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1.
Clin Cancer Res ; 27(24): 6815-6823, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34583970

RESUMO

PURPOSE: We assessed the immunogenicity and safety of the BNT162b2 vaccine in a large cohort of patients with cancer (CP). EXPERIMENTAL DESIGN: From March 1, 2021 to March 20, 2021, this prospective cohort study included 816 CP afferent to our institution and eligible for the vaccination. A cohort of 274 health care workers (HCW) was used as age- and sex-matched control group. BNT162b2 was administered as a two-dose regimen given 21 days apart. Blood samples to analyze anti-Spike (S) IgG antibodies (Ab) were collected prevaccination [timepoint (TP) 0], and at 3 weeks (TP1) and 7 weeks (TP2) after the first dose. RESULTS: Patients characteristics: median age 62 (range, 21-97); breast/lung cancer/others (31/21/48%); active treatment/follow-up (90/10%). In the whole CP cohort, the serologic response rate (RR) and the titre of anti-S IgG significantly increased across the TPs; at TP2, the responders (IgG >15 AU/mL) were 94.2%. Active chemotherapy and chronic use of steroids were independent predictors of lower RR. Adverse events (AE) after the booster predicted higher likelihood of response (OR, 4.04; 95% confidence interval, 1.63-9.99; P = 0.003). Comparing the matched cohorts, the responders were significantly lower in CP than in HCW at TP1 (61.2% vs. 93.2%) and TP2 (93.3% vs. 100%), while the geometric mean concentration of IgG did not significantly differ at TP2 being significantly lower in CP (23.3) than in HCW (52.1) at TP1. BNT162b2 was well tolerated in CP; severe-grade AEs were 3.5% and 1.3% after the first and second doses, respectively. CONCLUSIONS: BNT162b2 assures serologic immunization without clinically significant toxicity in CP. The second dose is needed to reach a satisfactory humoral response.


Assuntos
Anticorpos Antivirais/sangue , Neoplasias da Mama/tratamento farmacológico , COVID-19/prevenção & controle , Neoplasias Pulmonares/tratamento farmacológico , SARS-CoV-2/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Comorbidade , Feminino , Humanos , Imunização , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Glicoproteína da Espícula de Coronavírus/imunologia , Adulto Jovem
2.
J Bone Oncol ; 26: 100341, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33425672

RESUMO

BACKGROUND: Bone remodeling is disrupted in metastatic disease, which affects > 70% of metastatic castration-resistant prostate cancer (mCRPC) patients. As a result, abnormal levels of specific bone turnover biomarkers (BTMs) are released. In this prospective ancillary analysis of the Italian real-world study ABITUDE, four markers were measured during abiraterone acetate plus prednisone (AAP) treatment in chemotherapy-naïve mCRPC men failing androgen-deprivation therapy. METHODS: Patients were enrolled if a blood sample was obtained before the first administration of abiraterone (baseline); ad-hoc blood samples were withdrawn during routine tests after 3, 6, and 12 months. A centralized lab measured bone alkaline phosphatase (BALP, osteoblast activity marker), type-I collagen-C-telopeptide (CTX-1, bone resorption marker), parathyroid hormone (PTH) and vitamin D (vitD). At each time point, intra-patient variations vs baseline were compared by the signed-rank test (statistical significance: P-value < 0.05). RESULTS: Of 481 patients enrolled in ABITUDE, 186 (median age: 76 [range: 53-93] years) met the substudy criteria: 74.7% had bone metastases, 11.8% were on bone-targeted therapies (BTT) and 14.0% on vitD supplementation. BALP decreased significantly at month 6 (P = 0.0010) and 12 (P < 0.0001) and CTX-1 at month 6 (P = 0.0028); PTH increased at month 3 (P < 0.0001); no significant difference in vitD levels was observed. Similar findings were observed in BTT-untreated patients. The reduction in BALP and CTX-1 levels was more pronounced in patients with than without bone metastases; in the latter group, no significant variation in BALP and CTX-1 levels was observed. CONCLUSIONS: AAP seems to exert an effect on the microenvironment of metastatic but not of normal bone, which likely contributes to its antitumoral activity.

