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1.
Nature ; 575(7781): 217-223, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31666701

RESUMEN

KRAS is the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours1,2. The KRAS(G12C) mutant has a cysteine residue that has been exploited to design covalent inhibitors that have promising preclinical activity3-5. Here we optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity. Our efforts have led to the discovery of AMG 510, which is, to our knowledge, the first KRAS(G12C) inhibitor in clinical development. In preclinical analyses, treatment with AMG 510 led to the regression of KRASG12C tumours and improved the anti-tumour efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG 510 resulted in a pro-inflammatory tumour microenvironment and produced durable cures alone as well as in combination with immune-checkpoint inhibitors. Cured mice rejected the growth of isogenic KRASG12D tumours, which suggests adaptive immunity against shared antigens. Furthermore, in clinical trials, AMG 510 demonstrated anti-tumour activity in the first dosing cohorts and represents a potentially transformative therapy for patients for whom effective treatments are lacking.


Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Piperazinas/farmacología , Piperazinas/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Piridinas/farmacología , Piridinas/uso terapéutico , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Humanos , Inmunoterapia , Inflamación/inducido químicamente , Inflamación/inmunología , Inflamación/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Fosforilación/efectos de los fármacos , Piperazinas/administración & dosificación , Piperazinas/química , Proteínas Proto-Oncogénicas p21(ras)/genética , Piridinas/administración & dosificación , Piridinas/química , Pirimidinas/administración & dosificación , Pirimidinas/química , Transducción de Señal/efectos de los fármacos , Resultado del Tratamiento , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología
2.
Cancer ; 126(13): 3021-3030, 2020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-32320048

RESUMEN

BACKGROUND: Despite a protracted disease course and multiple available therapies, patients with well-differentiated neuroendocrine tumors (NETs) inevitably experience disease progression. Programmed death-ligand 1 (PD-L1) has been associated with NET progression and prognosis. The multicohort, phase 1 KEYNOTE-028 study (ClinicalTrials.gov identifier NCT02054806) evaluated the activity and safety of the anti-programmed cell death protein 1 immunotherapy pembrolizumab in patients with well-differentiated or moderately-differentiated NETs. METHODS: Patients with PD-L1-positive, locally advanced or metastatic carcinoid or well-differentiated or moderately-differentiated pancreatic NETs (pNETs) were enrolled into separate cohorts and received pembrolizumab at a dose of 10 mg/kg every 2 weeks for up to 2 years. The objective response rate was the primary endpoint (as per Response Evaluation Criteria in Solid Tumors version 1.1, by investigator review). Safety was a secondary endpoint. RESULTS: Of 170 and 106 patients, respectively, who had evaluable samples among those screened for the carcinoid and pNET cohorts, 21% and 25%, respectively, had PD-L1-positive tumors; of these, 25 and 16 patients, respectively, were eligible and treated. The median follow-up was 20 months (range, 2-35 months) and 21 months (range, 5-32 months), respectively. The objective response rate was 12.0% (95% CI, 2.5%-31.2%) and 6.3% (95% CI, 0.2%-30.2%), respectively; 3 partial responses occurred among the carcinoid cohort and 1 among the pNET cohort. The median duration of response in the carcinoid cohort was 9.2 months (range, 6.9-11.1 months), and was not reached in the pNET cohort. No complete responses occurred. Treatment-related adverse events occurred in 68% and 69% of patients, respectively, most often diarrhea (7 patients in the carcinoid cohort and 4 patients in the pNET cohort) and fatigue (6 patients in each cohort). Hypothyroidism was the most common immune-mediated adverse event (5 patients in the carcinoid cohort and 2 patients in the pNET cohort). CONCLUSIONS: Pembrolizumab demonstrated antitumor activity in a subset of patients with NETs and was well-tolerated.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Tumor Carcinoide/tratamiento farmacológico , Tumores Neuroendocrinos/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Alanina Transaminasa/metabolismo , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Aspartato Aminotransferasas/metabolismo , Tumor Carcinoide/química , Tumor Carcinoide/patología , Estudios de Cohortes , Diarrea/inducido químicamente , Progresión de la Enfermedad , Esquema de Medicación , Fatiga/inducido químicamente , Femenino , Estudios de Seguimiento , Humanos , Hipotiroidismo/inducido químicamente , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/química , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/patología
3.
Invest New Drugs ; 38(3): 821-830, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-31338636

