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1.
Invest New Drugs ; 42(1): 127-135, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38270822

RESUMO

Navitoclax (ABT-263) is an oral BCL2 homology-3 mimetic that binds with high affinity to pro-survival BCL2 proteins, resulting in apoptosis. Sorafenib, an oral multi kinase inhibitor also promotes apoptosis and inhibits tumor angiogenesis. The efficacy of either agent alone is limited; however, preclinical studies demonstrate synergy with the combination of navitoclax and sorafenib. In this phase 1 study, we evaluated the combination of navitoclax and sorafenib in a dose escalation cohort of patients with refractory solid tumors, with an expansion cohort in hepatocellular carcinoma (HCC). Maximum tolerated dose (MTD) was determined using the continual reassessment method. Navitoclax and sorafenib were administered continuously on days 1 through 21 of 21-day cycles. Ten patients were enrolled in the dose escalation cohort and 15 HCC patients were enrolled in the expansion cohort. Two dose levels were tested, and the MTD was navitoclax 150 mg daily plus sorafenib 400 mg twice daily. Among all patients, the most common grade 3 toxicity was thrombocytopenia (5 patients, 20%): there were no grade 4 or 5 toxicities. Patients received a median of 2 cycles (range 1-36 cycles) and all patients were off study treatment at data cut off. Six patients in the expansion cohort had stable disease, and there were no partial or complete responses. Drug-drug interaction between navitoclax and sorafenib was not observed. The combination of navitoclax and sorafenib did not increase induction of apoptosis compared with navitoclax alone. Navitoclax plus sorafenib is tolerable but showed limited efficacy in the HCC expansion cohort. These findings do not support further development of this combination for the treatment of advanced HCC. This phase I trial was conducted under ClinicalTrials.gov registry number NCT01364051.


Assuntos
Compostos de Anilina , Carcinoma Hepatocelular , Neoplasias Hepáticas , Sorafenibe , Humanos , Compostos de Anilina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Sorafenibe/uso terapêutico , Sulfonamidas/uso terapêutico
2.
Clin Adv Hematol Oncol ; 18(2): 106-115, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32558804

RESUMO

Pancreatic cancer is the fourth-leading cause of cancer-related death. It is commonly diagnosed at an advanced stage, when no curative options exist. Over the last decade, combination chemotherapy has shown a survival benefit compared with single-agent gemcitabine and has become established as first-line therapy in metastatic pancreatic cancer. The choice of frontline regimen, which is based on clinical factors, plays an important role in subsequent management. Limited second-line standard therapeutic options are available. Studies have not definitively established that chemotherapy with a fluoropyramidine (5-fluorouracil or capecitabine), gemcitabine, oxaliplatin, irinotecan, or a combination of oxaliplatin and irinotecan improves patient survival after the failure of first-line chemotherapy. Nanoliposomal irinotecan has been approved for use in patients who have progressive disease while on gemcitabine-based treatment. Although combination chemotherapy is associated with a modest survival benefit, this comes at the expense of increased toxicity and costs. Furthermore, the optimal sequencing of these agents in subsequent lines of treatment is unknown. Randomized controlled trials provide little evidence of greater benefit from second-line therapy compared with best supportive care alone. Therefore, treatment decisions should be patient-centered and based on functional status, medical comorbidities, and anticipated adverse effects. The clinical context and prior treatment-related toxicities have a significant influence on the choice of optimal salvage treatment. We review the published data focused on second-line treatment for advanced pancreatic cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Camptotecina/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Fluoruracila/uso terapêutico , Humanos , Irinotecano/uso terapêutico , Metástase Neoplásica , Oxaliplatina/uso terapêutico , Neoplasias Pancreáticas/patologia , Gencitabina
3.
J Natl Compr Canc Netw ; 16(10): 1183-1192, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30323088

RESUMO

Background: Use of chemotherapy in stage II colorectal cancer (CRC) is controversial because it improves survival only in some patients. We aimed to develop a statistical model using routine and readily available blood tests to predict the prognosis of patients with stage II CRC and to identify which patients are likely to benefit from chemotherapy. Methods: We divided 422 patients with stage II CRC into a training and a testing set. The association of routine laboratory variables and disease-free survival (DFS) was analyzed. A prognostic model was developed incorporating clinically relevant laboratory variables with demographic and tumor characteristics. A prognostic score was derived by calculating the sum of each variable weighted by its regression coefficient in the model. Model performance was evaluated by constructing receiver operating characteristic curves and calculating the area under the curve (AUC). Results: Significant associations were seen between 5 laboratory variables and patient DFS in univariate analyses. After stepwise selection, 3 variables (carcinoembryonic antigen, hemoglobin, creatinine) were retained in the multivariate model with an AUC of 0.75. Compared with patients with a low prognostic score, those with a medium and high prognostic score had a 1.99- and 4.78-fold increased risk of recurrence, respectively. The results from the training set were validated in the testing set. Moreover, chemotherapy significantly improved DFS in high-risk patients, but not in low- and medium-risk patients. Conclusions: A routine laboratory variable-based model may help predict DFS of patients with stage II CRC and identify high-risk patients more likely to benefit from chemotherapy.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Colorretais/terapia , Modelos Biológicos , Recidiva Local de Neoplasia/diagnóstico , Fatores Etários , Idoso , Quimioterapia Adjuvante/métodos , Neoplasias Colorretais/sangue , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/prevenção & controle , Estadiamento de Neoplasias , Seleção de Pacientes , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Estudos Retrospectivos , Medição de Risco/métodos
4.
Cancer ; 123(2): 345-356, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27622829