3.
J Clin Med ; 9(9)2020 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-32847113

RESUMO

BACKGROUND: Response to neoadjuvant chemotherapy (NACT) has been proven to be an established prognostic factor after open radical cystectomy (ORC). We evaluated the impact of NACT on survival outcomes of a single-institution robotic radical cystectomy (RARC) series. METHODS: From January 2012 to June 2020, 79 patients were identified. Baseline, demographic, perioperative, and pathologic data were described. Kaplan-Meier with the log-rank test was used to compare overall survival (OS) differences between complete, partial, and no-NACT responders, respectively. Univariable and multivariable regression analyses were performed to identify predictors of OS. RESULTS: Complete, partial, and absent response to NACT were recorded in 43 (54.4%), 21 (19%), and 15 (26.6%) patients, respectively. A complete response to NACT displayed a trend toward significant higher OS (p = 0.03). In univariable analysis, significant predictors of lower OS were hypertension (HR 3.37; CI 95% 1.31-8.62; p = 0.01); advanced nodal involvement (HR 2.41; CI 95% 0.53-10.9; p < 0.001); and incomplete response to NACT (HR 0.41; CI 95% 0.18-0.95; p = 0.039). In multivariable analysis, the only independent predictor of worse OS was advanced pathologic N stages (HR 10.1; CI: 95% CI 2.3-44.3; p = 0.002). CONCLUSIONS: Complete response to NACT is associated with increased OS probability, but significant nodal residual disease remains the only independent predictor of OS after RARC.

4.
PLoS One ; 14(3): e0213934, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30893350

RESUMO

BACKGROUND: We conducted a multicenter retrospective analysis to describe the characteristics, frequency of skeletal-related events (SREs), and prognosis of head and neck cancer (HNC) in patients with bone metastases (BM). PATIENTS AND METHODS: The data of 192 HNC patients with BMs were collected. Analyses were conducted separately in 64 nasopharyngeal cancer (NPC) patients and in 128 non-NPC patients. RESULTS: SREs occurred in 34 (27%) non-NPC and in 6 (9%) NPC patients, respectively. Median overall survival (OS) was 25 and 6 months in NPC and non-NPC patients, respectively. Locoregional recurrence (hazard ratio [HR] 2.33, 95% confidence interval (CI) 1.1-4.93), synchronous BM (HR 0.25, 95% CI 0.59-0.71) and bone-directed therapies (BDT) (HR 0.26, 95% CI 0.10-0.68) were independent prognostic factors for OS in NPC patients. Combined bone radiotherapy (RT) and BDT in NPC patients obtained longer survival (38 months) than either therapy alone (25 months) or neither of these therapies (8 months). CONCLUSIONS: Patients with BMs from non-NPC have a poor prognosis and are at high risk of SREs. NPC patients with BMs are at relatively low risk of SREs. BDT may potentially improve survival, particularly when combined with bone RT. This last finding deserves prospective confirmation.


Assuntos
Neoplasias Ósseas/patologia , Osso e Ossos/patologia , Neoplasias Nasofaríngeas/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/secundário , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Adulto Jovem
5.
Eur J Oncol Nurs ; 38: 8-12, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30717941

RESUMO

PURPOSE: To explore adherence to oral hormone treatment in patients with metastatic prostate cancer (mCRPC) and to identify the factors that influence it. METHODS: A qualitative exploratory study was conducted at the National Cancer Institute of Rome. Patients aged >18 years with castration-resistant prostate cancer (mCRPC) and who were using oral hormone drugs were recruited. Semi-structured interviews were used for data collection, subsequently transcribed verbatim and analysed using Ritchie and Spencer's framework analysis. RESULTS: The sample included 13 patients with a median age of 72 who were treated, on average, for seven months with abiraterone acetate (AA) (76.9%) and enzalutamide (ENZ) (23.1%). Five themes were identified: expression of the concept of adherence, favouring factors, obstacle factors, functional strategies and levels of adherence. CONCLUSIONS: The patients express a good level of adherence, which they define in different ways-the helping relationship with the attending physician, the support of the family members and the few side effects of the drugs. For the future, it is recommended to perform a multicentre mixed method study to explain the levels of adherence and distress in women with breast cancer.


Assuntos
Acetato de Abiraterona/uso terapêutico , Antineoplásicos/uso terapêutico , Adesão à Medicação , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/psicologia , Idoso , Idoso de 80 Anos ou mais , Benzamidas , Humanos , Masculino , Nitrilas , Feniltioidantoína/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/patologia , Pesquisa Qualitativa , Resultado do Tratamento
6.
Lancet Oncol ; 19(4): 474-485, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29482983