RESUMEN

Vantictumab is a fully human monoclonal antibody that inhibits Wnt pathway signaling through binding FZD1, 2, 5, 7, and 8 receptors. This phase Ib study evaluated vantictumab in combination with nab-paclitaxel and gemcitabine in patients with untreated metastatic pancreatic adenocarcinoma. Patients received vantictumab at escalating doses in combination with standard dosing of nab-paclitaxel and gemcitabine according to a 3 + 3 design. A total of 31 patients were treated in 5 dosing cohorts. Fragility fractures attributed to vantictumab occurred in 2 patients in Cohort 2 (7 mg/kg every 2 weeks), and this maximum administered dose (MAD) on study was considered unsafe. The dosing schedule was revised to every 4 weeks for Cohorts 3 through 5, with additional bone safety parameters added. Sequential dosing of vantictumab followed by nab-paclitaxel and gemcitabine was also explored. No fragility fractures attributed to vantictumab occurred in these cohorts; pathologic fracture not attributed to vantictumab was documented in 2 patients. The study was ultimately terminated due to concerns around bone-related safety, and thus the maximum tolerated dose (MTD) of the combination was not determined. The MAD of vantictumab according to the revised dosing schedule was 5 mg/kg (n = 16).


Asunto(s)
Albúminas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Desoxicitidina/análogos & derivados , Paclitaxel/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Vía de Señalización Wnt/efectos de los fármacos , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Anciano , Anticuerpos Monoclonales/uso terapéutico , Estudios de Cohortes , Desoxicitidina/uso terapéutico , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias Pancreáticas/metabolismo , Gemcitabina , Neoplasias Pancreáticas
4.
Support Care Cancer ; 27(6): 2077-2086, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30225573

RESUMEN

PURPOSE: The present study examined the degree to which loneliness mediated the influence of negative (social constraints) and positive (emotional support) relationship qualities on the global mental health of advanced gastrointestinal (GI) cancer patients and their family caregivers. METHODS: Fifty patient-caregiver dyads completed measures assessing social constraints (e.g., avoidance, criticism) from the other dyad members, emotional support from others, loneliness, and global mental health. Structural equation modeling was used to examine individual models, and Actor-Partner Interdependence Mediation Modeling was used to examine dyadic associations. RESULTS: Individual path analyses for patients and caregivers demonstrated that emotional support had a significant indirect effect on mental health through loneliness (Bs = 0.32 and 0.30, respectively), but no associations were found between social constraints and mental health. In dyadic analyses, participants' loneliness and mental health were not significantly related to their partner's emotional support, loneliness, or mental health (Bs = - 0.18 to 0.18). CONCLUSIONS: Findings suggest that for advanced GI cancer patients and caregivers, emotional support from others alleviates feelings of loneliness, which may lead to better mental health. However, the benefits of emotional support appear to be primarily intrapersonal rather than interpersonal in nature. Additionally, participants endorsed low levels of social constraints, which might explain their lack of relation to loneliness and mental health. Continued examination of interdependence in social processes between cancer patients and caregivers will inform intervention development.


Asunto(s)
Cuidadores/psicología , Neoplasias Gastrointestinales/complicaciones , Neoplasias Gastrointestinales/psicología , Soledad/psicología , Salud Mental/normas , Apoyo Social , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Neoplasias Gastrointestinales/patología , Humanos , Masculino , Persona de Mediana Edad
5.
Nanomedicine ; 18: 189-195, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30858085

RESUMEN

CRLX101 is a nanoparticle-drug conjugate with a camptothecin payload. We assessed the toxicity and pathologic complete response (pCR) rate of CRLX101 with standard neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer. A single-arm study was conducted with a 3 + 3 dose escalation phase Ib followed by phase II at the maximum tolerated dose (MTD). Thirty-two patients were enrolled with 29 (91%) patients having T3/4 and 26 (81%) N1/2 disease. In phase Ib, no patient experienced a dose limiting toxicity (DLT) with every other week dosing, while 1/9 patients experienced a DLT with weekly dosing. The weekly MTD was identified as 15 mg/m2. The most common grade 3-4 toxicity was lymphopenia, with only 1 grade 4 event. pCR was achieved in 6/32 (19%) patients overall and 2/6 (33%) patients at the weekly MTD. CRLX101 at 15 mg/m2 weekly with neoadjuvant CRT is a feasible combination strategy with an excellent toxicity profile. Clinicaltrials.gov registration NCT02010567.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/uso terapéutico , Capecitabina/uso terapéutico , Ciclodextrinas/uso terapéutico , Nanopartículas/química , Terapia Neoadyuvante , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Camptotecina/efectos adversos , Capecitabina/efectos adversos , Estudios de Cohortes , Ciclodextrinas/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias del Recto/patología
6.
Cancer ; 124(15): 3118-3126, 2018 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-29905927

