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1.
Oncology ; 101(7): 435-445, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37307799

RESUMO

INTRODUCTION: In locally advanced gastric cancer (GC), FLOT represents the standard perioperative regimen and combination with immunotherapy is under investigation. However, the role of immune tumor microenvironment (TME) is poorly recognized in this setting. We aimed to study TME characteristics and dynamics during FLOT. METHODS: Paired biopsy (PRE) and surgical (POST) samples of 25 patients treated with FLOT were prospectively analyzed. After collection of clinic-pathological data, NanoString analyses were performed. The primary objective of the study was to assess the changes induced by chemotherapy in POST compared to PRE samples. RESULTS: The unsupervised hierarchical method analysis clearly distinguished PRE and POST samples, even though some cases showed high immune gene expression at baseline. When POST samples were compared with PRE, a differential expression in hyper-expressed gene sets related to cytotoxicity, T-cell functions, complement system, tumor necrosis factor superfamily, cell cycle, and regulation was recognized. Downstaging of the primary tumor (T-regression, measured by pathologic compared to clinical T stage) was the covariate most frequently associated with these changes. Using the immune cell profiling, cases with T-regression reported a significant increase of T, CD8+ T and B cells and a decrease in mast cells, while nonresponders demonstrated an increase of T, B, cytotoxic, and mast cells. CONCLUSION: Our analysis shows that FLOT significantly influences immune TME of GC. While relevant modifications preferentially occur in tumors showing primary tumor regression, response to treatment seems to be associated with a specific immune profile.


Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/patologia , Docetaxel , Fluoruracila , Microambiente Tumoral , Leucovorina , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
2.
Am J Cancer Res ; 12(7): 3347-3356, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35968330

RESUMO

Ramucirumab plus paclitaxel is considered the standard of care in the second-line treatment of gastric carcinoma (GC). The aim of this study was to evaluate plasma vascular endothelial growth factor-A (VEGF-A), VEGF-D, and circulating soluble VEGF receptor-2 (sVEGFR-2) as possible markers of resistance or response to ramucirumab administered with paclitaxel in pretreated metastatic GC patients. Plasma samples were collected at different time points (on days 1 and 15 of the first 3 cycles, at best radiologic response and at disease progression). VEGF-A, VEGF-D and sVEGFR-2 were analysed by ELISA. Correlations of biomarker baseline levels or dynamic changes with outcome measures were assessed. Progression-free survival (PFS) was the primary endpoint of the study. Forty-one patients were enrolled. VEGF-A and VEGF-D, but not sVEGFR-2, values significantly increased during treatment compared to baseline (P < 0.001). A positive correlation between VEGF-A and sVEGFR-2 at cycle 2 was found (P=0.045). At univariate analysis, higher baseline levels of VEGF-A were associated with worse OS (P=0.015). Early increase of sVEGFR-2 levels after the first treatment cycle was the only factor associated with longer PFS (6.6 vs. 3.6 months, P=0.049) and OS (18.6 vs. 5.2 months, P=0.008). Significance of sVEGFR-2 early increase was retained at multivariate analysis for OS (HR 0.32; 95% CI 0.12-0.91; P=0.032). The reported results confirmed the prognostic role of baseline VEGF-A and, with the limitations of the limited sample size and the lack of a control arm, suggested that the early increase of sVEGFR-2 after 1 cycle of treatment could be a potential predictive biomarker of benefit from second-line ramucirumab plus paclitaxel in GC.

3.
J Clin Med ; 10(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807648

RESUMO

Sarcopenia is recognised as a predictor of toxicity and survival in localised and locally advanced gastric cancer (GC). Its prognostication power in advanced unresectable or metastatic GC (aGC) is debated. The survival impact of visceral and subcutaneous fat distribution (visceral fat area (VFA)/subcutaneous fat area (SFA)) is ambiguous. Our aim was to determine the influence of body composition parameters (BCp) on toxicity and survival in aGC patients undergoing palliative treatment. BCp were retrospectively assessed by baseline computed tomography for 78 aGC patients who received first-line chemotherapy from March 2010 to January 2017. Correlations between BCp and toxicity and survival were calculated by χ2-test and by log-rank-test and Cox-model, respectively. Sarcopenia fails to show association with progression-free survival (PFS) (p = 0.44) and overall survival (OS) (p = 0.88). However, sarcopenia influences the development of high-grade neutropenia (p = 0.048) and mucositis (p = 0.054). VFA/SFA (high vs. all the rest) results as a strong predictor of objective response (p = 0.02) and outcome (PFS, p = 0.001; OS, p = 0.02). At multivariate analysis for PFS, prognostic factors are VFA/SFA (p = 0.03) and a neutrophil-lymphocyte ratio >3. The same factors remain significant for OS (each p = 0.03) along with Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.008) and number of metastatic sites ≥2 (p < 0.001). In our cohort of aGC, VFA/SFA exhibit a robust impact on survival, with a higher sensitivity than sarcopenia.

