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1.
Clin Genitourin Cancer ; 17(3): e689-e703, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31072748

RESUMO

BACKGROUND: Axitinib resulted in significantly longer progression-free survival (PFS) versus sorafenib in patients with metastatic renal-cell carcinoma (mRCC) previously treated with sunitinib in the AXIS trial. We report post hoc analyses evaluating patient subgroups that may benefit more from axitinib in this setting. PATIENTS AND METHODS: AXIS was an open-label randomized phase 3 trial (NCT00678392) in mRCC patients with disease that failed to respond to one prior systemic therapy. Univariate and multivariate analyses evaluated potential prognostic factors for improved PFS and overall survival (OS) after sunitinib. PFS and OS of axitinib versus sorafenib were assessed within subgroups identified according to these factors. RESULTS: Of 723 patients, 389 received first-line sunitinib; 194 and 195 were randomized to second-line axitinib and sorafenib, respectively. Identified prognostic factors were: nonbulky disease (sum of the longest diameter < 98 mm), favorable/intermediate risk disease (Memorial Sloan Kettering Cancer Center or International Metastatic Renal Cell Carcinoma Database Consortium criteria), and no bone or liver metastases. In patients with all of these prognostic factors (n = 86), significantly longer PFS was observed for axitinib versus sorafenib (hazard ratio = 0.476; 95% confidence interval, 0.263-0.863; 2-sided P = .0126). OS (hazard ratio = 0.902; 95% confidence interval, 0.457-1.780; 2-sided P = .7661) was similar between treatments. Across subgroups, PFS was generally longer in patients treated with axitinib versus sorafenib, and OS was generally similar between the two treatments. CONCLUSION: In patients with mRCC, axitinib remains a suitable second-line treatment option across multiple subgroups. A relevant reduction in the risk of a PFS event was observed for axitinib compared to sorafenib in selected subgroups of patients.


Assuntos
Antineoplásicos/administração & dosagem , Axitinibe/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Sorafenibe/administração & dosagem , Antineoplásicos/efeitos adversos , Axitinibe/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Prognóstico , Sorafenibe/efeitos adversos , Resultado do Tratamento
2.
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
3.
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
4.
Can Urol Assoc J ; 9(7-8): 263-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26316911

RESUMO

INTRODUCTION: Treatment of metastatic renal cell carcinoma (mRCC) has improved with the use of targeted therapies, but bone metastases continue to be negative prognostic factor. METHODS: Patients with mRCC treated with everolimus (EV) or sorafenib (SO) after two previous lines of targeted therapies were included in the analysis. Overall survival (OS) and progression-free survival (PFS) were assessed based on the presence of bone metastases and type of therapy; they were also adjusted based on prognostic criteria. RESULTS: Of the 233 patients with mRCC, 76 had bone metastases. Of the 233 patients, EV and SO were administered in 143 and 90 patients, respectively. Median OS was 10.4 months in patients with BMs and 17.4 months in patients without bone metastases (p = 0.002). EV decreased the risk of death by 18% compared to SO (adjusted hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.74-0.91; p < 0.001), with comparable effects in patients with or without bone metastases. In the same manner, EV decreased the risk of progression by 12% compared to SO (adjusted HR 0.88, 95% CI 0.82-0.96; p = 0.002), but this difference was not significant in patients without bone metastases. The major limitations of the study are its retrospective nature, the heterogeneity of the methods to detect bone metastases, and the lack of data about patients treated with bisphosphonates. CONCLUSIONS: The relative benefit of targeted therapies in mRCC is not affected by the presence of bone metastases, but patients without bone metastases have longer response to therapy and overall survival.

