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1.
Int J Mol Sci ; 24(10)2023 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-37239898

RESUMO

A limited number of studies have focused on the mutational landscape of breast cancer in different ethnic populations within Europe and compared the data with other ethnic groups and databases. We performed whole-genome sequencing of 63 samples from 29 Hungarian breast cancer patients. We validated a subset of the identified variants at the DNA level using the Illumina TruSight Oncology (TSO) 500 assay. Canonical breast-cancer-associated genes with pathogenic germline mutations were CHEK2 and ATM. Nearly all the observed germline mutations were as frequent in the Hungarian breast cancer cohort as in independent European populations. The majority of the detected somatic short variants were single-nucleotide polymorphisms (SNPs), and only 8% and 6% of them were deletions or insertions, respectively. The genes most frequently affected by somatic mutations were KMT2C (31%), MUC4 (34%), PIK3CA (18%), and TP53 (34%). Copy number alterations were most common in the NBN, RAD51C, BRIP1, and CDH1 genes. For many samples, the somatic mutational landscape was dominated by mutational processes associated with homologous recombination deficiency (HRD). Our study, as the first breast tumor/normal sequencing study in Hungary, revealed several aspects of the significantly mutated genes and mutational signatures, and some of the copy number variations and somatic fusion events. Multiple signs of HRD were detected, highlighting the value of the comprehensive genomic characterization of breast cancer patient populations.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Hungria , Variações do Número de Cópias de DNA , Predisposição Genética para Doença , Mutação , Mutação em Linhagem Germinativa , Genômica
2.
Int J Mol Sci ; 22(23)2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34884782

RESUMO

Radiation-induced heart disease (RIHD) is a potential late side-effect of thoracic radiotherapy resulting in left ventricular hypertrophy (LVH) and fibrosis due to a complex pathomechanism leading to heart failure. Angiotensin-II receptor blockers (ARBs), including losartan, are frequently used to control heart failure of various etiologies. Preclinical evidence is lacking on the anti-remodeling effects of ARBs in RIHD, while the results of clinical studies are controversial. We aimed at investigating the effects of losartan in a rat model of RIHD. Male Sprague-Dawley rats were studied in three groups: (1) control, (2) radiotherapy (RT) only, (3) RT treated with losartan (per os 10 mg/kg/day), and were followed for 1, 3, or 15 weeks. At 15 weeks post-irradiation, losartan alleviated the echocardiographic and histological signs of LVH and fibrosis and reduced the overexpression of chymase, connective tissue growth factor, and transforming growth factor-beta in the myocardium measured by qPCR; likewise, the level of the SMAD2/3 protein determined by Western blot decreased. In both RT groups, the pro-survival phospho-AKT/AKT and the phospho-ERK1,2/ERK1,2 ratios were increased at week 15. The antiremodeling effects of losartan seem to be associated with the repression of chymase and several elements of the TGF-ß/SMAD signaling pathway in our RIHD model.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Insuficiência Cardíaca/prevenção & controle , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Losartan/uso terapêutico , Síndrome da Fibrose por Radiação/tratamento farmacológico , Animais , Quimases/metabolismo , Modelos Animais de Doenças , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Síndrome da Fibrose por Radiação/patologia , Síndrome da Fibrose por Radiação/prevenção & controle , Ratos , Ratos Sprague-Dawley , Proteína Smad2/análise , Proteína Smad3/análise , Fator de Crescimento Transformador beta1/análise
3.
Rep Pract Oncol Radiother ; 26(6): 990-1002, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34992873

RESUMO

BACKGROUND: The aim of the study was to individualize accelerated partial breast irradiation based on optimal dose distribution, protect risk organ and predict most advantageous technique. MATERIALS AND METHODS: 138 breast cancer patients receiving postoperative APBI were enrolled. APBI plans were generated using 3D-conformal (3D-CRT), sliding window intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT). In the case of superficial tumours, additional plans were developed by adding electron beam. To planning target volume (PTV) 37.5 Gy/10 fractions, 1 fraction/day was prescribed. A novel plan quality index (PQI) served as the basis for comparisons. RESULTS: IMRT was the most advantageous technique regarding homogeneity. VMAT provided best conformity, 3D-CR T - the lowest lung and heart exposure. PQI was the best in 45 (32.61%) VMAT, 13 (9.42%) IMRT, 9 (6.52%) 3D-CRT plans. In 71 cases (51.45%) no difference was detected. In patients with large PTV, 3D-CRT was the most favourable. Additional electron beam improved PQI of 3D-CRT plans but had no meaningful effect on IMRT or VMAT. IMRT was superior to VMAT if the tumour was superficial (p < 0.001), situated in the medial (p = 0.032) or upper quadrant (p = 0.046). CONCLUSIONS: In half of all cases, individually selected teletherapy techniques provide superior results over others; relevance of a certain technique may be predicted by volume and PTV localization.

