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3.
ESMO Open ; 6(2): 100099, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33819752

RESUMO

BACKGROUND: The current standard first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive (+) metastatic breast cancer is the combination of pertuzumab, trastuzumab and a taxane (P + T + taxane), while standard second-line is ado-trastuzumab-emtansine (T-DM1). The registration trial of pertuzumab, however, did not include early-relapsing patients, defined as patients experiencing tumor relapse ≤12 months from the end of (neo)adjuvant anti-HER2 therapy. Conversely, the pivotal trial of T-DM1 included some patients relapsing ≤6 months after the end of (neo)adjuvant trastuzumab. Thus, a proportion of early-relapsing patients are currently eligible to receive T-DM1 as first-line treatment. Nevertheless, no direct comparison exists between the two regimens in this clinical setting. PATIENTS AND METHODS: We retrospectively compared T-DM1 versus P + T + taxane as first-line treatment in two cohorts of early-relapsing patients in an Italian 'real-world' setting, involving 14 public health care institutions. The primary endpoint was progression-free survival. Secondary endpoints included patients' characterization, overall survival and post-progression survival. Univariate and multivariate analyses were carried out. All tests were two-sided and a P ≤ 0.05 was considered statistically significant. RESULTS: Among 1252 screened patients, 75 met the inclusion criteria. Forty-four (58.7%) received P + T + taxane and 31 (41.3%) received T-DM1. The two cohorts showed similar characteristics of aggressiveness and no significant differences in treatment history. T-DM1, compared with P + T + taxane was associated with worse progression-free survival (adjusted hazard ratio: 2.26, 95% confidence interval: 1.13-4.52, P = 0.021) and overall survival (adjusted hazard ratio: 3.95, 95% confidence interval: 1.38-11.32, P = 0.010), irrespective of previous (neo)adjuvant treatment, age, hormone receptors status, time-to-relapse (≤6 months or within 6-12 months) and presence of visceral/brain metastases. No differences were observed in post-progression survival (P = 0.095). CONCLUSIONS: Our study suggests superiority for P + T + taxane over T-DM1 as up-front treatment of early-relapsing HER2+ metastatic breast cancer, which merits further assessment in larger and prospective trials.


Assuntos
Neoplasias da Mama , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Itália , Recidiva Local de Neoplasia/tratamento farmacológico , Estudos Prospectivos , Receptor ErbB-2/genética , Receptor ErbB-2/uso terapêutico , Estudos Retrospectivos , Taxoides/uso terapêutico , Trastuzumab/uso terapêutico
4.
Expert Rev Clin Pharmacol ; 14(2): 261-268, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33472450

RESUMO

Background: The RESORT trial showed no longer relapse free survival (RFS) with sorafenib following radical metastasectomy in metastatic renal cell carcinoma. We present the updated 42-month follow-up data.Methods: The phase II RESORT trial randomized patients to sorafenib or observation within 12 weeks from surgery. RFS was the primary endpoint.Results: We analyzed 68 patients (32 in sorafenib and 36 in the observation arm), randomized between November 2012 and November 2017. Eighty-one percent in the sorafenib arm and 80% in the observation arm had one metastasis . At a median follow-up of 42 months (interquartile range 31-58), in the observation arm the median RFS was 35 months, RFS probability was 57% (95% CI 42-76%) at 24 and 44% (95% CI 30-65%) at 48 months. In the sorafenib arm, median RFS was 21 months, RFS probability was 50% (95% CI 34-71%) at 24 and 32% (95% CI 18-57%) at 48 months (p = 0.342;HR 1.35;95% CI 0.72-2.54). Forty-seven percent and 37.5% of the patients in the two arms, respectively, are disease free. The site of relapses was independent of the previous metastasectomy site.Expert commentary: Sorafenib after metastasectomy did not improve RFS, but surgery in selected patients should be considered in order to potentially improve survival.Clinical trial registration: www.clinicaltrials.gov identifier is NCT0144480.