5.
PLoS One ; 10(4): e0120427, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25885920

RESUMO

BACKGROUND: Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved for the treatment of metastatic renal cell carcinoma (mRCC). We aimed to assess the association between the baseline values and treatmentrelated modifications of total serum cholesterol (C), triglycerides (T), body mass index (BMI), fasting blood glucose level (FBG) and blood pressure (BP) levels and the outcome of patients treated with everolimus for mRCC. METHODS: 177 patients were included in this retrospective analysis. Time to progression (TTP), clinical benefit (CB) and overall survival (OS) were evaluated. RESULTS: Basal BMI was significantly higher in patients who experienced a CB (p=0,0145). C,T and C+T raises were significantly associated with baseline BMI (p=0.0412, 0.0283 and 0.0001). Median TTP was significantly longer in patients with T raise compared to patients without T (10 vs 6, p=0.030), C (8 vs 5, p=0.042) and C+T raise (10.9 vs 5.0, p=0.003). At the multivariate analysis, only C+T increase was associated with improved TTP (p=0.005). T raise (21.0 vs 14.0, p=0.002) and C+T increase (21.0 vs 14.0, p=0.006) were correlated with improved OS but were not significant at multivariate analysis. CONCLUSION: C+T raise is an early predictor for everolimus efficacy for patients with mRCC.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Everolimo/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Metabolismo dos Lipídeos/fisiologia , Adolescente , Adulto , Biomarcadores/metabolismo , Glicemia/análise , Pressão Sanguínea , Índice de Massa Corporal , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Colesterol/sangue , Progressão da Doença , Humanos , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Estadiamento de Neoplasias , Estudos Retrospectivos , Taxa de Sobrevida , Triglicerídeos/sangue , Adulto Jovem
6.
J Exp Clin Cancer Res ; 34: 10, 2015 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-25651794

RESUMO

PURPOSE: Aim of this study was to investigate for the presence of existing prognostic factors in patients with bone metastases (BMs) from RCC since bone represents an unfavorable site of metastasis for renal cell carcinoma (mRCC). MATERIALS AND METHODS: Data of patients with BMs from RCC were retrospectively collected. Age, sex, ECOG-Performance Status (PS), MSKCC group, tumor histology, presence of concomitant metastases to other sites, time from nephrectomy to bone metastases (TTBM, classified into three groups: <1 year, between 1 and 5 years and >5 years) and time from BMs to skeletal-related event (SRE) were included in the Cox analysis to investigate their prognostic relevance. RESULTS: 470 patients were enrolled in this analysis. In 19 patients (4%),bone was the only metastatic site; 277 patients had concomitant metastases in other sites. Median time to BMs was 16 months (range 0 - 44y) with Median OS of 17 months. Number of metastatic sites (including bone, p = 0.01), concomitant metastases, high Fuhrman grade (p < 0.001) and non-clear cell histology (p = 0.013) were significantly associated with poor prognosis. Patients with TTBM >5 years had longer OS (22 months) compared to patients with TTBM <1 year (13 months) or between 1 and 5 years (19 months) from nephrectomy (p < 0.001), no difference was found between these two last groups (p = 0.18). At multivariate analysis, ECOG-PS, MSKCC group and concomitant lung or lymph node metastases were independent predictors of OS in patients with BMs. CONCLUSIONS: Our study suggest that age, ECOG-PS, histology, MSKCC score, TTBM and the presence of concomitant metastases should be considered in order to optimize the management of RCC patients with BMs.


Assuntos
Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/secundário , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida
7.
Future Oncol ; 10(10): 1741-50, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24641206

RESUMO

AIM: The Italian Retrospective Analysis of Sorafenib as First or Second Target Therapy study assessed the efficacy and safety of sorafenib in metastatic renal cell carcinoma patients treated in the community. PATIENTS & METHODS: Patients receiving first- or second-line single-agent sorafenib between January 2008 and December 2010 were eligible. Retrospective data collection started in 2012 and covers at least 1-year follow-up. The primary end point was overall survival (OS). RESULTS: Median OS was 17.2 months (95% CI: 15.5-19.6): 19.9 months (95% CI: 15.9-25.3) in patients treated with first-line sorafenib and 16.3 months (95% CI: 13.1-18.2) with second-line sorafenib. Overall median (95% CI) progression-free survival was 5.9 months (95% CI: 4.9-6.7): 6.6 (95% CI: 4.9-9.3) and 5.3 months (95% CI: 4.3-6.0) in first- and second-line patients, respectively. CONCLUSION: The efficacy and safety of sorafenib in routine community practice was generally good, especially in relation to OS in patients treated in the second line, where results were similar to those seen in recent prospective clinical trials.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/mortalidade , Feminino , Seguimentos , Humanos , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Niacinamida/uso terapêutico , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Estudos Retrospectivos , Sorafenibe , Resultado do Tratamento
8.
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
9.
Expert Rev Anticancer Ther ; 13(6): 697-709, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23773104

RESUMO

With seven agents approved for renal cell carcinoma within the past few years, there has undoubtedly been progress in treating this disease. However, patients with poor-risk features remain a challenging and difficult-to-treat population, with the mTOR inhibitor, temsirolimus, the only agent approved in the first-line setting. Phase III trial data are still lacking VEGF-pathway inhibitors in patients with poor prognostic features. Poor-risk patients need to be considered as a heterogeneous population. Further understanding of biomarkers can lead to a better selection of patients who may benefit the most from treatment and improvements in prognosis. The presence of poor Karnofsky scores and liver or CNS disease may affect the outcome of these patients much more than other identified factors. This consideration may provide the rationale to further stratify poor-risk patients further subgroups destined to receive either cure or palliation.