4.
BMC Cancer ; 19(1): 122, 2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30727980

RESUMO

BACKGROUND: Treatment with recombinant human granulocyte-colony stimulating factor (G-CSF) is accepted standard for prevention of chemotherapy-induced neutropenia. RGB-02 (Gedeon Richter) is a proposed biosimilar to pegylated G-CSF (Neulasta®, Amgen) with sustained release properties. This is a randomized, comparative, double-blind, multicenter study to evaluate efficacy and safety of RGB-02 in breast cancer patients receiving cytotoxic regimen. METHODS: Two hundred thirty-nine women presenting with breast cancer were randomized to RGB-02 (n = 121) and the reference product (n = 118). All patients received up to 6 cycles of docetaxel/doxorubicin chemotherapy combination and a once-per-cycle injection of a fixed 6 mg dose of pegfilgrastim. Primary endpoint was the duration of severe neutropenia (ANC < 0.5 × 109/L) in Cycle 1 (2-sided CI 95%). Secondary endpoints included incidence and duration of severe neutropenia (in cycles 2-4), incidence of febrile neutropenia, time to ANC recovery, depth of ANC nadir, and safety outcomes. RESULTS: The mean duration of severe neutropenia in Cycle 1 was 1.7 (RGB-02) and 1.6 days (reference), with a difference (LS Mean) of 0.1 days (95% CI -0.2, 0.4). Equivalence could be established as the CI for the difference in LS Mean lay entirely within the pre-defined range of ±1 day. This positive result was supported by the analysis of secondary endpoints, which also revealed no clinical meaningful differences. Safety profiles were comparable between groups. No neutralizing antibodies against pegfilgrastim were identified. CONCLUSIONS: Treatment equivalence in reducing the duration of chemotherapy induced neutropenia between RGB-02 and Neulasta® could be demonstrated. Similar efficacy and safety profiles of the once-per-cycle administration of RGB-02 and the pegfilgrastim reference were demonstrated. TRIAL REGISTRATION: The trial was registered prospectively, prior to study initiation. EudraCT number ( 2013-003166-14 ). The date of registration was 12 July, 2013.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Medicamentos Biossimilares/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Filgrastim/administração & dosagem , Fármacos Hematológicos/administração & dosagem , Neutropenia/prevenção & controle , Polietilenoglicóis/administração & dosagem , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Medicamentos Biossimilares/efeitos adversos , Medicamentos Biossimilares/normas , Neoplasias da Mama/patologia , Docetaxel/administração & dosagem , Docetaxel/efeitos adversos , Método Duplo-Cego , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Filgrastim/efeitos adversos , Fármacos Hematológicos/efeitos adversos , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neutropenia/induzido quimicamente , Polietilenoglicóis/efeitos adversos , Equivalência Terapêutica
5.
Acta Oncol ; 58(11): 1603-1611, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31271119

RESUMO

Background: Chemotherapeutic agents are often mutagenic. Induction of mutation associated neo-epitopes is one of the mechanisms by which chemotherapy is thought to increase the number of tumor-infiltrating lymphocytes. It is not known, however, whether treatment with various chemotherapeutic agents with different mutagenic capacity induce a significantly different number of stromal tumor-infiltrating lymphocytes (StrTIL) in residual cancer.Methods: One hundred and twenty breast carcinoma cases with residual disease that were treated with one of three types of pre-operative chemotherapy regimens were selected for the study. The percentage of StrTIL was evaluated in pretreatment core biopsies (pre-StrTIL) and post-treatment surgical tumor samples (post-StrTIL). TIL changes (ΔStrTIL) were calculated from the difference between post-StrTIL and pre-StrTIL.Results: When analyzing the pre-StrTIL and post-StrTIL among the three treatment groups, we detected significant StrTIL increase independently of the treatment applied. Based on distant metastases-free survival analysis, both post-StrTIL and ΔStrTIL was found to be independent prognostic factor in HR negative cases. Conclusions: Significant increase of StrTIL in the residual disease was observed in patients treated with the highly (platinum), moderately (cyclophosphamide) and marginally mutagenic chemotherapeutic agents (taxane, anthracycline). Increase in StrTIL in residual cancer compared to pretreatment tumor tissue is associated with improved distant metastasis-free survival in cases with HR negative breast carcinoma.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Neoplasia Residual/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/imunologia , Feminino , Humanos , Pessoa de Meia-Idade , Mutagênicos , Neoplasia Residual/imunologia , Cuidados Pré-Operatórios
6.
Future Oncol ; 15(18): 2083-2092, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31210542

RESUMO

Pegfilgrastim is widely used for the prevention of chemotherapy-induced neutropenia. The development and use of biosimilar agents help to rationalize healthcare expenditure and improve access to modern therapies to all who need them. This review focuses on pegfilgrastims with important role in oncology supportive care. RGB-02 (Gedeon Richter) is a proposed biosimilar to pegylated granulocyte-colony stimulating factor (Neulasta®, Amgen) with sustained release properties. The clinical analyses in three randomized clinical studies provided comparative data between RGB-02 and Neulasta, in a Phase III study patients receiving docetaxel-doxorubicin chemotherapy treatment equivalence was found. No difference was detected in any safety measure including immunogenicity; treatment switch, from the reference product to RGB-02 proved safe. Long-acting pegylated filgrastim RGB-02 has successfully accomplished various steps of biosimilar development.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Medicamentos Biossimilares/uso terapêutico , Neutropenia Febril Induzida por Quimioterapia/tratamento farmacológico , Filgrastim/uso terapêutico , Neoplasias/complicações , Polietilenoglicóis/uso terapêutico , Medicamentos Biossimilares/farmacologia , Aprovação de Drogas , Farmacoeconomia , Europa (Continente) , Filgrastim/farmacologia , Humanos , Contagem de Leucócitos , Neoplasias/tratamento farmacológico , Neutrófilos , Polietilenoglicóis/farmacologia , Resultado do Tratamento , Estados Unidos
7.
BMC Med Inform Decis Mak ; 19(1): 204, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31664991