Assuntos
Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , Metastasectomia/métodos , Sorafenibe/administração & dosagem , Antineoplásicos/administração & dosagem , Carcinoma de Células Renais/patologia , Intervalo Livre de Doença , Seguimentos , Humanos , Neoplasias Renais/patologia , Recidiva Local de Neoplasia , Probabilidade
7.
Biomed Res Int ; 2014: 351252, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24877084

RESUMO

BACKGROUND: No established chemotherapeutic regimen exists for the treatment of recurrent malignant gliomas (rMGs). Herein, we report the activity and safety results of the bevacizumab (B) plus fotemustine (FTM) combination for the treatment of rMGs. PATIENTS AND METHODS: An induction phase consisted of B 10 mg/kg days 1, 15 plus FTM 65 mg/m(2) days 1, 8, and 15. Nonprogressive patients entered the maintenance phase with B 10 mg/kg plus FTM 75 mg/m(2) every 3 weeks. The primary endpoint was response rate; secondary endpoints included safety, progression free survival (PFS), and overall survival (OS). RESULTS: Twenty-six patients affected by recurrent MGs (50% glioblastoma) were enrolled. Eight partial responses (31%) were observed. Median PFS and OS were 4 (95% C.I.: 2.8-5.1) and 6 months (95% C.I.: 4.2-7.8), respectively. Responses were significantly associated with both improved PFS and OS (P = 0.002 and P = 0.001, resp.). Treatment adverse events were mostly mild to moderate in intensity. Bevacizumab-related adverse events included grade 3 venous thromboembolic event (8%), grade 2 epistaxis (4%), hypertension (8%), and gastrointestinal perforation (4%). CONCLUSIONS: Bevacizumab plus FTM showed activity and good tolerability in pretreated MGs. Further investigations are needed in order to verify the benefits deriving from the addition of B to a cytotoxic in this clinical setting of patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Encefálicas , Glioma/tratamento farmacológico , Recidiva Local de Neoplasia , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/mortalidade , Intervalo Livre de Doença , Feminino , Glioma/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/mortalidade , Compostos de Nitrosoureia/administração & dosagem , Compostos de Nitrosoureia/efeitos adversos , Compostos Organofosforados/administração & dosagem , Compostos Organofosforados/efeitos adversos , Taxa de Sobrevida
8.
Gynecol Oncol ; 130(1): 31-7, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23234805

RESUMO

BACKGROUND: In platinum-sensitive relapsed ovarian cancer, paclitaxel plus carboplatin is a standard second-line treatment. Zibotentan (ZD4054) is an oral, specific ETA-receptor antagonist with demonstrated antitumour activity in xenograft models of human ovarian cancer. METHODS: In this Phase II, randomized, placebo-controlled study, patients with relapsed ovarian cancer sensitive to platinum-based chemotherapy received zibotentan 10mg or placebo once-daily, plus paclitaxel 175 mg/m(2) iv followed by carboplatin iv (AUC 5) on day 1 of every 3-week cycle for a maximum of eight cycles. The primary endpoint was progression-free survival (PFS), evaluated by Response Evaluation Criteria In Solid Tumours (RECIST). Secondary and exploratory endpoints included objective tumour response rate, tumour size, CA-125/RECIST progression, and safety and tolerability. RESULTS: A total of 120 patients were randomized (zibotentan: n=59; placebo: n=61). Addition of zibotentan 10mg/day to carboplatin and paclitaxel did not improve PFS compared with placebo (median PFS, 7.6 versus 10.0 months, respectively; HR=1.46, [80% CI: 1.10-1.94]; P=0.0870). No improvements in any of the secondary or exploratory efficacy endpoints were observed for patients receiving zibotentan compared with placebo. Median duration of total treatment exposure was 6.7 months. Total chemotherapy dose received was lower for zibotentan-treated versus placebo-treated patients (carboplatin: -16%; paclitaxel: -14%). The most common adverse events in the zibotentan arm were anaemia, nausea, alopecia, headache and neutropenia (43-48% of patients). CONCLUSIONS: Zibotentan 10mg/day plus carboplatin and paclitaxel did not result in an improvement in PFS compared with chemotherapy alone in patients with advanced ovarian cancer sensitive to platinum-based chemotherapy. No unexpected safety concerns were identified.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carcinoma Epitelial do Ovário , Intervalo Livre de Doença , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Placebos , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , Adulto Jovem
9.
Eur J Cancer ; 48(5): 642-7, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21757335

