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1.
Support Care Cancer ; 23(3): 661-70, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25160493

RESUMO

PURPOSE: Calcium aluminosilicate clay (CASAD) is a naturally occurring clay that serves as a cation exchange absorbent. We hypothesized that oral administration of CASAD would reduce the rate of grade 3/4 diarrhea associated with irinotecan use for metastatic colorectal cancer (CRC) by adsorbing the SN-38 metabolite. METHODS: Patients receiving irinotecan-based chemotherapy were randomized equally between CASAD and placebo arms in this multicenter trial in order to assess differences in the proportions of patients with grade 3/4 diarrhea within 6 weeks. Additionally, we compared symptom severity between the two arms using the M.D. Anderson Symptom Inventory. RESULTS: Between May 2009 and May 2012, 100 patients were enrolled. In evaluable patients, 7 of 43 (16 %) on the CASAD arm compared to 3 of 32 (9 %) on the placebo arm experienced grade 3/4 diarrhea (P = 0.70). The rate of any diarrhea among all patients was similar (CASAD arm, 64 % vs. placebo arm, 70 %). The rate of study dropout was 14 % in the CASAD arm and 38 % in the placebo arm (P = 0.01). No differences were found in symptom severity, individual symptom items, and in serious adverse events between the two arms. CONCLUSION: Compared to placebo, CASAD use was safe but ineffective in preventing diarrhea in metastatic CRC patients treated with irinotecan-containing chemotherapy regimens. There were no distinct signals in terms of patient symptoms between arms, but there was significantly more patient dropout in the placebo arm. Future CASAD trials will focus on the active treatment of diarrhea.


Assuntos
Silicatos de Alumínio/uso terapêutico , Antineoplásicos Fitogênicos/efeitos adversos , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Diarreia/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Fitogênicos/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Argila , Neoplasias Colorretais/patologia , Diarreia/induzido quimicamente , Método Duplo-Cego , Feminino , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Placebos , Resultado do Tratamento , Adulto Jovem
2.
J Clin Oncol ; 28(3): 453-9, 2010 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-20008624

RESUMO

PURPOSE: We investigated the efficacy of fluorouracil (FU), leucovorin, irinotecan, and bevacizumab (FOLFIRI + B) in a phase II trial in patients previously untreated for metastatic colorectal cancer (mCRC), and changes during treatment in plasma cytokines and angiogenic factors (CAFs) as potential markers of treatment response and therapeutic resistance. PATIENTS AND METHODS: We conducted a phase II, two-institution trial of FOLFIRI + B. Each 14-day cycle consisted of bevacizumab (5 mg/kg), irinotecan (180 mg/m(2)), bolus FU (400 mg/m(2)), and leucovorin (400 mg/m(2)) followed by a 46-hour infusion of FU (2,400 mg/m(2)). Levels of 37 CAFs were assessed using multiplex-bead assays and enzyme-linked immunosorbent assay at baseline, during treatment, and at the time of progressive disease (PD). RESULTS: Forty-three patients were enrolled. Median progression-free survival (PFS), the primary end point of the study, was 12.8 months. Median overall survival was 31.3 months, with a response rate of 65%. Elevated interleukin-8 at baseline was associated with a shorter PFS (11 v 15.1 months, P = .03). Before the radiographic development of PD, several CAFs associated with angiogenesis and myeloid recruitment increased compared to baseline, including basic fibroblast growth factor (P = .046), hepatocyte growth factor (P = .046), placental growth factor (P < .001), stromal-derived factor-1 (P = .04), and macrophage chemoattractant protein-3 (P < .001). CONCLUSION: Efficacy and tolerability of FOLFIRI + B appeared favorable to historical controls in this single arm study. Before radiographic progression, there was a shift in balance of CAFs, with a rise in alternate pro-angiogenic cytokines and myeloid recruitment factors in subsets of patients that may represent mechanisms of resistance.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Indutores da Angiogênese/sangue , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Bevacizumab , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Neoplasias Colorretais/sangue , Neoplasias Colorretais/secundário , Citocinas/sangue , Resistencia a Medicamentos Antineoplásicos , Feminino , Fluoruracila/uso terapêutico , Humanos , Irinotecano , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
3.
J Clin Oncol ; 27(6): 843-50, 2009 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-19139433