RESUMO

BACKGROUND: Radiotherapy is a standard treatment option for breast cancer, but it may lead to significant late morbidity, including radiation heart damage. Breast irradiation performed individually in the supine or prone position may aid in minimizing the irradiation dose to the heart and LAD coronary artery. A series of CT scans and therapy plans are needed in both positions for the 'gold standard' decision on the preferable treatment position. This method is expensive with respect to technology and physician workload. Our ultimate goal is to develop a predictive tool to identify the preferable treatment position using easily measurable patient characteristics. In this article, we describe the details of how model building and consequently validation of the best model are done. METHODS: Different models were used: both logistic regression and multiple linear regressions were used to estimate the LAD mean dose difference (the difference between the mean dose to the LAD in the supine position versus prone position); predicted dose differences were analysed compared to the 'gold standard' values, and the best model was selected accordingly. The final model was checked by random cross-validation. In addition to generally used measures (ROC and Brier score), decision curves were employed to evaluate the performance of the models. RESULTS: ROC analysis demonstrated that none of the predictors alone was satisfactory. Multiple logistic regression models and the linear regression model lead to high values of net benefit for a wide range of threshold probabilities. Multiple linear regression seemed to be the most useful model. We also present the results of the random cross-validation for this model (i.e. sensitivity of 80.7% and specificity of 87.5%). CONCLUSIONS: Decision curves proved to be useful to evaluate our models. Our results indicate that any of the models could be implemented in clinical practice, but the linear regression model is the most useful model to facilitate the radiation treatment decision. In addition, it is in use in everyday practice in the Department of Oncotherapy, University of Szeged, Hungary.


Assuntos
Neoplasias da Mama/radioterapia , Tomada de Decisões Assistida por Computador , Posicionamento do Paciente , Planejamento da Radioterapia Assistida por Computador/métodos , Simulação por Computador , Feminino , Humanos , Dosagem Radioterapêutica , Tomografia Computadorizada por Raios X , Carga de Trabalho
8.
BMC Cancer ; 18(1): 296, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29544452

RESUMO

BACKGROUND: In patients with metastatic renal cell cancer, based on limited evidence, increased sunitinib exposure is associated with better outcome. The survival and toxicity data of patients receiving individualized dose escalated sunitinib therapy as compared to standard management were analyzed in this study. METHODS: From July 2013, the data of metastatic renal cell cancer patients with slight progression but still a stable disease according to RECIST 1.1 criteria treated with an escalated dose of sunitinib (first level: 62.5 mg/day in 4/2 or 2 × 2/1 scheme, second level: 75 mg/day in 4/2 or 2 × 2/1 scheme) were collected prospectively. Regarding characteristics, outcome, and toxicity data, an explorative retrospective analysis of the register was carried out, comparing treatments after and before July 1, 2013 in the study (selected patients for escalated dose) and control (standard dose) groups, respectively. RESULTS: The study involved 103 patients receiving sunitinib therapy with a median overall and progression free survival of 25.36 ± 2.62 and 14.2 ± 3.22 months, respectively. Slight progression was detected in 48.5% of them. First and second-level dose escalation were indicated in 18.2% and 4.1% of patients, respectively. The dosing scheme was modified in 22.2%. The median progression free survival (39.7 ± 5.1 vs 14.2 ± 1.3 months (p = 0.037)) and the overall survival (57.5 ± 10.7 vs 27.9 ± 2.5 months (p = 0.044)) were significantly better in the study group (with dose escalation) than in the control group. Patients with nephrectomy and lower Memorial Sloan Kettering Cancer Center (MSKCC) scores showed more favorable outcomes. After dose escalation, the most common adverse events were worsening or development of fatigue, hypertension, stomatitis, and weight loss of over 10%. CONCLUSIONS: Escalation of sunitinib dosing in selected patients with metastatic renal cell cancer, especially in case of slight progression, based on tolerable toxicity is safe and improves outcome. Dose escalation in 12.5 mg steps may be recommended for properly educated patients.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Relação Dose-Resposta a Droga , Indóis/administração & dosagem , Pirróis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Intervalo Livre de Doença , Feminino , Humanos , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Nefrectomia , Pirróis/efeitos adversos , Sunitinibe , Resultado do Tratamento
9.
Breast Cancer Res ; 19(1): 18, 2017 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-28183331