RESUMEN

BACKGROUND: Regorafenib, a multikinase inhibitor that inhibits angiogenesis, growth, and proliferation, prolongs survival as monotherapy in patients with refractory colorectal cancer. This international, double-blind, placebo-controlled, multicenter trial assessed the efficacy of regorafenib with folinic acid, fluorouracil, and irinotecan (FOLFIRI) as a second-line treatment for metastatic colorectal cancer. METHODS: Patients with metastatic colorectal cancer who progressed on first-line oxaliplatin and fluoropyrimidine enrolled at 45 sites in the United States and Ireland. Patients, stratified by prior bevacizumab use, were randomized 2:1 to regorafenib or placebo. The treatment consisted of FOLFIRI on days 1 and 2 and days 15 and 16 with 160 mg of regorafenib or placebo on days 4 to 10 and days 18 to 24 of every 28-day cycle. Crossover was not allowed. The primary endpoint was progression-free survival (PFS). Under the assumption of a 75% event rate, 180 patients were required for 135 events to achieve 90% power to detect a hazard ratio (HR) of 0.65 with a 1-sided α value of .1. RESULTS: One hundred eighty-one patients were randomized (120 to regorafenib-FOLFIRI and 61 to placebo-FOLFIRI) with a median age of 62 years. Among these, 117 (65%) received prior bevacizumab or aflibercept. PFS was longer with regorafenib-FOLFIRI than placebo-FOLFIRI (median, 6.1 vs 5.3 months; HR, 0.73; 95% confidence interval [CI], 0.53-1.01; log-rank P = .056). The median overall survival was not longer (HR, 1.01; 95% CI, 0.71-1.44). The response rate was higher with regorafenib-FOLFIRI (34%; 95% CI, 25%-44%) than placebo-FOLFIRI (21%; 95% CI, 11%-33%; P = .07). Grade 3/4 adverse events with a >5% absolute increase from regorafenib included diarrhea, neutropenia, febrile neutropenia, hypophosphatemia, and hypertension. CONCLUSIONS: The addition of regorafenib to FOLFIRI as second-line therapy for metastatic colorectal cancer only modestly prolonged PFS over FOLFIRI alone. Cancer 2018. © 2018 American Cancer Society.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Camptotecina/análogos & derivados , Neoplasias Colorrectales/tratamiento farmacológico , Compuestos de Fenilurea/administración & dosificación , Piridinas/administración & dosificación , Adulto , Anciano , Camptotecina/administración & dosificación , Neoplasias Colorrectales/patología , Método Doble Ciego , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Fluorouracilo/administración & dosificación , Humanos , Irinotecán/administración & dosificación , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión
7.
Qual Life Res ; 27(2): 515-528, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-28601957

RESUMEN

PURPOSE: At the end of life, spiritual well-being is a central aspect of quality of life for many patients and their family caregivers. A prevalent spiritual value in advanced cancer patients is the need to actively give. To address this need, the current randomized trial examined whether adding a peer helping component to a coping skills intervention leads to improved meaning in life and peace for advanced gastrointestinal cancer patients and their caregivers. Feasibility and acceptability outcomes were also assessed. METHODS: Advanced gastrointestinal cancer patients and caregivers (n = 50 dyads) were randomly assigned to a 5-session, telephone-based coping skills intervention or a peer helping + coping skills intervention. One or both dyad members had moderate-severe distress. Peer helping involved contributing to handouts on coping skills for other families coping with cancer. Patients and caregivers completed measures of meaning in life/peace, fatigue, psychological symptoms, coping self-efficacy, and emotional support. Patient pain and caregiver burden were also assessed. RESULTS: Small effects in favor of the coping skills group were found regarding meaning in life/peace at 1 and 5 weeks post-intervention. Other outcomes did not vary as a function of group assignment, with both groups showing small decreases in patient and caregiver fatigue and caregiver distress and burden. High recruitment and retention rates supported feasibility, and high participant satisfaction ratings supported acceptability. CONCLUSIONS: Although a telephone-based intervention is feasible and acceptable for this population, peer helping in the context of a coping skills intervention does not enhance spiritual well-being relative to coping skills alone.


Asunto(s)
Adaptación Psicológica/fisiología , Neoplasias Gastrointestinales/psicología , Cuidadores/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Grupo Paritario , Calidad de Vida/psicología , Espiritualidad
8.
Am J Gastroenterol ; 112(4): 537-554, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28139655

RESUMEN

In this article, we review our multidisciplinary approach for patients with pancreatic cancer. Specifically, we review the epidemiology, diagnosis and staging, biliary drainage techniques, selection of patients for surgery, chemotherapy, radiation therapy, and discuss other palliative interventions. The areas of active research investigation and where our knowledge is limited are emphasized.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Ductal Pancreático/terapia , Pancreatectomía/métodos , Neoplasias Pancreáticas/terapia , Pancreaticoduodenectomía/métodos , Grupo de Atención al Paciente , Radioterapia/métodos , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/epidemiología , Carcinoma Ductal Pancreático/patología , Drenaje , Endosonografía , Humanos , Imagen por Resonancia Magnética , Estadificación de Neoplasias , Cuidados Paliativos/métodos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/patología , Selección de Paciente , Tomografía Computarizada por Rayos X
9.
Invest New Drugs ; 35(1): 68-78, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27853996