Assuntos
Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Humanos , Indazóis , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Terapia de Alvo Molecular/métodos , Cuidados Paliativos , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sirolimo/análogos & derivados , Sirolimo/uso terapêutico , Sulfonamidas/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores
10.
PLoS One ; 8(12): e83026, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24386138

RESUMO

BACKGROUND: Bone metastasis represents an increasing clinical problem in advanced renal cell carcinoma (RCC) as disease-related survival improves. There are few data on the natural history of bone disease in RCC. PATIENTS AND METHODS: Data on clinicopathology, survival, skeletal-related events (SREs), and bone-directed therapies for 398 deceased RCC patients (286 male, 112 female) with evidence of bone metastasis were statistically analyzed. RESULTS: Median time to bone metastasis was 25 months for patients without bone metastasis at diagnosis. Median time to diagnosis of bone metastasis by MSKCC risk was 24 months for good, 5 months for intermediate, and 0 months for poor risk. Median number of SREs/patient was one, and 71% of patients experienced at least one SRE. Median times to first, second, and third SRE were 2, 5, and 12 months, respectively. Median survival was 12 months after bone metastasis diagnosis and 10 months after first SRE. Among 181 patients who received zoledronic acid (ZOL), median time to first SRE was significantly prolonged versus control (n = 186) (3 months vs 1 month for control; P<0.05). CONCLUSIONS: RCC patients with bone metastasis are at continuous risk of SREs, and in this survey ZOL effectively reduced this risk.


Assuntos
Neoplasias Ósseas/secundário , Neoplasias Renais/patologia , Neoplasias Ósseas/epidemiologia , Difosfonatos/uso terapêutico , Progressão da Doença , Feminino , Humanos , Itália/epidemiologia , Neoplasias Renais/epidemiologia , Masculino , Estudos Retrospectivos
11.
Expert Rev Anticancer Ther ; 12(12): 1545-57, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23253221

RESUMO

With seven targeted agents, directed against the VEGF/VEGF receptor (VEGFR) axis or the mTOR pathway, approved for the treatment of metastatic renal cell carcinoma and more active agents in advanced phase of clinical testing, questions have arisen with regard to their optimal use, either in combination or in sequence. One of the most compelling (and debated) issues is whether continued VEGF/VEGFR inhibition with agents hitting the same targets (TKI-TKI) affords better results than switching mechanisms of action by alternating VEGFR and mTOR inhibition (TKI-mTOR). In this article, the authors review the (little) available evidence coming from randomized Phase III clinical trials and try to fill in the (many) remaining gaps using evidence from small-size, single-arm Phase II studies and retrospective series, as well as reviewing preclinical evidence supporting either strategy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Serina-Treonina Quinases TOR/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Humanos , Terapia de Alvo Molecular
12.
J Cancer ; 2: 369-73, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21850209

RESUMO

In the past ten years we have made exceptional progresses in the understanding of RCC biology, particularly by recognizing the crucial pathogenetic role of activation of the HIF/VEGF and mTOR pathways. This has resulted in the successful clinical development of anti-angiogenic and mTOR-targeted drugs, which have profoundly impacted on the natural history of the disease and have improved the duration and quality of RCC patient lives. However, further improvements are still greatly needed: 1) even in patients who obtain striking clinical responses early in the course of treatment, disease will ultimately escape control and progress to a treatment-resistant state, leading to therapeutic failure; 2) prolonged disease control usually requires 'continuous' treatment, even across different treatment lines, making the impact of chronic, low-grade, toxicities on quality of life greater and precluding, for most patients, the possibility of experiencing 'drug-free holidays'; 3) although we have successfully identified classes of drugs (or molecular mechanisms of action) that are effective in a substantial proportion of patients, we still fall short of molecular predictive factors that identify individual patients who will (or will not) benefit from a specific intervention and still proceed on a trial-and-error basis, far from a truly 'personalized' therapeutic approach; 4) finally (and perhaps most importantly), even in the best case scenario, currently available treatments inevitably fail to definitively 'cure' metastatic RCC patients. In this review we briefly summarize recent developments in the understanding of the molecular pathogenesis of RCC, the development of resistance/escape mechanisms, the rationale for sequencing agents with different mechanisms of action, and the importance of host-related factors. Unraveling the complex mechanisms by which RCC shapes host microenvironment and immune response and therapeutic treatments, in turn, shape both cancer cell biology and tumor-host interactions may hold the key to future advances in such a complex and challenging disease.