RESUMO

BACKGROUND: Uncertainty exists about the optimal schedule of adjuvant treatment of breast cancer with aromatase inhibitors and, to our knowledge, no trial has directly compared the three aromatase inhibitors anastrozole, exemestane, and letrozole. We investigated the schedule and type of aromatase inhibitors to be used as adjuvant treatment for hormone receptor-positive early breast cancer. METHODS: FATA-GIM3 is a multicentre, open-label, randomised, phase 3 trial of six different treatments in postmenopausal women with hormone receptor-positive early breast cancer. Eligible patients had histologically confirmed invasive hormone receptor-positive breast cancer that had been completely removed by surgery, any pathological tumour size, and axillary nodal status. Key exclusion criteria were hormone replacement therapy, recurrent or metastatic disease, previous treatment with tamoxifen, and another malignancy in the previous 10 years. Patients were randomly assigned in an equal ratio to one of six treatment groups: oral anastrozole (1 mg per day), exemestane (25 mg per day), or letrozole (2·5 mg per day) tablets upfront for 5 years (upfront strategy) or oral tamoxifen (20 mg per day) for 2 years followed by oral administration of one of the three aromatase inhibitors for 3 years (switch strategy). Randomisation was done by a computerised minimisation procedure stratified for oestrogen receptor, progesterone receptor, and HER2 status; previous chemotherapy; and pathological nodal status. Neither the patients nor the physicians were masked to treatment allocation. The primary endpoint was disease-free survival. The minimum cutoff to declare superiority of the upfront strategy over the switch strategy was assumed to be a 2% difference in disease-free survival at 5 years. Primary efficacy analyses were done by intention to treat; safety analyses included all patients for whom at least one safety case report form had been completed. Follow-up is ongoing. This trial is registered with the European Clinical Trials Database, number 2006-004018-42, and ClinicalTrials.gov, number NCT00541086. FINDINGS: Between March 9, 2007, and July 31, 2012, 3697 patients were enrolled into the study. After a median follow-up of 60 months (IQR 46-72), 401 disease-free survival events were reported, including 211 (11%) of 1850 patients allocated to the switch strategy and 190 (10%) of 1847 patients allocated to upfront treatment. 5-year disease-free survival was 88·5% (95% CI 86·7-90·0) with the switch strategy and 89·8% (88·2-91·2) with upfront treatment (hazard ratio 0·89, 95% CI 0·73-1·08; p=0·23). 5-year disease-free survival was 90·0% (95% CI 87·9-91·7) with anastrozole (124 events), 88·0% (85·8-89·9) with exemestane (148 events), and 89·4% (87·3 to 91·1) with letrozole (129 events; p=0·24). No unexpected serious adverse reactions or treatment-related deaths occurred. Musculoskeletal side-effects were the most frequent grade 3-4 events, reported in 130 (7%) of 1761 patients who received the switch strategy and 128 (7%) of 1766 patients who received upfront treatment. Grade 1 musculoskeletal events were more frequent with the upfront schedule than with the switch schedule (924 [52%] of 1766 patients vs 745 [42%] of 1761 patients). All other grade 3-4 adverse events occurred in less than 2% of patients in either group. INTERPRETATION: 5 years of treatment with aromatase inhibitors was not superior to 2 years of tamoxifen followed by 3 years of aromatase inhibitors. None of the three aromatase inhibitors was superior to the others in terms of efficacy. Therefore, patient preference, tolerability, and financial constraints should be considered when deciding the optimal treatment approach in this setting. FUNDING: Italian Drug Agency.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Idoso , Anastrozol/administração & dosagem , Androstadienos/administração & dosagem , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Letrozol/administração & dosagem , Pessoa de Meia-Idade , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Tamoxifeno/administração & dosagem
7.
Anticancer Drugs ; 28(1): 110-115, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27763885

RESUMO

Abiraterone acetate (AA) demonstrated its efficacy in the treatment of patients with metastatic castration resistance prostate cancer (mCRPC) in predocetaxel and postdocetaxel setting. However, we learn from pivotal studies that forms of primary and acquired resistance to this drug exist. Patient selection becomes so crucial to optimize treatment results. Potential predictive biomarkers have been identified but are not yet validated. In this scenario, clinical features and disease characteristics may still be of value in selecting patients for different treatments. The objective of this retrospective study was to assess whether or not a correlation between duration of response to first androgen deprivation therapy (ADT), time to castration-resistant prostate cancer (TTCRPC), and outcome of AA therapy exists. A retrospective analysis of clinical data of mCRPC patients treated with AA at two Italian cancer centers was carried out. The Kaplan-Meier method and Cox proportional hazard model were used to analyze survival data. Correlation between median duration of response to first ADT or median TTCRPC and the outcome of patients treated with AA was analyzed. From January 2015 to November 2015, data of 59 patients with mCRPC were collected. We observed no differences in patient's median progression-free survival (PFS) and biochemical progression-free survival (bPFS), according to both median duration of response to first-line ADT (duration of first ADT<13 months: median PFS and bPFS were 11 and 5 months, respectively; duration of ADT≥13 months: median PFS and bPFS were 9 and 6 months, respectively) and median TTCRPC (TTCRPC<28 months: median PFS and bPFS were 8 and 5 months, respectively; TTCRPC≥28 months: median PFS and bPFS were 10 and 9 months, respectively). Overall survival, in the same group, did not differ between patients with a duration of response to first ADT over or under 13 months (P=0.90) but in patients with a TTCRPC of 28 months or more, there was a trend toward longer survival than patients with TTCRPC less than 28 months (5-year overall survival was 74 vs. 50%; P=0.14). The duration of response to first-line ADT and the TTCRPC showed no significant association with outcome of AA therapy in patients with mCRPC. However, large prospective trials are desirable to confirm these data.