RESUMEN

Background HER3/EGFR heterodimers have been implicated as a mode of resistance to EGFR-directed therapies. Methods This Phase 1 trial assessed the tolerability, maximum tolerated dose (MTD) and pharmacokinetic (PK) properties of the HER-3 antibody seribantumab in combination with cetuximab (Part I) or cetuximab and irinotecan (Part II) in patients with EGFR-dependent cancers. In Part I, escalating doses of seribantumab and cetuximab were administered. In Part II of the trial, escalating doses of seribantumab/cetuximab were combined with irinotecan 180 mg/m2 administered every two weeks. Results 34 patients were enrolled in Part I (seribantumab/cetuximab) and 14 patients were enrolled in Part II (seribantumab/cetuximab/irinotecan). Common toxicities of seribantumab/cetuximab included acneiform rash, diarrhea, stomatitis, and paronychia. The MTD of Part I was seribantumab 40 mg/kg bolus, then 20 mg/kg weekly combined with cetuximab 400 mg/m2 bolus, then 250 mg/m2 IV weekly. Common toxicities reported in the seribantumab/cetuximab/irinotecan combination were similar to the Part I portion. However, toxicities were more frequent and severe with the triplet combination. There was one treatment-related death in Part II secondary to Grade 4 neutropenia and grade 3 diarrhea. Other dose-limiting toxicities in Part II were Grade 3 mucositis and Grade 3 diarrhea. A cholangiocarcinoma patient, previously untreated with EGFR-directed therapy, had a confirmed partial response (PR). One colorectal cancer patient, previously treated with EGFR-directed therapy, had an unconfirmed PR. Conclusions Seribantumab/cetuximab was well tolerated and patients experienced toxicities typical to EGFR inhibition. Unlike the seribantumab/cetuximab doublet, seribantumab/cetuximab/irinotecan was difficult to tolerate in this heavily pretreated population. There was limited efficacy of the combination therapy.


Asunto(s)
Anticuerpos Monoclonales , Antineoplásicos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/análogos & derivados , Cetuximab , Receptor ErbB-3/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Camptotecina/efectos adversos , Camptotecina/farmacología , Camptotecina/uso terapéutico , Cetuximab/efectos adversos , Cetuximab/farmacología , Cetuximab/uso terapéutico , Receptores ErbB/genética , Femenino , Humanos , Irinotecán , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Resultado del Tratamiento , Adulto Joven
10.
JAMA ; 317(23): 2392-2401, 2017 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-28632865

RESUMEN

Importance: Combining biologic monoclonal antibodies with chemotherapeutic cytotoxic drugs provides clinical benefit to patients with advanced or metastatic colorectal cancer, but the optimal choice of the initial biologic therapy in previously untreated patients is unknown. Objective: To determine if the addition of cetuximab vs bevacizumab to the combination of leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) regimen or the combination of leucovorin, fluorouracil, and irinotecan (FOLFIRI) regimen is superior as first-line therapy in advanced or metastatic KRAS wild-type (wt) colorectal cancer. Design, Setting, and Participants: Patients (≥18 years) enrolled at community and academic centers throughout the National Clinical Trials Network in the United States and Canada (November 2005-March 2012) with previously untreated advanced or metastatic colorectal cancer whose tumors were KRAS wt chose to take either the mFOLFOX6 regimen or the FOLFIRI regimen as chemotherapy and were randomized to receive either cetuximab (n = 578) or bevacizumab (n = 559). The last date of follow-up was December 15, 2015. Interventions: Cetuximab vs bevacizumab combined with either mFOLFOX6 or FOLFIRI chemotherapy regimen chosen by the treating physician and patient. Main Outcomes and Measures: The primary end point was overall survival. Secondary objectives included progression-free survival and overall response rate, site-reported confirmed or unconfirmed complete or partial response. Results: Among 1137 patients (median age, 59 years; 440 [39%] women), 1074 (94%) of patients met eligibility criteria. As of December 15, 2015, median follow-up for 263 surviving patients was 47.4 months (range, 0-110.7 months), and 82% of patients (938 of 1137) experienced disease progression. The median overall survival was 30.0 months in the cetuximab-chemotherapy group and 29.0 months in the bevacizumab-chemotherapy group with a stratified hazard ratio (HR) of 0.88 (95% CI, 0.77-1.01; P = .08). The median progression-free survival was 10.5 months in the cetuximab-chemotherapy group and 10.6 months in the bevacizumab-chemotherapy group with a stratified HR of 0.95 (95% CI, 0.84-1.08; P = .45). Response rates were not significantly different, 59.6% vs 55.2% for cetuximab and bevacizumab, respectively (difference, 4.4%, 95% CI, 1.0%-9.0%, P = .13). Conclusions and Relevance: Among patients with KRAS wt untreated advanced or metastatic colorectal cancer, there was no significant difference in overall survival between the addition of cetuximab vs bevacizumab to chemotherapy as initial biologic treatment. Trial Registration: clinicaltrials.gov identifier: NCT00265850.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Cetuximab/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/efectos adversos , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/efectos adversos , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/análogos & derivados , Canadá , Cetuximab/efectos adversos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/secundario , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Genes ras , Humanos , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Resultado del Tratamiento , Estados Unidos
11.
Oncologist ; 21(9): 1113-20, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27185615