4.
Eur J Cancer ; 137: 108-116, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32750500

RESUMO

BACKGROUND: Gemcitabine plus nab-paclitaxel (Gem-Nab) represents a standard first-line treatment for metastatic pancreatic cancer (mPC), but few data are available for elderly patients. We aimed to add evidence about safety and efficacy of Gem-Nab in this population. METHODS: We collected data of 156 patients with mPC aged ≥65 years receiving Gem-Nab. Patients were stratified according to age: <70 (group 1: 65 patients) and ≥70 years (group 2: 91 patients). RESULTS: The median age was 71 years (range: 65-87 years). The toxicity profile was similar between group 1 and 2, except for all-grade anaemia (92.1% vs. 78.7%, respectively; p = 0.04) and neurotoxicity (61.9% vs. 40.4%, respectively; p = 0.02), also as a result of a lower dose intensity of nab-paclitaxel (83.3% vs. 90.5%, respectively; p = 0.04) administered to oldest patients. The response rate was 25.6% (group 1 vs. 2: 20.0% vs. 29.7%; p = 0.12). After a median follow-up of 26.5 months, median overall survival (OS) and progression-free survival (PFS) were similar between the groups (p > 0.05). The starting dose of Gem-Nab did not affect PFS and OS (p > 0.05). CONCLUSION: Gem-Nab is active and effective in older patients with mPC, with the results in line with the general mPC population enrolled in clinical trials. Mild dose modifications for elderly patients might be considered to improve safety without impairing efficacy.


Assuntos
Albuminas/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Desoxicitidina/análogos & derivados , Paclitaxel/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Albuminas/farmacologia , Antimetabólitos Antineoplásicos/farmacologia , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Feminino , Humanos , Masculino , Metástase Neoplásica , Paclitaxel/farmacologia , Neoplasias Pancreáticas/patologia , Gencitabina
5.
Oncologist ; 25(10): 886-893, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32353192

RESUMO

BACKGROUND: HER2 overexpression has been investigated as a potential biomarker and therapeutic target in biliary tract cancer (BTC), but a prognostic role of such alteration has not been demonstrated yet. MATERIALS AND METHODS: We retrospectively evaluated HER2 protein expression by immunohistochemistry (IHC) in 100 patients with radically resected BTC. HER2 gene amplification was assessed by fluorescence in situ hybridization (FISH) in 2+ and 3+ cases at IHC. High HER2 protein expression was defined as either IHC 3+ or 2+ associated with FISH positivity. The primary objective of the study was to evaluate the prognostic role of HER2 overexpression in terms of disease-free survival (DFS) and overall survival (OS). Secondary endpoints were the prevalence of HER2 overexpression and the possible correlation with other clinicopathological features. RESULTS: HER2 overexpression was identified in 11 patients and was not related to other clinicopathological factors. DFS was significantly shorter in HER2-positive compared with HER2-negative patients (10.6 vs. 20.9 months, log-rank p = .017). HER2 confirmed its prognostic value for DFS at multivariate analysis (hazard ratio 2.512; 95% confidence interval, 1.232-5.125; p = .011) together with nodal stage (p < .001), resection margin (p = .027), and tumor site (p = .030). There was no difference in OS between HER2-positive and -negative patients (p = .068). CONCLUSION: HER2 overexpression represents an independent prognostic factor for disease recurrence in patients with BTC treated with potentially curative surgery. IMPLICATIONS FOR PRACTICE: HER2 overexpression may play an independent role in promoting an aggressive behavior in resectable biliary tract cancer. This evidence could be helpful in improving prognostic stratification after resection and, primarily, should endorse the rationale to investigate HER2 as a therapeutic target in biliary tract cancer.