Assuntos
Acetato de Abiraterona/uso terapêutico , Antagonistas de Androgênios/administração & dosagem , Antineoplásicos Hormonais/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Hormônio Liberador de Gonadotropina/análogos & derivados , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos , Resultado do Tratamento
8.
Crit Rev Oncol Hematol ; 102: 101-10, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27157527

RESUMO

BACKGROUND: In the last several decades, combined radiotherapy (RT) and chemotherapy (CT) have been recognized as feasible in locally-advanced-squamous-cell-carcinoma of the head-and-neck (LA-HNSCC). Several meta-analyses identified concurrent RT+CT (CRT) most likely effective approach respect to RT-alone. However, radiobiological models comparing different chemotherapeutic schedules against delivered RT fractionation schedule for overall survival and toxicity are still needed. METHODS AND MATERIALS: Based on 9 randomized trials (2785 patients), radiobiological models and multivariate logistic regression model were used to derive dose-response curves and estimate the 5-year-overall survival (OS) and ≥G3 acute mucositis rate of CRT or RT-alone. RESULTS: Equivalent dose at 2 Gy/fraction (EQD2) was calculated using the linear quadratic model. The effect of CRT schedules, considering the CT type and its administration schedule and the HPV status of tumors were estimated using the univariate/multivariate logistic regression. The multivariate logistic regression model for 5y-OS indicated EQD2 and the type of CT, the chemo-sensitization fraction and the HPV status significant prognostic factors, while for toxicity both EQD2 and the concomitant administration of 5-fluorouracil (5Fu) resulted as significant prognostic factors. Combined schedules cisplatin (DDP)+/-5Fu+RT produced the higher OS compared with combined carboplatin+/-5Fu+RT or RT-alone. The concomitant administration of Fu and schedule with high EQD2 increase the rate of observed ≥G3 acute mucositis. CONCLUSION: Multivariate logistic regression models can be used to predict CRT effect in terms of OS and ≥G3-mucositis, contributing to the identification of novel treatment schedules.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia , Neoplasias de Cabeça e Pescoço/terapia , Membrana Mucosa/efeitos dos fármacos , Lesões por Radiação , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimiorradioterapia/efeitos adversos , Humanos , Modelos Biológicos , Ensaios Clínicos Controlados Aleatórios como Assunto , Carcinoma de Células Escamosas de Cabeça e Pescoço
9.
Crit Rev Oncol Hematol ; 98: 254-63, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26638863

RESUMO

We performed a sensitivity analysis, cumulating all randomized clinical trials (RCTs) in which patients with metastatic castration-resistant prostate cancer (mCRPC) received systemic therapy, to evaluate if the comparison of RCTs may drive to biased survival estimations. An overall survival (OS) significant difference according to therapeutic strategy was more likely be determined in RCTs evaluating hormonal drugs versus those studies testing immunotherapy, chemotherapy or other strategies. With regard to control arm, an OS significant effect was found for placebo-controlled trials versus studies comparing experimental treatment with active therapies. Finally, regarding to docetaxel (DOC) timing, the OS benefit was more likely to be proved in Post-DOC setting in comparison with DOC and Pre-DOC. These data suggest that clinical trial design should take into account new benchmarks such as the type of treatment strategy, the choice of the comparator and the phase of the disease in relation to the administration of standard chemotherapy.