RESUMEN

BACKGROUND: Phase III trials show sorafenib improves survival in advanced hepatocellular carcinoma (HCC). Because of narrow trial eligibility, results may not be generalizable to a broader HCC population. We sought to evaluate the effectiveness of initial sorafenib versus no treatment among Medicare beneficiaries with advanced HCC. MATERIALS AND METHODS: Patients with advanced HCC diagnosed from 2008 to 2011 were identified from the Surveillance, Epidemiology, and End Results-Medicare database. Eligible patients received initial sorafenib or no therapy and were covered by Medicare parts A, B, and D. Sorafenib use and outcomes were described in this population. Using a propensity score (PS)-matched sample, we compared the effectiveness of sorafenib versus no treatment by Cox proportional hazards and binomial regression, using a landmark requiring all patients to survive ≥60 days after diagnosis. RESULTS: Of 1,532 patients, 27% received initial sorafenib. Median duration of sorafenib use was 60 days (interquartile range [IQR], 30-107 days), and median survival from first prescription was 3 months (IQR, 1-8 months). In the PS-matched cohort, median survival was 3 months from the 60-day landmark in sorafenib-treated (n = 223) and 2 months in untreated (n = 223) patients (adjusted hazard ratio, 0.95 [95% confidence interval (CI), 0.78-1.16]). Sorafenib was associated with a nonsignificant reduction in mortality at 3 months (44% versus 51%; adjusted risk ratio, 0.88 [95% CI, 0.72-1.07]), but no reduction thereafter. CONCLUSION: Survival after sorafenib initiation in newly diagnosed Medicare beneficiaries with HCC is exceptionally short, suggesting trial results are not generalizable to all HCC patients. The downsides of sorafenib use-high drug-related symptom burden and high drug cost-must be considered in light of this minimal benefit. IMPLICATIONS FOR PRACTICE: The findings of a median survival of only 3 months in Medicare beneficiaries with HCC prescribed sorafenib as first-line therapy highlight the questionable value of sorafenib in this population. Patients should be cautioned that outside of the narrow confines of randomized trials, their life expectancy may be very short, and any benefit of sorafenib is likely to be quite small. Given that sorafenib causes considerable adverse effects and offers no symptom palliation, supportive care should be discussed as a reasonable alternative to sorafenib, particularly for patients who have a poor performance status or advanced cirrhosis.


Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/administración & dosificación , Adulto , Anciano , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/patología , Ensayos Clínicos Fase III como Asunto , Supervivencia sin Enfermedad , Costos de los Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Estimación de Kaplan-Meier , Cirrosis Hepática/complicaciones , Cirrosis Hepática/patología , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Niacinamida/administración & dosificación , Niacinamida/efectos adversos , Compuestos de Fenilurea/efectos adversos , Sorafenib , Resultado del Tratamiento
12.
Oncologist ; 21(2): 172-7, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26786262

