=0·30). IDFS (HR 0·93, 95% CI 0·82-1·05; p=0·22), overall survival (0·93, 0·81-1·08; p=0·37), and distant recurrences (0·93, 0·81-1·07; p=0·29) were much the same in both groups. Zoledronic acid reduced the development of bone metastases, both as a first event (HR 0·78, 95% CI 0·63-0·96; p=0·020) and at any time during follow-up (0·81, 0·68-0·97; p=0·022). The effects of zoledronic acid on DFS were not affected by oestrogen-receptor status. However, zoledronic acid improved IDFS in those who were over 5 years since menopause at trial entry (n=1041; HR 0·77, 95% CI 0·63-0·96) but not in all other (premenopause, perimenopause, and unknown status) menopausal groups (n=2318; HR 1·03, 95% CI 0·89-1·20). 33 cases of suspected osteonecrosis of the jaw have been reported, with 26 confirmed on central review, all in the zoledronic acid group (1·7%, 95% CI 1·0-2·4). INTERPRETATION: These results suggest no overall benefit from the addition of zoledronic acid to standard adjuvant treatments for early breast cancer. However, zoledronic acid does reduce the development of bone metastases and, for women with established menopause, improved disease outcomes. FUNDING: Novartis Global and NIHR Cancer Research Network.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Conservadores de la Densidad Ósea/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Difosfonatos/uso terapéutico , Imidazoles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Intervalos de Confianza , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Detección Precoz del Cáncer , Femenino , Estudios de Seguimiento , Humanos , Infusiones Intravenosas , Cooperación Internacional , Estimación de Kaplan-Meier , Persona de Mediana Edad , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Estudios Prospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Ácido ZoledrónicoRESUMEN
BACKGROUND: Bisphosphonates are routinely used in the treatment of metastatic bone disease from breast cancer to reduce pain and bone destruction. Zoledronic acid given by intravenous infusion has been widely used, but places a substantial logistical burden on both patient and hospital. As a result, the use of oral ibandronic acid has increased, despite the absence of comparative data. In the ZICE trial, we compared oral ibandronic acid with intravenous zoledronic acid for the treatment of metastatic breast cancer to bone. METHODS: This phase 3, open-label, parallel group active-controlled, multicentre, randomised, non-inferiority phase 3 study was done in 99 UK hospitals. Eligibility criteria included at least one radiologically confirmed bone metastasis from a histologically confirmed breast cancer. Patients with ECOG performance status 0 to 2 and clinical decision to treat with bisphosphonates within 3 months of randomisation were randomly assigned to receive 96 weeks of treatment with either intravenous zoledronic acid at 4 mg every 3-4 weeks or oral ibandronic acid 50 mg daily. Randomisation (1:1) was done via a central computerised system within stratified block sizes of four. Randomisation was stratified on whether patients had current or planned treatment with chemotherapy; current or planned treatment with hormone therapy; and whether they had a previous skeletal-related event within the last 3 months or had planned radiotherapy treatment to the bone or planned orthopaedic surgery due to bone metastases. The primary non-inferiority endpoint was the frequency and timing of skeletal-related events over 96 weeks, analysed using a per-protocol analysis. All active (non-withdrawn) patients have now reached the 96-week timepoint and the trial is now in long-term follow-up. The trial is registered with ClinicalTrials.gov, number NCT00326820. FINDINGS: Between Jan 13, 2006, and Oct 4, 2010, 705 patients were randomly assigned to receive ibandronic acid and 699 to receive zoledronic acid; three patients withdrew immediately after randomisation. The per-protocol analysis included 654 patients in the ibandronic acid group and 672 in the zoledronic acid group. Annual rates of skeletal-related events were 0·499 (95% CI 0·454-0·549) with ibandronic acid and 0·435 (0·393-0·480) with zoledronic acid; the rate ratio for skeletal-related events was 1·148 (95% CI 0·967-1·362). The upper CI was greater than the margin of non-inferiority of 1·08; therefore, we could not reject the null hypothesis that ibandronic acid was inferior to zoledronic acid. More patients in the zoledronic acid group had renal toxic effects than in the ibandronic acid group (226 [32%] of 697 vs 172 [24%] of 704) but rates of osteonecrosis of the jaw were low in both groups (nine [1%] of 697 vs five [<1%] of 704). The most common grade 3 or 4 adverse events were fatigue (97 [14%] of 697 patients allocated zoledronic acid vs 98 [14%] of 704 allocated ibandronic acid), increased bone pain (91 [corrected] [13%] vs 85 [corrected] [12%]), joint pain (41 [corrected] [6%] vs 38 [5%]), infection (31 [5%] vs 23 [corrected] [3%]), and nausea or vomiting (38 [5%] vs 41 [6%]). INTERPRETATION: Our results suggest that zoledronic acid is preferable to ibandronic acid in preventing skeletal-related events caused by bone metastases. However, both drugs have acceptable side-effect profiles and the oral formulation is more convenient, and could still be considered if the patient has a strong preference or if difficulties occur with intravenous infusions. FUNDING: Roche Products Ltd (educational grant), supported by National Institute for Health Research Cancer Network, following endorsement by Cancer Research UK (CRUKE/04/022).