Assuntos
Ensaios Clínicos como Assunto , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Humanos , Masculino , Metástase Neoplásica , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia
10.
Future Oncol ; 11(22): 3083-90, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26437324

RESUMO

BACKGROUND: We evaluated the possible advantages of a docetaxel (DCT) rechallenge strategy in metastatic castration-resistant prostate cancer (mCRPC) patients, also given the possible earlier positioning of this treatment option in the modern scenario. PATIENTS & METHODS: All mCRPC patients planned for DCT chemotherapy rechallenge in our institutions were evaluated. RESULTS: Of 128 patients, 98 achieved disease control on the initial DCT round. After a treatment holiday of 8.3 months, the 98 responsive patients underwent a second DCT round, with 56 cases achieving again disease control. After a 5.7-month off-treatment period, 32 of these cases underwent a third DCT round, and 16 responded. Lastly, after a further 4.2-month treatment holiday, eight patients underwent a fourth DCT round and two responded. Median time to definitive disease progression for the whole population was 16.4 months. CONCLUSIONS: Rechallenge with DCT may be considered a suitable treatment option for mCRPC patients recurring after a successful DCT chemotherapy. The interest in this strategy may be increased because of the showed efficacy of early DCT chemotherapy in patients with bulky disease (CHAARTED study) and the potential lower efficacy of the new hormonal agents abiraterone acetate and enzalutamide when used in a immediate sequencing.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Taxoides/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Progressão da Doença , Docetaxel , Seguimentos , Humanos , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Neoplasias de Próstata Resistentes à Castração/mortalidade , Retratamento , Estudos Retrospectivos , Taxoides/administração & dosagem , Resultado do Tratamento
11.
Future Oncol ; 9(9): 1375-88, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23980684

RESUMO

AIM: The aim of our study was to investigate the association of docetaxel and metronomic cyclophosphamide (CYC) in castration-resistant prostate cancer (CRPC). MATERIALS & METHODS: CRPC xenografts were established with PC3 cells. Mice were treated with a combination of CYC (50 mg/kg/day) and docetaxel (10-30 mg/kg/week) or with docetaxel alone. Docetaxel plasma levels were analyzed in patients receiving the drug alone or combined with CYC. RESULTS: Metronomic CYC is an effective adjuvant in blocking tumor growth in vivo, with comparable efficacy and less toxic effects compared with docetaxel treatment. CYC acts by downregulating cell proliferation and inducing apoptosis thorough upregulation of p21 and inhibition of angiogenesis. Finally, CYC increases docetaxel plasma levels in patients. CONCLUSION: Metronomic CYC exerts anti-tumoral effects in an in vivo model of prostate cancer and in patients with CRPC, and also increases the bioavailability of docetaxel. These results explain the favorable toxicity and activity profiles observed in patients treated with this regimen.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/genética , Proliferação de Células/efeitos dos fármacos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Animais , Biomarcadores Tumorais/metabolismo , Western Blotting , Ciclofosfamida/administração & dosagem , Docetaxel , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Masculino , Camundongos , Camundongos Nus , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxoides/administração & dosagem , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Artigo em Inglês | MEDLINE | ID: mdl-22826702

RESUMO

Prostate cancer (PC) is the leading cause of cancer and the second leading cause of cancer-death among men in the Western world. About 10-20% of men with PC present with metastatic disease at diagnosis, while 20-30% of patients diagnosed with localized disease will eventually develop metastases. Although most respond to initial androgen-deprivation therapy (ADT), progression to castration-resistant PC (CRPC) is universal. In 2004 the docetaxel/prednisone regimen was approved for the management of patients with metastatic CRPC, becoming the standard first-line therapy. Recent advances have now led to an unprecedented number of new drug approvals within the past years, providing many new treatment options for patients with metastatic CRPC. Four new drugs have received U.S. Food and Drug Administration (FDA)-approval in 2010 and 2011: sipuleucel-T, an immunotherapeutic agent; cabazitaxel, a novel microtubule inhibitor; abiraterone acetate, a new androgen biosynthesis inhibitor; and denosumab, a bone-targeting agent. The data supporting the approval of each of these agents are described in this review, as are current approaches in the treatment of metastatic CRPC and ongoing clinical trials of novel treatments and strategies.

