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1.
Clin Adv Hematol Oncol ; 14(3 Suppl 3): 1-15, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-27007241

RESUMEN

Until recently, treatment options for patients with metastatic colorectal cancer (CRC) were limited to chemotherapy, vascular endothelial growth factor­targeted therapy, and, for patients with RAS-wild type tumors, epidermal growth factor receptor­targeted therapy. For patients with disease progression after treatment, newer agents are now available: the multitargeted tyrosine kinase inhibitor regorafenib and the cytotoxic combination of trifluridine and tipiracil (TAS-102). Both regorafenib and trifluridine/tipiracil have demonstrated significant improvements in overall survival in patients with refractory metastatic CRC. Durable responses exceeding a year have been reported with regorafenib. The agents differ in their safety profiles. Regorafenib is associated with hand-foot skin reaction and fatigue, primarily in the first cycle. Alternative dosing strategies appear to improve the tolerability of regorafenib, and randomized dosing studies are underway to define the optimal strategy. Trifluridine/tipiracil is associated primarily with myelosuppression. Sequencing of these agents can be guided by patient characteristics, such as comorbidities and adverse reactions to previous treatments. Patients with a poor performance status are not likely to benefit from regorafenib. Ongoing studies are further defining the role of regorafenib and trifluridine/tipiracil in the treatment of metastatic CRC.


Asunto(s)
Antineoplásicos/uso terapéutico , Ensayos Clínicos como Asunto/normas , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/secundario , Terapia Molecular Dirigida , Neoplasias Colorrectales/metabolismo , Guías como Asunto , Humanos
2.
Cancer ; 121(13): 2193-7, 2015 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-25827820

RESUMEN

BACKGROUND: The AKT inhibitor MK-2206 at a dose of 60 mg every other day was evaluated in gastric/gastroesophageal junction cancers. METHODS: Patients who had progressed after first-line treatment were eligible. Pertinent eligibility criteria included adequate organ function, a fasting serum glucose level ≤ 150 mg/dL, and less than grade 2 malabsorption or chronic diarrhea. MK-2206 was given orally (60 evaluable patients required). The primary endpoint was overall survival, and a median survival of 6.5 months (power, 89%; significance level, 0.07) was considered encouraging for further investigation. RESULTS: Seventy patients were included in the final analyses. The median age was 59.8 years (range, 30.4-86.7 years); 70% were male, 89% were white, and 7% were Asian. There were 2 deaths possibly related to the study drug (cardiac arrest and respiratory failure). Grade 4 adverse events included hyperglycemia, anemia, and lung infection (1 each). Grade 3 adverse events occurred in < 5% of patients except for fatigue (6%). Other adverse events (all grades) included anemia (17%), anorexia (30%), diarrhea (26%), fatigue (50%), hyperglycemia (30%), nausea (40%), vomiting (22%), dry skin (19%), maculopapular rash (30%), and acneiform rash (13%). The response rate was 1%, the median progression-free survival was 1.8 months (95% confidence interval, 1.7-1.8 months), and the median overall survival was 5.1 months (95% confidence interval, 3.7-9.4 months) CONCLUSIONS: MK-2206 as second-line therapy was well tolerated by an unselected group of patients with gastric/gastroesophageal junction cancers, but it did not have sufficient activity (response rate, 1%; overall survival, 5.1 months) to warrant further testing in this population.


Asunto(s)
Neoplasias Esofágicas/tratamiento farmacológico , Unión Esofagogástrica/patología , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Esofágicas/patología , Humanos , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Análisis de Supervivencia
3.
J Clin Oncol ; 36(4): 359-366, 2018 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-29232172

RESUMEN

Purpose Metastatic pancreatic ductal adenocarcinoma is characterized by excessive hyaluronan (HA) accumulation in the tumor microenvironment, elevating interstitial pressure and impairing perfusion. Preclinical studies demonstrated pegvorhyaluronidase alfa (PEGPH20) degrades HA, thereby increasing drug delivery. Patients and Methods Patients with previously untreated metastatic pancreatic ductal adenocarcinoma were randomly assigned to treatment with PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) or nab-paclitaxel/gemcitabine (AG). Tumor HA levels were measured retrospectively using a novel affinity histochemistry assay. Primary end points were progression-free survival (PFS; overall) and thromboembolic (TE) event rate. Secondary end points included overall survival, PFS by HA level, and objective response rate. An early imbalance in TE events in the PAG arm led to a clinical hold; thereafter, patients with TE events were excluded and enoxaparin prophylaxis was initiated. Results A total of 279 patients were randomly assigned; 246 had HA data; 231 were evaluable for efficacy; 84 (34%) had HA-high tumors (ie, extracellular matrix HA staining ≥ 50% of tumor surface at any intensity). PFS was significantly improved with PAG treatment overall (hazard ratio [HR], 0.73; 95% CI, 0.53 to 1.00; P = .049) and for patients with HA-high tumors (HR, 0.51; 95% CI, 0.26 to 1.00; P = .048). In patients with HA-high tumors (PAG v AG), the objective response rate was 45% versus 31%, and median overall survival was 11.5 versus 8.5 months (HR, 0.96; 95% CI, 0.57 to 1.61). The most common treatment-related grade 3/4 adverse events with significant differences between arms (PAG v AG) included muscle spasms (13% v 1%), neutropenia (29% v 18%), and myalgia (5% v 0%). TE events were comparable after enoxaparin initiation (14% PAG v 10% AG). Conclusion This study met its primary end points of PFS and TE event rate. The largest improvement in PFS was observed in patients with HA-high tumors who received PAG. A similar TE event rate was observed between the treatment groups in stage 2 of the trial.