RESUMO

AIMS: Triple-negative breast cancers (TNBCs) lack expression of oestrogen, progesterone, and Human Epidermal Growth Factor 2 receptors. The NEMESI study described current Italian treatment practices in patients with operable, early-stage breast cancer (EBC). PATIENTS AND METHODS: Retrospective, observational study involving 63 Italian oncology centres. Eligible patients were aged ≥ 18 years with EBC (stage I-II) who had undergone surgery, received ≥ 1 cycle of adjuvant chemotherapy and/or adjuvant hormonal therapy and attended an oncology centre between 1 January 2008 and 30 June 2008. This subanalysis focused on patients with TNBC. Variables evaluated included: demographic data/clinical characteristics; tumour characteristics; adjuvant therapy; compliance to chemotherapy. Continuous variables were summarised using descriptive statistics. RESULTS: Of 1894 patients in the NEMESI study, 185 patients (9.8%) had TNBC. At diagnosis, 98 patients were aged 50-70 years and 114 were post-menopausal. Tumours were subcategorised as pT1mic/pT1a/pT1b/pT1c in 108 patients and pT2/pT3/pT4b in 77 patients. Mean tumour size was 2.1cm, tumours were highly undifferentiated in 144 patients and 128 patients were pNO. 179 patients received adjuvant chemotherapy; anthracyclines with or without taxanes were commonly used. 145 patients received radiotherapy. CONCLUSIONS: Adherence of Italian clinical practice to International Guidelines in the management of early-stage TNBC is satisfactory.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Terapia Combinada , Feminino , Humanos , Itália , Pessoa de Meia-Idade , Radioterapia Adjuvante , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos
10.
Ann Oncol ; 23(3): 695-700, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21859900

RESUMO

BACKGROUND: The purpose of the study was to evaluate the benefit of adjuvant chemotherapy (AC) versus surgery alone in patients with muscle-invasive bladder cancer (MIBC). PATIENTS AND METHODS: One hundred and ninety-four patients with pT2G3, pT3-4, N0-2 transitional cell bladder carcinoma were randomly allocated to control (92 patients) or to four courses of AC (102 patients). These latter patients were further randomly assigned to receive gemcitabine 1000 mg/m(2) days 1, 8 and 15 and cisplatin 70 mg/m(2) day 2 or gemcitabine as above plus cisplatin 70 mg/m(2) day 15, every 28 days. RESULTS: At a median follow-up of 35 months, the 5-year overall survival (OS) was 48.5%, with no difference between the two arms [P = 0.24, hazard ratio (HR) 1.29, 95% confidence interval (CI) 0.84-1.99]. Mortality hazard was significantly correlated with Nodes (N) and Tumor (T) stage. The control and AC arms had comparable disease-free survival (42.3% and 37.2%, respectively; P = 0.70, HR 1.08, 95% CI 0.73-1.59). Only 62% of patients received the planned cycles. A significant higher incidence of thrombocytopenia was observed in patients receiving cisplatin on day 2 (P = 0.006). A similar global quality of life was observed in the two arms. CONCLUSION: The study was underpowered to demonstrate that AC with cisplatin and gemcitabine improves OS and disease-free survival in patients with MIBC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células de Transição/tratamento farmacológico , Desoxicitidina/análogos & derivados , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/cirurgia , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Cistectomia , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Itália , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Recidiva , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/cirurgia , Gencitabina
11.
Ann Oncol ; 23(6): 1436-41, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22039084

