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1.
Cancer ; 128(7): 1381-1391, 2022 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-34890045

RESUMEN

BACKGROUND: Enthusiasm for precision oncology may obscure the psychosocial and ethical considerations associated with the implementation of tumor genetic sequencing. METHODS: Patients with advanced cancer undergoing tumor-only genetic sequencing in the National Cancer Institute Molecular Analysis for Therapy Choice (MATCH) trial were randomized to a web-based genetic education intervention or usual care. The primary outcomes were knowledge, anxiety, depression, and cancer-specific distress collected at baseline (T0), posteducation (T1) and after results (T2). Two-sided, 2-sample t tests and univariate and multivariable generalized linear models were used. RESULTS: Five hundred ninety-four patients (80% from NCI Community Oncology Research Program sites) were randomized to the web intervention (n = 293) or usual care (n = 301) before the receipt of results. Patients in the intervention arm had greater increases in knowledge (P for T1-T0 < .0001; P for T2-T0 = .003), but there were no significant differences in distress outcomes. In unadjusted moderator analyses, there was a decrease in cancer-specific distress among women (T0-T1) in the intervention arm but not among men. Patients with lower health literacy in the intervention arm had greater increases in cancer-specific distress and less decline in general anxiety (T0-T1) and greater increases in depression (T0-T2) in comparison with those receiving usual care. CONCLUSIONS: Web-based genetic education before tumor-only sequencing results increases patient understanding and reduces distress in women. Refinements to the intervention could benefit low-literacy groups and men.


Asunto(s)
Neoplasias , Ansiedad , Femenino , Humanos , Masculino , Oncología Médica , Neoplasias/genética , Neoplasias/terapia , Medicina de Precisión , Calidad de Vida
2.
Am J Clin Oncol ; 44(6): 239-246, 2021 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-33867481

RESUMEN

OBJECTIVE: Preclinical studies with muscadine grape extract (MGE) show antitumor activity and decreased systemic inflammation. This phase I study (NCT02583269) assessed safety and tolerability of a proprietary MGE preparation in patients with advanced solid tumors. METHODS: Patients with metastatic or unresectable cancers who were progressing on standard therapies were assigned to MGE in a standard 3+3 design. Five dose levels were tested (320 to 1600 mg total phenolics/d). Safety and maximum-tolerated dose were assessed after 4 weeks. Patients were evaluated for response at 8 weeks and continued on MGE if clinically stable. Secondary outcomes were response, survival, adherence, fatigue, and quality of life (QOL). RESULTS: In total, 23 patients (lung, n=7; gastrointestinal, n=7; genitourinary, n=6; other, n=3) received MGE capsules by mouth twice daily. The cohort [median age 72 years, 48% Eastern Cooperative Oncology Group (ECOG) 2] was heavily pretreated. After 4 weeks on MGE, possibly attributable adverse events grade 2 or higher were fatigue (n=1), decreased lymphocyte count (n=1), and constipation (n=2), including 1 dose-limiting toxicity for grade 3 constipation. Maximum-tolerated dose was not reached. No partial responses were observed. Median time on therapy was 8 weeks, with 29% of patients treated beyond 16 weeks and a median overall survival of 7.2 months. QOL and fatigue levels were stable from baseline to 8 weeks. Higher MGE dose was correlated with improvement in self-reported physical well-being QOL at 8 weeks (r=0.6; P=0.04). CONCLUSIONS: MGE is safe and well-tolerated in heavily pretreated and older cancer patients.  The potential anticancer properties and the effects of MGE on physical well-being and QOL metrics will be evaluated in future studies.