Asunto(s)
Albúminas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Hialuronoglucosaminidasa/metabolismo , Paclitaxel/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Albúminas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/secundario , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Enoxaparina/administración & dosificación , Femenino , Fibrinolíticos/administración & dosificación , Humanos , Ácido Hialurónico/metabolismo , Hialuronoglucosaminidasa/administración & dosificación , Masculino , Persona de Mediana Edad , Paclitaxel/efectos adversos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Supervivencia sin Progresión , Tromboembolia/inducido químicamente , Tromboembolia/prevención & control , Factores de Tiempo , Gemcitabina
4.
JAMA Oncol ; 3(4): 516-522, 2017 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-27978579

RESUMEN

IMPORTANCE: KRAS mutations are common in pancreatic cancer, but directly targeting the KRAS protein has thus far been unsuccessful. The aim of this trial was to block the MEK and PI3K/AKT pathways downstream of the KRAS protein as an alternate treatment strategy to slow cancer growth and prolong survival. This was the first cooperative group trial to evaluate this strategy using molecularly targeted oral combination therapy for the treatment of chemotherapy-refractory pancreatic cancer. OBJECTIVE: To compare selumetinib and MK-2206 vs modified FOLFOX (mFOLFOX) in patients with metastatic pancreatic cancer for whom gemcitabine-based therapy had failed. DESIGN, SETTING, AND PARTICIPANTS: SWOG S1115 was a randomized phase 2 clinical trial. Between September 2012 and May 2014, 137 patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed were randomized to selumetinib plus MK-2206 or mFOLFOX. Patients were randomized in a 1:1 fashion and stratified according to duration of prior systemic therapy and presence of liver metastases. INTERVENTIONS: Patients received selumetinib 100 mg orally per day plus MK-2206 135 mg orally once per week or mFOLFOX (oxaliplatin, 85 mg/m2 intravenous, and fluorouracil, 2400 mg/m2 intravenous infusion over 46-48 hours) on days 1 and 15 of a 28-day cycle. MAIN OUTCOMES AND MEASURES: The primary end point of the study was overall survival. Secondary objectives included evaluating toxic effects, objective tumor response, and progression-free survival. RESULTS: There were 58 patients in the selumetinib plus MK-2206 (experimental) arm (60% male; median [range] age, 69 [54-88] years) and 62 patients in the mFOLFOX arm (35% male; median [range] age, 65 [34-82] years). In the experimental arm, median overall survival was shorter (3.9 vs 6.7 months; HR, 1.37; 95% CI, 0.90-2.08; P = .15), as was median progression-free survival (1.9 vs 2.0 months; HR, 1.61; 95% CI, 1.07-2.43; P = .02). One vs 5 patients had a partial response and 12 vs 14 patients had stable disease in the experimental arm vs mFOLFOX arm. Grade 3 or higher toxic effects were observed in 39 patients treated with selumetinib and MK-2206 vs 23 patients treated with mFOLFOX. More patients in the experimental arm discontinued therapy due to adverse events (13 vs 7 patients). CONCLUSIONS AND RELEVANCE: Dual targeting of the MEK and PI3K/AKT pathways downstream of KRAS by selumetinib plus MK-2206 did not improve overall survival in patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed. This was the first randomized prospective evaluation of mFOLFOX in the US population that showed comparable results to CONKO-003 and PANCREOX. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01658943.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencimidazoles/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Terapia Recuperativa/métodos , Adenocarcinoma/mortalidad , Anciano , Anciano de 80 o más Años , Bencimidazoles/efectos adversos , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Oxaliplatino , Neoplasias Pancreáticas/mortalidad , Modelos de Riesgos Proporcionales
5.
J Gastrointest Surg ; 18(3): 592-8, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24297651

RESUMEN

INTRODUCTION: The benefit of an operation to remove the primary tumor among patients with synchronous stage IV colorectal cancer is controversial. This study analyzed the survival benefits associated with primary tumor resection among chemotherapy-treated stage IV colorectal cancer patients. METHODS: The study analyzed 11,716 chemotherapy-treated stage IV colorectal cancer patients in the California Cancer Registry between 1996 and 2007, with follow-up through 2009. Patients were stratified into operation and non-operation groups. Estimates of median overall and colorectal cancer-specific survival were generated. RESULTS: Patients undergoing operation compared to those who are not had higher median overall and colorectal cancer-specific survival, 21 versus 10 months (p < 0.0001) and 22 versus 12 months (p < 0.0001), respectively. Patients who were offered surgery but refused had decreased median overall and colorectal cancer-specific survival when compared to patients who underwent resection, 8 versus 21 months (p < 0.001) and 7 versus 22 months (p < 0.001), respectively. In multivariate regression models, patients who underwent resection of primary tumor had improved overall (hazard ratio (HR), 0.42; 95% confidence interval (CI) 0.40-0.44, p < 0.0001) and colorectal cancer-specific survival (HR, 0.43; 95% CI, 0.41-0.45; p < 0.0001). CONCLUSION: Primary tumor resection is associated with improved survival among stage IV chemotherapy-treated colorectal cancer patients.