Assuntos
Neoplasias do Sistema Biliar , Recidiva Local de Neoplasia , Neoplasias do Sistema Biliar/genética , Neoplasias do Sistema Biliar/cirurgia , Humanos , Hibridização in Situ Fluorescente , Recidiva Local de Neoplasia/genética , Estadiamento de Neoplasias , Prognóstico , Receptor ErbB-2/genética , Estudos Retrospectivos
6.
Int J Mol Sci ; 21(5)2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32121290

RESUMO

Esophageal cancer remains a challenging disease due to limited treatment options and poor prognosis. In recent years, immune checkpoint inhibitors (ICI) have been proven to be safe and effective in the treatment of highly lethal malignancies, such as non-small cell lung cancer and melanoma. Recent clinical trials also showed promising activity in immune checkpoint inhibitors in pretreated advanced esophageal carcinoma and a potentially significant impact on the outcome of selected patients, independently of histology. Combination studies evaluating immunotherapy and chemotherapy and, in localized disease, radiotherapy are in progress and will hopefully confirm their promises in the near future. However, reliable predictive biomarkers are still lacking. Indeed, at present, the role of programmed cell death ligand 1 expression and other factors (such as microsatellite instability and tumor mutational burden) as predictive biomarkers of benefit to immune checkpoint inhibitors is still controversial. Our aim was to explore the rationale of ICIs in esophageal cancer, review the results already available in multiple settings, and investigate future perspectives with single-agent and combination strategies.


Assuntos
Neoplasias Esofágicas/imunologia , Neoplasias Esofágicas/terapia , Imunoterapia , Animais , Ensaios Clínicos como Assunto , Dano ao DNA , Neoplasias Esofágicas/patologia , Microbioma Gastrointestinal , Humanos
7.
Cancers (Basel) ; 11(7)2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31277449

RESUMO

Early tumor shrinkage (ETS) and depth of response (DoR) predict favorable outcomes in metastatic colorectal cancer. We aim to evaluate their prognostic role in metastatic pancreatic cancer (PC) patients treated with first-line modified-FOLFIRINOX (FOLFOXIRI) or Gemcitabine + Nab-paclitaxel (GemNab). Hence, 138 patients were tested for ETS, defined as a ≥20% reduction in the sum of target lesions' longest diameters (SLD) after 6-8 weeks from baseline, and DoR, i.e., the maximum percentage shrinkage in the SLD from baseline. Association of ETS and DoR with progression-free survival (PFS) and overall survival (OS) was assessed. ETS was reached in 49 patients (39.5% in the FOLFOXIRI, 29.8% in the GemNab group; p = 0.280). In the overall population, ETS was significantly associated with better PFS (8.0 vs. 4.8 months, p < 0.001) and OS (13.2 vs. 9.7 months, p = 0.001). Median DoR was -27.5% (-29.4% with FOLFOXIRI and -21.4% with GemNab, p = 0.016): DoR was significantly associated with better PFS (9.0 vs. 6.7 months, p < 0.001) and OS (14.3 vs. 11.1 months, p = 0.031). Multivariate analysis confirmed both ETS and DoR are independently associated with PFS and OS. In conclusion, our study added evidence on the role of ETS and DoR in the prediction of outcome of PC patients treated with first-line combination chemotherapy.

8.
Br J Cancer ; 120(5): 522-526, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30745584

RESUMO

BACKGROUND: HER2 is the only validated predictive biomarker in gastro-oesophageal carcinoma (GOC). However, several factors, such as heterogeneity in protein expression, shortage of evaluable tumour tissue and need for quick target assessment, underline the usefulness of a pre-screening tool in order to anticipate HER2 status. METHODS: Data from 723 consecutive GOC analysed for HER2 at four Italian Institutions were collected. HER2 positivity was defined as 3+ by immunohistochemistry (IHC) or 2+ with gene amplification by in situ hybridisation (ISH). A multivariate logistic regression model was built using data from 413 cases, whereas 310 patients served as validation cohort. C-index, visual inspection of the calibration plot, Brier score and Spiegelhalter z-test were used to assess the performance of the nomogram. RESULTS: HER2 positive rate was 17.4%. Four variables were retained after adjustment in the final model: grading, Lauren's histotype, pathologic material analysed (surgical specimen/biopsy) and site of tissue collection (primary tumour/metastases). Visual inspection of the calibration plot revealed a very good overlap between predicted and observed probabilities, with a Brier score of 0.101 and a non-significant Spiegelhalter z-test (P = 0.319). C-index resulted in 0.827 (95%CI 0.741-0.913). CONCLUSION: A simple nomogram based on always-available pathologic information accurately predicts the probability of HER2 positivity in GOC.


