RESUMEN
Small bowel adenocarcinoma (SBA) is a rare tumor with an unfavorable prognosis, and due to its rarity, few studies on its treatment are available. Chemotherapy remains the standard of treatment in advanced disease. Recently immunotherapy has demonstrated to be a valid therapeutic option for many solid tumors. We reviewed the data published in literature to understand the impact of immunotherapy in this cancer.
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Adenocarcinoma , Neoplasias Duodenales , Neoplasias del Íleon , Neoplasias del Yeyuno , Humanos , Intestino Delgado/patología , Neoplasias del Yeyuno/tratamiento farmacológico , Neoplasias del Yeyuno/patología , Neoplasias del Íleon/tratamiento farmacológico , Neoplasias del Íleon/patología , Neoplasias Duodenales/patología , Neoplasias Duodenales/terapia , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , InmunoterapiaRESUMEN
The association of anti-EGFR to gemcitabine and oxaliplatin (GEMOX) chemotherapy did not improve survival in biliary tract carcinoma (BTC) patients. Multiple mechanisms might be involved in the resistance to anti-EGFR. Here, we explored the mutation profile of EGFR extracellular domain (ECD), of tyrosine kinase domain (TKD), and its amplification status. EGFR mutational status of exons 12, 18-21 was analyzed in 57 tumors by Sanger sequencing. EGFR amplification was evaluated in 37 tumors by Fluorescent In Situ Hybridization (FISH). Kaplan-Meier curves were calculated using the log-rank test. Six patients had mutations in exon 12 of EGFR ECD and 7 in EGFR TKD. Neither EGFR ECD nor TKD mutations affected progression free survival (PFS) or overall survival (OS) in the entire population. In the panitumumab plus GEMOX (P-GEMOX) arm, ECD mutated patients had a worse OS, while EGFR TKD mutated patients had a trend towards shorter PFS and OS. Overall, the presence of mutations in EGFR or in its transducers did not affect PFS or OS, while the extrahepatic cholangiocarcinoma (ECC) mutated patients had a worse prognosis compared to WT. Nineteen out of 37 tumors were EGFR amplified, but the amplification did not correlate with survival. ECC EGFR amplified patients had improved OS, whereas the amplification significantly correlated with poor PFS (p = 0.03) in gallbladder carcinoma patients. The high molecular heterogeneity is a predominant feature of BTC: the alterations found in this work seem to have a prognostic impact rather than a predictive role towards anti-EGFR therapy.
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Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/genética , Receptores ErbB/genética , Genes erbB-1 , Mutación , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/metabolismo , Neoplasias del Sistema Biliar/metabolismo , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Análisis Mutacional de ADN , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Neoplasias de la Vesícula Biliar/genética , Neoplasias de la Vesícula Biliar/metabolismo , Amplificación de Genes , Humanos , Hibridación Fluorescente in Situ , Estimación de Kaplan-Meier , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/uso terapéutico , Oxaliplatino , Panitumumab , Pronóstico , GemcitabinaRESUMEN
OBJECTIVE: The aim of our preliminary study was to compare the efficacy of drug-eluting beads preloaded with irinotecan (DEBIRI) vs drug-eluting beads preloaded with doxorubicin (DEBDOX) as second-line treatment of unresectable liver metastases from cholangiocarcinoma (CCA). METHODS: In 2013, 10 patients affected by multiple liver metastases from CCA, resistant to the first-line chemotherapy regimen, were enrolled: 5 patients were submitted to lobar/segmental transarterial chemoembolization (TACE) with DEBIRI (100-mg irinotecan/1 vial) and 5 patients with DEBDOX (50-mg doxorubicin/1 vial), performed every 3 weeks. Patients treated with DEBIRI received antipain premedication consisting of 30-mg of morphine and 3-4 ml of intra-arterial lidocaine. Complications and efficacy were assessed (response evaluation criteria in solid tumour 1.1). RESULTS: A total of 32 TACE were performed (mean: 3.2 TACE/patient), all well tolerated, with only 1 case of asymptomatic cholecystitis spontaneously recovered. Response rates of patients treated with DEBDOX and DEBIRI were: 4/5 progressive disease and 1/5 partial response vs 2/5 partial response, 2/5 stable disease and 1/5 progressive disease, respectively, with the appearance of variable necrosis percentage. Progression-free survival from the first procedure and progressive disease were 12.67 weeks for DEBIRI and 15.78 weeks for DEBDOX, respectively. Overall survival from time of primary diagnosis was 176 weeks for DEBIRI and 125 weeks for DEBDOX, respectively. CONCLUSION: In our preliminary experience, DEBIRI was more effective than DEBDOX as a second-line treatment for hepatic metastases from CCA. Antipain drug administration and the use of the microcatheter led to a good treatment tolerability and a low complication rate. Advances in knowledge: In our preliminary experience, DEBIRI was more effective than DEBDOX as a second-line treatment of hepatic metastases from CCA; further studies involving a larger cohort of patients are needed.