RESUMO

BACKGROUND: Overexpression of fibroblast growth factor receptor 1 (FGFR1), found in ≤8% of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer cases, is correlated with decreased overall survival and resistance to endocrine therapy (ET). Dovitinib, a potent FGFR inhibitor, has demonstrated antitumor activity in heavily pretreated patients with FGFR pathway-amplified breast cancer. METHODS: In this randomized, placebo-controlled phase II trial, we evaluated whether the addition of dovitinib to fulvestrant would improve outcomes in postmenopausal patients with HR+, HER2- advanced breast cancer that had progressed during or after prior ET. Patients were stratified by FGF pathway amplification and presence of visceral disease, and they were randomized 1:1 to receive fulvestrant plus dovitinib or placebo. The primary endpoint was progression-free survival (PFS). RESULTS: From 15 May 2012 to 26 November 2014, 97 patients from 36 centers were enrolled. The frequency of FGF pathway amplification was lower than anticipated, and the study was terminated early owing to slow accrual of patients with FGF pathway amplification. The median PFS (95% CI) was 5.5 (3.8-14.0) months vs 5.5 (3.5-10.7) months in the dovitinib vs placebo arms, respectively (HR, 0.68; did not meet predefined efficacy criteria). For the FGF pathway-amplified subgroup (n = 31), the median PFS (95% CI) was 10.9 (3.5-16.5) months vs 5.5 (3.5-16.4) months in the dovitinib vs placebo arms, respectively (HR, 0.64; met the predefined superiority criteria). Frequently reported adverse events in the dovitinib (diarrhea, nausea, vomiting, asthenia, and headache) and placebo (diarrhea, fatigue, nausea, and asthenia) arms were mostly low grade. CONCLUSIONS: The safety profile of dovitinib plus fulvestrant was consistent with the known safety profile of single-agent dovitinib. Dovitinib in combination with fulvestrant showed promising clinical activity in the FGF pathway-amplified subgroup. However, the data reported herein should be interpreted with caution, given that fewer PFS events occurred in the FGF pathway-amplified patients than was expected and that an effect of dovitinib regardless of FGR pathway amplification status cannot be excluded, because the population was smaller than expected. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01528345 . Registered 31 January 2012.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/administração & dosagem , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Progressão da Doença , Estradiol/administração & dosagem , Estradiol/análogos & derivados , Feminino , Fulvestranto , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Pós-Menopausa , Quinolonas/administração & dosagem , Retratamento , Análise de Sobrevida , Resultado do Tratamento
10.
Lancet Oncol ; 17(9): 1230-9, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27501767

RESUMO

BACKGROUND: The randomised phase 3 TURANDOT trial compared two approved bevacizumab-containing regimens for HER2-negative metastatic breast cancer in terms of efficacy, safety, and quality of life. The interim analysis did not confirm non-inferior overall survival (stratified hazard ratio [HR] 1·04; 97·5% repeated CI [RCI] -∞ to 1·69). Here we report final results of our study aiming to show non-inferior overall survival with first-line bevacizumab plus capecitabine versus bevacizumab plus paclitaxel for locally recurrent or metastatic breast cancer. METHODS: In this multinational, open-label, randomised phase 3 TURANDOT trial, patients aged 18 years or older who had an Eastern Cooperative Oncology Group performance status 0-2 and measurable or non-measurable HER2-negative locally recurrent or metastatic breast cancer who had received no previous chemotherapy for locally recurrent or metastatic breast cancer were stratified and randomly assigned (1:1) using permuted blocks of size six to either bevacizumab plus paclitaxel (bevacizumab 10 mg/kg on days 1 and 15 plus paclitaxel 90 mg/m(2) on days 1, 8, and 15 every 4 weeks) or bevacizumab plus capecitabine (bevacizumab 15 mg/kg on day 1 plus capecitabine 1000 mg/m(2) twice daily on days 1-14 every 3 weeks) until disease progression, unacceptable toxicity, or withdrawal of consent. Stratification factors were oestrogen or progesterone receptor status, country, and menopausal status. The primary objective was to show non-inferior overall survival with bevacizumab plus capecitabine versus bevacizumab plus paclitaxel in the per-protocol population by rejecting the null hypothesis of inferiority (HR ≥1·33) using a stratified Cox proportional hazard model. This trial is registered with ClinicalTrials.gov, number NCT00600340. FINDINGS: Between Sept 10, 2008, and Aug 30, 2010, 564 patients were randomised, representing the intent-to-treat population. The per-protocol population comprised 531 patients (266 in the bevacizumab plus paclitaxel group and 265 in the bevacizumab plus capecitabine group). At the final overall survival analysis after 183 deaths (69%) in 266 patients receiving bevacizumab plus paclitaxel and 201 (76%) in 265 receiving bevacizumab plus capecitabine in the per-protocol population, median overall survival was 30·2 months (95% CI 25·6-32·6 months) versus 26·1 months (22·3-29·0), respectively. The stratified HR was 1·02 (97·5% RCI -∞ to 1·26; repeated p=0·0070), indicating non-inferiority. The unstratified Cox model (HR 1·13 [97·5% RCI -∞ to 1·39]; repeated p=0·061) did not support the primary analysis. Intent-to-treat analyses were consistent with the per-protocol results. The most common grade 3 or worse adverse events were neutropenia (54 [19%] of 284 patients in the bevacizumab plus paclitaxel group vs 5 [2%] of 277 patients in the bevacizumab plus capecitabine group), hand-foot syndrome (1 [<1%] vs 43 [16%]), peripheral neuropathy (39 [14%] vs 1 [<1%]), leucopenia (20 [7%] vs 1 [<1%]), and hypertension (12 [4%] vs 16 [6%]). Serious adverse events were reported in 65 (23%) of 284 patients receiving bevacizumab plus paclitaxel and 68 (25%) of 277 receiving bevacizumab plus capecitabine. Deaths in two (1%) of 284 patients in the bevacizumab plus paclitaxel group were deemed by the investigator to be treatment-related. No treatment-related deaths occurred in the bevacizumab plus capecitabine group. INTERPRETATION: Bevacizumab plus capecitabine represents a valid first-line treatment option for HER2-negative locally recurrent or metastatic breast cancer, offering good tolerability without compromising overall survival compared with bevacizumab plus paclitaxel. Although progression-free survival with the bevacizumab plus capecitabine combination is inferior to that noted with bevacizumab plus paclitaxel, we suggest that physicians should consider possible predictive risk factors for overall survival, individual's treatment priorities, and the differing safety profiles. FUNDING: Roche.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Qualidade de Vida , Receptor ErbB-2/metabolismo , Idoso , Bevacizumab/administração & dosagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Capecitabina/administração & dosagem , Feminino , Seguimentos , Humanos , Metástase Neoplásica , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Prognóstico , Taxa de Sobrevida
11.
Br J Cancer ; 114(2): 163-70, 2016 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-26657657