Assuntos
Carcinoma/metabolismo , Junção Esofagogástrica/metabolismo , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/metabolismo , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma/tratamento farmacológico , Feminino , Amplificação de Genes , Humanos , Imuno-Histoquímica , Modelos Logísticos , Masculino , Análise Multivariada , Nomogramas , Reprodutibilidade dos Testes , Neoplasias Gástricas/tratamento farmacológico , Trastuzumab/uso terapêutico
9.
Cancer Biomark ; 21(3): 731-741, 2018 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-29278885

RESUMO

PURPOSE: The evaluation of molecular targets in gastric cancer has demonstrated the predictive role of HER2 amplification for trastuzumab treatment in metastatic gastric cancer. Besides HER2, other molecular targets are under evaluation in metastatic gastric tumors. However, very little is known about their role in resected tumors. We evaluated the expression of HER2, EGFR, MET, AKT1 and phospho-mTOR in resected stage II-III adenocarcinomas. METHODS: Ninety-two patients with resected stomach (63%) or gastro-esophageal adenocarcinomas (27%) were evaluated. Antibodies anti-HER2, EGFR, MET, AKT1 and phospho-mTOR were used for immunostaining of formalin-fixed paraffin-embedded slides. Using FISH, HER2 amplification was evaluated in cases with an intermediate (+2) staining. RESULTS: EGFR overexpression (11%) was a poor prognostic factor for overall survival (3-year OS: 47% vs 77%; Log-Rank p= 0.033). MET overexpression (36%) was associated with a trend for a worse survival (3-year OS: 65% vs 77%; Log-Rank p= 0.084). HER2 amplification/overexpression and mTOR hyper-phosphorylation were observed in 13% and 48% of tumors, respectively. AKT1 overexpression (8%) was not a prognostic factor by itself (p= 0.234). AKT1 and EGFR overexpression was mutually exclusive and patients with EGFR or AKT1 overexpression experienced a poor prognosis (3-year OS: 52% vs. 79%, Log-Rank p= 0.005). CONCLUSIONS: EGFR is confirmed a poor prognostic factor in resected gastric cancers. We firstly describe a mutually exclusive overexpression of EGFR and AKT1 with potential prognostic implications, suggesting the relevance of this pathway for the growth of gastric cancers.


Assuntos
Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Receptores ErbB/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Terapia Combinada , Receptores ErbB/genética , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Estudos Retrospectivos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia
10.
Future Oncol ; 13(25): 2265-2275, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28976226

RESUMO

AIM: To evaluate the impact on overall survival (OS) of gastrectomy in asymptomatic metastatic esophago-gastric cancer. PATIENTS & METHODS: Five hundred and thirteen patients were included. The role of surgery and other clinico-pathological factors was evaluated by univariate and Cox regression analyses. OS was the primary end point. RESULTS: Multivariate analysis confirmed that gastrectomy was a predictor of longer OS (p < 0.001), as well as preserved performance status and benefit from first-line chemotherapy. None of the investigated clinico-pathological variables identified preferable candidates for surgery (all p > 0.05). CONCLUSION: Palliative gastrectomy might play a role in asymptomatic metastatic esophago-gastric cancer patients with good performance status who received benefit from first-line chemotherapy. Future prospective trials integrating tumor biology among inclusion criteria may help defining the optimal candidates.


Assuntos
Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Junção Esofagogástrica/patologia , Gastrectomia , Seleção de Pacientes , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Neoplasias Esofágicas/diagnóstico por imagem , Neoplasias Esofágicas/mortalidade , Feminino , Gastrectomia/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Estudos Retrospectivos , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/mortalidade , Resultado do Tratamento
11.
Oncotarget ; 8(9): 14408-14415, 2017 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-28122337

RESUMO

The ARQ 197-215 study randomized patients to tivantinib or placebo and pre-specified efficacy analyses indicated the predictive value of MET expression as a marker of benefit from tivantinib in hepatocellular carcinoma (HCC). We aimed to explore the neutrophil-to-lymphocyte ratio (NLR) in 98 ARQ 197-215 patients with available absolute neutrophil count and absolute lymphocyte count at baseline. The cut-off value used to define high versus low NLR was 3.0. In univariate analysis, high NLR was associated with hazard ratio (HR) for overall survival (OS) of 1.58 [95% confidence interval (CI) 1.01; 2.47; P <0.046], corresponding to median OS of 5.1 months versus 7.8 months in patients with low NLR (P = 0.044). In contrast, time to progression was not significantly affected by NLR (P = 0.20). Multivariable model confirmed that both NLR >3 (P = 0.03) and presence of vascular invasion (P = 0.017) were negatively associated with OS. After adjustment for vascular invasion, NLR independently predicted survival in both the placebo and the tivantinib cohort. For OS, no interaction was detected between NLR status and treatment (Pinteraction = 0.40). Baseline NLR is an independent prognostic biomarker in patients with HCC and compensated liver function who are candidate for second-line treatments.


Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Linfócitos/patologia , Neutrófilos/patologia , Pirrolidinonas/uso terapêutico , Quinolinas/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Seguimentos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Invasividade Neoplásica , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida
12.
Oncology ; 91(6): 311-316, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27705972

RESUMO

PURPOSE: The aim of this study was to evaluate the activity of the combination of 5-fluorouracil/folinic acid and irinotecan (FOLFIRI) as third-line chemotherapy (CT) in metastatic gastric cancer (mGC) patients pretreated with platinum derivatives, fluoropyrimidines, and taxanes. METHODS: We prospectively collected data of mGC patients treated with third-line FOLFIRI at our institution from 2009 to 2014. Eligible patients should be treated with a fluoropyrimidine-platinum first-line CT and a subsequent taxane-based second-line CT. FOLFIRI consisted of irinotecan 180 mg/m2 and leucovorin 200 mg/m2, followed by 5-fluorouracil 2,800 mg/m2 (administered as 48-hour i.v. continuous infusion from day 1 to 3), with cycles repeated every 2 weeks. Response rate (RR) was evaluated according to RECIST version 1.0, while progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: A total of 33 patients were included. The majority (97%) had good performance status (0-1 according to ECOG), while median PFS after first-line and second-line CT was 5.2 and 4.4 months, respectively. Two patients experienced an objective response (RR: 6%), while 14 patients achieved disease stabilization (disease control rate: 42%). Median PFS and OS from the start of third-line CT were 3.3 and 7.5 months, respectively. Hematological and nonhematological grade 3-4 toxicities were uncommon and included neutropenia (6.1%), diarrhea (9.1%), vomiting (3%), and asthenia (3%). Febrile neutropenia was not reported. CONCLUSIONS: Third-line CT with FOLFIRI may be an option in heavily pretreated mGC patients with preserved performance status and organ function. This regimen has a favorable safety profile, and signs of activity have been observed after standard first- and second-line CT.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Astenia/induzido quimicamente , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Diarreia/induzido quimicamente , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Irinotecano , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Estudos Prospectivos , Critérios de Avaliação de Resposta em Tumores Sólidos , Retratamento , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Vômito/induzido quimicamente , População Branca
13.
Oncotarget ; 7(45): 72622-72633, 2016 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-27579536

RESUMO

ARQ 197-215 was a randomized placebo-controlled phase II study testing the MET inhibitor tivantinib in second-line hepatocellular carcinoma (HCC) patients. It identified tumor MET as a key biomarker in HCC.Aim of this research was to study the prognostic and predictive value of tumor (MET, the receptor tyrosine kinase encoded by the homonymous MNNG-HOS transforming gene) and circulating (MET, hepatocyte growth factor [HGF], alpha-fetoprotein [AFP], vascular endothelial growth factor [VEGF]) biomarkers in second-line HCC. Tumor MET-High status was centrally assessed by immunohistochemistry. Circulating biomarkers were centrally analyzed on serum samples collected at baseline and every 4-8 weeks, using medians as cut-off to determine High/Low status. Tumor MET, tested in 77 patients, was more frequently High after (82%) versus before (40%) sorafenib. A significant interaction (p = 0.04) between tivantinib and baseline tumor MET in terms of survival was observed. Baseline circulating MET and HGF (102 patients) High status correlated with shorter survival (HR 0.61, p = 0.03, and HR 0.60, p = 0.02, respectively), while the association between AFP (104 patients) or VEGF (103 patients) status and survival was non-significant. CONCLUSIONS: Tumor MET levels were higher in patients treated with sorafenib. Circulating biomarkers such as MET and HGF may be prognostic in second-line HCC. These results need to be confirmed in larger randomized clinical trials.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/uso terapêutico , Pirrolidinonas/uso terapêutico , Quinolinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-met/administração & dosagem , Proteínas Proto-Oncogênicas c-met/farmacologia , Pirrolidinonas/administração & dosagem , Pirrolidinonas/farmacologia , Quinolinas/administração & dosagem , Quinolinas/farmacologia , Análise de Sobrevida
14.
Medicine (Baltimore) ; 95(13): e3151, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27043676