13.
J Exp Clin Cancer Res ; 30: 10, 2011 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-21244695

RESUMO

BACKGROUND: To evaluate the therapeutic strategies commonly employed in the clinic for the management of brain metastases (BMs) and to correlate disease outcome with type of treatment and therapeutic resources available at the treating center. METHODS: Four Cancer centres participated to the survey. Data were collected through a questionnaire filled in by one physician for each centre. RESULTS: Clinical data regarding 290 cancer patients with BMs from solid tumors were collected. Median age was 59 and 59% of patients had ≤ 3 brain metastases. A local approach (surgery and stereotactic radiosurgery) was adopted in 31% of patients. The local approach demonstrated to be superior in terms of survival compared to the regional/systemic approach (whole brain radiotherapy and chemotherapy, p = <.0001 for survival at 2 years). In the multivariate analysis local treatment was an independent prognostic factor for survival. When patients were divided into 2 groups whether they were treated in centers where local approaches were available or not (group A vs group B respectively, 58% of patients with ≤ 3 BMs in both cohorts), more patients in group A received local strategies although no difference in time to brain progression at 1 year was observed between the two groups of patients. CONCLUSIONS: In clinical practice, local strategies should be integrated in the management of brain metastases. Proper selection of patients who are candidate to local treatments is of crucial importance.


Assuntos
Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Serviço Hospitalar de Oncologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/mortalidade , Feminino , Pesquisas sobre Atenção à Saúde , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Resultado do Tratamento , Adulto Jovem
14.
Eur Urol ; 58(6): 906-11, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20884115

RESUMO

BACKGROUND: Sunitinib and everolimus have been approved for first- and second-line treatment, respectively, in metastatic renal cell carcinoma (mRCC). The role of sorafenib, which is approved for second-line treatment after cytokines failure, is presently to be defined. OBJECTIVE: To determine whether third-line sorafenib after sequential use of sunitinib and mammalian target of rapamycin inhibitors (everolimus or temsirolimus) is feasible and effective. DESIGN, SETTING, AND PARTICIPANTS: One hundred fifty medical records of patients with mRCC treated with first-line sunitinib between January 2006 and January 2010 were reviewed at four participating centers. Data regarding patients treated with the sequence sunitinib-everolimus or temsirolimus-sorafenib were extracted. Central analysis of radiographic images was performed using RECIST criteria to determine progression-free survival (PFS) and overall response rate (oRR) to sorafenib treatment. MEASUREMENTS: PFS and oRR to sorafenib were the primary end points. Secondary outcomes were safety and overall survival (OS). RESULTS AND LIMITATIONS: Thirty-four patients were eligible for the study. A median PFS of 4 mo (range: 3-6 mo) and a median OS of 7 mo since sorafenib treatment (range: 6-10 mo) were reported. Of the patients, 23.5% showed response to sorafenib, with an overall disease control rate (complete responses plus partial responses plus stable disease) of 44%. Selection bias, data incompleteness, and absence of study design are inevitable limitations of the study, although central review can strengthen the quality of presented data. CONCLUSIONS: Third-line sorafenib appears to be active and well tolerated in mRCC after first-line sunitinib and second-line everolimus or temsirolimus, with no patients interrupting sorafenib because of toxicity or lack of compliance. Prospective, placebo-controlled trials are completely lacking and are required in this setting.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adulto , Idoso , Inibidores da Angiogênese/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzenossulfonatos/administração & dosagem , Carcinoma de Células Renais/enzimologia , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/secundário , Intervalo Livre de Doença , Everolimo , Estudos de Viabilidade , Feminino , Humanos , Indóis/administração & dosagem , Itália , Estimativa de Kaplan-Meier , Neoplasias Renais/enzimologia , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Compostos de Fenilureia , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Pirróis/administração & dosagem , Estudos Retrospectivos , Sirolimo/administração & dosagem , Sirolimo/análogos & derivados , Sorafenibe , Sunitinibe , Taxa de Sobrevida , Serina-Treonina Quinases TOR/metabolismo , Fatores de Tempo , Resultado do Tratamento
17.
Clin Pharmacokinet ; 48(2): 131-41, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19271785