RESUMO

BACKGROUND: Increased susceptibility to 5-fluorouracil (5-FU)/capecitabine can lead to rapidly occurring toxicity caused by impaired clearance, dihydropyrimidine dehydrogenase deficiency, and other genetic variations in the enzymes that metabolize 5-FU. Life-threatening 5-FU overdoses occur because of infusion pump errors, dosage miscalculations, and accidental or suicidal ingestion of capecitabine. Uridine triacetate (Vistogard) was approved in 2015 for adult and pediatric patients who exhibit early-onset severe or life-threatening 5-FU/capecitabine toxicities or present with an overdose. Uridine triacetate delivers high concentrations of uridine, which competes with toxic 5-FU metabolites. METHODS: In 2 open-label clinical studies, patients who presented with a 5-FU/capecitabine overdose or an early onset of severe toxicities were treated. Patients received uridine triacetate as soon as possible (most within the first 96 hours after 5-FU/capecitabine). Outcomes included survival, resumption of chemotherapy, and safety. Their survival was compared with the survival of a historical cohort of overdose patients who received only supportive care. RESULTS: A total of 137 of 142 overdose patients (96%) treated with uridine triacetate survived and had a rapid reversal of severe acute cardiotoxicity and neurotoxicity; in addition, mucositis and leukopenia were prevented, or the patients recovered from them. In the historical cohort, 21 of 25 patients (84%) died. Among the 141 uridine triacetate-treated overdose patients with a diagnosis of cancer (the noncancer patients included 6 intentional or accidental pediatric overdoses), 53 resumed chemotherapy in < 30 days (median time after 5-FU, 19.6 days), and this indicated a rapid recovery from toxicity. Adverse reactions in patients receiving uridine triacetate included vomiting (8.1%), nausea (4.6%), and diarrhea (3.5%). CONCLUSIONS: In these studies, uridine triacetate was a safe and effective lifesaving antidote for capecitabine and 5-FU overexposure, and it facilitated the rapid resumption of chemotherapy. Cancer 2017;123:345-356. © 2016 American Cancer Society.


Assuntos
Acetatos/uso terapêutico , Antimetabólitos Antineoplásicos/efeitos adversos , Capecitabina/efeitos adversos , Overdose de Drogas/tratamento farmacológico , Fluoruracila/efeitos adversos , Uridina/análogos & derivados , Capecitabina/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Uridina/uso terapêutico
5.
J Natl Compr Canc Netw ; 13(2): 194-227, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25691612

RESUMO

Esophageal cancer is the sixth most common cause of cancer deaths worldwide. Adenocarcinoma is more common in North America and Western European countries, originating mostly in the lower third of the esophagus, which often involves the esophagogastric junction (EGJ). Recent randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival in patients with resectable cancer. Targeted therapies with trastuzumab and ramucirumab have produced encouraging results in the treatment of advanced or metastatic EGJ adenocarcinomas. Multidisciplinary team management is essential for patients with esophageal and EGJ cancers. This portion of the NCCN Guidelines for Esophageal and EGJ Cancers discusses management of locally advanced adenocarcinoma of the esophagus and EGJ.


Assuntos
Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/terapia , Junção Esofagogástrica/patologia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/terapia , Humanos
6.
J Natl Compr Canc Netw ; 12(8): 1152-82, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25099447

RESUMO

Hepatobiliary cancers include a spectrum of invasive carcinomas arising in the liver (hepatocellular carcinoma), gall bladder, and bile ducts (cholangiocarcinomas). Gallbladder cancer and cholangiocarcinomas are collectively known as biliary tract cancers. Gallbladder cancer is the most common and aggressive type of all the biliary tract cancers. Cholangiocarcinomas are diagnosed throughout the biliary tree and are typically classified as either intrahepatic or extrahepatic cholangiocarcinoma. Extrahepatic cholangiocarcinomas are more common than intrahepatic cholangiocarcinomas. This manuscript focuses on the clinical management of patients with gallbladder cancer and cholangiocarcinomas (intrahepatic and extrahepatic).