RESUMO

To investigate the prognostic value of tumor metabolism measurements on serial 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography and computed tomography scans in patients with locally advanced esophageal cancer undergoing neoadjuvant chemoradiotherapy. Forty-five patients (63 ±â€Š7 years, 6 female) treated with concomitant chemoradiotherapy before surgery were followed up for 24 ±â€Š18 months (range 4-71). Positron emission tomography and computed tomography scans were obtained within 1 week before the start (PET1) and 1 month after the completion of the treatment (PET2). Total body tumor metabolic activity was measured as the sum of the parameters: SUVmax, SUV corrected for lean body mass, and total lesion glycolysis (TLG40/50/70%). Then, delta values for the parameters between PET1 and PET2 were calculated and expressed as percentage of PET1 results. At the time of the analysis, 27 patients were dead and 18 were alive. There was no difference between the 2 groups in terms of age, sex, site of the disease, histology, and the presence/absence of linfonodal metastases (P = NS). Survival random forest analysis (20,000 trees) resulted in an estimate of error rate of 36%. The nonparametric approach identified ΔTLG40 as the most predictive factor of survival (relative importance 100%). Moreover, T (17%), N (5%), and M (5%) stage of the disease, cancer histology (11%), TLG70 (5%) at the end of chemioradioterapy, and ΔTLG(50-70) (17%-5%) were positively associated with patient outcome. The nonparametric analysis confirmed the prognostic importance of some clinical parameters, such as TNM stage and cancer histology. Moreover, ΔTLG resulted to be the most important factor in predicting outcome and should be considered in risk stratification of patients treated with neoadjuvant chemoradiotherapy.


Assuntos
Neoplasias Esofágicas/mortalidade , Fluordesoxiglucose F18/administração & dosagem , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Tomografia Computadorizada por Raios X/métodos , Idoso , Composição Corporal , Quimiorradioterapia Adjuvante/métodos , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estatísticas não Paramétricas
15.
Int J Cancer ; 139(4): 938-45, 2016 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-27038273

RESUMO

FOLFIRINOX is a standard first-line treatment for advanced pancreatic cancer (aPC). The Gruppo Oncologico Nord Ovest (GONO) FOLFOXIRI regimen demonstrated efficacy in metastatic colorectal cancer. We aimed to evaluate activity and tolerability of FOLFOXIRI regimen in patients with aPC and to explore putative prognostic factors. One hundred thirty-seven consecutive aPC patients were treated with FOLFOXIRI in our institution between 2008 and 2014. Clinical, laboratory and pathological data were collected and their association with activity, progression free survival (PFS) and overall survival (OS) was investigated. After a median follow up of 30 months, median PFS and OS were 8.0 months (95% CI 6.19-9.81) and 12 months (95% CI 9.75-14.25), respectively. Response rate was 38.6%, while disease-control rate 72.2%. At multivariate analysis liver metastases (p = 0.019; Hazard Ratio, HR, 0.59, 95% Confidence Interval, CI, 0.380.96), Eastern Cooperative Oncology Group (ECOG) performance status (PS) 1 (p = 0.001; HR 2.26, 95%CI 1.42-3.59) and neutrophil-lymphocyte ratio (NLR)> 4 (p= 0.002; HR: 2.42; 95% CI 1.38-4.25) were associated with poorer OS. We categorized 119 pts with complete available data as good-risk (0 factors, 38 pts), intermediate-risk (1 factor, 49 pts) and poor-risk (≥2 factors, 32 pts). Median OS for these three groups were 17.6, 11.1 and 7.4 months, respectively (p < 0.001). FOLFOXIRI is active and feasible in aPC. Prognosis of aPC pts treated with FOLFOXIRI is influenced by easily available factors: our analysis revealed ECOG PS, liver metastases and NLR as the most important predictors of survival. These factors could be helpful for treatment decision and clinical trial design.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/efeitos adversos , Camptotecina/uso terapêutico , Estudos de Coortes , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Leucovorina/efeitos adversos , Leucovorina/uso terapêutico , Contagem de Leucócitos , Linfócitos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Neutrófilos , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/uso terapêutico , Neoplasias Pancreáticas/mortalidade , Prognóstico , Análise de Sobrevida , Resultado do Tratamento
16.
Future Oncol ; 12(7): 901-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26883177

RESUMO

BACKGROUND: FOLFIRINOX is a standard first-line treatment for advanced pancreatic cancer (aPC) and no accepted second-line regimen exists. MATERIAL & METHODS: We enrolled 71 aPC patients progressed to modified FOLFIRINOX (mFOLFIRINOX) treated with second-line chemotherapy. RESULTS: Five partial responses (7.1%) and 19 (27.1%) disease stabilizations were reported. After a median follow-up of 20.1 months, median progression-free survival was 2.5 months (95% CI: 2.1-2.9 months) and median overall survival was 6.2 months (95% CI: 5.3-7.1 months). At multivariate analysis, CA19.9 level ≥ 59 upper normal limit resulted associated with worse survival (hazard ratio: 2.32; 95% CI: 1.12-4.78; p = 0.023). CONCLUSION: Salvage chemotherapy could be useful for a subgroup of aPC patients. Prognostic factors might be helpful to identify patients with greater benefit.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Feminino , Humanos , Masculino , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Neoplasias Pancreáticas/mortalidade , Prognóstico , Retratamento , Resultado do Tratamento
17.
Lancet Oncol ; 14(1): 55-63, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23182627