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Antibióticos Antineoplásicos/administración & dosificación , Antineoplásicos Fitogénicos/administración & dosificación , Neoplasias de los Conductos Biliares/patología , Camptotecina/análogos & derivados , Quimioembolización Terapéutica/métodos , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/secundario , Doxorrubicina/administración & dosificación , Sistemas de Liberación de Medicamentos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Camptotecina/administración & dosificación , Medios de Contraste , Femenino , Humanos , Irinotecán , Masculino , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
PURPOSE: We aimed to assess the safety and efficacy of metformin for treating patients with metastatic pancreatic cancer and to identify endocrine and metabolic phenotypic features or tumor molecular markers associated with sensitivity to metformin antineoplastic action. EXPERIMENTAL DESIGN: We designed an open-label, randomized, phase II trial to assess the efficacy of adding metformin to a standard systemic therapy with cisplatin, epirubicin, capecitabine, and gemcitabine (PEXG) in patients with metastatic pancreatic cancer. Patients ages 18 years or older with metastatic pancreatic cancer were randomly assigned (1:1) to receive PEXG every 4 weeks in combination or not with 2 g oral metformin daily. The primary endpoint was 6-months progression-free survival (PFS-6) in the intention-to-treat population. RESULTS: Between August 2010 and January 2014, we randomly assigned 60 patients to receive PEXG with (n = 31) or without metformin (n = 29). At the preplanned interim analysis, the study was ended for futility. PFS-6 was 52% [95% confidence interval (CI), 33-69] in the control group and 42% (95% CI, 24-59) in the metformin group (P = 0.61). Furthermore, there was no difference in disease-free survival and overall survival between groups. Despite endocrine metabolic modifications induced by metformin, there was no correlation with the outcome. Single-nucleotide polymorphism rs11212617 predicted glycemic response, but not tumor response to metformin. Gene expression on tumor tissue did not predict tumor response to metformin. CONCLUSIONS: Addition of metformin at the dose commonly used in diabetes did not improve outcome in patients with metastatic pancreatic cancer treated with standard systemic therapy. See related commentary by Yang and Rustgi, p. 1031.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Metformina/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Adulto , Anciano , Capecitabina/administración & dosificación , Cisplatino/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Epirrubicina/administración & dosificación , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/patología , Resultado del Tratamiento , GemcitabinaRESUMEN
BACKGROUND: Biliary tract cancer (BTC) is a rare and lethal disease with few therapeutic options. Preclinical data suggest that the epidermal growth factor receptor (EGFR) pathway could be involved in its progression. METHODS: This open-label, randomized phase 2 trial recruited chemotherapy-naive patients with advanced BTC displaying a wild-type (WT) KRAS status. Patients were randomized to gemcitabine (1000 mg/m(2) ) and oxaliplatin (100 mg/m(2) ) with (arm A) or without (arm B) panitumumab (6 mg/kg) for up to 12 cycles. The primary endpoint was progression-free survival (PFS) analyzed in an intention-to-treat fashion. RESULTS: Eighty-nine patients (45 in arm A and 44 in arm B) were enrolled between June 2010 and September 2013. After a median follow-up of 10.1 months, the median PFS was 5.3 months (95% confidence interval, 3.3-7.2 months) in arm A and 4.4 months (95% confidence interval, 2.6-6.2 months) in arm B (P = .27). No survival differences were observed: the median overall survival was 9.9 months in arm A and 10.2 months in arm B (P = .42). In a subgroup analysis, no differences in PFS according to the site of the primary tumor were observed; patients with intrahepatic cholangiocarcinoma treated with panitumumab may have had a survival benefit in comparison with the control group (15.1 vs 11.8 months, P = .13). As for safety, skin toxicity was the main adverse event in arm A (80% of the patients). A higher incidence of diarrhea (55.5% vs 31.8%), mucositis (22.2% vs 13.6%), and constipation (24.4% vs 15.9%) was seen in arm A. CONCLUSIONS: These results confirm the marginal role of anti-EGFR therapy even for WT KRAS-selected BTC.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Conductos Biliares Extrahepáticos/patología , Conductos Biliares Intrahepáticos/patología , Colangiocarcinoma/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patología , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/patología , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/genética , Neoplasias del Sistema Biliar/patología , Colangiocarcinoma/genética , Colangiocarcinoma/patología , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Femenino , Neoplasias de la Vesícula Biliar/genética , Neoplasias de la Vesícula Biliar/patología , Humanos , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Panitumumab , Pronóstico , Proteínas Proto-Oncogénicas p21(ras)/genética , Resultado del Tratamiento , GemcitabinaRESUMEN