Assuntos
Neoplasias dos Ductos Biliares/terapia , Carcinoma Hepatocelular/terapia , Colangiocarcinoma/terapia , Neoplasias da Vesícula Biliar/terapia , Neoplasias dos Ductos Biliares/epidemiologia , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Carcinoma Hepatocelular/patologia , Colangiocarcinoma/epidemiologia , Colangiocarcinoma/patologia , Neoplasias da Vesícula Biliar/epidemiologia , Neoplasias da Vesícula Biliar/patologia , Guias como Assunto , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto
7.
Abdom Imaging ; 39(4): 744-52, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24549880

RESUMO

PURPOSE: To confirm the feasibility of breath-hold DCE-MRI and DWI at 3T to obtain the intra-abdominal quantitative physiologic parameters, K(trans), k ep, and ADC, in patients with untreated pancreatic ductal adenocarcinomas. METHODS: Diffusion-weighted single-shot echo-planar imaging (DW-SS-EPI) and dynamic contrast-enhanced (DCE) MRI were used for 16 patients with newly diagnosed biopsy-proven pancreatic ductal adenocarcinomas. K(trans), k ep, and apparent diffusion coefficient (ADC) values of pancreatic tumors, non-tumor adjacent pancreatic parenchyma (NAP), liver metastases, and normal liver tissues were quantitated and statistically compared. RESULTS: Fourteen patients were able to adequately hold their breath for DCE-MRI, and 15 patients for DW-SS-EPI. Four patients had liver metastases within the 6 cm of Z axis coverage centered on the pancreatic primary tumors. K(trans) values (10(-3) min(-1)) of primary pancreatic tumors, NAP, liver metastases, and normal liver tissues were 7.3 ± 4.2 (mean ± SD), 25.8 ± 14.9, 8.1 ± 5.9, and 45.1 ± 15.6, respectively, k ep values (10(-2) min(-1)) were 3.0 ± 0.9, 7.4 ± 3.1, 5.2 ± 2.0, and 12.1 ± 2.8, respectively, and ADC values (10(-3) mm(2)/s) were 1.3 ± 0.2, 1.6 ± 0.3, 1.1 ± 0.1, and 1.3 ± 0.1, respectively. K(trans), k ep, and ADC values of primary pancreatic tumors were significantly lower than those of NAP (p < 0.05), while K(trans) and k ep values of liver metastases were significantly lower than those of normal liver tissues (p < 0.05). CONCLUSIONS: 3T breath-hold quantitative physiologic MRI is a feasible technique that can be applied to a majority of patients with pancreatic adenocarcinomas.


Assuntos
Adenocarcinoma/diagnóstico , Imagem de Difusão por Ressonância Magnética/métodos , Pâncreas/patologia , Neoplasias Pancreáticas/diagnóstico , Análise de Variância , Suspensão da Respiração , Imagem Ecoplanar , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Reprodutibilidade dos Testes
8.
Radiat Oncol ; 19(1): 65, 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38812040

RESUMO

BACKGROUND: Local treatment options for locally recurrent pancreatic adenocarcinoma (LR-PAC) are limited, with median survival time (MST) of 9-13 months (mos) following recurrence. MRI-guided stereotactic body radiation therapy (MRgSBRT) provides the ability to dose escalate while sparing normal tissue. Here we report on the early outcomes of MRgSBRT for LR-PAC. METHODS: Patients with prior resection of pancreatic adenocarcinoma with local recurrence treated with MRgSBRT at a single tertiary referral center from 5-2021 to 2-2023 were identified from our prospective database. MRgSBRT was delivered to 40-50 Gy in 4-5 fractions with target and OAR delineation per institutional standards. Endpoints included local control per RECIST v1.1, distant failure, overall survival (OS), and acute and chronic toxicities per Common Terminology Criteria for Adverse Events, v5. RESULTS: Fifteen patients with LR-PAC were identified with median follow-up of 10.6 mos (2.8-26.5 mos) from MRgSBRT. There were 8 females and 7 males, with a median age of 69 years (50-83). One patient underwent neoadjuvant radiation for 50.4 Gy in 28 fractions followed by resection, and one underwent adjuvant radiation for 45 Gy in 25 fractions prior to recurrence. MRgSBRT was delivered a median of 18.8 mos (3.5-52.8 mos) following resection. OS following recurrence at 6 and 12 mos were 87% and 51%, respectively, with a median survival time of 14.1 mos (3.2-27.4 mos). Three patients experienced local failure at 5.9, 7.8, and 16.6 months from MgSBRT with local control of 92.3% and 83.9% at 6 and 12 months. 10 patients experienced distant failure at a median of 2.9 mos (0.3-6.7 mos). Grade 1-2 acute GI toxicity was noted in 47% of patients, and chronic GI toxicity in 31% of patients. No grade > 3 toxicities were noted. CONCLUSIONS: This is the first report on toxicity and outcomes of MRgSBRT for LR-PAC in the literature. MRgSBRT is a safe, feasible treatment modality with the potential for improved local control in this vulnerable population. Future research is necessary to better identify which patients yield the most benefit from MRgSBRT, which should continue to be used with systemic therapy as tolerated. TRIAL REGISTRATION: Jefferson IRB#20976, approved 2/17/21.