RESUMO

BACKGROUND: Tivantinib (ARQ 197), a selective oral inhibitor of MET, has shown promising antitumour activity in hepatocellular carcinoma as monotherapy and in combination with sorafenib. We aimed to assess efficacy and safety of tivantinib for second-line treatment of advanced hepatocellular carcinoma. METHODS: In this completed, multicentre, randomised, placebo-controlled, double-blind, phase 2 study, we enrolled patients with advanced hepatocellular carcinoma and Child-Pugh A cirrhosis who had progressed on or were unable to tolerate first-line systemic therapy. We randomly allocated patients 2:1 to receive tivantinib (360 mg twice-daily) or placebo until disease progression. The tivantinib dose was amended to 240 mg twice-daily because of high incidence of treatment-emergent grade 3 or worse neutropenia. Randomisation was done centrally by an interactive voice-response system, stratified by Eastern Cooperative Oncology Group performance status and vascular invasion. The primary endpoint was time to progression, according to independent radiological review in the intention-to-treat population. We assessed tumour samples for MET expression with immunohistochemistry (high expression was regarded as ≥2+ in ≥50% of tumour cells). This study is registered with ClinicalTrials.gov, number NCT00988741. FINDINGS: 71 patients were randomly assigned to receive tivantinib (38 at 360 mg twice-daily and 33 at 240 mg twice-daily); 36 patients were randomly assigned to receive placebo. At the time of analysis, 46 (65%) patients in the tivantinib group and 26 (72%) of those in the placebo group had progressive disease. Time to progression was longer for patients treated with tivantinib (1·6 months [95% CI 1·4-2·8]) than placebo (1·4 months [1·4-1·5]; hazard ratio [HR] 0·64, 90% CI 0·43-0·94; p=0·04). For patients with MET-high tumours, median time to progression was longer with tivantinib than for those on placebo (2·7 months [95% CI 1·4-8·5] for 22 MET-high patients on tivantinib vs 1·4 months [1·4-1·6] for 15 MET-high patients on placebo; HR 0·43, 95% CI 0·19-0·97; p=0·03). The most common grade 3 or worse adverse events in the tivantinib group were neutropenia (ten patients [14%] vs none in the placebo group) and anaemia (eight [11%] vs none in the placebo group). Eight patients (21%) in the tivantinib 360 mg group had grade 3 or worse neutropenia compared with two (6%) patients in the 240 mg group. Four deaths related to tivantinib occurred from severe neutropenia. 24 (34%) patients in the tivantinib group and 14 (39%) patients in the placebo group had serious adverse events. INTERPRETATION: Tivantinib could provide an option for second-line treatment of patients with advanced hepatocellular carcinoma and well-compensated liver cirrhosis, particularly for patients with MET-high tumours. Confirmation in a phase 3 trial is needed, with a starting dose of tivantinib 240 mg twice-daily. FUNDING: ArQule, Daiichi Sankyo (Daiichi Sankyo Group).


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Neoplasias Hepáticas/tratamento farmacológico , Pirrolidinonas/administração & dosagem , Quinolinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/patologia , Intervalo Livre de Doença , Método Duplo-Cego , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Feminino , Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-met/metabolismo , Pirrolidinonas/efeitos adversos , Quinolinas/efeitos adversos
18.
Cancer Chemother Pharmacol ; 69(3): 773-80, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22033636

RESUMO

PURPOSE: Sorafenib improves overall survival and time to progression of advanced hepatocellular (aHCC) patients such as demonstrated in 2 phase III trials. However, aHCC patients' outcome is still poor despite these results. In order to improve the efficacy of systemic treatment for aHCC, we evaluated the combination of sorafenib plus 5-fluorouacil infusion in a phase II trial. METHODS: Patients with aHCC not eligible for loco-regional therapies, Child-Pugh A-B, ECOG-PS 0-1, and without history of anti-cancer systemic treatment were enrolled. Treatment schedule was: sorafenib 400 mg/bid continuously and continuum infusion of 5-fluorouracil 200 mg/sqm/daily day 1-14 every 3 weeks. RESULTS: Thirty-nine patients were enrolled: ECOG-PS 0-1: 29-10, Child-Pugh A-B: 36-3. Grade 3/4 (%) toxicities included: diarrhea 5.1/0, mucositis 20.5/2.6, hand foot skin reaction 20.5/0, skin rash 10.5/0, hypertension 10.3/0, hyperbilirubinemia 5.1/2.6, glutamic-oxaloacetic transaminase increase 10.3/0, glutamic-pyruvic transaminase increase 7.7/0, cardiac toxicity (one heart failure, two atrial fibrillation cases) 7.7/0, and bleeding (melena) in 2.6/0. One partial response was observed. Stable disease was obtained in 46.2% of patients with a median duration of 16.2 months. Median time to progression was 8 months (CI 95% = 5.7-10.4), and median overall survival was 13.7 months (CI 95% = 9.5-17.9). CONCLUSIONS: The results show an encouraging disease control rate, time to progression, and overall survival. The combination of sorafenib and 5-fluorouracil was feasible, and the side effects were manageable for patients carefully selected for liver function and performance status.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzenossulfonatos/administração & dosagem , Benzenossulfonatos/efeitos adversos , Benzenossulfonatos/uso terapêutico , Carcinoma Hepatocelular/patologia , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Infusões Intravenosas , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Sorafenibe
19.
Brachytherapy ; 9(2): 185-91, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-19875341