RESUMO

BACKGROUND: Correlations between development of hand-foot syndrome (HFS) and efficacy in patients receiving capecitabine (CAP)-containing therapy are reported in the literature. We explored the relationship between HFS and efficacy in patients receiving CAP plus bevacizumab (BEV) in the TURANDOT randomised phase III trial. METHODS: Patients with HER2-negative locally recurrent/metastatic breast cancer (LR/mBC) who had received no prior chemotherapy for LR/mBC were randomised to BEV plus paclitaxel or BEV-CAP until disease progression or unacceptable toxicity. This analysis included patients randomised to BEV-CAP who received ⩾1 CAP dose. Potential associations between HFS and both overall survival (OS; primary end point) and progression-free survival (PFS; secondary end point) were explored using Cox proportional hazards analyses with HFS as a time-dependent covariate (to avoid overestimating the effect of HFS on efficacy). Landmark analyses were also performed. RESULTS: Among 277 patients treated with BEV-CAP, 154 (56%) developed HFS. In multivariate analyses, risk of progression or death was reduced by 44% after the occurrence of HFS; risk of death was reduced by 56%. The magnitude of effect on OS increased with increasing HFS grade. In patients developing HFS within the first 3 months, median PFS from the 3-month landmark was 10.0 months vs 6.2 months in patients without HFS. Two-year OS rates were 63% and 44%, respectively. CONCLUSIONS: This exploratory analysis indicates that HFS occurrence is a strong predictor of prolonged PFS and OS in patients receiving BEV-CAP for LR/mBC. Early appearance of HFS may help motivate patients to continue therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Síndrome Mão-Pé/etiologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/administração & dosagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Capecitabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais , Receptor ErbB-2/metabolismo , Resultado do Tratamento
12.
Pharmacol Res ; 111: 859-866, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27480202

RESUMO

Despite the great clinical significance of radiation-induced cardiac damage, experimental investigation of its mechanisms is an unmet need in medicine. Beneficial effects of growth hormone-releasing hormone (GHRH) agonists in regeneration of the heart have been demonstrated. The aim of this study was the evaluation of the potential of modern GHRH agonistic analogs in prevention of radiation damage in an in vitro cardiac myocyte-based model. Cultures of cardiac myocytes isolated from newborn rats (NRVM) were exposed to a radiation dose of 10Gy. The effects of the agonistic analogs, JI-34 and MR-356, of human GHRH on cell viability, proliferation, their mechanism of action and the protein expression of the GHRH/SV1 receptors were studied. JI-34 and MR-356, had no effect on cell viability or proliferation in unirradiated cultures. However, in irradiated cells JI-34 showed protective effects on cell viability at concentrations of 10 and 100nM, and MR-356 at 500nM; but no such protective effect was detected on cell proliferation. Both agonistic analogs decreased radiation-induced ROS level and JI-34 interfered with the activation of SAFE/RISK pathways. Using Western blot analysis, a 52kDa protein isoform of GHRHR was detected in the samples in both irradiated and unirradiated cells. Since GHRH agonistic analogs, JI-34 and MR-356 alleviated radiation-induced damage of cardiac myocytes, they should be tested in vivo as potential protective agents against radiogenic heart damage.