Assuntos
Adenocarcinoma , Recidiva Local de Neoplasia , Neoplasias Pancreáticas , Radiocirurgia , Humanos , Masculino , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/cirurgia , Feminino , Idoso , Radiocirurgia/métodos , Radiocirurgia/efeitos adversos , Pessoa de Meia-Idade , Adenocarcinoma/radioterapia , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adenocarcinoma/mortalidade , Recidiva Local de Neoplasia/radioterapia , Recidiva Local de Neoplasia/patologia , Idoso de 80 Anos ou mais , Imageamento por Ressonância Magnética , Radioterapia Guiada por Imagem/métodos , Taxa de Sobrevida , Estudos Prospectivos , Estudos Retrospectivos
9.
J Natl Compr Canc Netw ; 11(5): 531-46, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23667204

RESUMO

The NCCN Clinical Practice Guidelines in Oncology for Gastric Cancer provide evidence- and consensus-based recommendations for a multidisciplinary approach for the management of patients with gastric cancer. For patients with resectable locoregional cancer, the guidelines recommend gastrectomy with a D1+ or a modified D2 lymph node dissection (performed by experienced surgeons in high-volume centers). Postoperative chemoradiation is the preferred option after complete gastric resection for patients with T3-T4 tumors and node-positive T1-T2 tumors. Postoperative chemotherapy is included as an option after a modified D2 lymph node dissection for this group of patients. Trastuzumab with chemotherapy is recommended as first-line therapy for patients with HER2-positive advanced or metastatic cancer, confirmed by immunohistochemistry and, if needed, by fluorescence in situ hybridization for IHC 2+.


Assuntos
Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/terapia , Terapia Combinada , Gastrectomia , Humanos , Excisão de Linfonodo , Estadiamento de Neoplasias , Receptor ErbB-2/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia
10.
AJR Am J Roentgenol ; 194(3): 615-22, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20173136

RESUMO

OBJECTIVE: The purpose of this study was to determine whether preoperative neoadjuvant therapy in patients with locally advanced pancreatic cancer affects the ability of multiphasic MDCT to predict successful surgical resection. MATERIALS AND METHODS: From 2000 to 2006, there were 12 patients with prior neoadjuvant therapy successfully downstaged by CT and 31 age-matched pancreatic cancer patients without preoperative therapy who underwent pancreatic MDCT followed by attempted pancreaticoduodenectomy. Three readers blinded to surgical findings independently analyzed immediate preoperative MDCT scans of 43 patients comprising the retrospective data set in random order for vascular involvement (degree of contact and narrowing) and distant metastases. Individual reader sensitivity and specificity for resectability prediction were compared for study and control groups using the Fisher's exact test. Interobserver agreement was assessed using the kappa statistic. RESULTS: Seven (58%) of 12 neoadjuvant-treated adenocarcinomas and 10 (32%) of 31 control pancreatic carcinomas were resectable (p > 0.05). For resectable disease, sensitivities were 86%, 71%, and 14% for the neoadjuvant group and 90%, 90%, and 60% for the control group (p > 0.05). Specificities were 80%, 100%, and 100% for the neoadjuvant group and 57%, 43%, and 76% for the control group (reader 2 specificity difference, p = 0.04). The multi rater kappa value of resectability prediction for neoadjuvant patients was 0.28, and that for control subjects was 0.63 (p < 0.001). In the neoadjuvant group, the majority of individual reader errors were false-negative resectability interpretations resulting from overestimation of vascular involvement. Consideration of degrees of venous abutment did not improve estimation of resectability in patients with neoadjuvant therapy. CONCLUSION: Sensitivity for prediction of resectability tends to be lower for patients with locally advanced pancreatic cancer that has been downstaged by neoadjuvant therapy, but this trend is not statistically significant. Interobserver variability for determination of resectability is statistically higher than for controls who did not receive preoperative therapy.