RESUMO

PURPOSE: The aim of this work was to analyze the efficacy of high-dose-rate brachytherapy in the management of patients with esophageal cancer. METHODS AND MATERIALS: Between 2001 and 2008, 104 patients (88 males and 16 females) received a brachytherapy treatment as a part of a personalized multimodal approach. The median age was 72 years, and the median Karnofsky performance status was 60. Brachytherapy was used in different situations: to complete a primary treatment with radical intent in patients not suitable for surgery; to control local recurrences; or to obtain a rapid and durable palliation of dysphagia in patients with metastases or in poor general condition. In selected cases, endoscopic ultrasound images were integrated in treatment planning procedure to obtain a more accurate volume definition. Efficacy in controlling dysphagia was assessed 1 month after brachytherapy. RESULTS: Fifty-one patients received a radical treatment, and 53 patients were treated to relieve the symptoms. The median overall survival was 20.8 months. Lymph node involvement was found to be a significant prognostic factor for overall survival and dysphagia. Dysphagia was controlled in 88 patients (84.6%), and the median dysphagia-free interval was 17.5 months. Early and late adverse events were generally mild to moderate. The most severe effects were esophagotracheal fistulas, observed in 3 patients. CONCLUSIONS: Brachytherapy has an important role in the management of esophageal cancer with a low rate of complications. endoscopic ultrasound-assisted treatment planning can be useful for a better individualization of curative treatments.


Assuntos
Braquiterapia/métodos , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/prevenção & controle , Neoplasias Esofágicas/complicações , Neoplasias Esofágicas/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
20.
Clin Cancer Res ; 14(9): 2749-55, 2008 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-18451241

RESUMO

PURPOSE: To evaluate 5-fluorouracil (5-FU) and 5-fluoro-5,6-dihydrouracil (5-FDHU) pharmacokinetics and disease-free survival (DFS) in colorectal cancer patients given 5-FU-based adjuvant chemotherapy within a nonrandomized, retrospective, pharmacokinetic study. EXPERIMENTAL DESIGN: One hundred fifteen patients including 72 men (median age, 63 years; range, 36-79 years) and 43 women (median age, 60 years; range, 36-73 years) received 6 cycles of l-leucovorin 100 mg/m(2)/day and 5-FU 370 mg/m(2)/day i.v. boluses (5 days every 4 weeks). Individual plasma concentrations of 5-FU and 5-FDHU were determined on day 1 of the first cycle with a validated high performance liquid chromatography method, and the main pharmacokinetic variables were determined. Follow-up of all patients was extended up to 5 years after the end of adjuvant chemotherapy, and DFS was recorded. Univariate and multivariate analyses were conducted to evaluate any correlation among 5-FU pharmacokinetics, clinical and pathologic variables, and DFS. RESULTS: The area under the time/concentration curve (AUC) of 5-FU was significantly lower in 58 subjects who recurred (7.5 +/- 2.9 h x mg/L) with respect to other patients (9.3 +/- 4.1 h x mg/L). Furthermore, AUC values lower than 8.4 h x mg/L together with lymph node involvement and the interruption of treatment or reduction of doses were identified as risk factors at univariate analysis. The completion of 6 cycles of adjuvant treatment without dosage modifications was the only independent risk factor at multivariate analysis, despite a trend toward significance for 5-FU AUC values (cutoff value, 8.4 hxmg/L) was observed (P = 0.06). CONCLUSIONS: Pharmacokinetics of 5-FU should be regarded as an important factor for predicting disease recurrence in colorectal cancers.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/análogos & derivados , Fluoruracila/farmacocinética , Leucovorina/uso terapêutico , Adulto , Idoso , Análise de Variância , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/uso terapêutico , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos
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