RESUMO

PURPOSE: The study objective was to determine the proportion of patients with hepatocellular carcinoma (HCC) treated with the combination of bevacizumab (B) and erlotinib (E) who were alive and progression free at 16 weeks (16-week progression-free survival [PFS16]) of continuous therapy. Secondary objectives included response rate, median PFS, survival, and toxicity. PATIENTS AND METHODS: Patients who had advanced HCC that was not amenable to surgical or regional therapies, up to one prior systemic treatment; Childs-Pugh score A or B liver function; Eastern Cooperative Oncology Group performance status 0, 1, or 2 received B 10 mg/kg every 14 days and E 150 mg orally daily, continuously, for 28-day cycles. Tumor response was evaluated every 2 cycles by using Response Evaluation Criteria in Solid Tumors Group criteria. A total of 40 patients were treated. RESULTS: The primary end point of PFS16 was 62.5%. Ten patients achieved a partial response for a confirmed overall response rate (intent-to-treat) of 25%. The median PFSevent was 39 weeks (95% CI, 26 to 45 weeks; 9.0 months), and the median overall survival was 68 weeks (95% CI, 48 to 78 weeks; 15.65 months). Grades 3 to 4 drug-related toxicity included fatigue (n = 8; 20%), hypertension (n = 6; 15%), diarrhea (n = 4; 10%) elevated transaminases (n = 4; 10%), gastrointestinal hemorrhage (n = 5; 12.5%), wound infection (n = 2; 5%) thrombocytopenia (n = 1; 2.5%), and proteinuria, hyperbilirubinemia, back pain, hyperkalemia, and anorexia (n = 1 each). CONCLUSION: The combination of B + E in patients who had advanced HCC showed significant, clinically meaningful antitumor activity. B + E warrant additional evaluation in randomized controlled trials.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Quinazolinas/administração & dosagem , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Bevacizumab , Quimioterapia Combinada , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
4.
J Hepatol ; 50(2): 334-41, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19070394

RESUMO

BACKGROUND/AIMS: The study aimed at addressing the connection between positive family history of liver cancer and hepatocellular carcinoma (HCC) development in the USA. METHODS: At The University of Texas M.D. Anderson Cancer Center, 347 patients with pathologically confirmed HCC and 1075 healthy controls were studied. All subjects were interviewed for their family history of cancer, including the number of relatives with cancer, the type of cancer, the individual's relationship with the relative, and the age at which the relative was diagnosed. RESULTS: Independently of hepatitis B virus (HBV) and hepatitis C virus (HCV), a history of liver cancer in first degree relatives was significantly associated with HCC development (AOR=4.1 [95% CI, 1.3-12.9]). Multiple relatives with liver cancer were only observed among HCC patients with chronic HBV/HCV infection. Affected siblings with liver cancer is significantly associated with HCC development with and without HBV/HCV infection; (AOR=5.7 [95% CI, 1.2-27.3]) and (AOR=4.3 [95% CI, 1.01-20.9]), respectively. Individuals with HBV/HCV and a family history of liver cancer were at higher risk for HCC (AOR=61.9 [95% CI, 6.6-579.7]). CONCLUSIONS: First degree family history of liver cancer is associated with HCC development in the USA. Further research exploring the genetic-environment interactions associated with risk of HCC is warranted.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Adulto , Idoso , Carcinoma Hepatocelular/etiologia , Estudos de Casos e Controles , Feminino , Hepatite B/complicações , Hepatite C/complicações , Humanos , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Estados Unidos
5.
J Clin Oncol ; 26(33): 5344-51, 2008 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-18936472