Assuntos
Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/cirurgia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia , Tomografia Computadorizada por Raios X/métodos , Adenocarcinoma/patologia , Meios de Contraste , Feminino , Humanos , Iohexol , Iopamidol , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Neoplasias Pancreáticas/patologia , Estudos Retrospectivos , Sensibilidade e Especificidade
11.
Am Soc Clin Oncol Educ Book ; 39: e88-e95, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31099690

RESUMO

The incidence of gastroesophageal junction (GEJ) adenocarcinomas has been rising over the past few decades, creating a need for effective therapeutic strategies. Treatment of locally advanced GEJ tumors, in particular, present a unique challenge because these tumors have generally been approached as either esophageal or gastric cancers, and thus optimal preoperative management remains uncertain. Both neoadjuvant chemoradiation and perioperative chemotherapy have been widely adopted in standard practice; however, it is unclear which approach offers the optimal outcome for the fit patient capable of receiving any planned strategy. In this review, we debate the management of locally advanced GEJ adenocarcinoma, and discuss areas of ongoing investigation which may provide more effective and individualized treatment of patients with GEJ cancers.


Assuntos
Adenocarcinoma/diagnóstico , Adenocarcinoma/terapia , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/terapia , Junção Esofagogástrica/patologia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/terapia , Tomada de Decisão Clínica , Ensaios Clínicos como Assunto , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Gerenciamento Clínico , Humanos , Resultado do Tratamento
12.
Clin Gastroenterol Hepatol ; 6(8): 842-848.e3, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18585978

RESUMO

By using experimental combined adjuvant and neoadjuvant therapies in pancreatic ductal adenocarcinoma patients, progress has been made in survival, clinical benefit response, and even downstaging of tumors to allow surgical resection. The use of combined modality approaches in pancreatic ductal adenocarcinoma is associated with increased gastrointestinal toxicity, which may manifest as bowel wall abnormalities and peripancreatic inflammatory changes on multiphasic multidetector computed tomography and affect assessment of the pancreatic tumor. During preoperative neoadjuvant therapy, occult metastatic disease may be given the opportunity to manifest, thus preventing the morbidity of attempted resection or laparotomy. Although advances in the neoadjuvant and adjuvant treatment of patients with pancreatic carcinoma have thus far yielded only a modest impact on prognosis, in the future greater numbers of patients will undergo these treatments in searching for cure. As therapy with targeted agents evolves, the team of gastroenterologists, oncologists, surgeons, and radiologists caring for these complex patients should become familiar with the varied tumor response and host reactions to newer therapies that may be depicted on multiphase multidetector computed tomography.


Assuntos
Adenocarcinoma/diagnóstico , Adenocarcinoma/terapia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/terapia , Tomografia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
14.
Clin Cancer Res ; 11(21): 7866-71, 2005 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-16278410

RESUMO

PURPOSE: To determine the maximal tolerated dose and dose-limiting toxicities (DLT) of pegamotecan (polyethylene glycol-camptothecin) in patients with advanced malignancies when administered in cycles of once weekly for 3 of 4 weeks. EXPERIMENTAL DESIGN: Eligible patients had advanced solid tumors that failed to respond to standard therapy or for which no standard therapy was available, including also the following criteria: measurable disease, Eastern Cooperative Oncology Group performance status of < or =2, and acceptable organ function. Pegamotecan was administered as a 60-minute infusion, with successive patient cohorts receiving escalating doses from 800 to 4,300 mg/m(2). The primary end point was to determine the maximal tolerated dose. Other end points were toxicity, pharmacokinetics, pharmacodynamics, and efficacy. Pharmacokinetic analysis measured free camptothecin. Pharmacodynamic analysis correlated drug effects with pegamotecan dose and pharmacokinetic variables. RESULTS: Twenty-seven patients were enrolled. The maximal tolerated dose was 3,240 mg/m(2). Grade 4 neutropenia, the DLT, was noted in two of four patients treated at 4,300 mg/m(2). Other grade 3 and 4 toxicities were anemia, thrombocytopenia, fatigue, prolonged partial thromboplastin time, hemorrhagic cystitis, dysuria, and urinary frequency. Pharmacokinetic analysis showed the apparent terminal elimination half-life to be 46 +/- 12.8 hours. Pharmacodynamic analysis showed that hematuria occurred in 8 of 15 patients with an area under the curve extrapolated to infinity (AUC(0-infinity)) > 20 ng h/mL and 0 of 10 patients with an AUC(0-infinity) < or = 20 ng h/mL. Unconfirmed partial responses were observed in two patients, one with metastatic small bowel adenocarcinoma and the other with metastatic esophageal cancer. CONCLUSIONS: The maximal tolerated dose of pegamotecan when administered weekly for 3 of 4 weeks is 3,240 mg/m(2). The DLT was neutropenia. Among nonhematologic toxicities, the incidence of gastrointestinal toxicity was low, but genitourinary toxicity seems to occur in the same effective dose range as noted with native camptothecin in earlier trials (27-43 mg/m(2)). The observed antitumor activity suggests that pegamotecan has single-agent activity and merits further investigation in phase 2 studies.