Asunto(s)
Neoplasias/tratamiento farmacológico , Extractos Vegetales/farmacocinética , Extractos Vegetales/uso terapéutico , Vitis/química , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias/patología , Pronóstico , Distribución Tisular
3.
JAMA Netw Open ; 4(4): e2110848, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33909058
4.
JCO Oncol Pract ; 17(8): e1110-e1119, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33539182

RESUMEN

PURPOSE: Immunotherapy or chemoimmunotherapy is now standard treatment for most patients with metastatic non-small-cell lung cancer (mNSCLC), yet patient supportive care needs (SCNs) on immunotherapy are not well defined. This study characterized the SCNs and financial hardship of patients with mNSCLC treated with immunotherapy or chemoimmunotherapy and examined the relationship between patient and caregiver cancer-related employment reductions and patient financial hardship. METHODS: Patients with mNSCLC on immunotherapy or chemoimmunotherapy from a single academic medical center completed the SCNs Survey-34, items indexing material, psychological, and behavioral financial hardship, and the Comprehensive Score for Financial Toxicity. Univariate and bivariate analyses examined care needs, financial hardship, and impact of cancer-related employment reductions on patient financial hardship. RESULTS: Sixty patients (40% male; 75% White, mean age = 62.5 years, 57% on immunotherapy alone) participated. Fifty-five percent reported unmet needs in physical or daily living and psychological domains. Financial hardship was common (33% material, 63% psychological, and 57% behavioral). Fifty-two percent reported hardship in at least two domains. Forty percent reported a caregiver cancer-related employment reduction. Caregiver employment reduction was related to patient financial hardship (68% of those reporting caregiver employment reduction reported at least two domains of hardship v 40% of those without reduction, P = .03) and patient financial distress (mean Comprehensive Score for Financial Toxicity = 19.6 among those with caregiver employment reduction v 26.8 without, P = .01). CONCLUSION: Patients with mNSCLC treated with immunotherapy or chemoimmunotherapy report multiple unmet care needs and financial hardship. Psychological, functional, financial, and caregiver concerns merit assessment and intervention in this population.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/terapia , Empleo , Femenino , Estrés Financiero , Humanos , Inmunoterapia , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad
5.
JCO Oncol Pract ; 17(1): e77-e93, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33186085

RESUMEN

PURPOSE: Cancer clinical trials offices (CTOs) support the investigation of cancer prevention, early detection, and treatment at cancer centers across North America. CTOs are a centralized resource for clinical trial conduct and typically use research staff with expertise in four functional areas of clinical research: finance, regulatory, clinical, and data operations. To our knowledge, there are no publicly available benchmark data sets that characterize the size, cost, volume, and efficiency of these offices, nor whether the metrics differ by National Cancer Institute (NCI) designation. The Association of American Cancer Institutes (AACI) Clinical Research Innovation (CRI) steering committee developed a survey to address this knowledge gap. METHODS: An 11-question survey that addressed CTO budget, accrual and trial volume, full-time equivalents (FTEs), staff turnover, and activation timelines was developed by the AACI CRI steering committee and sent to 92 academic cancer research centers in North America (n = 90 in the United States; n = 2 in Canada), with 79 respondents completing the survey (86% completion rate). RESULTS: The number of FTE employees working in the CTOs ranged from 4.5 to 811 (median, 104). The median number of analytic cases (ie, newly diagnosed or received first course of treatment) reported by the main center was 3,856. Annual CTO budgets ranged from $250,000 to $23,900,000 (median, $8.2 million). The median trial activation time, based on 61 centers, was 167 days. The median number of accruals per center was 480 (range, 5-6,271) and median number of trials per center was 282 (range, 31-1,833). Budget and FTE ranges varied by NCI designation. CONCLUSION: The response rate to the survey was high. These data will allow cancer centers to evaluate their CTO infrastructure, funding, portfolio, and/or accrual goals as compared with peers. A wide range in each of the outcomes was noted, in keeping with the wide variation in size and scope of cancer center CTOs across the United States and Canada. These variations may warrant additional investigation.