RESUMEN

BACKGROUND: Effective new agents for patients with colorectal cancer (CRC) with disease progression during standard therapy regimens are needed. We hypothesized that poly ADP ribose polymerase (PARP) inhibitor therapy in patients with CRC and inefficient tumor DNA repair mechanisms, such as those with high-level microsatellite instability (MSI-H), would result in synthetic lethality. METHODS: This was an open-label phase II trial testing olaparib 400 mg p.o. b.i.d. for patients with disseminated, measurable CRC failing standard therapies with centrally confirmed tumor MSI status. The primary endpoint was the tumor response, assessed by RECIST, version 1.0. The secondary endpoints were safety/toxicity, progression-free survival (PFS), and overall survival (OS). RESULTS: Thirty-three patients (20 microsatellite stable [MSS], 13 MSI-H) were enrolled. The median age for all patients was 57 years and for MSS and MSI-H patients was 51 and 61 years, respectively. All patients received at least one 28-day cycle of olaparib. No patient had a complete or partial response. Nausea (48%), fatigue (36%), and vomiting (33%) were the most commonly reported treatment-related adverse events. The median PFS for all patients was 1.84 months. No statistically significant differences were found in the median PFS or OS for the MSS group compared with the MSI-H group. CONCLUSION: Single-agent olaparib delivered after failure of standard systemic therapy did not demonstrate activity for CRC patients, regardless of microsatellite status. Future trials, testing PARP inhibitors in patients with CRC should focus on the use of DNA-damaging chemotherapy and/or radiation therapy, combined with PARP inhibitors, remembering the toxicity reported in the present study. IMPLICATIONS FOR PRACTICE: Microsatellite instability (MSI-H) colorectal tumors exhibit hypermethylation in tumor mismatch repair genes, or have mutations in one or more of these genes resulting from a germ-line defect (Lynch syndrome). PARP inhibitors such as olaparib are most effective in tumors associated with inability to repair DNA damage. However, in this trial, single agent olaparib failed to elicit responses in patients with MSI-H colorectal tumors, and in those with microsatellite-stable tumors. It is possible that by adding olaparib to radiation therapy, or to a systemic DNA damaging agent, tumor lethality could be obtained. However, the price would be increased toxicity.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Inestabilidad de Microsatélites/efectos de los fármacos , Ftalazinas/administración & dosificación , Piperazinas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Adulto , Anciano , Neoplasias Colorrectales/patología , Metilación de ADN/efectos de los fármacos , Reparación de la Incompatibilidad de ADN/genética , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ftalazinas/efectos adversos , Piperazinas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos
13.
Psychooncology ; 25(11): 1261-1270, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-26315692

RESUMEN

OBJECTIVE: This article reviews literature on adults' mental health outcomes during acute and long-term colorectal cancer (CRC) survivorship. METHODS: We identified articles that included at least one measure of psychological symptoms or mental quality of life or well-being through a search of databases (CINAHL, MEDLINE, PsycINFO, and PsycARTICLES). Articles were published between January 2004 and April 2015. RESULTS: A significant proportion of CRC survivors experience clinically meaningful levels of anxiety and depressive symptoms or reduced mental well-being across the trajectory of the illness. Demographic, medical, and psychosocial predictors of mental health outcomes were identified. However, few studies were theory-driven, and gaps remain in our understanding of risk and protective factors with respect to mental health outcomes, especially during long-term CRC survivorship. CONCLUSIONS: Theory-driven longitudinal research with larger samples is required to identify subgroups of CRC survivors with different trajectories of psychological adjustment. Such research would assess adjustment as a function of internal resources (e.g., personality and coping) and external resources (e.g., finances and social support) to inform future interventions for CRC survivors. Copyright © 2015 John Wiley & Sons, Ltd.


Asunto(s)
Supervivientes de Cáncer/psicología , Neoplasias Colorrectales/psicología , Salud Mental , Calidad de Vida/psicología , Supervivencia , Adaptación Psicológica , Adulto , Ansiedad/epidemiología , Humanos , Masculino , Personalidad , Resiliencia Psicológica , Apoyo Social
14.
Support Care Cancer ; 24(5): 2017-2024, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26530227

RESUMEN

PURPOSE: Family caregivers of advanced colorectal cancer patients may be at increased risk for psychological distress. Yet their key challenges in coping with the patient's illness are not well understood. Soliciting both patient and caregiver perspectives on these challenges would broaden our understanding of the caregiving experience. Thus, the purpose of this research was to identify caregivers' key challenges in coping with their family member's advanced colorectal cancer from the perspective of patients and caregivers. METHODS: Individual, semi-structured qualitative interviews were conducted with 23 advanced colorectal cancer patients and 23 primary family caregivers. Interview data were analyzed via thematic analysis. RESULTS: In nearly all cases, patient and caregiver reports of the caregiver's key challenge were discrepant. Across patient and caregiver reports, caregivers' key challenges included processing emotions surrounding the patient's initial diagnosis or recurrence and addressing the patient's practical and emotional needs. Other challenges included coping with continual uncertainty regarding the patient's potential functional decline and prognosis and observing the patient suffer from various physical symptoms. CONCLUSIONS: Findings suggest that eliciting the perspectives of both patients and caregivers regarding caregivers' challenges provides a more comprehensive understanding of their experience. Results also point to the need to assist caregivers with the emotional and practical aspects of caregiving.