BACKGROUND: After progression to a standard first-line platinum and gemcitabine combination (GP), there is no established second-line therapy for patients with advanced biliary tract cancers (aBTC). Indeed, literature data suggest limited activity of most second-line agents evaluated so far. METHODS: We collected a large retrospective series of aBTC patients treated with second-line chemotherapy after progression to a first-line GP regimen at different Italian institutions. We then pooled the data with those reported in previous studies, which were identified with a Medline search and the on-line abstract datasets of major international oncology meetings. RESULTS: A total of 174 patients were included in the multicenter survey: response rate (RR) with second-line chemotherapy was low (3.4 %), with median PFS and OS of 3.0 months and 6.6 months, respectively. At multivariate analysis, preserved performance status, low CA19.9 levels and absence of distant metastases were favorable prognostic factors. Data from other five presented or published series were identified, for a total of 499 patients included in the pooled analysis. The results confirmed marginal activity of second-line chemotherapy (RR: 10.2 %), with limited efficacy in unselected patient populations (median PFS: 3.1 months; median OS: 6.3 months). CONCLUSIONS: The current analysis highlights the limited value of second-line chemotherapy after a first-line GP combination in aBTC. While waiting for effective biologic agents in this setting, ongoing randomized trials will identify the optimal second-line chemotherapy regimen and validate prognostic factors for individual patient management.
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Neoplasias del Sistema Biliar/tratamiento farmacológico , Cisplatino/administración & dosificación , Desoxicitidina/análogos & derivados , Compuestos Organoplatinos/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Desoxicitidina/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oxaliplatino , Estudios Retrospectivos , Resultado del Tratamiento , GemcitabinaAsunto(s)
Adenocarcinoma/radioterapia , Antimetabolitos Antineoplásicos/uso terapéutico , Quimioradioterapia/métodos , Desoxicitidina/análogos & derivados , Fluorouracilo/análogos & derivados , Neoplasias Pancreáticas/terapia , Radioterapia Guiada por Imagen/métodos , Radioterapia de Intensidad Modulada/métodos , Femenino , Humanos , MasculinoRESUMEN
PURPOSE: To determine the maximum tolerated radiation dose (MTD) of an integrated boost to the tumor subvolume infiltrating vessels, delivered simultaneously with radical dose to the whole tumor and concomitant capecitabine in patients with pretreated advanced pancreatic adenocarcinoma. METHODS AND MATERIALS: Patients with stage III or IV pancreatic adenocarcinoma without progressive disease after induction chemotherapy were eligible. Patients underwent simulated contrast-enhanced four-dimensional computed tomography and fluorodeoxyglucose-labeled positron emission tomography. Gross tumor volume 1 (GTV1), the tumor, and GTV2, the tumor subvolume 1 cm around the infiltrated vessels, were contoured. GTVs were fused to generate Internal Target Volume (ITV)1 and ITV2. Biological tumor volume (BTV) was fused with ITV1 to create the BTV+Internal Target Volume (ITV) 1. A margin of 5/5/7 mm (7 mm in cranium-caudal) was added to BTV+ITV1 and to ITV2 to create Planning Target Volume (PTV) 1 and PTV2, respectively. Radiation therapy was delivered with tomotherapy. PTV1 received a fixed dose of 44.25 Gy in 15 fractions, and PTV2 received a dose escalation from 48 to 58 Gy as simultaneous integrated boost (SIB) in consecutive groups of at least 3 patients. Concomitant chemotherapy was capecitabine, 1250 mg/m(2) daily. Dose-limiting toxicity (DLT) was defined as any treatment-related G3 nonhematological or G4 hematological toxicity occurring during the treatment or within 90 days from its completion. RESULTS: From June 2005 to February 2010, 25 patients were enrolled. The dose escalation on the SIB was stopped at 58 Gy without reaching the MTD. One patient in the 2(nd) dose level (50 Gy) had a DLT: G3 acute gastric ulcer. Three patients had G3 late adverse effects associated with gastric and/or duodenal mucosal damage. All patients received the planned dose of radiation. CONCLUSIONS: A dose of 44.25 Gy in 15 fractions to the whole tumor with an SIB of 58 Gy to small tumor subvolumes concomitant with capecitabine is feasible in chemotherapy-pretreated patients with advanced pancreatic cancer.