Assuntos
Antineoplásicos/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/farmacocinética , Linfoma/tratamento farmacológico , Neoplasias/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Adulto , Idoso , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Área Sob a Curva , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Polietilenoglicóis/uso terapêutico , Fatores de Tempo
15.
J Cancer Surviv ; 10(6): 981-989, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27138993

RESUMO

PURPOSE: To conduct a telephone survey establishing pancreatic cancer survivors' level of interest in, preferences for, and perceived barriers and facilitators to participating in exercise and diet intervention programming. These data will inform the development of such interventions for newly-diagnosed patients. METHODS: Seventy-one survivors treated for resectable pancreatic adenocarcinoma from October 2011 to August 2014 were identified through an institutional cancer registry and contacted via telephone. A telephone survey was conducted to query survivors' level of interest in, preferences for, and perceived barriers and facilitators to participating in an exercise and dietary intervention program shortly after disease diagnosis. Acceptability of a technology-based visual communication (e.g., Skype™, FaceTime®) intervention was also assessed. RESULTS: Fifty participants completed the survey (response rate 71.8 %). Over two-thirds of participants reported interest in exercise and diet intervention programming. Over half reported comfort with a technology-delivered visual communication intervention. Barriers to participation included older age and physical, personal, and emotional problems. The most common facilitator was program awareness. Outcomes for future research important to participants were supportive care and quality of life. CONCLUSIONS: Most pancreatic cancer patients are interested in exercise and diet interventions shortly after diagnosis; however, some barriers to program participation exist. IMPLICATIONS FOR CANCER SURVIVORS: Future research and intervention planning for pancreatic cancer survivors should focus on developing messaging and strategies that provide support for survivorship outcomes, increase survivor awareness, address lack of familiarity with technology, reduce fears about potential barriers, and help survivors overcome these barriers. In so doing, survivorship needs can be better met and quality of life improved in this understudied population.


Assuntos
Dieta , Exercício Físico/fisiologia , Neoplasias Pancreáticas/terapia , Qualidade de Vida/psicologia , Sobreviventes/psicologia , Idoso , Feminino , Humanos , Masculino , Neoplasias Pancreáticas/mortalidade , Inquéritos e Questionários
16.
Mol Oncol ; 10(8): 1169-82, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27282075

RESUMO

BACKGROUND: Pancreatic adenocarcinoma patients have low survival rates due to late-stage diagnosis and high rates of cancer recurrence even after surgical resection. It is important to understand the molecular characteristics associated with survival differences in pancreatic adenocarcinoma tumors that may inform patient care. RESULTS: RNA sequencing was performed for 51 patient tumor tissues extracted from patients undergoing surgical resection, and expression was associated with overall survival time from diagnosis. Our analysis uncovered 323 transcripts whose expression correlates with survival time in our pancreatic patient cohort. This genomic signature was validated in an independent RNA-seq dataset of 68 additional patients from the International Cancer Genome Consortium. We demonstrate that this transcriptional profile is largely independent of markers of cellular division and present a 19-transcript predictive model built from a subset of the 323 transcripts that can distinguish patients with differing survival times across both the training and validation patient cohorts. We present evidence that a subset of the survival-associated transcripts is associated with resistance to gemcitabine treatment in vitro, and reveal that reduced expression of one of the survival-associated transcripts, Angiopoietin-like 4, impairs growth of a gemcitabine-resistant pancreatic cancer cell line. CONCLUSIONS: Gene expression patterns in pancreatic adenocarcinoma tumors can distinguish patients with differing survival outcomes after undergoing surgical resection, and the survival difference could be associated with the intrinsic gemcitabine sensitivity of primary patient tumors. Thus, these transcriptional differences may impact patient care by distinguishing patients who would benefit from a non-gemcitabine based therapy.


Assuntos
Adenocarcinoma/genética , Angiopoietinas/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas/genética , Análise de Sequência de RNA/métodos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Idoso , Proteína 4 Semelhante a Angiopoietina , Angiopoietinas/genética , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Curva ROC , Análise de Sobrevida , Fatores de Tempo , Gencitabina , Neoplasias Pancreáticas
17.
Cancer Chemother Pharmacol ; 56(2): 182-8, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15838660