Asunto(s)
Adenocarcinoma/secundario , Adenocarcinoma/cirugía , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Adenocarcinoma/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , California , Colectomía , Neoplasias Colorrectales/tratamiento farmacológico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Sistema de Registros , Tasa de Supervivencia , Adulto Joven
6.
Clin Mol Hepatol ; 20(2): 218-22, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25032190

RESUMEN

Hepatocellular carcinomas are highly vascular tumors, showing progressive hypervascularity by the process of neoangiogenesis. Tumor angiogenesis is critical for tumor growth as well as metastatic spread therefore, imaging and quantification of tumor neo-angiogenesis is essential for monitoring response to targeted therapies and predicting disease progression. Sorafenib is a molecular targeting agent used for treating hypervascular tumors. This drug is now the standard of care in treatment of patients with advanced hepatocellular carcinoma. Due to its anti-angiogenic and anti-proliferative actions, imaging findings following treatment with Sorafenib are quite distinct when compared to conventional chemotherapeutic agents. Liver MRI is a widely adopted imaging modality for assessing treatment response in hepatocellular carcinoma and imaging features may reflect pathophysiological changes within the tumor. In this mini-review, we will discuss MRI findings after Sorafenib treatment in hepatocellular carcinoma and review the feasibility of MRI as an early biomarker in differentiating responders from non-responders after treatment with molecular targeting agents.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/diagnóstico por imagen , Neoplasias Hepáticas/diagnóstico por imagen , Imagen por Resonancia Magnética , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Anciano , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/fisiopatología , Femenino , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/fisiopatología , Masculino , Persona de Mediana Edad , Niacinamida/uso terapéutico , Sorafenib , Tomografía Computarizada por Rayos X
7.
J Gastrointest Surg ; 17(2): 374-81, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23242847

RESUMEN

INTRODUCTION: Persistent lymph node-positive disease after preoperative radiotherapy for rectal cancer is associated with adverse outcomes. We quantified mortality risks of persistent pathologic lymph nodes in lymph node-positive rectal cancer patients treated with preoperative versus postoperative chemoradiation. METHODS: This was a retrospective population-based analysis of 2,038 patients with stage III rectal cancer diagnosed 1994-2005 with follow-up through 2007 using data from the California Cancer Registry. Survival estimates were generated using the Kaplan-Meier method. Multivariate cancer-specific and overall mortality analyses were performed using Cox proportional hazard ratios with adjustment for age, gender, race/ethnicity, tumor grade, T stage, N stage, socioeconomic status, and time period (1994-1997, 1998-2001, and 2002-2005). RESULTS: Overall survival was higher among lymph node-positive patients receiving postoperative chemoradiation compared to lymph node-positive patients receiving preoperative chemoradiation (median overall survival = 87 versus 62 months, P = 0.0002). In adjusted analyses, patients with persistent lymph node-positive disease after preoperative chemoradiation treatment had increased overall (HR = 1.69; 95 % CI, 1.42-2.01) and CRC-specific (HR = 1.78; 95 % CI, 1.44-2.19) mortality risk compared to lymph node-positive disease after postoperative chemoradiation treatment. CONCLUSIONS: Stage III rectal cancer patients with persistent pathologic lymph nodes after preoperative chemoradiation represent a high-risk group, with higher mortality than those treated with postoperative chemoradiation.


Asunto(s)
Neoplasias del Recto/mortalidad , Neoplasias del Recto/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Terapia Combinada , Femenino , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Cuidados Posoperatorios , Cuidados Preoperatorios , Pronóstico , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/radioterapia , Neoplasias del Recto/cirugía , Estudios Retrospectivos , Factores de Riesgo , Adulto Joven
8.
Cancer Chemother Pharmacol ; 64(4): 647-55, 2009 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19543728

RESUMEN

Temozolomide (TMZ) is an oral alkylating agent that is regarded as a tolerable and effective drug. When combined with radiotherapy in patients with newly diagnosed glioblastoma, survival is significantly prolonged. This finding has led to widespread use of TMZ for patients with this disease. We summarize developing concerns regarding the use of TMZ, imaging of malignant gliomas, and the pharmacology of TMZ-mechanism of action, scheduling and strategies for overcoming resistance.


Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Dacarbazina/análogos & derivados , Glioma/tratamiento farmacológico , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/farmacocinética , Antineoplásicos Alquilantes/farmacología , Dacarbazina/efectos adversos , Dacarbazina/farmacocinética , Dacarbazina/farmacología , Dacarbazina/uso terapéutico , Resistencia a Antineoplásicos , Humanos , Temozolomida
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