Asunto(s)
Adenocarcinoma/radioterapia , Antimetabolitos Antineoplásicos/uso terapéutico , Quimioradioterapia/métodos , Desoxicitidina/análogos & derivados , Fluorouracilo/análogos & derivados , Neoplasias Pancreáticas/terapia , Radioterapia Guiada por Imagen/métodos , Radioterapia de Intensidad Modulada/métodos , Adenocarcinoma/irrigación sanguínea , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Anciano , Vasos Sanguíneos/efectos de los fármacos , Vasos Sanguíneos/efectos de la radiación , Capecitabina , Quimioradioterapia/efectos adversos , Desoxicitidina/uso terapéutico , Fraccionamiento de la Dosis de Radiación , Duodeno/efectos de la radiación , Estudios de Factibilidad , Femenino , Fluorouracilo/uso terapéutico , Mucosa Gástrica/efectos de la radiación , Humanos , Quimioterapia de Inducción/efectos adversos , Quimioterapia de Inducción/métodos , Mucosa Intestinal/efectos de la radiación , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Estadificación de Neoplasias/métodos , Órganos en Riesgo/efectos de la radiación , Neoplasias Pancreáticas/irrigación sanguínea , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Radioterapia de Intensidad Modulada/efectos adversos , Carga TumoralRESUMEN
BACKGROUND: New strategies to prolong disease control warrant investigation in patients with metastatic pancreatic adenocarcinoma. This open-label, randomised, multi-centre phase II trial explored the role of maintenance sunitinib after first-line chemotherapy in this setting. METHODS: Patients with pathologic diagnosis of metastatic pancreatic adenocarcinoma, performance status >50%, no progression after 6 months of chemotherapy were centrally randomised by an independent contract research organisation, which was also responsible for data collection and monitoring, to observation (arm A) or sunitinib at 37.5mg daily until progression or a maximum of 6 months (arm B). The primary outcome measure was the probability of being progression-free at 6 months (PFS-6) from randomisation. Assuming P0 = 10%; P1 = 30%, α .10; ß .10, the target accrual was 26 patients per arm. RESULTS: 28 per arm were randomised. One arm B patient had kidney cancer and was excluded. Sunitinib was given for a median of 91 days (7-186). Main grade 3-4 toxicity was thrombocytopenia, neutropenia and hand-foot syndrome (12%), diarrhoea 8%. In arm A versus B, PFS-6 was 3.6% (95% confidence interval (CI): 0-10.6%) and 22.2% (95% CI: 6.2-38.2%; P<0.01); 2 y overall survival was 7.1% (95% CI: 0-16.8%) and 22.9% (95% CI: 5.8-40.0%; P = 0.11), stable disease 21.4% and 51.9% (P = 0.02). CONCLUSION: This is the first randomised trial on maintenance therapy in metastatic pancreatic adenocarcinoma. The primary end-point was fulfilled and 2 y overall survival was remarkably high, suggesting that maintenance sunitinib is promising and should be further explored in this patient population.
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Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Indoles/uso terapéutico , Quimioterapia de Mantención , Neoplasias Pancreáticas/tratamiento farmacológico , Pirroles/uso terapéutico , Adenocarcinoma/mortalidad , Adenocarcinoma/secundario , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Sunitinib , Análisis de SupervivenciaRESUMEN
Biliary tract cancer is a rare malignant tumor. Accordingly, to perform prospective and randomized trials is difficult and the knowledge of its natural history and optimal management remains limited. Chemotherapy is commonly used to improve the outcome and to delay tumor progression in advanced disease. Only recently, cisplatin-gemcitabine combination was identified as the new standard first-line therapy. Despite the outcome improvement, disease progression is a constant and approximately half of patients failing upfront treatment maintain a good performance status and are willing to undergo further treatment. No standard salvage chemotherapy regimen has been identified yet. Experiences of salvage therapy in advanced biliary tract cancer are sparse and yielded disappointing results. Well designed multi-institutional randomized trials are warranted to clarify the role and the activity of a second-line therapy.