RESUMO

PURPOSE: The primary goal of this study was to evaluate whether pathologic response to chemotherapy predicts patient survival after preoperative chemotherapy and resection of colorectal liver metastases (CLM). The secondary goal of the study was to identify the clinical predictors of pathologic response. PATIENTS AND METHODS: A retrospective review was performed of 305 patients who underwent preoperative irinotecan- or oxaliplatin-based chemotherapy, followed by resection of CLM. Pathologic response was systematically evaluated and reported as the mean of the percentage of cancer cells remaining within each tumor. Univariate and multivariate analyses were performed to identify the predictors of pathologic response and survival. RESULTS: Cumulative 5-year overall survival rates by pathologic response status were as follows: 75% complete response (no residual cancer cells), 56% major response (1% to 49% residual cancer cells), and 33% minor response (> or = 50% residual cancer cells; complete v major response, P = .037; major v minor response, P = .028). Multivariate analysis revealed that only surgical margin status (P = .050; hazard ratio [HR], 1.77) and pathologic response (major response: P = .034; HR, 4.80; minor response: P = .007; HR, 6.93) were independent predictors of survival. Multivariate analysis of the predictors of pathologic response revealed that carcinoembryonic antigen level < or = 5 ng/mL, tumor size < or = 3 cm, and chemotherapy with fluoropyrimidine plus oxaliplatin and bevacizumab were independent predictors of pathologic response. CONCLUSION: Pathologic response predicts survival after preoperative chemotherapy and resection of CLM. Degree of pathologic response represents a new outcome end point for prognosis after resection of CLM.


Assuntos
Adenocarcinoma/secundário , Adenocarcinoma/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/patologia , Hepatectomia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Bevacizumab , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Quimioterapia Adjuvante , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Irinotecano , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Taxa de Sobrevida
6.
Int J Cancer ; 123(8): 1883-91, 2008 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-18688864

RESUMO

The International Agency for Research on Cancer has declared smoking to be a risk factor for hepatocellular carcinoma (HCC). However, passive exposure to cigarette smoke and use of noncigarette tobacco products on the risk of HCC has not been examined. Therefore, we evaluated the independent effects of different types of smoking exposure along with multiple risk factors for HCC and determined whether the magnitude of smoking was modified by other risk factors in men and women. We conducted a case-control study at The University of Texas M. D. Anderson Cancer Center where 319 HCC patients and 1,061 healthy control subjects were personally interviewed for several HCC risk factors. Multivariate logistic regression analysis was performed to estimate the adjusted odds ratio (AOR) and 95% confidence interval (CI) for each potential risk factor. Use of smokeless tobacco (chewing tobacco and snuff), cigars, pipes and passive smoking exposure were not related to HCC among noncigarette smokers. However, regular cigarette smoking was associated with HCC in men: AOR, 1.9 (95% CI, 1.1-3.1). Heavy alcohol consumption was associated with HCC in women: AOR, 7.7 (95% CI, 2.3-25.1). Cigarette smoking interacted synergistically with chronic infection of hepatitis C virus in men: AOR, 136.3 (95% CI, 43.2-429.6) and with heavy alcohol consumption in women: AOR, 13.7 (95% CI, 3.2-57.9). We conclude that sex differences were observed in HCC relationship with cigarette smoking and alcohol consumption. Controlling for smoking exposure might be a prudent approach to the prevention of HCC, especially in patients with chronic viral hepatitis infections.


Assuntos
Carcinoma Hepatocelular/epidemiologia , Hepatite C Crônica/epidemiologia , Neoplasias Hepáticas/epidemiologia , Fumar/efeitos adversos , Poluição por Fumaça de Tabaco/efeitos adversos , Adulto , Idoso , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/virologia , Estudos de Casos e Controles , Cocarcinogênese , Feminino , Hepatite C Crônica/complicações , Humanos , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Fatores Sexuais , Estados Unidos/epidemiologia
7.
J Clin Oncol ; 26(12): 2000-5, 2008 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-18421052