Assuntos
Alprostadil/análogos & derivados , Hormônio Liberador de Hormônio do Crescimento/análogos & derivados , Hormônio Liberador de Hormônio do Crescimento/agonistas , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/efeitos da radiação , Fragmentos de Peptídeos/farmacologia , Protetores contra Radiação/farmacologia , Alprostadil/farmacologia , Animais , Animais Recém-Nascidos , Cardiotoxicidade , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Células Cultivadas , Citoproteção , Relação Dose-Resposta a Droga , Hormônio Liberador de Hormônio do Crescimento/metabolismo , Hormônio Liberador de Hormônio do Crescimento/farmacologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Receptores de Neuropeptídeos/agonistas , Receptores de Neuropeptídeos/metabolismo , Receptores de Hormônios Reguladores de Hormônio Hipofisário/agonistas , Receptores de Hormônios Reguladores de Hormônio Hipofisário/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação
13.
Magy Onkol ; 60(3): 229-39, 2016 09.
Artigo em Húngaro | MEDLINE | ID: mdl-27579722

RESUMO

The radiotherapy expert panel revised and updated the radiotherapy (RT) guidelines accepted in 2009 at the 2nd Hungarian Breast Cancer Consensus Conference based on new scientific evidence. Radiotherapy of the conserved breast is indicated in ductal carcinoma in situ (St. 0), as RT decreases the risk of local recurrence by 60%. In early stage (St. I-II) invasive breast cancer RT remains a standard treatment following breast conserving surgery. However, in elderly (≥70 years) patients with stage I, hormone receptor positive tumour hormonal therapy without RT can be considered. Hypofractionated (15×2.67 Gy) whole breast irradiation and for selected cases accelerated partial breast irradiation are validated treatment alternatives of conventional (25×2 Gy) whole breast irradiation. Following mastectomy RT significantly decreases the risk of locoregional recurrence and improves overall survival of patients having 1 to 3 (pN1a) or ≥4 (pN2a, pN3a) positive axillary lymph nodes. In selected cases of patients with 1 to 2 positive sentinel lymph nodes axillary dissection can be omitted and substituted with axillary RT. After neoadjuvant chemotherapy (NAC) followed by breast conserving surgery whole breast irradiation is mandatory, while after NAC followed by mastectomy locoregional RT should be given in cases of initial stage III-IV and ypN1 axillary status.


Assuntos
Neoplasias da Mama/terapia , Mastectomia Segmentar , Terapia Neoadjuvante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , Feminino , Humanos , Mastectomia , Estadiamento de Neoplasias , Radioterapia Adjuvante
14.
Magy Onkol ; 60(3): 258-68, 2016 09.
Artigo em Húngaro | MEDLINE | ID: mdl-27579724

RESUMO

The development of a recommendation was intended for the follow-up of breast cancer patients treated with curative intent in Hungary. Follow-up includes the permanent contact with and health education of the patient, the surveillance and control of the adverse effects of oncological therapies or radiotherapy, the screening of metachron cancers, and the comprehensive (physical, psychological and social) rehabilitation of the patient. The early detection of local/regional tumor relapse is essential with careful follow-up, but there is no need for screening of distant metastases by means of imaging studies or tumor marker tests. If adjuvant endocrine therapy is needed, optimal adherence should be ensured with supportive therapy. In rare cases, special issues such as breast cancer risk/genetic mutation, pregnancy are raised, which should be thoughtfully discussed in view of recent advances in oncology. Follow-up is generally practised by the oncologist, however, in some cases the social worker, the physiotherapist, the psychooncologist, or in special cases, the lymphoedema expert is to be involved. The follow-up approach should be comprehensive and holistic.


Assuntos
Neoplasias da Mama/terapia , Assistência ao Paciente , Psico-Oncologia , Neoplasias da Mama/psicologia , Humanos , Hungria , Recidiva Local de Neoplasia/prevenção & controle
15.
Magy Onkol ; 60(3): 241-57, 2016 09.
Artigo em Húngaro | MEDLINE | ID: mdl-27579723

RESUMO

The article presents the practice guideline of systemic treatment of breast cancer and recommendations of the 3rd Hungarian Breast Cancer Consensus Conference. It reflects the recent international guidelines (ESMO, NCCN, ABC2, St Gallen's) irrespectively of the current financial opportunities. Here we follow the early - locally advanced - locally relapsed - metastatic breast cancer line for didactic considerations and we discuss the different subgroups of breast cancer based on hormone receptor and HER2 receptor status. Diagnosis and treatment options of rare clinical entities are summarised at the end of the paper.


Assuntos
Neoplasias da Mama/terapia , Guias de Prática Clínica como Assunto , Antineoplásicos/uso terapêutico , Quimioterapia Adjuvante , Consenso , Feminino , Humanos
16.
Acta Oncol ; 53(1): 58-64, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23544358

RESUMO

BACKGROUND: Prone positioning has been found feasible and appropriate for the reduction of radiation exposure of the lungs, but its effects on the heart dose remain controversial. Individual anatomical features were sought for the selection of optimal treatment positioning. MATERIAL AND METHODS: In 138 left-sided breast cancer cases awaiting postoperative whole-breast radiotherapy, conformal radiotherapy plans were generated in both prone and supine positions. RESULTS: The radiation doses to the left anterior descending coronary artery (LAD) and heart in the two positions differed individually, and were strongly related to the body mass index (BMI). Image fusion of the CT scans revealed that prone positioning was detrimental if the heart was situated distant from the chest wall in the supine position, but moved to the chest wall in the prone position. For characterization of the geography of the heart and the breast, the median distance between the LAD and the chest wall (dmedian), and the heart area included in the radiation field on a single CT scan at the middle of the heart in the supine position (Aheart) proved most appropriate. CONCLUSION: A validated statistical model, utilizing the BMI, dmedian and Aheart, permits individualized positioning for maximum heart protection.