RESUMO

BACKGROUND AND OBJECTIVES: Gemcitabine (2,2-difluorodeoxycytidine [dFdC]) can be administered in a standard 30-minute infusion or in a fixed-dose-rate (FDR) infusion to maximize the rate of accumulation of triphosphate, its major intracellular metabolite. The standard 30-minute infusion requires dose adjustment in patients with organ dysfunction, especially in patients with elevated baseline serum bilirubin levels. On the other hand, the FDR infusion is burdened by increased haematological toxicity. The primary aim of this study was to evaluate the pharmacokinetics of dFdC and its metabolite difluorodeoxyuridine (dFdU) in patients with normal and impaired hepatic function. PATIENTS AND METHODS: In this prospective study, patients with pancreatic or biliary tract carcinoma and normal or impaired hepatic function tests were considered eligible for recruitment. Patients were recruited according to the following criteria: (i) serum bilirubin <1.6 mg/dL and AST and ALT <2 times the upper the limit of normal (ULN) [cohort I]; and (ii) serum bilirubin >1.6 mg/dL and/or AST/ALT >2 times the ULN (cohort II). An FDR infusion of gemcitabine 1000 mg/m2 was administered on days 1, 8 and 15 every 4 weeks. The pharmacokinetic analysis of gemcitabine and dFdU was performed with high-performance liquid chromatography-tandem mass spectrometry assay in cycles 1 and 2. RESULTS: Thirteen patients were enrolled, four in cohort I and nine in cohort II. All patients were assessable for toxicity and pharmacokinetic analysis. The grade and rate of toxicities were similar in both groups, and patients with elevation of bilirubin and/or transaminases did not require dose reduction of gemcitabine. Pharmacokinetic analysis revealed a reduction of the experimental area under the plasma concentration-time curve for gemcitabine and dFdU in patients with hepatic dysfunction when compared with patients with normal hepatic function. All other pharmacokinetic parameters were similar in the two cohorts. No statistical difference was demonstrated for all parameters evaluated between cycle 1 and cycle 2 in the two groups. CONCLUSION: Gemcitabine 1000 mg/m2 can be administered as an FDR infusion in patients with altered hepatic function without causing additional toxicity compared with patients with normal hepatic function.


Assuntos
Adenocarcinoma/sangue , Antimetabólitos Antineoplásicos/farmacocinética , Neoplasias do Sistema Biliar/sangue , Desoxicitidina/análogos & derivados , Hepatopatias/sangue , Neoplasias Pancreáticas/sangue , Adenocarcinoma/complicações , Adenocarcinoma/tratamento farmacológico , Adulto , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Área Sob a Curva , Neoplasias do Sistema Biliar/complicações , Neoplasias do Sistema Biliar/tratamento farmacológico , Cromatografia Líquida de Alta Pressão , Desoxicitidina/farmacocinética , Desoxicitidina/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Floxuridina/análogos & derivados , Floxuridina/farmacocinética , Humanos , Infusões Intravenosas , Hepatopatias/complicações , Hepatopatias/fisiopatologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/tratamento farmacológico , Estudos Prospectivos , Espectrometria de Massas em Tandem , Gencitabina
18.
Anticancer Res ; 28(2B): 1245-58, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18505062

RESUMO

The management of human epidermal receptor-2 (HER-2) negative metastatic breast cancer (MBC) is usually problematic, since no standard therapy exists in this setting. For some patients, combination chemotherapy represents a valuable approach, although its use is often limited by the risks of increased toxicity as well as impairments in quality of life (QoL) that often outweigh the marginal efficacy benefit. Against this background, the use of taxanes, either paclitaxel or docetaxel, in combination with gemcitabine as first-line treatment of HER-2 negative MBC is supported by the evidence of the single-agent activity of these drugs, beneficial pharmacological interactions, different mechanisms of action and largely non superimposable toxicity profiles. A number of phase II studies have explored the activity of a taxane plus gemcitabine in both chemonaïve and pretreated MBC patients, all showing remarkably high response rates and exceptional tolerability. In randomized phase III trials, the paclitaxel and gemcitabine combination showed significant improvements in objective responses, time to progression and overall survival, as compared to paclitaxel monotherapy, whereas the docetaxel and gemcitabine doublet demonstrated equal efficacy and better tolerability, as compared to docetaxel plus capecitabine. In addition to standard threeweekly dosing regimens, alternative schedules of administration of taxanes and gemcitabine doublets (weekly, twoweekly) might deserve further investigation due to their potential usefulness in reducing pharmacological toxicity while maintaining or increasing dose-intensity and clinical efficacy. Furthermore, uncertainty exists on which taxane should be preferred in combination with gemcitabine, since no head-to-head comparison between paclitaxel-gemcitabine and docetaxel-gemcitabine has been performed so far. Ongoing trials will address these issues and future investigations will also include the evaluation of bevacizumab, the monoclonal antibody targeted against vascular endothelial growth factor (VEGF), in combination with taxanes and gemcitabine doublets.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Receptor ErbB-2/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ensaios Clínicos Fase III como Assunto , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Docetaxel , Esquema de Medicação , Humanos , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Gencitabina
19.
Cancer ; 113(2): 238-46, 2008 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-18470908