Asunto(s)
Adaptación Psicológica , Cuidadores/psicología , Neoplasias Colorrectales , Relaciones Familiares/psicología , Estrés Psicológico , Adulto , Anciano , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/psicología , Emociones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Investigación Cualitativa , Estrés Psicológico/etiología , Estrés Psicológico/prevención & control , Incertidumbre , Estados Unidos
15.
Invest New Drugs ; 33(6): 1225-31, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26490655

RESUMEN

PURPOSE: The oral PI3K inhibitor BKM120 has been reported as safe and well tolerated in early phase clinical trials of advanced cancer patients. We performed a phase I trial of BKM120 plus mFOLFOX6 (5-FU/LV + oxaliplatin), a common chemotherapeutic backbone in GI malignancies, to establish the maximum tolerated dose (MTD) and characterize the safety and tolerability of the combination. METHODS: Patients with advanced solid tumors received oral BKM120 daily combined with standard doses of mFOLFOX6 every 2 weeks of a 28 day cycle. The study utilized a standard 3 + 3 dose escalation schema. RESULTS: A total of 17 patients received treatment with BKM120, 13 of which were evaluate for dose limited toxicity (DLT). The most common tumor types were colorectal cancer, cholangiocarcinoma, pancreatic cancer and hepatocellular carcinoma. DLT included grade 3 hyperglycemia, grade 3 AST/ALT elevation, grade 4 neutropenia and grade 4 thrombocytopenia. A total of 76 % of patients experienced treatment related grade 3/4 adverse events (AEs), the most common of which were neutropenia, fatigue, leukopenia, hyperglycemia and thrombocytopenia. One patient demonstrated an unconfirmed partial response and three patients had stable disease. DISCUSSION: The MTD of BKM120 in combination with standard doses of mFOLFOX6 was 40 mg daily, which is well below the 100 mg daily dose proven effective and tolerable both as a single agent and in combination with other chemotherapeutics. In addition, the regimen of BKM120 with mFOLFOX6 in patients with refractory solid tumors resulted in increased toxicity than would be expected from either the PI3K inhibitor or the chemotherapy backbone alone.


Asunto(s)
Aminopiridinas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Morfolinas/administración & dosificación , Neoplasias/tratamiento farmacológico , Inhibidores de las Quinasa Fosfoinosítidos-3 , Administración Oral , Adulto , Anciano , Aminopiridinas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Progresión de la Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Leucopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Morfolinas/efectos adversos , Náusea/inducido químicamente , Neoplasias/diagnóstico , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos
16.
Invest New Drugs ; 33(2): 505-9, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25613083

RESUMEN

PURPOSE: Few treatment options are available for patients with advanced or metastatic hepatocellular carcinoma (HCC). Based on preclinical and early clinical efficacy signals and lack of overlapping toxicity, we undertook this multicenter phase II trial to estimate efficacy and safety of everolimus and pasireotide in advanced HCC. METHODS: Patients with advanced HCC not amenable to locoregional therapy and Child-Pugh A cirrhosis received everolimus 7.5 mg PO daily and pasireotide LAR 60 mg IM every 28 days. The primary endpoint was time to progression (TTP), with 26 events needed to evaluate if everolimus + pasireotide improved TTP from 2.8 to 4.4 months, with 80% power and an alpha of 0.05. Secondary endpoints included response as measured by RECIST modified for HCC, treatment-emergent adverse events, and overall survival. RESULTS: After 24 patients were enrolled, results of a randomized trial showing no benefit of everolimus in HCC were released prompting an unplanned interim analysis that found the conditional probability of rejecting the null hypothesis based on events in those patients was 0.08. Therefore accrual was halted. Patients had a median age of 59 years, 21 (88%) had BCLC stage C cancer, and 11 (46%) metastatic disease. Median TTP was 3.5 months (95% CI 2-5.8) and median survival 6.7 months (95% CI 6-infinity). Best response was stable disease in ten patients. Grade 3 hyperglycemia occurred in 6 (25%). There were no grade 4 treatment-emergent events. CONCLUSION: Despite promising early efficacy signals, we found no benefit for the combination of everolimus and pasireotide in HCC.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Everolimus/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Somatostatina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Supervivencia sin Enfermedad , Everolimus/administración & dosificación , Everolimus/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Criterios de Evaluación de Respuesta en Tumores Sólidos , Somatostatina/administración & dosificación , Somatostatina/efectos adversos , Somatostatina/uso terapéutico
17.
Curr Treat Options Oncol ; 16(9): 43, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26187794

RESUMEN

Colorectal cancer (CRC) is a worldwide health problem leading to significant morbidity and mortality. Several strategies based on either lifestyle modifications or pharmacological interventions have been developed in an attempt to reduce the risk of CRC. In this review article, we discuss these interventions including aspirin (and other non-steroidal anti-inflammatory drugs), vitamin D, exercise, diet, statins, and metformin. Depending upon the risk of developing CRC, the current evidence supports the beneficial role of aspirin, vitamin D, diet, and exercise especially in high-risk individuals (advanced adenoma or CRC). However, even with these established interventions, there are significant knowledge gaps such as doses of aspirin and 25-hydroxy vitamin D are not well established. Similarly, there is no convincing data from randomized controlled trials that a high fiber diet or a low animal fat diet reduces the risk of CRC. Some potential interventions, such as statins and metformin, do not have convincing data for clinical use even in high-risk individuals. However, these may have emerging roles in the prevention and treatment of CRC. Greater understanding of molecular mechanisms and the application of genomic tools to risk stratify an individual and tailor the interventions based on that individual's risk will help further advance the field. Some of this work is already underway and is a focus of this article.


Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Aspirina/uso terapéutico , Neoplasias Colorrectales/prevención & control , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Vitamina D/análogos & derivados , Quimioprevención , Neoplasias Colorrectales/terapia , Dieta , Ejercicio Físico , Humanos , Estudios Observacionales como Asunto , Medición de Riesgo , Conducta de Reducción del Riesgo , Vitamina D/uso terapéutico
18.
Oncologist ; 19(9): 959-65, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25117066

RESUMEN

BACKGROUND: Pharmacokinetically guided (PK-guided) versus body surface area-based 5-fluorouracil (5-FU) dosing results in higher response rates and better tolerability. A paucity of data exists on PK-guided 5-FU dosing in the community setting. PATIENTS AND METHODS: Seventy colorectal cancer patients, from one academic and five community cancer centers, received the mFOLFOX6 regimen (5-FU 2,400 mg/m(2) over 46 hours every 2 weeks) with or without bevacizumab at cycle 1. The 5-FU continuous-infusion dose was adjusted for cycles 2-4 using a PK-guided algorithm to achieve a literature-based target area under the concentration-time curve (AUC). The primary objective was to demonstrate that PK-guided 5-FU dosing improves the ability to achieve a target AUC within four cycles of therapy. The secondary objective was to demonstrate reduced incidence of 5-FU-related toxicities. RESULTS: At cycles 1 and 4, 27.7% and 46.8% of patients achieved the target AUC (20-25 mg × hour/L), respectively (odds ratio [OR]: 2.20; p = .046). Significantly more patients were within range at cycle 4 compared with a literature rate of 20% (p < .0001). Patients had significantly higher odds of not being underdosed at cycle 4 versus cycle 1 (OR: 2.29; p = .037). The odds of a patient being within range increased by 30% at each subsequent cycle (OR: 1.30; p = .03). Less grade 3/4 mucositis and diarrhea were observed compared with historical data (1.9% vs 16% and 5.6% vs 12%, respectively); however, rates of grade 3/4 neutropenia were similar (33% vs 25%-50%). CONCLUSION: PK-guided 5-FU dosing resulted in significantly fewer underdosed patients and less gastrointestinal toxicity and allows for the application of personalized colorectal cancer therapy in the community setting.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/administración & dosificación , Fluorouracilo/farmacocinética , Medicina de Precisión , Adulto , Área Bajo la Curva , Superficie Corporal , Neoplasias Colorrectales/patología , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/clasificación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Fluorouracilo/efectos adversos , Humanos , Masculino , Persona de Mediana Edad
19.
J Oncol Pharm Pract ; 20(6): 409-16, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24243920

RESUMEN

PURPOSE: The primary purpose of this study was to determine the rate of infusion reactions to cetuximab in oncology patients treated at the University of North Carolina Cancer Hospital. Secondarily, we sought to evaluate predictors of grade 3-4 hypersensitivity, including geography. METHODS: Data were collected by retrospective chart review for patients treated with cetuximab at the University of North Carolina Cancer Hospital between 15 November 2006 and 31 December 2010. Data were analyzed for occurrence of hypersensitivity reaction in 125 patients with various cancer types. RESULTS: Of the 125 subjects, 31 (24.8%) experienced an infusion reaction of any grade. Of 125, 18 (14.4%) experienced a grade 3 or 4 reaction. The odds ratio for patients with an allergy history having a grade 3 or 4 reaction was 2.57 (95% CI 0.93 to 7.09, p = 0.07). Pretreatment with steroids was associated with absence of grade 3 or 4 reaction with an odds ratio of 0.21 (95% CI 0.05 to 0.83, p = 0.04). Mapping of reaction rates by county revealed higher rates in some of the more rural counties of North Carolina, however, statistical power was lacking. CONCLUSIONS: Rates of hypersensitivity reaction at UNC are similar to rates seen in other areas of the southeastern United States and higher than in other regions of the United States and Europe. Rates of both hypersensitivity reactions and grade 3 to 4 hypersensitivity reactions have not substantially changed over time. Geography, allergy history, and perhaps smoking or cancer type may help predict who will react to cetuximab. Steroids should be strongly considered as premedication in addition to diphenhydramine.


Asunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos/efectos adversos , Hipersensibilidad a las Drogas/etiología , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Instituciones Oncológicas , Cetuximab , Hipersensibilidad a las Drogas/epidemiología , Femenino , Humanos , Incidencia , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Neoplasias/patología , North Carolina/epidemiología , Estudios Retrospectivos , Factores de Tiempo , Adulto Joven
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