13.
J Exp Clin Cancer Res ; 30: 54, 2011 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-21569417

RESUMO

BACKGROUND: Although the addition of bevacizumab significantly improves the efficacy of chemotherapy for advanced breast cancer, regulatory concerns still exist with regard to the magnitude of the benefits and the overall safety profile. METHODS: A literature-based meta-analysis to quantify the magnitude of benefit and safety of adding bevacizumab to chemotherapy for advanced breast cancer patients was conducted. Meta-regression and sensitivity analyses were also performed to identify additional predictors of outcome and to assess the influence of trial design. RESULTS: Five trials (3,841 patients) were gathered. A significant interaction according to treatment line was found for progression-free survival (PFS, p = 0.027); PFS was significantly improved for 1(st) line (Hazard Ratio, HR 0.68, p < 0.0001), with a 1-yr absolute difference (AD) of 8.4% (number needed to treat, NNT 12). A non-significant trend was found in overall survival (OS), and in PFS for 2(nd) line. Responses were improved with the addition of bevacizumab, without interaction between 1(st) line (Relative Risk, RR 1.46, p < 0.0001) and 2(nd) line (RR 1.58, p = 0.05). The most important toxicity was hypertension, accounting for a significant AD of 4.5% against bevacizumab (number needed to harm, NNH 22). Other significant, although less clinically meaningful, adverse events were proteinuria, neurotoxicity, febrile neutropenia, and bleeding. At the meta-regression analysis for 1(st)-line, more than 3 metastatic sites (p = 0.032), no adjuvant chemotherapy (p = 0.00013), negative hormonal receptor status (p = 0.009), and prior anthracyclines-exposure (p = 0.019), did significantly affect PFS. CONCLUSIONS: Although with heterogeneity, the addition of bevacizumab to 1st-line chemotherapy significantly improves PFS, and overall activity. Hypertension should be weighted with the overall benefit on the individual basis.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antineoplásicos/efeitos adversos , Bevacizumab , Feminino , Humanos , Estadiamento de Neoplasias , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Resultado do Tratamento
14.
BMC Cancer ; 10: 675, 2010 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-21143897

RESUMO

BACKGROUND: Hormone therapy plus radiotherapy significantly decreases recurrences and mortality of patients affected by locally advanced prostate cancer. In order to determine if difference exists according to the hormonal treatment duration, a literature-based meta-analysis was performed. METHODS: Relative risks (RR) were derived through a random-effect model. Differences in primary (biochemical failure, BF; cancer-specific survival, CSS), and secondary outcomes (overall survival, OS; local or distant recurrence, LR/DM) were explored. Absolute differences (AD) and the number needed to treat (NNT) were calculated. Heterogeneity, a meta-regression for clinic-pathological predictors and a correlation test for surrogates were conducted. RESULTS: Five trials (3,424 patients) were included. Patient population ranged from 267 to 1,521 patients. The longer hormonal treatment significantly improves BF (with significant heterogeneity) with an absolute benefit of 10.1%, and a non significant trend in CSS. With regard to secondary end-points, the longer hormonal treatment significantly decrease both the LR and the DM with an absolute difference of 11.7% and 11.5%. Any significant difference in OS was observed. None of the three identified clinico-pathological predictors (median PSA, range 9.5-20.35, Gleason score 7-10, 27-55% patients/trial, and T3-4, 13-77% patients/trial), did significantly affect outcomes. At the meta-regression analysis a significant correlation between the overall treatment benefit in BF, CSS, OS, LR and DM, and the length of the treatment was found (p ≤ 0.03). CONCLUSIONS: Although with significant heterogeneity (reflecting different patient' risk stratifications), a longer hormonal treatment duration significantly decreases biochemical, local and distant recurrences, with a trend for longer cancer specific survival.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Esquema de Medicação , Medicina Baseada em Evidências , Humanos , Masculino , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Radioterapia Adjuvante , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento
15.
Expert Rev Anticancer Ther ; 10(8): 1239-53, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20735310

RESUMO

Aromatase inhibitors (AIs) are becoming the hormonal treatment of choice for postmenopausal women with early breast cancer. Large, well-controlled clinical studies have established the efficacy and safety of initial adjuvant therapy with letrozole or anastrozole versus the previous standard of 5 years of adjuvant tamoxifen and support using an AI (exemestane, anastrozole or letrozole) following tamoxifen for 2-3 years (early 'switch' treatment) or 5 years (extended adjuvant treatment). Reducing recurrence risk is a primary goal of adjuvant hormonal therapy. There is an early peak of recurrences 2 years after surgery; most are distant metastases rather than local or regional events. Therefore, treatment strategies such as initial therapy with AIs, which reduce early distant recurrence events, can be expected to improve long-term survival outcomes. Switching to an AI following 2-3 years of initial adjuvant tamoxifen is an effective option for patients unable to begin treatment with an AI.


Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/enzimologia , Tamoxifeno/uso terapêutico , Animais , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/diagnóstico , Feminino , Humanos , Recidiva Local de Neoplasia/diagnóstico , Fatores de Risco , Fatores de Tempo
16.
J Exp Clin Cancer Res ; 29: 58, 2010 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-20504361

RESUMO

BACKGROUND: Although the addition of bevacizumab to 1st line chemotherapy provides a significant survival benefit for advanced colorectal cancer, the magnitudes of both advantages and toxicities have not been extensively investigated. METHODS: A literature-based meta-analysis was conducted; Hazard Ratios were extracted from randomized trials for primary end-points (Progression Free Survival, PFS, Overall Survival OS). The log of event-based risk ratio were derived for secondary endpoints (objective/partial response rate, ORR/PR; severe hypertension, bleeding and proteinuria). Absolute differences and the number needed to treat/harm (NNT/NNH) were calculated. A meta-regression analysis with clinical predictors and a sensitivity analysis according to the trial phase-design were conducted as well. RESULTS: Five trials (2,728 pts) were selected. The addition of bevacizumab to 1st line chemotherapy significantly increased both PFS (although with significant heterogeneity) and OS over exclusive chemotherapy by 17.1% and 8.6% (NNT 6 and 12), regardless of the study setting (non significant interaction between phase II and III). The chance to improve PR was significantly increased by 6.5% (NNT 15), with a trend for ORR. The risk of hypertension was significantly increased by 6.2% (NNH 16). According to the meta-regression analysis, female gender and rectal primary site were significant predictors for PFS benefit. CONCLUSIONS: Notwithstanding all the concerns related to costs and the significant HTN risk, the significant outcome improvement provided by bevacizumab in first-line treatment for unselected advanced colorectal cancer patients, should be considered when choosing the appropriate up-front therapy.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Terapia de Salvação , Anticorpos Monoclonais Humanizados , Bevacizumab , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
17.
Cancer ; 115(15): 3446-56, 2009 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-19484790

RESUMO

BACKGROUND: To quantify the magnitude of benefit of the addition of hormone treatment (HT) to exclusive radiotherapy for locally advanced prostate cancer, a literature-based meta-analysis was conducted. METHODS: Event-based relative risks (RR) with 95% confidence intervals (CIs) were derived through a random-effect model. Differences in primary (biochemical failure and clinical progression-free survival) and secondary outcomes (cancer-specific survival, overall survival [OS], recurrence patterns, and toxicity) were explored. Absolute differences and numbers of patients needed to treat (NNT) were calculated. A heterogeneity test, a metaregression analysis with clinical predictors of outcome, and a correlation analysis for surrogate endpoints were also performed. RESULTS: Seven trials (4387 patients) were gathered. Hormone suppression significantly decreased both biochemical failure (RR, 0.76; 95% CI, 0.70-0.82; P<.0001) and clinical progression-free survival (RR, 0.81; 95% CI 0.71-0.93; P=.002), with absolute differences of 10% and 7.7%, respectively, which translates into 10 and 13 NNT. cancer-specific survival (RR, 0.76; 95% CI, 0.69-0.83; P<.0001) and OS (RR, 0.86; 95% CI, 0.80-0.93; P<.0001) were also significantly improved by the addition of HT, without significant heterogeneity, with absolute differences of 5.5% and 4.9%, respectively, which translates into 18 and 20 NNT. Local and distant relapse were significantly decreased by HT, by 36% and 28%, respectively, and no significant differences in toxicity were found. Primary and secondary efficacy outcomes were significantly correlated. CONCLUSIONS: Hormone suppression plus radiotherapy significantly decreases recurrence and mortality of patients with localized prostate cancer, without affecting toxicity.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Quimioterapia Adjuvante , Terapia Combinada , Intervalo Livre de Doença , Humanos , Masculino , Neoplasias da Próstata/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Taxa de Sobrevida , Resultado do Tratamento
18.
J Exp Clin Cancer Res ; 28: 66, 2009 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-19463172

RESUMO

Molecularly targeted agents for the treatment of solid tumors had entered the market in the last 5 years, with a great impact upon both the scientific community and the society. Many randomized phase III trials conducted in recent years with new targeted agents, despite previous data coming from preclinical research and from phase II trials were often promising, have produced disappointingly negative results. Some other trials have actually met their primary endpoint, demonstrating a statistically significant result favouring the experimental treatment. Unfortunately, with a few relevant exceptions, this advantage is often small, if not negligible, in absolute terms. The difference between statistical significance and clinical relevance should always be considered when translating clinical trials' results in the practice. The reason why this 'revolution' did not significantly impact on cancer treatment to displace chemotherapy from the patient' bedside is in part due to complicated, and in many cases, unknown, mechanisms of action of such drugs; indeed, the traditional way the clinical investigators were used to test the efficacy of 'older' chemotherapeutics, has become 'out of date' from the methodological perspective. As these drugs should be theoretically tailored upon featured bio-markers expressed by the patients, the clinical trial design should follow new rules based upon stronger hypotheses than those developed so far. Indeed, the early phases of basic and clinical drug development are crucial in the correct process which is able to correctly identify the target (when present). Targeted trial designs can result in easier studies, with less, better selected, and supported by stronger proofs of response evidences, patients, in order to not waste time and resources.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Ensaios Clínicos como Assunto , Desenho de Fármacos , Humanos
19.
J Clin Invest ; 119(5): 1093-108, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19363294