Asunto(s)
Benchmarking , Neoplasias , Canadá , Humanos , National Cancer Institute (U.S.) , Neoplasias/terapia , América del Norte , Estados Unidos
6.
Clin Lung Cancer ; 21(3): 255-263.e4, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31917067

RESUMEN

INTRODUCTION: Immunotherapy and chemoimmunotherapy clinical trials for metastatic non-small-cell lung cancer (mNSCLC) have generally excluded patients with poor performance status (PS) and have utilized patient-reported measures that could miss some symptoms associated with immunotherapy. The goals of this study were to describe quality of life and symptom burden among mNSCLC patients receiving immunotherapy in clinical practice, and to examine burden by Eastern Cooperative Oncology Group performance status (ECOG PS) and age. PATIENTS AND METHODS: Between 2017 and 2018, mNSCLC patients receiving immuno/chemoimmunotherapy at an academic medical center completed the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) and the National Cancer Institute Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Univariate and bivariate analyses described EORTC-QLQ-C30 subscales and the proportion reporting at least moderate PRO-CTCAE symptoms, and compared scores by ECOG PS (0/1 vs. 2/3) and age (< 70 vs. ≥ 70 years). RESULTS: Sixty patients (60% female; 75% < 70 years old; 68% ECOG PS 0/1; 57% receiving single-agent immunotherapy) participated. The mean EORTC-QLQ-C30 global health score was 62.6; EORTC symptoms were highest for fatigue, insomnia, dyspnea, and financial concerns (all > 30). Global health and pain were worse in ECOG PS 2/3 patients. For PRO-CTCAE, 20% to 40% reported at least moderate gastrointestinal, respiratory, dermatologic, arthralgia, or myalgia symptoms. The PRO-CTCAE pain score was higher among ECOG PS 2/3 patients. CONCLUSION: In clinical practice, global health was largely comparable to published clinical trials, but PRO-CTCAE items indicated a higher symptom prevalence. Closer monitoring of symptoms is warranted in ECOG PS 2/3 patients.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia/mortalidad , Neoplasias Pulmonares/mortalidad , Medición de Resultados Informados por el Paciente , Pautas de la Práctica en Medicina/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/secundario , Estudios Transversales , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia
7.
Clin Cancer Res ; 24(14): 3263-3272, 2018 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-29643063

RESUMEN

Purpose: Prexasertib, a checkpoint kinase 1 inhibitor, demonstrated single-agent activity in patients with advanced squamous cell carcinoma (SCC) in the dose-escalation portion of a phase I study (NCT01115790). Monotherapy prexasertib was further evaluated in patients with advanced SCC.Patients and Methods: Patients were given prexasertib 105 mg/m2 as a 1-hour infusion on day 1 of a 14-day cycle. Expansion cohorts were defined by tumor and treatment line. Safety, tolerability, efficacy, and exploratory biomarkers were analyzed.Results: Prexasertib was given to 101 patients, including 26 with SCC of the anus, 57 with SCC of the head and neck (SCCHN), and 16 with squamous cell non-small cell lung cancer (sqNSCLC). Patients were heavily pretreated (49% ≥3 prior regimens). The most common treatment-related adverse event was grade 4 neutropenia (71%); 12% of patients had febrile neutropenia. Median progression-free survival was 2.8 months [90% confidence interval (CI), 1.9-4.2] for SCC of the anus, 1.6 months (90% CI, 1.4-2.8) for SCCHN, and 3.0 months (90% CI, 1.4-3.9) for sqNSCLC. The clinical benefit rate at 3 months (complete response + partial response + stable disease) across tumors was 29% (23% SCC of the anus, 28% SCCHN, 44% sqNSCLC). Four patients with SCC of the anus had partial or complete response [overall response rate (ORR) = 15%], and three patients with SCCHN had partial response (ORR = 5%). Biomarker analyses focused on genes that altered DNA damage response or increased replication stress.Conclusions: Prexasertib demonstrated an acceptable safety profile and single-agent activity in patients with advanced SCC. The prexasertib maximum-tolerated dose of 105 mg/m2 was confirmed as the recommended phase II dose. Clin Cancer Res; 24(14); 3263-72. ©2018 AACR.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazinas/uso terapéutico , Pirazoles/uso terapéutico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidad , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/genética , Terapia Combinada , Femenino , Perfilación de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Pirazinas/administración & dosificación , Pirazinas/efectos adversos , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , Retratamiento , Resultado del Tratamiento
8.
Mol Cancer ; 17(1): 81, 2018 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-29650000