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Neoplasias del Sistema Biliar/patología , Neoplasias del Sistema Biliar/terapia , Terapia Recuperativa , Neoplasias del Sistema Biliar/mortalidad , Humanos , Estadificación de Neoplasias , Pronóstico , Nivel de AtenciónRESUMEN
BACKGROUND AND PURPOSE: Hypofractionated radiotherapy (RT) of pancreatic adenocarcinoma is limited by the tolerance of adjacent normal tissues. A better understanding of the influence of dosimetric variables on the rate of toxicity after RT must be considered an important goal. METHODS AND MATERIALS: Sixty-one patients with histologically proven locally advanced disease (LAPD) were analyzed. The therapeutic strategy consisted of induction chemotherapy (ChT) followed by concurrent chemoradiotherapy (CRT). In 39 out of 61 patients the target volume was based on a four-dimensional CT (4D-CT) procedure. Delivered dose was 44.25Gy in 15 fractions to PTV2, which consisted of pancreatic tumor and regional lymph nodes considered radiologically involved; 23 out of 61 patients received a simultaneous integrated boost (SIB) to a tumor sub-volume infiltrating the great abdominal vessels (PTV1) with dose in the range of 48-58Gy. RT was delivered with Helical Tomotherapy. Dose-volume histograms (DVHs) of target volumes and organs at risk (OARs) were collected for analysis. The predictive value of clinical/dosimetric parameters was tested by univariate/multivariate analyses. RESULTS: The crude incidence of acute gastrointestinal (GI) grade 2 toxicity was 33%. The 12-month actuarial rate of "anatomical" (gastro-duodenal mucosa damage) toxicity was 13% (95% CI: 4-22%). On univariate analysis, several stomach and duodenum DVH endpoints are predictive of toxicity after moderately hypofractionated radiotherapy. Multivariate analysis confirmed that baseline performance status and the stomach V20[%] were strong independent predictors of acute GI grade ⩾2 toxicity. The high-dose region of duodenum DVH (V45[%]; V40[%]) was strongly correlated with grade ⩾2 "anatomical" toxicity; the best V40[%] and V45[%] cut-off values were 16% and 2.6% respectively. CONCLUSION: Regarding dosimetric indices, stomach V20[%] correlates with a higher rate of acute toxicity; more severe acute and late anatomical toxicities are related to the high dose region of duodenum DVH.
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Adenocarcinoma/terapia , Quimioradioterapia , Fraccionamiento de la Dosis de Radiación , Neoplasias Pancreáticas/terapia , Anciano , Quimioradioterapia/efectos adversos , Femenino , Humanos , Quimioterapia de Inducción/efectos adversos , Masculino , Dosificación Radioterapéutica , Neoplasias PancreáticasRESUMEN
The use of platinated agents in combination chemotherapy regimens for advanced pancreatic cancer is controversial owing to the lack of an outstanding impact on the outcome and a substantial increase in hematologic and extra-hematologic toxicities. Pharmacogenetic studies to identify patients who could benefit most from such therapies are urgently needed. The Xeroderma-Pigmentosum group-D polymorphism at codon-751 (XPD-Lys751Gln) emerged as the most significant independent predictor for death- and progression-risk in our previous study on functional polymorphisms in 122 advanced pancreatic cancer patients treated with cisplatin-docetaxel-capecitabine-gemcitabine and cisplatin-epirubicin-capecitabine-gemcitabine (or EC-GemCap). To confirm the prognostic role of this variable, we further evaluated the correlation of XPD-Lys751Gln with outcome in another 125 patients treated with the same regimens, and 90 treated with gemcitabine monotherapy. Genotyping was successfully carried out in the vast majority of DNA samples. Genotype frequencies followed Hardy-Weinberg equilibrium, and XPD-Lys751Gln was associated with differential progression-free and overall-survival. Multivariate analysis confirmed its prognostic significance in platinum-based regimens. In particular, XPD-Gln751Gln was significantly associated with risk of death (hazard ratio, HR = 1.7, 95% confidence interval [CI], 1.1-2.6, p = 0.011) and risk of progression (HR = 1.7, 95% CI, 1.1-2.5, p = 0.013). No correlation was observed in gemcitabine monotherapy-treated patients. The analysis of DNA damage using extra-long-PCR in lymphocytes supported the association of XPD-Gln751Gln with greater resistance to cisplatin-induced damage. The increasing evidence of XPD-Lys751Gln impact on the outcome of gemcitabine-cisplatin-based polychemotherapy leads to plan prospective studies to validate the role of this polymorphism as a new tool for optimization of the currently available treatments in pancreatic cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Glicina/genética , Lisina/genética , Neoplasias Pancreáticas/tratamiento farmacológico , Polimorfismo Genético , Proteína de la Xerodermia Pigmentosa del Grupo D/genética , Anciano , Cisplatino/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/genética , Reacción en Cadena de la Polimerasa , Pronóstico , Proteína de la Xerodermia Pigmentosa del Grupo D/química , GemcitabinaRESUMEN