RESUMO

BACKGROUND: Preclinical data suggest that treatment with lapatinib reinduces sensitivity to trastuzumab in human epidermal growth factor receptor 2(HER2)-positive breast cancer cells. PATIENTS AND METHODS: Between January 2007 and November 2010, 179 HER2-positive metastatic breast cancer patients were treated with lapatinib and capecitabine at nine Italian institutions. We evaluated the clinical outcome of 69 patients (38.5%) retreated with trastuzumab after lapatinib progression. RESULTS: Visceral metastases were identified in 51 (74%) and brain metastases in 16 patients (23%). All patients were pretreated with both trastuzumab- and lapatinib-based therapy. We observed with retreatment with trastuzumab-based therapy: 1 complete remission (2%), 18 partial remission (29%) and 10 stable disease ≥6 months (14%) and 47% of clinical benefit (CB). Median duration of response was 8.1 months [95% confidence interval (CI) 5.5-10.7]. No unexpected toxic effects occurred. At a median follow-up of 13 months, median progression-free survival was 4.9 months (95% CI 4.2-5.6) and overall survival (OS) 19.4 months (95% CI 14.0-25.0). Median OS was longer for patients experiencing CB (not reached versus 13.4 months for patients without CB, P = 0.002). Brain involvement was associated with lower median OS (17.3 versus 23.3 months for patients without brain disease; P = 0.021). CONCLUSION: Retreatment with trastuzumab-based therapy showed CB in 47% of patients progressing during lapatinib-based therapy, leading to a prolonged OS.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quinazolinas/farmacologia , Receptor ErbB-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Progressão da Doença , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Estimativa de Kaplan-Meier , Lapatinib , Pessoa de Meia-Idade , Análise Multivariada , Metástase Neoplásica , Modelos de Riscos Proporcionais , Quinazolinas/uso terapêutico , Estudos Retrospectivos , Trastuzumab , Falha de Tratamento
12.
Ann Oncol ; 22(10): 2277-85, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21325444

RESUMO

BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are effective as first-line treatment of advanced non-small-cell lung cancer patients with EGFR mutations (EGFR-M+). PATIENTS AND METHODS: We conducted a literature-based meta-analysis to quantify the magnitude of benefit with upfront EGFR TKI in EGFR-M+ patients. Meta-regression and sensitivity analyses were also carried out to identify additional predictors of outcome and to assess the influence of trial design. RESULTS: Five trials (805 patients) were identified (three trials prospectively enrolling EGFR-M+ patients and two retrospective analyses of EGFR-M+ patients). TKI significantly increased progression-free survival (PFS) [hazard ratio (HR) 0.45, 95% confidence interval (CI) 0.36-0.58, P < 0.0001] and overall response rate (ORR) (HR 2.08, 95% CI 1.75-2.46, P < 0.0001)] over chemotherapy, while significantly decreasing neutropenia. No significant difference was observed in overall survival. The rate of exon-19 mutations, female gender, and nonsmoking status were identified as additional predictors of outcome at meta-regression analysis. A significant interaction with trial design was found for both PFS (P = 0.028) and ORR (P = 0.008), suggesting a larger advantage for patients treated within prospective trials. CONCLUSIONS: In EGFR-M+ patients, first-line TKI increase both PFS and ORR by ~25%, while significantly decreasing toxicity. The role of additional predictive factors and the influence of trial design on the magnitude of the observed benefit warrant further investigation.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Inibidores de Proteínas Quinases/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores Sexuais
13.
Eur J Surg Oncol ; 37(4): 364-9, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21194881