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Conservadores de la Densidad Ósea/administración & dosificación , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Neoplasias de la Mama/patología , Difosfonatos/administración & dosificación , Imidazoles/administración & dosificación , Administración Oral , Anciano , Neoplasias Óseas/mortalidad , Difosfonatos/efectos adversos , Femenino , Humanos , Ácido Ibandrónico , Imidazoles/efectos adversos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Ácido ZoledrónicoRESUMEN
BACKGROUND: New therapeutic options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor designed to provide prolonged tumour-cell exposure to SN38, the active metabolite. We aimed to assess the efficacy and safety of two etirinotecan pegol dosing schedules in patients with previously treated metastatic breast cancer to determine an optimum dosing schedule for phase 3 trials. METHODS: In this randomised, two-stage, open-label phase 2 trial, we recruited patients aged 18 years or older who had received taxane therapy and undergone two or fewer previous chemotherapy regimens for metastatic breast cancer, with an Eastern Cooperative Oncology Group performance status of 0 or 1, from 18 sites in three countries. Eligible patients were randomly assigned (1:1) to etirinotecan pegol 145 mg/m(2) every 14 days or every 21 days. The primary endpoint was the proportion of patients with a confirmed objective response as defined by Response Evaluation Criteria in Solid Tumors version 1.0, analysed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug. FINDINGS: 70 patients (35 in each group) were randomly assigned to treatment between Feb 17, 2009 and April 13, 2010. Of the 70 patients, 20 (29%; 95% CI 18·4-40·6) achieved an objective response (two [3%] had a complete response and 18 [26%] had a partial response). Ten patients on the 14-day schedule achieved an objective response (29%; 95% CI 14·6-46·3; eight partial responses, two complete responses) as did ten on the 21-day schedule (29%; 95% CI 14·6-46·3; all partial responses). The most common grade 3 or worse adverse events were delayed diarrhoea (seven [20%] of 35 patients on the 14-day schedule vs eight [23%] of 35 patients on the 21-day schedule), fatigue (five [14%] vs three [9%]), neutropenia (four [11%] vs four [11%]), and dehydration (three [9%] vs four [11%]); 14 [20%] patients discontinued treatment because of drug-related toxicity. There were two possible drug-related deaths (acute renal failure and septic shock) in the 14-day group; other drug-related serious adverse events reported by more than one patient included ten [14%] patients with diarrhoea (six [17%] patients on the 14-day schedule vs four [11%] on the 21-day schedule), six [9%] with dehydration (two [6%] vs four [11%]), two [3%] with nausea (two [6%] vs none), and two [3%] with vomiting (two [6%] vs none). INTERPRETATION: On the basis of the overall clinical data, pharmacokinetics, and tolerability profile, etirinotecan pegol 145 mg/m(2) every 21 days has been selected for a phase 3 trial against treatment of physician's choice in patients with advanced breast cancer.
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Neoplasias de la Mama/tratamiento farmacológico , Camptotecina/análogos & derivados , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Polietilenglicoles/administración & dosificación , Inhibidores de Topoisomerasa I/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/secundario , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/farmacocinética , Esquema de Medicación , Europa (Continente) , Femenino , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Humanos , Análisis de Intención de Tratar , Irinotecán , Estimación de Kaplan-Meier , Persona de Mediana Edad , Polietilenglicoles/efectos adversos , Polietilenglicoles/farmacocinética , Factores de Tiempo , Inhibidores de Topoisomerasa I/efectos adversos , Inhibidores de Topoisomerasa I/farmacocinética , Resultado del Tratamiento , Estados UnidosRESUMEN
BACKGROUND: This qualitative sub-study aimed to explore the experiences of participants on the National Cancer Research Institute ZICE clinical trial, a randomised trial assessing two types of bisphosphonate treatment in breast cancer patients with bone metastases. Participants in the clinical trial were randomly allocated to receive either zoledronate, delivered by an intravenous (IV) infusion at clinic, or oral ibandronate, taken at home. METHODS: Qualitative research interviews were conducted with participant groups organised by treatment and location. Interviews covered experiences and understanding of bisphosphonate treatment, the experience of the delivery mechanisms (IV or oral), side effects and benefits, and quality of life issues. The analytic framework was interpretative phenomenological analysis. RESULTS: This paper reports on one of four superordinate themes: participants' experience of the ZICE trial, which explores the participants' experiences with clinical trial-related processes. Results show that participants were generally satisfied with their randomised treatment, although most participants had an initial preference for oral bisphosphonates. Some difficulties were reported from participants for both interventions: needle phobia, poor veins, difficulty with swallowing and gastric side effects, but pain control was improved with both modes of delivery. However, the infused bisphosphonate was reported to lose effectiveness after three weeks for some participants, whereas the oral bisphosphonate was reported to give consistent pain control. Geographical location and distance to travel made little difference to convenience of access to clinic as the reported lengths of travel time were similar due to traffic congestion in the urban areas. Most participants understood the trial processes, such as randomisation, and information about bisphosphonates but some participants showed little understanding of certain aspects of the trial. Some participants reported difficulties in accessing dental treatment due to their dentist's perceptions of bisphosphonate treatment. CONCLUSIONS: In trials of medicinal products, especially when testing for non-inferiority, participants' preferences and idiosyncrasies in relation to treatments should not be assumed. This study has shown that in a trial context, participants' views can usefully add to the main trial outcomes and they should be taken into account when prescribing in the real world. TRIAL REGISTRATION: ISRCTN13914201. Main ZICE MREC: 05/MRE09/57. CRUK E/04/022.