RESUMO

PURPOSE: Anti-tumor activity can often be enhanced with combination therapy in managing patients with metastatic cancer. However, dose sequence and schedule of delivery can alter the pharmacokinetics, toxicity, and anti-tumor response. Therefore, attention to drug-drug interactions which may be sequence or schedule-dependent are necessary. Docetaxel and topotecan are non-cross-resistance cytotoxic agents with activity in a variety of malignancies. The goal of this study was to determine the maximum tolerated dose of docetaxel and continuous infusion topotecan using two sequences of administration. EXPERIMENTAL DESIGN: Patients were randomized to schedule A or B and enrolled in four escalating-dose cohorts. On schedule A, docetaxel was administered over 1 h and followed by topotecan administered over 72 h. On schedule B, topotecan was given as a 72 h continuous infusion followed by a 1 h infusion of docetaxel. While the doses for the docetaxel and topotecan were the same for schedule A and schedule B, the toxicities, and thus the determination of maximum tolerated dose (MTD), were assessed independently. The plasma pharmacokinetic disposition of topotecan and docetaxel were evaluated during the first cycle of each sequence to assess drug interactions. RESULTS: Thirty patients, 20 males and 10 females were evaluable for toxicity and response. Four patients were chemonaive. Mean number cycles given were 3. Grade 3/4 thrombocytopenia and neutropenia were comparable on both schedules, as was the dose-limiting toxicity (DLT) for both schedules. There were no apparent differences in absolute neutrophil count or platelet nadirs between schedules A and B for three of the four cohorts. The principal non-hematologic toxicity was nausea and vomiting. The time of overlap of topotecan lactone or total concentrations and docetaxel concentrations were greater on schedule A as compared with schedule B and was associated with reduced clearance of docetaxel on schedule A as compared to schedule B. However, the mean clearance for docetaxel (18 for all 16 L h(-1) m(-2) and 29 for all 28 L h(-1) m(-2) on schedules A and B, respectively, and topotecan 16 for all 10 L h(-1) m(-2) and 7 for all 6 L h(-1) m(-2) on schedules A and B, respectively) were not statistically different (P > 0.05). CONCLUSIONS: The observed toxicity was not sequence-dependent, despite the observed change in kinetics. Docetaxel and topotecan can be administered with acceptable toxicity at the recommended phase-II dose of docetaxel 60 mg m(-2) and topotecan 0.85 mg m(-2) day(-1)x3 days.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Docetaxel , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Taxoides/administração & dosagem , Topotecan/administração & dosagem
18.
Clin Cancer Res ; 9(4): 1323-32, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12684400

RESUMO

PURPOSE: Angiogenesis plays an important role in colorectal cancer progression. Stimulation of vascular endothelial growth factor receptor (VEGFR), a transmembrane glycoprotein, results in endothelial mitogenesis. Within this family of receptors, VEGFR 2/kinase-insert-domain-containing receptor (KDR) appear to be principally up-regulated during tumorigenesis. A chimeric anti-KDR antibody, IMC-1C11, blocks VEGFR-KDR interaction and inhibits VEGFR-induced endothelial cell proliferation. This trial seeks to assess the safety, tolerability and feasibility of targeting an important pathway in tumorigenesis. EXPERIMENTAL DESIGN: In a dose-escalation, single-agent study of IMC-1C11, we enrolled 14 patients with colorectal carcinoma and hepatic metastases. Safety-, pharmacokinetic-, immunogenicity-, and magnetic resonance imaging-assessed alteration of vascular effects of IMC-1C11 were evaluated in this trial. IMC-1C11 was infused weekly at 0.2 mg/kg (n = 3), 0.6 mg/kg (n = 4), 2.0 mg/kg (n = 3), and 4.0 mg/kg (n = 4) for 4 weeks, which constituted a cycle. RESULTS: No grade-3 or -4 IMC-1C11-related toxicities were observed. Minor grade-1 bleeding events were observed in four patients [0.2 mg/kg (n = 1) and 0.6 mg/kg (n = 3)]. Each resolved quickly and required no intervention. The starting dose of IMC-1C11 was selected to achieve a C(max) of approximately 5 micro g/ml. This concentration prevented KDR phosphorylation in vitro. Pharmacokinetic analysis demonstrated that the plasma t(1/2) and C(max) were dose dependent with a plasma t(1/2) of 67 +/- 3 h at the 4-mg/kg dose level. Human antichimeric antibodies were detected in 7 of 14 patients. The antibodies to IMC-1C11 inhibited the circulation of the agent in two patients. One patient had prolonged stable disease for seven cycles (28 weeks). The mean changes in tumor-influx volume-transfer constant k(in) (min(-1)) and enhancement factor after 4 weeks of therapy were significantly decreased compared with pretreatment values in 11 patients. CONCLUSION: IMC-1C11 was both safe and well tolerated. Drug levels of IMC-1C11 were reliably predicted. Further clinical investigation of anti-VEGFR/KDR agents is warranted.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos/química , Antineoplásicos/farmacologia , Carcinoma/patologia , Neoplasias Colorretais/patologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/imunologia , Adulto , Idoso , Divisão Celular , Células Cultivadas , Relação Dose-Resposta a Droga , Endotélio Vascular/citologia , Feminino , Humanos , Cinética , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Perfusão , Estrutura Terciária de Proteína , Fatores de Tempo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química
19.
Clin Cancer Res ; 8(10): 3092-9, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12374676