RESUMO

PURPOSE: The current strategy of drug development has been criticized as being highly inefficient. In 2004, the US Food and Drug Administration (FDA) released recommendations to improve this process, including a push for increased use of enrichment trials. It is unclear to what extent aspects of this "Critical Path Initiative" have been adopted in trial designs in metastatic colorectal cancer. METHODS: A systematic review was conducted of actively enrolling treatment trials in metastatic colorectal cancer. Trials were identified from the National Cancer Institute's clinicaltrials.gov and Investigative Drug Branch databases. Trials were categorized based on the number of prior treatments allowed, phase of the trial, agent mechanism of action, and FDA approval status of agents under investigation. RESULTS: One hundred two trials are enrolling, with a combined enrollment goal of more than 20,000 patients. Thirteen percent of trials investigated an agent not yet FDA-approved for any oncology indication. The most common study design was a phase II study limited to previously untreated patients; compared with the remaining trials, these phase II trials were more than 10 times more likely to only use agents FDA-approved for colorectal cancer. Three percent of patients were enrolled onto trials enriched for tumor characteristics that were hypothesized to improve clinical benefit. CONCLUSION: Current clinical trials for metastatic colorectal cancer are deficient in the investigation of agents directed at a novel therapeutic target, overuse phase II studies of FDA-approved agents, and fail to incorporate enrichment trial designs as encouraged by the FDA initiative.


Assuntos
Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto/métodos , Neoplasias Colorretais/tratamento farmacológico , Ensaios Clínicos Fase II como Assunto/métodos , Neoplasias Colorretais/patologia , Aprovação de Drogas , Humanos , Metástase Neoplásica , Estados Unidos , United States Food and Drug Administration
8.
Clin Colorectal Cancer ; 7(1): 55-9, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18279578

RESUMO

BACKGROUND: Improved survival of patients with metastatic colorectal cancer (CRC) has been shown to correlate with increased utilization of the 3 active cytotoxic chemotherapeutic agents: 5-fluorouracil (5-FU), irinotecan, and oxaliplatin, usually administered in 2 lines of therapy. However, it is unclear which patient, disease, and treatment characteristics are associated with the utilization of a second-line regimen. PATIENTS AND METHODS: We performed a retrospective chart review. Patients with metastatic CRC treated with bevacizumab outside of a clinical trial and any infusional 5-FU/leucovorin (LV) regimen off-protocol (ie, 5-FU/LV/irinotecan [FOLFIRI]/bevacizumab or 5-FU/LV/oxaliplatin [FOLFOX]/bevacizumab) at the University of Texas M. D. Anderson Cancer Center between February 2004 and September 2005 were included. Prespecified characteristics of age, tumor burden, severe toxicity, and front-line regimen efficacy were compared with exploratory analyses of additional patient, disease, and treatment characteristics. RESULTS: Eighty-seven sequential patients treated with the specified front-line regimens were identified. Seventy-six percent of the eligible patients were treated with a second-line regimen. Despite equal treatment durations, patients with a better response of stable disease were significantly less likely to receive a third cytotoxic agent than patients with a partial response (68% vs. 95%; odds ratio, 8.2; P = .02) due to declining performance status (86%) or patient preference (14%). This was associated with a decreased 2-year overall survival (86% vs. 55%). Neither age, tumor burden, nor development of toxicities were associated with a different utilization of a second-line regimen. CONCLUSION: Failure to obtain a response to initial chemotherapy for metastatic disease appears to be associated with decreased utilization of a second-line regimen.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Terapia de Salvação/estatística & dados numéricos , Resistencia a Medicamentos Antineoplásicos , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Retrospectivos , Resultado do Tratamento
9.
Cancer ; 110(5): 1059-67, 2007 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-17623837