RESUMO

BACKGROUND: In patients with locally advanced and operable breast cancer, neoadjuvant chemotherapy has been demonstrated to increase the chance of breast-conserving surgery (BCS) when compared with adjuvant treatment; moreover, patients who achieve a pathologic complete response (pCR) have a better outcome. A literature-based meta-analysis of randomized clinical trials (RCTs) to 'weigh' how much taxanes add to anthracyclines as primary treatment over standard chemotherapy was conducted. METHODS: Event-based relative risk ratios (RR) with 95% confidence intervals (95% CI) were derived through both a fixed-effect and a random-effect model; a heterogeneity test was applied as well. Absolute differences (AD) and the number (of patients) needed to treat (NNT) were calculated. Primary endpoints were: 1) pCR rate and 2) BCS rate. A sensitivity analysis of 3 subgroups according to taxane strategies was conducted. RESULTS: Data for primary endpoints were available for 7 RCTs (2455 patients). The rate of BCS was significantly higher for patients receiving taxanes, with an AD of 3.4% (P = .012), which translates into 29 patients NNT, without significant heterogeneity. The rate of pCR was higher for patients receiving taxanes, although not statistically significant. In the sensitivity analysis, patients receiving taxanes as a sequential schedule had a significant higher probability to achieve pCR, with an AD of 2.4% (P = .013), which translates into 41 patients NNT, without significant heterogeneity. Patients receiving taxanes as a concomitant schedule had a significantly higher probability to achieve BCS, with an AD of 5.3% (P = .027), which translates into 19 patients NNT, without significant heterogeneity. The complete response rate was significantly higher in the taxane arms, regardless of the adopted strategy, with an AD ranging from 6.7% to 15.5%. CONCLUSIONS: The combination of taxanes and anthracyclines as neoadjuvant chemotherapy for early breast cancer improves the chance of achieving both higher BCS and pCR rates.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Taxoides/uso terapêutico , Neoplasias da Mama/epidemiologia , Humanos , Terapia Neoadjuvante , Estadiamento de Neoplasias , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
20.
Breast ; 17(5): 499-505, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18450443

RESUMO

Though preclinical evidence supports the protracted use of trastuzumab to reach sustained anti-tumor activity, the activity of trastuzumab beyond disease progression remains controversial in HER-2 over-expressing (HER-2+) metastatic breast cancer (MBC) patients. We retrospectively evaluated a total of 59 patients with HER-2 + MBC treated at our institution with trastuzumab-based therapies. Our results were added to those obtained in similar observational studies and summary estimates for overall response (OR) and clinical benefit (CB) to first and second trastuzumab-based lines were calculated. In our series of patients we observed an OR of 59.3% and 27% for first and second trastuzumab-based lines, respectively, with a corresponding CB of 83% and 62.2%, respectively. Time to first and second progression were 9.5 months and 6.7 months, respectively. The combined analysis showed an OR of 50% for first trastuzumab-based regimen and 21.2% for second trastuzumab-based line. The corresponding values for CB were 77.6% and 42.6%, respectively. A second trastuzumab-containing regimen beyond progression yields a considerable rate of OR and CB in HER-2 + MBC patients. Randomized trials are warranted.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Receptor ErbB-2/metabolismo , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Antineoplásicos/administração & dosagem , Neoplasias da Mama/patologia , Progressão da Doença , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/genética , Receptor ErbB-2/uso terapêutico , Estudos Retrospectivos , Trastuzumab , Resultado do Tratamento
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