Conflicting results have been reported on the role of extracellular matrix (ECM) proteins in pancreatic cancer. Preclinical studies suggest that the overexpression of biglycan (proteoglycan-I, PG-I), a leucine-rich protein of the ECM, may induce growth arrest of pancreatic cancer cells. The aim of this study was to assess the prognostic role of biglycan expression in pancreatic cancer. We also evaluated MIB-1 and COX-2 expressions (as potential markers of growth and aggressiveness) to better characterize the biology of the tumors. The classical pathological parameters (grading, desmoplasia, perineural, or vascular invasion) as well as molecular determinants of prognosis were examined. MIB-1 (a proliferative index associated with prognosis in most tumors), COX-2, and PG-I expressions were detected by immunohistochemistry and immunofluorescence on tissue samples from 53 patients with pancreatic cancer and reviewed by two independent pathologists. To verify PG-I expression, three rabbit sera (LF104, LF112, and LF121 from NIH, Bethesda, MA, US) were tested. Logrank test and Cox's model were applied for statistical analysis. Out of 53 patients, 40 had stage III and IV pancreatic cancer. Fourteen patients did not express any of the PG-I epitopes. The patients who expressed at least two PG-I epitopes had shorter survival compared to those with single epitope or lacking any expression (28 vs 44 weeks, P = 0.0021). The MIB-1 higher expression predicted shorter survival (25 vs 41 weeks, P = 0.0059). The other parameters were not associated with clinical outcome. Multivariate analyses confirmed PG-I expression and MIB-1 as independent negative prognostic factors. Patients who presented PG-I expression in the ECM had the worse prognosis compared to those who did not. Our results are not in contrast with the hypothesis that ECM proteins are a potential barrier to metastatic spread in localized pancreatic cancer. Rather, we underline the complexity of tumor-stroma interactions in the advanced stage of cancer and the need of further study.
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Adenocarcinoma/metabolismo , Biglicano/metabolismo , Ciclooxigenasa 2/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidad , Ubiquitina-Proteína Ligasas/metabolismo , Adenocarcinoma/mortalidad , Adenocarcinoma/cirugía , Biomarcadores de Tumor/metabolismo , Matriz Extracelular/metabolismo , Femenino , Humanos , Antígeno Ki-67 , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/cirugía , Sobrevida , Resultado del TratamientoRESUMEN
BACKGROUND: Preoperative chemotherapy (PCHT) has recently been proposed also in patients with resectable pancreatic adenocarcinoma. Few data are currently available on the impact of PCHT on short-term postoperative outcome after pancreatic resection. The objective of this study is to assess the impact of PCHT on pancreatic structure and short-term outcome after surgical resection. METHODS: Fifty consecutive patients successfully underwent resection after PCHT. Each patient was matched with two control patients with pancreatic adenocarcinoma selected from our prospective electronic database. Match criteria were age (±3 years), gender, American Society of Anesthesiologist score, type of resection, pancreatic duct diameter (±1 mm), and tumor size (±5 mm). Primary endpoint was morbidity rate. Secondary endpoints were pancreatic parenchymal structure, mortality rate, and length of hospital stay (LOS). RESULTS: Both degree of fibrosis and fatty infiltration of the pancreas were similar in the two groups. Overall morbidity rate was 48.0 % in the PCHT group vs. 54.0 % in the control group (p = 0.37). Pancreatic fistula rate was 18.0 % in the PCHT group vs. 25.0 % in the control group (p = 0.41). Mortality was 4.0 % in the PCHT group vs. 2.0 % in the control group (p = 0.60). Mean LOS (days) was 12.7 in the PCHT group vs. 12.4 in the control group (p = 0.74). There was no difference in resection margin status, while the rate of patients without nodal involvement was higher in the PCHT group (46.0 vs. 23.0 %, p = 0.004). CONCLUSION: PCHT did not induce significant structural changes in pancreatic parenchyma and did not adversely affect short-term outcome after surgery.
Asunto(s)
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Páncreas/patología , Pancreatectomía/efectos adversos , Fístula Pancreática/etiología , Neoplasias Pancreáticas/terapia , Hemorragia Posoperatoria/etiología , Tejido Adiposo , Anciano , Quimioterapia Adyuvante , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Fibrosis , Humanos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Páncreas/efectos de los fármacos , Pancreaticoduodenectomía/efectos adversos , Hemorragia Posoperatoria/cirugía , Factores de Tiempo , Resultado del Tratamiento , GemcitabinaRESUMEN
BACKGROUND: Pancreatic cancer is among the deadliest tumors. Due to intrinsic chemo- and radio-resistance, surgical resection remains the only chance for cure. However surgery alone is unable to considerably improve survival and complementary chemotherapy and radiotherapy in a multimodal approach have been tested. Adjuvant chemotherapy yielded a modest outcome improvement, whereas the use of adjuvant chemoradiation is highly controversial. In this scenario, the neoadjuvant approach has a strong theoretical rationale, but limited information on the efficacy of this strategy is available. MATERIALS AND METHODS: This review critically overviews the current knowledge, the rationale, the available data and information on neoadjuvant treatment in resectable pancreatic cancer. RESULTS: The very early systemic dissemination of pancreatic cancer endorses the rationale for an up-front use of systemic therapy. However, evidence collected so far depends on retrospective data, small case series that did not balance the different characteristics of patients suitable for surgery before or after neoadjuvant chemotherapy. CONCLUSION: Currently there is no straightforward evidence to support the routine clinical use of this strategy. Only a properly designed randomized trial testing combination chemotherapy regimens selected on the basis of their efficacy and activity against metastatic disease can address this issue.