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Conservadores de la Densidad Ósea/administración & dosificación , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Neoplasias de la Mama/patología , Difosfonatos/administración & dosificación , Conocimientos, Actitudes y Práctica en Salud , Imidazoles/administración & dosificación , Satisfacción del Paciente , Pacientes/psicología , Administración Oral , Conservadores de la Densidad Ósea/efectos adversos , Neoplasias Óseas/psicología , Neoplasias de la Mama/psicología , Comprensión , Difosfonatos/efectos adversos , Inglaterra , Femenino , Accesibilidad a los Servicios de Salud , Humanos , Ácido Ibandrónico , Imidazoles/efectos adversos , Infusiones Intravenosas , Dimensión del Dolor , Prioridad del Paciente , Investigación Cualitativa , Calidad de Vida , Factores de Tiempo , Resultado del Tratamiento , Gales , Ácido ZoledrónicoRESUMEN
BACKGROUND: 5-year results of the UK Standardisation of Breast Radiotherapy (START) trials suggested that lower total doses of radiotherapy delivered in fewer, larger doses (fractions) are at least as safe and effective as the historical standard regimen (50 Gy in 25 fractions) for women after primary surgery for early breast cancer. In this prespecified analysis, we report the 10-year follow-up of the START trials testing 13 fraction and 15 fraction regimens. METHODS: From 1999 to 2002, women with completely excised invasive breast cancer (pT1-3a, pN0-1, M0) were enrolled from 35 UK radiotherapy centres. Patients were randomly assigned to a treatment regimen after primary surgery followed by chemotherapy and endocrine treatment (where prescribed). Randomisation was computer-generated and stratified by centre, type of primary surgery (breast-conservation surgery or mastectomy), and tumour bed boost radiotherapy. In START-A, a regimen of 50 Gy in 25 fractions over 5 weeks was compared with 41·6 Gy or 39 Gy in 13 fractions over 5 weeks. In START-B, a regimen of 50 Gy in 25 fractions over 5 weeks was compared with 40 Gy in 15 fractions over 3 weeks. Eligibility criteria included age older than 18 years and no immediate surgical reconstruction. Primary endpoints were local-regional tumour relapse and late normal tissue effects. Analysis was by intention to treat. Follow-up data are still being collected. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779. FINDINGS: START-A enrolled 2236 women. Median follow-up was 9·3 years (IQR 8·0-10·0), after which 139 local-regional relapses had occurred. 10-year rates of local-regional relapse did not differ significantly between the 41·6 Gy and 50 Gy regimen groups (6·3%, 95% CI 4·7-8·5 vs 7·4%, 5·5-10·0; hazard ratio [HR] 0·91, 95% CI 0·59-1·38; p=0·65) or the 39 Gy (8·8%, 95% CI 6·7-11·4) and 50 Gy regimen groups (HR 1·18, 95% CI 0·79-1·76; p=0·41). In START-A, moderate or marked breast induration, telangiectasia, and breast oedema were significantly less common normal tissue effects in the 39 Gy group than in the 50 Gy group. Normal tissue effects did not differ significantly between 41·6 Gy and 50 Gy groups. START-B enrolled 2215 women. Median follow-up was 9·9 years (IQR 7·5-10·1), after which 95 local-regional relapses had occurred. The proportion of patients with local-regional relapse at 10 years did not differ significantly between the 40 Gy group (4·3%, 95% CI 3·2-5·9) and the 50 Gy group (5·5%, 95% CI 4·2-7·2; HR 0·77, 95% CI 0·51-1·16; p=0·21). In START-B, breast shrinkage, telangiectasia, and breast oedema were significantly less common normal tissue effects in the 40 Gy group than in the 50 Gy group. INTERPRETATION: Long-term follow-up confirms that appropriately dosed hypofractionated radiotherapy is safe and effective for patients with early breast cancer. The results support the continued use of 40 Gy in 15 fractions, which has already been adopted by most UK centres as the standard of care for women requiring adjuvant radiotherapy for invasive early breast cancer. FUNDING: Cancer Research UK, UK Medical Research Council, UK Department of Health.