RESUMO

OBJECTIVE: To evaluate the feasibility and morbidity of total laparoscopic class C2 radical hysterectomy (TLRH) with pelvic lymphadenectomy in patients with locally advanced cervical cancer stage IB2 to IIB after neoadjuvant chemotherapy (NACT). METHODS: A prospective study was conducted from October 2004 to September 2009. Cervical cancer patients, stage IB2-IIB with complete clinical response after 3 courses of NACT with paclitaxel 175 mg/m(2), ifosfamide 5 g/m(2) and cisplatin 75 mg/m(2) (TIP) underwent TLRH. RESULTS: Forty patients were included, with a median age of 46 years (range, 25-65), BMI of 24 kg/m(2) (range, 15-49). FIGO staging was IB2 in 23, IIA > 4 cm in 6 and IIB in 11 patients. Four patients required conversion to laparotomy. Pathological evaluation showed 9 complete response (pCR), 9 partial response (pPR1) with microscopic tumour, and 15 partial response (pPR2) with macroscopic tumour. Three patients had no response. The median operative time was 305 min (range, 215-430); the median estimated blood loss was 250 ml (range, 100-400), with four postoperative blood transfusion; the median number of removed pelvic lymph nodes was 25 (range, 11-64). The median length of hospital stay was 6 days (range, 3-12). The median follow-up time was 37 months (range, 10-69), with three patients having a recurrence. One patient died of disease (DOD) after 12 months. CONCLUSIONS: TLRH can be safely performed in patients with stage IB2-IIB carcinoma of cervix after NACT, with advantages of minimal blood loss and morbidity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Histerectomia/métodos , Laparoscopia , Excisão de Linfonodo , Terapia Neoadjuvante/métodos , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/cirurgia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma/patologia , Carcinoma/cirurgia , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Histerectomia/efeitos adversos , Histerectomia/instrumentação , Itália , Laparoscopia/efeitos adversos , Tempo de Internação , Excisão de Linfonodo/efeitos adversos , Pessoa de Meia-Idade , Morbidade , Estadiamento de Neoplasias , Pelve , Estudos Prospectivos , Resultado do Tratamento
14.
Ann Oncol ; 22(3): 625-630, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20724575

RESUMO

BACKGROUND: In the present study, we investigated the clinical outcome of patients with brain metastases (BMs) from human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) treated with lapatinib and capecitabine (LC). METHODS: Of 81 HER2+ metastatic BC patients treated with LC at two Italian institutions, 30 patients with BMs eligible for the analysis were identified. All patients were pretreated with trastuzumab for metastatic disease. No patients had received prior lapatinib and/or capecitabine. RESULTS: Median age was 45 years (range 24-75) and 26 of 30 patients (86.7%) had received prior cranial radiotherapy. In the 22 patients with BMs evaluable for response, 7 partial responses (31.8%) and 6 disease stabilizations (27.3%) were observed. Overall, the median brain-specific progression-free survival was 5.6 months (95% confidence interval 4.4-6.8). Patients treated with LC had a median overall survival (from the time of development of BMs) significantly longer compared with 23 patients treated with trastuzumab-based therapies only beyond brain progression (27.9 months versus 16.7 months, respectively, P = 0.01). CONCLUSIONS: LC is active for BMs from HER2+ BC in patients not pretreated with either lapatinib or capecitabine. The introduction of LC after the development of BMs may further improve survival compared with trastuzumab-based therapies only beyond brain progression.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/secundário , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Receptor ErbB-2/metabolismo , Adulto , Idoso , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antineoplásicos/uso terapêutico , Encéfalo/patologia , Neoplasias Encefálicas/terapia , Neoplasias da Mama/metabolismo , Capecitabina , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Humanos , Estimativa de Kaplan-Meier , Lapatinib , Pessoa de Meia-Idade , Quinazolinas/administração & dosagem , Estudos Retrospectivos , Trastuzumab , Resultado do Tratamento , Adulto Jovem
15.
Br J Cancer ; 103(10): 1542-7, 2010 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-20959822