Asunto(s)
Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/cirugía , Humanos , Terapia Neoadyuvante , Neoplasias Pancreáticas/radioterapiaRESUMEN
BACKGROUND: New therapies are needed for pancreatic cancer. OBJECTIVE: To determine the feasibility and safety of a new endoscopic treatment. Secondary endpoints were to determine effects on tumor growth measured with CT scan and to find the overall survival. DESIGN: A cohort study of patients with local progression of advanced pancreatic adenocarcinoma after neoadjuvant therapy. The cryotherm probe (CTP), a flexible bipolar device that combines radiofrequency with cryogenic cooling, was used under EUS guidance. SETTING: San Raffaele Hospital, Milan, Italy; University Medical Center, Hamburg-Eppendorf, Germany. PATIENTS: A total of 22 patients (male/female 11/11; mean age 61.9 years) were enrolled from September 2009 to May 2011. INTERVENTION: Radiofrequency heating: 18 W; pressure for cooling: 650 psi (Pounds per Square Inch); application time: depending on tumor size. MAIN OUTCOME MEASUREMENTS: Feasibility was evaluated during the procedure. A clinical and radiologic follow-up was planned. RESULTS: The CTP was successfully applied in 16 patients (72.8%); in 6 it was not possible because of stiffness of the GI wall and of the tumor. Amylase arose in 3 of 16 patients; none had clinical signs of pancreatitis. Late complications arose in 4 cases: 3 were mostly related to tumor progression. Median postablation survival time was 6 months. A CT scan was performed in all patients, but only in 6 of 16 was it possible to clearly define the tumor margins after ablation. In these patients, the tumor appeared smaller compared with the initial mass (P = .07). LIMITATIONS: Small sample of patients, difficulty of objectifying the size of the ablated zone by CT scan. CONCLUSION: EUS-guided CTP ablation is feasible and safe. Further investigations are needed to demonstrate progression-free survival and local control.
Asunto(s)
Adenocarcinoma/cirugía , Ablación por Catéter/métodos , Criocirugía/métodos , Endosonografía , Neoplasias Pancreáticas/cirugía , Ultrasonografía Intervencional , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/mortalidad , Adenocarcinoma/terapia , Adulto , Anciano , Anciano de 80 o más Años , Quimioradioterapia Adyuvante , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/terapia , Complicaciones Posoperatorias , Estudios Prospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Pancreatic cancer is one of the most deadly cancers and is characterized by a poor prognosis. Single agent gemcitabine, despite its limited activity and modest impact on disease outcome, is considered as the standard therapy in pancreatic cancer. Most of the combination regimens used in the treatment of this disease, also including the targeted agents, did not improve the outcome of patients. Also, taxanes have been tested as single agent and in combination chemotherapy, both in first line and as salvage chemotherapy, as another possible option for treating pancreatic cancer. The inclusion of taxanes in combination with gemcitabine as upfront therapy obtained promising results. Accordingly, taxanes, and above all, new generation taxanes, appear to be suitable candidates for further testing to assess their role against pancreatic cancer in various clinical settings.
Asunto(s)
Paclitaxel/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Taxoides/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica , Terapia Combinada , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Docetaxel , Humanos , Radioterapia , Terapia Recuperativa , Resultado del Tratamiento , GemcitabinaRESUMEN
Biliary tract cancer is a rare malignant tumor. There is limited knowledge about biology and natural history of this disease and considerable uncertainty remains regarding its optimal diagnostic and therapeutic management. The role of adjuvant therapy is object of debate and controversy. Although resection is identified as the most effective and the only potentially curative treatment, there is no consensus on the impact of adjuvant chemotherapy and/or radiotherapy on the high incidence of disease recurrence and on survival. This is mainly due to the rarity of this disease and the consequent difficulty in performing randomized trials. The only two prospectively controlled trials concluded that adjuvant chemotherapy did not improve survival. Most of the retrospective trials, which had limited sample size and included heterogeneous patients population and non-standardized therapies, suggested a marginal benefit of chemoradiotherapy in reducing locoregional recurrence and an uncertain impact on survival. Well-designed multi-institutional randomized trials are necessary to clarify the role of adjuvant therapy. Two ongoing phase III trials may provide relevant information.