RESUMO

PURPOSE: Our purpose in the study was to establish the maximum tolerated dose and toxicity profile of SGN-10 (or BR96 sFv-PE40), a single-chain immunotoxin. SGN-10 is composed of the fused gene products encoding the translocating and ADP-ribosylating domains of Pseudomonas exotoxin (PE40) and the variable heavy (V(H)) and variable light (V(L)) regions of BR96 monoclonal antibody. This antibody is specific for a Lewis(Y) (Le(Y))-related carbohydrate antigen expressed on multiple carcinomas. EXPERIMENTAL DESIGN: A total of 46 patients with Le(Y)-positive metastatic carcinoma were enrolled in a Phase I dose-escalation study in cohorts of three to six patients who received SGN-10 at doses ranging from 0.024 to 0.962 mg/m(2), administered on days 1, 4, 8, and 11, followed by 2 weeks of rest and a second cycle of therapy. Pharmacokinetics and human antibody response to SGN-10 were also determined. RESULTS: The maximum tolerated dose of SGN-10 was 0.641 mg/m(2) with gastrointestinal dose-limiting toxicity. Pharmacokinetic studies performed in eight patients at the 0.641-mg/m(2) dose revealed a t([1/2]) of 2.5 +/- 0.3 h and a C(max) of 389 +/- 112 ng/ml. Pharmacodynamic analyses demonstrated a rapid clearance of the drug by day 11 associated with an antitoxin human antitoxin antibody (HATA) response in most patients. Signs consistent with a modest vascular leak syndrome, specifically, transient hypoalbuminemia, were observed in patients treated with doses of > or =0.384 mg/m(2). No complete or partial tumor responses were observed at an 8-week evaluation, although 31% of patients had stable disease. CONCLUSIONS: The maximal tolerated dose of SGN-10 given twice weekly for 2 weeks is 0.641 mg/m(2) with gastrointestinal dose-limiting toxicity. The immunogenicity of the toxin moiety limits the ability of SGN-10 to circulate by day 11 of therapy. Studies are ongoing to evaluate strategies to ameliorate toxicities and to inhibit the development of the anti-SGN-10 immune response.


Assuntos
Imunotoxinas/uso terapêutico , Neoplasias/terapia , Proteínas Recombinantes de Fusão/uso terapêutico , Adulto , Idoso , Anticorpos Monoclonais , Estudos de Coortes , Feminino , Humanos , Imunotoxinas/efeitos adversos , Imunotoxinas/farmacocinética , Antígenos do Grupo Sanguíneo de Lewis/imunologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/patologia , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/farmacocinética , Resultado do Tratamento
20.
J Gastrointest Cancer ; 46(2): 149-55, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25782589

RESUMO

PURPOSE: The purpose of this study was to investigate the effect of radiotherapy on local control and mordibity for patients with resected lymph node-positive pancreatic cancer as compared to gemcitabine-based chemotherapy alone. MATERIALS AND METHODS: Sixty-nine patients received adjuvant therapy for pancreatic adenocarcinoma with lymph node involvement after surgical resection and met the inclusion criteria for this analysis. Forty (58 %) patients received postoperative radiotherapy (PORT) to a median dose of 50.4 Gy with capecitabine or 5-fluorouracil concurrently in all but one case; 15 patients also received gemcitabine prior to PORT. Twenty-nine (42 %) patients received gemcitabine-based chemotherapy without PORT for a median of 6 cycles. RESULTS: The median overall survival for patients receiving PORT was 24.4 months compared to 25.6 months for patients not receiving PORT (p = 0.943). At 2 years, the rate of local control was 57 % for patients receiving PORT compared to 37 % for those who did not (p = 0.034). At 2 years, the rate of palliative local interventions was 16 % for patients receiving PORT compared to 18 % for patients who did not (p = 0.821). CONCLUSION: The use of PORT was associated with improved local control in the gemcitabine era for patients with resected, node-positive, pancreatic adenocarcinoma. The rates of overall survival and palliative interventions did not differ between the two groups.


Assuntos
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfonodos/cirurgia , Recidiva Local de Neoplasia/terapia , Neoplasias Pancreáticas/terapia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Quimioterapia Adjuvante , Terapia Combinada , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Radioterapia Adjuvante , Estudos Retrospectivos , Taxa de Sobrevida , Falha de Tratamento , Gencitabina
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