RESUMO

BACKGROUND: Growth factor overexpression, including epidermal growth factor receptor (EGFR) expression, is common in hepatocellular cancers. Erlotinib is a receptor tyrosine kinase inhibitor with specificity for EGFR. The primary objective of this study was to determine the proportion of hepatocellular carcinoma (HCC) patients treated with erlotinib who were alive and progression-free (PFS) at 16 weeks of continuous treatment. METHODS: Patients with unresectable HCC, no prior systemic therapy, performance status (PS) of 0, 1, or 2, and Childs-Pugh (CP) cirrhosis A or B received oral erlotinib 150 mg daily for 28-day cycles. Tumor response was assessed every 2 cycles by using Response Evaluation Criteria in Solid Tumors (RECIST; National Cancer Institute Cancer Therapy Evaluation Program, Bethesda, Md) criteria. Patients accrued to either "low" or "high" EGFR expression cohorts; each cohort had stopping rules applied when there was a lack of efficacy. RESULTS: Forty HCC patients were enrolled. Median age was 64 years (range, 33-83 years), sex distribution was 32 males and 8 females, performance scores were 40% PS 0, 55% PS 1, Childs-Pugh distribution was 75% A and 20% B. There were no complete or partial responses; however, 17 of 40 patients achieved stable disease at 16 weeks of continuous therapy. The PFS at 16 weeks was 43%, and the median overall survival (OS) was 43 weeks (10.75 months). No patients required dose reductions of erlotinib. No correlation between EGFR expression and outcome was found. CONCLUSIONS: Results of this study indicated that single-agent erlotinib is well tolerated and has modest disease-control benefit in HCC, manifested as modestly prolonged PFS and OS when compared with historical controls.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Quinazolinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Diarreia/virologia , Esquema de Medicação , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Cloridrato de Erlotinib , Exantema/induzido quimicamente , Fadiga/induzido quimicamente , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/efeitos adversos , Resultado do Tratamento
10.
Semin Oncol ; 31(1 Suppl 1): 83-92, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14981585

RESUMO

Overexpression of the epidermal growth factor receptor is commonly seen in a variety of epithelial tumors including lung cancer, and it is particularly common in the non-small cell histologic variant. Despite intense research efforts, therapeutic advances to date have failed to result in a significant survival benefit for patients with advanced disease. The lack of overall survival benefit and high toxicity associated with cytotoxic chemotherapy indicates the need for novel therapies that have a favorable effect on survival with minimal toxicity. Greater understanding of molecular biology and the intricate cellular pathways has resulted in the development of a new field of targeted therapeutics that will arrest dysregulated cell growth in malignant cells. Tyrosine kinases represent an important category of signaling proteins that catalyze phosphorylation of tyrosine residues leading to reactions ultimately resulting in cell growth, differentiation, proliferation, and death. Inhibition of tyrosine kinase activity represents a logical targeted approach in malignancies with overexpression of tyrosine kinase. Several small-molecule epidermal growth factor receptor tyrosine kinase inhibitors have been developed and are currently undergoing clinical trials. This article will review several of these agents as well as their role in the treatment of non-small cell lung cancer.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , Gefitinibe , Humanos , Quinazolinas/uso terapêutico
11.
Curr Oncol Rep ; 5(2): 152-7, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12583833

RESUMO

Squamous cell carcinoma of the head and neck is the most common epithelial neoplasm of the upper aerodigestive tract and represents a major health concern in the United States and worldwide. Invasive squamous cell carcinoma is the end result of a multiyear, multistep process of accumulation of genetic and phenotypic damage. Chemoprevention is defined as the use of pharmacologic or natural agents that inhibit the development of invasive cancer whether by blocking the DNA damage that initiates carcinogenesis or by arresting or reversing the progression of premalignant cells in which such damage has already occurred. Chemoprevention is widely recognized as an important area of research in head and neck cancer. This article reviews the field of chemoprevention and recent advances in molecular epidemiology and genetics. Current clinical trials are described.


Assuntos
Anticarcinógenos/uso terapêutico , Carcinoma de Células Escamosas/prevenção & controle , Quimioprevenção/métodos , Neoplasias de Cabeça e Pescoço/prevenção & controle , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/genética , Transformação Celular Neoplásica/genética , Ensaios Clínicos como Assunto , Neoplasias de Cabeça e Pescoço/epidemiologia , Neoplasias de Cabeça e Pescoço/genética , Humanos
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