Assuntos
Neoplasias da Mama/radioterapia , Coração/efeitos da radiação , Posicionamento do Paciente , Lesões por Radiação/prevenção & controle , Planejamento da Radioterapia Assistida por Computador , Radioterapia Conformacional , Adulto , Idoso , Algoritmos , Índice de Massa Corporal , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Decúbito Ventral , Estudos Prospectivos , Dosagem Radioterapêutica , Decúbito Dorsal , Tomografia Computadorizada por Raios X
17.
Eur J Public Health ; 24(5): 761-7, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24029456

RESUMO

BACKGROUND: Reducing treatment delay improves outcomes in breast cancer. The aim of this study was to determine factors influencing patient- and system-related delays in commencing breast cancer treatment in different countries. METHODS: A total of 6588 female breast cancer patients from 12 countries were surveyed. Total delay time was determined as the sum of the patient-related delay time (time between onset of the first symptoms and the first medical visit) and system-related delay time (time between the first medical visit and the start of therapy). RESULTS: The average patient-related delay time and total delay time were 4.7 (range: 3.4-6.2) weeks and 14.4 (range: 11.5-29.4) weeks, respectively. Longer patient-related delay times were associated with distrust and disregard, and shorter patient-related delay times were associated with fear of breast cancer, practicing self-examination, higher education level, being employed, having support from friends and family and living in big cities. The average system-related delay time was 11.1 (range: 8.3-24.7) weeks. Cancer diagnosis made by an oncologist versus another physician, higher education level, older age, family history of female cancers and having a breast lump as the first cancer sign were associated with shorter system-related delay times. Longer patient-related delay times and higher levels of distrust and disregard were predictors of longer system-related delay times. CONCLUSIONS: The delay in diagnosis and treatment of breast cancer remains a serious problem. Several psychological and behavioural patient attributes strongly determine both patient-related delay time and system-related delay time, but their strength is different in particular countries.


Assuntos
Atitude Frente a Saúde , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/psicologia , Comportamentos Relacionados com a Saúde , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Adulto , Fatores Etários , Idoso , Ásia , Europa (Continente) , Medo/psicologia , Feminino , Humanos , Pessoa de Meia-Idade , Autoexame/psicologia , Autoexame/estatística & dados numéricos , Fatores Socioeconômicos , Inquéritos e Questionários , Fatores de Tempo , Confiança/psicologia
18.
Magy Onkol ; 58(3): 167-72, 2014 Sep.
Artigo em Húngaro | MEDLINE | ID: mdl-25260080

RESUMO

Sunitinib is a basic medicine in the therapy of metastatic clear cell renal carcinoma. Our aim was to retrospectively evaluate the efficacy of sunitinib in the everyday clinical practice taking the most common side effects and clinical features into consideration. Data of ninety-four patients with metastatic, clear cell renal carcinoma, receiving sunitinib therapy were analyzed retrospectively, regarding efficacy and toxicity. Factors potentially influencing progression-free survival (PFS) and overall survival (OS) [age, nephrectomy, "off-target" side effects that are not connected to vascular endothelial growth factor receptor (VEGFR)] were studied. Complete remission, partial remission and stable disease occurred in 8 (8.5%), 30 (31.9%) and 50 (53.1%) patients, respectively. Objective tumor response developed in 38 (40.4%) cases. Median PFS and OS were 18.3 (95% CI 14.45-22.14) and 27.9 (95% CI 20.95-34.85) months, respectively. PFS and OS were more favorable in case of hypothyreosis (pPFS=0.005, pOS=0.043), hand-foot syndrome (pPFS=0.006, pOS=0.008), grade ≥2 neutropenia (pPFS=0.003, pOS=0.008) and thrombocytopenia (pPFS=0.01, pOS=0.011). Effective therapy of manageable side effects (most of which have potential predictive effect) is important for favorable survival results. Maintenance of dose intensity is also essential in order to compare the daily routine with the efficacy and safety results of clinical trials.


Assuntos
Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Síndrome Mão-Pé/etiologia , Hipertensão/induzido quimicamente , Hipotireoidismo/induzido quimicamente , Indóis/efeitos adversos , Neoplasias Renais/tratamento farmacológico , Pirróis/efeitos adversos , Adulto , Idoso , Inibidores da Angiogênese/efeitos adversos , Antineoplásicos/administração & dosagem , Carcinoma de Células Renais/secundário , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Indóis/administração & dosagem , Estimativa de Kaplan-Meier , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Pirróis/administração & dosagem , Estudos Retrospectivos , Estomatite/induzido quimicamente , Sunitinibe , Resultado do Tratamento
19.
Magy Onkol ; 58(1): 4-9, 2014 Mar.
Artigo em Húngaro | MEDLINE | ID: mdl-24712001