Asunto(s)
Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/radioterapia , Quimioterapia Adyuvante/métodos , Radioterapia Adyuvante/métodos , Quimioradioterapia/métodos , Ensayos Clínicos como Asunto , Terapia Combinada/métodos , Guías como Asunto , Humanos , Oncología Médica/métodos , Pronóstico , Recurrencia , Proyectos de Investigación , Resultado del TratamientoRESUMEN
BACKGROUND: Information from randomized trials on the role of combination chemotherapy in the adjuvant treatment of pancreatic adenocarcinoma is limited. This randomized phase II trial aimed to identify the most promising regimen warranting phase III evaluation. METHODS: Therapy-naive patients, age 18-75 years, Karnofsky Performance Status (KPS)>60, gross total resection of stage IB-III pancreatic adenocarcinoma, stratified for center and surgical margins, were randomly assigned to receive either gemcitabine 1 g/m2 weekly on days 1, 8, and 15 (arm A) or the PEFG regimen (cisplatin and epirubicin 40 mg/m2, day 1; gemcitabine 600 mg/m2, days 1, 8; 5-fluorouracil 200 mg/m2 daily, days 1-28) (arm B). Chemotherapy was administered every 4 weeks for 3 months and followed by irradiation concurrent to continuous infusion of 5-fluorouracil 250 mg/m2 daily. Primary endpoint was the probability of being disease-free at 1 year from surgery. Assuming P0=35% and P1=55%, α=.05 and ß=.10, the study was to enroll 51 patients per arm. RESULTS: A total of 102 patients were randomized; 100 were eligible (arm A: 51; arm B: 49). Baseline characteristic (A/B) were: Median age was 61/60 years; 75% had KPS>80 75/76%; 36% grade 3 tumor 29/43%, 79% stage IIB/III 75/84%, 31% R1 resection 35/29%. Survival figures (A/B) were: Median disease-free survival was 11.7 and 15.2 months; 1-year disease-free survival 49.0% (95% confidence interval [95% CI] 35-63%) and 69.4% (95% CI 56-83%); median survival 24.8 and 28.9 months. Combination chemotherapy produced more hematological toxicity without relevant differences in nonhematological toxicities. CONCLUSIONS: The 4-drug regimen deserves further assessment in resectable pancreatic cancer.
Asunto(s)
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioradioterapia , Recurrencia Local de Neoplasia/terapia , Neoplasias Pancreáticas/terapia , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adolescente , Adulto , Anciano , Quimioterapia Adyuvante , Cisplatino/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Epirrubicina/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Pronóstico , Tasa de Supervivencia , Adulto Joven , GemcitabinaRESUMEN
PURPOSE: PEFG regimen (P:cisplatin, E:epirubicin, F:5-fluorouracil, G:gemcitabine) significantly prolonged progression-free (PFS) and overall survival (OS) of patients with advanced pancreatic adenocarcinoma (PA) with respect to standard gemcitabine. The current trial was aimed at assessing whether the replacement of E with docetaxel (D) may improve 6 months PFS (PFS6). METHODS: Chemo-naive patients with stage III or metastatic PA received P (30 mg/m(2) day 1 and 15), G (800 mg/m(2) day 1 and 15), and capecitabine (1,250 mg/m(2)/day days 1-28, without a break) and were randomized to receive either D at 25-30 mg/m(2) day 1 and 15 (arm A: PDXG regimen) or E at 30 mg/m(2) day 1 and 15 (arm B: PEXG regimen). Cycles were repeated every 28 days for a maximum of 6 months. The Fleming design was used to calculate the sample size on the probability of being PFS6. Assuming P0 = 40% and P1 = 60%, α = 0.05 and ß = 0.10; the study was to enroll 52 patients per arm. RESULTS: Between July 2005 and September 2008, 105 patients were enrolled, stratified by stage and randomized. Patients' characteristics were (A/B) the following: median age 61/59, PS >70 92/88%, metastatic disease 66/65%. PFS6 was 58%, and median OS was 11 months in both arms. A partial response was observed in 60/37% of patients. Main per cycle G3-4 toxicity was the following: neutropenia 4/13%, thrombocytopenia 2/4%, anemia 4/4%, and fatigue 6/3%. CONCLUSIONS: The inclusion of D instead of E yielded more objective response and less G3-4 neutropenia but did not improve PFS and OS. The present trial confirms the relevant impact on outcome of advanced PA of 4-drug regimens.