RESUMO

The identification of biomarkers that distinguish between aggressive and indolent forms of prostate cancer (PCa) is crucial for diagnosis and treatment. In this study, we used cultured cells derived from prostate tissue from patients with PCa to define a molecular mechanism underlying the most aggressive form of PCa that involves the functional activation of eNOS and HIFs in association with estrogen receptor beta (ERbeta). Cells from patients with poor prognosis exhibited a constitutively hypoxic phenotype and increased NO production. Upon estrogen treatment, formation of ERbeta/eNOS, ERbeta/HIF-1alpha, or ERbeta/HIF-2alpha combinatorial complexes led to chromatin remodeling and transcriptional induction of prognostic genes. Tissue microarray analysis, using an independent cohort of patients, established a hierarchical predictive power for these proteins, with expression of eNOS plus ERbeta and nuclear eNOS plus HIF-2alpha being the most relevant indicators of adverse clinical outcome. Genetic or pharmacologic modulation of eNOS expression and activity resulted in reciprocal conversion of the transcriptional signature in cells from patients with bad or good outcome, respectively, highlighting the relevance of eNOS in PCa progression. Our work has considerable clinical relevance, since it may enable the earlier diagnosis of aggressive PCa through routine biopsy assessment of eNOS, ERbeta, and HIF-2alpha expression. Furthermore, proposing eNOS as a therapeutic target fosters innovative therapies for PCa with NO inhibitors, which are employed in preclinical trials in non-oncological diseases.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Receptor beta de Estrogênio/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Neoplasias da Próstata/diagnóstico , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Biomarcadores , Hipóxia Celular/fisiologia , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Montagem e Desmontagem da Cromatina/fisiologia , Citoplasma/metabolismo , Inibidores Enzimáticos/farmacologia , Estradiol/farmacologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Transportador de Glucose Tipo 1/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/genética , Prognóstico , Regiões Promotoras Genéticas/genética , Neoplasias da Próstata/metabolismo , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Elementos de Resposta/genética , Telomerase/genética , Telomerase/metabolismo , Análise Serial de Tecidos , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
20.
Oncology ; 76(4): 254-61, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19246950

RESUMO

OBJECTIVE: An increasing number of patients with advanced pancreatic or biliary tract cancer who progress after a gemcitabine-containing regimen are candidates for further chemotherapy. We therefore evaluated a fully oral regimen of capecitabine and celecoxib (CapCel) as second-line treatment in these patients. METHODS: Thirty-five patients with documented progressive disease after first-line treatment were enrolled. Capecitabine was administered at a dose of 1,000 mg/m(2) b.i.d. for 2 consecutive weeks followed by 1 week of rest; celecoxib was given continuously at 200 mg b.i.d. Progression-free survival at 3 months was the primary study endpoint. RESULTS: The CapCel combination was associated with an overall response rate of 9% and median survival duration of 19 weeks. Sixty percent of patients were free from progression 3 months after the start of treatment. Multivariate analysis identified a positive clinical benefit response and a decline in CA 19.9 serum levels >25% compared with baseline levels as independent predictors of prolonged survival. The treatment protocol was well tolerated with negligible hematological toxicity. The most common grade 3 non-hematological toxicities were hypertransaminasemia, diarrhea and asthenia. CONCLUSIONS: The CapCel combination is a safe treatment option with moderate activity in patients with pancreatic/biliary tract cancer after failure of a previous gemcitabine-containing regimen.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Pirazóis/administração & dosagem , Sulfonamidas/administração & dosagem , Adenocarcinoma/mortalidade , Adulto , Idoso , Neoplasias do Sistema Biliar/mortalidade , Capecitabina , Carcinoma Ductal Pancreático/mortalidade , Celecoxib , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/mortalidade , Estudos Prospectivos , Pirazóis/efeitos adversos , Sulfonamidas/efeitos adversos
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