RESUMO

BACKGROUND: We assessed the effectiveness of cetuximab plus chronomodulated irinotecan, 5-fluorouracil (5-FU), leucovorin (FA) and oxaliplatin (L-OHP) (chrono-IFLO) administered as neoadjuvant chemotherapy to increase the resectability of colorectal liver metastases. METHODS: This was a phase II prospective trial with rate of liver metastases resection as primary end point. Forty-three patients with unresectable metastases were enroled: 9 with metastases >5 cm; 29 with multinodular (>4) disease; 1 with hilar location; 4 with extrahepatic lung disease. Treatment consisted of cetuximab at day 1 plus chronomodulated irinotecan 5-FU, FA and L-OHP for 2-6 days every 2 weeks. After the first 17 patients, doses were reduced for irinotecan to 110 mg m⁻², 5-FU to 550 mg m⁻² per day and L-OHP to 15 mg m⁻² per day. RESULTS: Macroscopically complete resections were performed in 26 out of 43 patients (60%) after a median of 6 (range 3-15) cycles. Partial response was noticed in 34 patients (79%). Median overall survival was 37 months (95% CI: 21-53 months), with a 2-year survival of 68% in the entire population, 80.6% in resected patients and 47.1% in unresected patients (P=0.01). Grade 3/4 diarrhoea occurred in 93% and 36% of patients before and after dose reduction. CONCLUSION: Cetuximab plus chrono-IFLO achieved 60% complete resectability of colorectal liver metastases.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/secundário , Neoplasias Hepáticas/patologia , Terapia Neoadjuvante/métodos , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Cetuximab , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/cirurgia , Diarreia/induzido quimicamente , Intervalo Livre de Doença , Receptores ErbB/metabolismo , Feminino , Fluoruracila/administração & dosagem , Hepatectomia , Humanos , Irinotecano , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Projetos de Pesquisa , Taxa de Sobrevida , Tomografia Computadorizada por Raios X
16.
Oncology ; 78(2): 141-9, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20389136

RESUMO

OBJECTIVE: The phosphatase and tensine homologue gene (PTEN) plays a crucial role in proliferation and survival of cancer cells by antagonizing the function of phosphatidylinositol 3'-kinase (PI3K), which, in turn, results in decreased Akt activity. We investigated the clinical impact of the expression of PTEN, p-Akt and PI3K in HER2-positive metastatic breast cancer (MBC) patients treated with trastuzumab-based therapies. METHODS: Seventy-three patients treated with trastuzumab-based therapies were included and followed prospectively. PTEN, p-Akt and PI3K expression was determined by immunohistochemistry. RESULTS: PTEN, p-Akt and PI3K resulted positive in 48%, 71% and 46.5% of patients, respectively. A significant correlation between PTEN and p-Akt (kappa 0.22, p = 0.03) and p-Akt and PI3K (kappa 0.20, p = 0.05) was observed. PTEN-positive patients had a progression-free survival (PFS) longer than PTEN-negative ones (p = 0.06). When grouped together, patients co-expressing PTEN and p-Akt had a statistically significant longer PFS as compared to the rest of patients (p = 0.01). At the multivariate analysis, PTEN and p-Akt co-expression was an independent predictor of lower risk of progression (hazard ratio 0.53, p = 0.05). CONCLUSION: In HER2-positive MBC, basal co-expression of PTEN and p-Akt might identify those patients who are more likely to benefit from trastuzumab-based therapies.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/genética , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas c-akt/genética , Receptor ErbB-2/genética , Adolescente , Idoso , Anticorpos Monoclonais Humanizados , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Metástase Neoplásica/patologia , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor ErbB-2/metabolismo , Trastuzumab
17.
Neurology ; 74(9): 762-6, 2010 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-20194916