RESUMO

Everolimus is indicated for the therapy of adults with advanced renal cell carcinoma after failure of treatment with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI). The aim of the study was a multicenter evaluation of efficiency and toxicity of everolimus in patients with metastatic renal carcinoma who received one line of VEGFR-TKI therapy. Data of one hundred and one patients were analyzed retrospectively. Patients received everolimus therapy between January 2010 and July 2013. Data were collected in 7 different oncology institutes in Hungary. Starting daily dose of everolimus was 10 mg in 28-day cycles. Physical and laboratory examinations were done monthly. Imaging tests were performed every 3 months. Tumor response and toxicity were evaluated according to RECIST 1.0 and NCI CTCAE 3.0, respectively. Statistical analysis was performed with SPPS version 20.0 for Windows. Currently 26 (27%) patients are being treated, 52 (54.1%) patients are alive. Median progression-free survival (PFS) was 5.7 months (95% CI 4.07-7.33). Partial remission, stable disease and progression occurred in 6 (6%), 71 (74%) and 19 (20%) patients, respectively. Median overall survival (OS) was 14.3 months (95% CI 6.99-19.81). PFS and OS results were more favorable in patients with ECOG 0-1. Survival was poorer in case of anemia, while better if PFS was longer than 12 months. In anemic patients with ECOG 0-1 and ECOG 2-3 OS was 30.9 and 7.7 months, respectively (p=0.031). Dose reduction and treatment delay happened in 8 (7.9%) and 12 (11.9%) cases, respectively. The most common side effects were the following: exanthema, edema, stomatitis, pneumonitis, anemia and abnormal kidney-, liver functions, blood sugar and cholesterol levels. According to the Hungarian experience, everolimus can safely be administered. PFS and OS results representing the centers' everyday practice, are similar to the results of the respective subgroups in the registration study.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/secundário , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Sirolimo/análogos & derivados , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Toxidermias/etiologia , Edema/induzido quimicamente , Everolimo , Feminino , Humanos , Hungria , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Estudos Retrospectivos , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Sirolimo/uso terapêutico , Estomatite/induzido quimicamente , Falha de Tratamento , Resultado do Tratamento
20.
Lancet Oncol ; 14(2): 125-33, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23312888

RESUMO

BACKGROUND: Randomised phase 3 trials in metastatic breast cancer have shown that combining bevacizumab with either paclitaxel or capecitabine significantly improves progression-free survival and response rate compared with chemotherapy alone but the relative efficacy of bevacizumab plus paclitaxel versus bevacizumab plus capecitabine has not been investigated. We compared the efficacy of the two regimens. METHODS: In this open-label, non-inferiority, phase 3 trial, patients with HER2-negative metastatic breast cancer who had received no chemotherapy for advanced disease were randomised (by computer-generated sequence; 1:1 ratio; block size six; stratified by hormone receptor status, country, and menopausal status) to receive either intravenous bevacizumab (10 mg/kg on days 1 and 15) plus intravenous paclitaxel (90 mg/m(2) on days 1, 8, and 15) repeated every 4 weeks (paclitaxel group) or intravenous bevacizumab (15 mg/kg on day 1) plus oral capecitabine (1000 mg/m(2) twice daily on days 1-14) repeated every 3 weeks (capecitabine group) until disease progression or unacceptable toxic effects. Treatment allocation was not masked because of the differences in routes of administration and cycle lengths. The primary objective was to show non-inferior overall survival with bevacizumab plus capecitabine versus bevacizumab plus paclitaxel. We report results of an interim overall survival analysis, which was planned for after 175 deaths in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT00600340. FINDINGS: Between Sept 10, 2008, and Aug 30, 2010, we randomised 564 patients (paclitaxel group n=285; capecitabine group n=279) from 51 centres in 12 countries. The per-protocol population consisted of 533 patients (paclitaxel group n=268; capecitabine group n=265). After median follow-up of 18·6 months (IQR 14·9-24·7), 181 patients in the per-protocol population had died (89 [33%] in the paclitaxel group; 92 [35%] in the capecitabine group). The hazard ratio [HR] for overall survival was 1·04 (97·5% repeated CI -∞ to 1·69; p=0·059); the non-inferiority criterion of the interim analysis (interim α=0·00105) was not met. More patients who received bevacizumab plus paclitaxel had an objective response than did those who received bevacizumab plus capecitabine (125 [44%] of 285 patients vs 76 [27%] of 279; p<0·0001). Similarly, progression-free survival was significantly longer in the paclitaxel group than in the capecitabine group (median progression-free survival 11·0 months [95% CI 10·4-12·9] vs 8·1 months [7·1-9·2]; HR 1·36 [95% CI 1·09-1·68], p=0·0052). The most common adverse events of grade 3 or higher were neutropenia (51 [18%]), peripheral neuropathy (39 [14%]), and leucopenia (20 [7%]) in the paclitaxel group and hand-foot syndrome (44 [16%]), hypertension (16 [6%]), and diarrhoea (15 [5%]) in the capecitabine group. One treatment-related death occurred in the paclitaxel group; no deaths in the capecitabine group were deemed to be treatment-related. INTERPRETATION: In this planned interim analysis, the non-inferiority criterion was not met and overall survival results are inconclusive. Final results are expected in 2014. Progression-free survival was better, and more patients achieved an objective response, with bevacizumab plus paclitaxel than with bevacizumab plus capecitabine. Efficacy results in both groups were consistent with previous reports. FUNDING: Central European Cooperative Oncology Group; Roche.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Paclitaxel/uso terapêutico , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Neoplasias da Mama/mortalidade , Capecitabina , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Paclitaxel/administração & dosagem , Receptor ErbB-2
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