RESUMO

OBJECTIVE: The clinical use of cisplatin chemotherapy is limited by severe peripheral neurotoxicity reported in up to 90% of patients receiving a cumulative dose higher than 300 mg/m(2). The present study evaluates the neuroprotective effect of antioxidant supplementation (vitamin E) in patients treated with cisplatin chemotherapy. METHODS: A total of 108 patients treated with cisplatin chemotherapy were randomly assigned to receive vitamin E supplementation (alpha-tocopherol 400 mg/day) or placebo. Treatment was started orally before chemotherapy and continued for 3 months after the suspension of cisplatin. RESULTS: Of 108 randomized patients, 68 received at least one clinical and neurophysiologic examination after cisplatin CT; 41 patients received a cumulative dose of cisplatin higher than 300 mg/m(2) and were eligible for statistical analysis: 17 in the vitamin E group (group 1) and 24 in the placebo group (group 2). The incidence of neurotoxicity was significantly lower in group 1 (5.9%) than in group 2 (41.7%) (p < 0.01). The severity of neurotoxicity, measured with a validated neurotoxicity score (Total Neuropathy Score [TNS]), was significantly lower in patients receiving vitamin E than those receiving placebo (mean TNS 1.4 vs 4.1; p < 0.01). CONCLUSIONS: This phase III study confirms the neuroprotective role of vitamin E against cisplatin peripheral neurotoxicity. Vitamin E supplementation should be adopted in patients receiving cisplatin-based chemotherapy. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that vitamin E supplementation significantly reduces the relative risk of developing signs or symptoms of neurotoxicity (relative risk = 0.14) (95% confidence interval = 0.02-1.00, p < 0.05).


Assuntos
Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Fármacos Neuroprotetores/uso terapêutico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , alfa-Tocoferol/uso terapêutico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antioxidantes/administração & dosagem , Antioxidantes/uso terapêutico , Cisplatino/administração & dosagem , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Fármacos Neuroprotetores/administração & dosagem , Risco , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , alfa-Tocoferol/administração & dosagem
18.
Cancer Invest ; 28(2): 172-80, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19968494

RESUMO

Ribonucleotide reductase 1 (RRM1) is a determinant of gemcitabine efficacy in non-small-cell lung cancer and pancreatic cancer. We investigated the protein levels of RRM1 and two other DNA repair enzymes, ERCC1 and BRCA1, in 55 metastatic breast cancer (MBC) patients undergoing gemcitabine-based chemotherapy. With automated in situ protein quantification (AQUA v1.6), the average scores for RRM1, ERCC1, and BRCA1 ranged from 245.6-2774.1, 74.0-410.3, and 54.4-1833.1, respectively. They were significantly associated with each other (Spearman's rho > or = .36; p < or = .007). Given their pattern of distribution, RRM1 and BRCA1 are potentially suitable markers for clinical decision making in MBC.


Assuntos
Proteína BRCA1/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Proteínas de Ligação a DNA/metabolismo , Desoxicitidina/análogos & derivados , Endonucleases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Desoxicitidina/uso terapêutico , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Ribonucleosídeo Difosfato Redutase , Gencitabina
19.
Oncology ; 76(1): 49-54, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19039248

RESUMO

BACKGROUND: Based on the efficacy of pegylated liposomal doxorubicin (PLD) in relapsed ovarian cancer, we are conducting a phase III study comparing carboplatin plus either paclitaxel or PLD as first-line therapy in advanced ovarian cancer. Because of limited phase I and II data on PLD plus carboplatin in this setting, we conducted an interim activity analysis. PATIENTS AND METHODS: Patients with stage 1c-IV epithelial ovarian cancer were randomized to carboplatin AUC 5 plus either paclitaxel 175 mg/m(2) or PLD 30 mg/m(2) every 3 weeks for 6 cycles. The interim activity analysis was planned according to a single-stage phase II design with an auspicated 50% response rate; 50 patients eligible for response assessment were required. Response was defined according to RECIST (Response Evaluation Criteria in Solid Tumors). RESULTS: A complete response was achieved in 14 patients (28%) and a partial response in 20 (40%), which produced an overall response rate of 68%. The activity exceeded the minimum required for study continuation. Stable disease was reported in an additional 10 patients (20%). CONCLUSIONS: The adopted schedule of PLD plus carboplatin demonstrates activity as a first-line treatment for advanced ovarian cancer.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/uso terapêutico , Doxorrubicina/análogos & derivados , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/uso terapêutico , Polietilenoglicóis/uso terapêutico , Adulto , Idoso , Antineoplásicos/uso terapêutico , Área Sob a Curva , Carboplatina/administração & dosagem , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Polietilenoglicóis/administração & dosagem , Análise de Sobrevida , Resultado do Tratamento
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