RESUMEN

Mutations in polymerase ε (POLE) confer favorable prognosis and outcomes in various cancer types, but their role in non-small cell lung cancer (NSCLC) is unknown. Utilizing the data of 513 patients with adenocarcinoma (LUAD) and 497 patients with squamous cell carcinoma (LUSC) from The Cancer Genome Atlas (TCGA) cohort, we tested the prognostic value of POLE mutations and programmed cell death ligand 1 (PD-L1) expression in the two main subtypes of NSCLC. POLE mutation is a favorable biomarker for the improved overall survival (OS) of the LUSC patients (P = 0.033, 28 mutant vs. 469 wildtype patients), but not that of the LUAD patients (P = 0.12, 31 mutant vs. 482 wildtype patients). POLE-mutant LUAD patients with high expression of PD-L1 (Mut-High, n = 6) exhibited improved OS (P = 0.024) when compared to POLE-mutant patients with low PD-L1 expression (Mut-Low, n = 24) and other patients without POLE mutation (n = 476). This benefit was not due to the high content of the tumor infiltrating lymphocytes. Instead, the antitumor immune response was activated in Mut-High patients so that these patients were likely responding more effectively to immuno-oncology (IO) treatments; whereas genes involved with metabolic pathways were enriched in Mut-Low group, which may cause the decreased OS of these patients. Our study sheds light on the molecular basis of NSCLC and adds to our understanding of responses to chemotherapy and IO therapy.


Asunto(s)
Adenocarcinoma del Pulmón/genética , Antígeno B7-H1/genética , Carcinoma de Células Escamosas/genética , ADN Polimerasa II/genética , Neoplasias Pulmonares/genética , Proteínas de Unión a Poli-ADP-Ribosa/genética , Biomarcadores de Tumor/genética , Regulación hacia Abajo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Mutación , Pronóstico , Análisis de Supervivencia
9.
Theranostics ; 7(11): 2914-2923, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28824725

RESUMEN

Background: Cancers related to tobacco use and African-American ancestry are under-characterized by genomics. This gap in precision oncology research represents a major challenge in the health disparities in the United States. Methods: The Precision Oncology trial at the Wake Forest Baptist Comprehensive Cancer Center enrolled 431 cancer patients from March 2015 to May 2016. The composition of these patients consists of a high representation of tobacco-related cancers (e.g., lung, colorectal, and bladder) and African-American ancestry (13.5%). Tumors were sequenced to identify mutations to gain insight into genetic alterations associated with smoking and/or African-American ancestry. Results: Tobacco-related cancers exhibit a high mutational load. These tumors are characterized by high-frequency mutations in TP53, DNA damage repair genes (BRCA2 and ATM), and chromatin remodeling genes (the lysine methyltransferases KMT2D or MLL2, and KMT2C or MLL3). These tobacco-related cancers also exhibit augmented tumor heterogeneities. Smoking related genetic mutations were validated by The Cancer Genome Atlas dataset that includes 2,821 cases with known smoking status. The Wake Forest and The Cancer Genome Atlas cohorts (431 and 7,991 cases, respectively) revealed a significantly increased mutation rate in the TP53 gene in the African-American subgroup studied. Both cohorts also revealed 5 genes (e.g. CDK8) significantly amplified in the African-American population. Conclusions: These results provide strong evidence that tobacco is a major cause of genomic instability and heterogeneity in cancer. TP53 mutations and key oncogene amplifications emerge as key factors contributing to cancer outcome disparities among different racial/ethnic groups.


Asunto(s)
Neoplasias Colorrectales/patología , Neoplasias Pulmonares/patología , Mutación , Fumar Tabaco/efectos adversos , Neoplasias de la Vejiga Urinaria/patología , Negro o Afroamericano , Humanos , Patología Molecular , Análisis de Secuencia de ADN , Proteína p53 Supresora de Tumor/genética , Población Blanca
10.
J Hematol Oncol ; 10(1): 100, 2017 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-28472989

RESUMEN

BACKGROUND: Solid tumors residing in tissues and organs leave footprints in circulation through circulating tumor cells (CTCs) and circulating tumor DNAs (ctDNA). Characterization of the ctDNA portraits and comparison with tumor DNA mutational portraits may reveal clinically actionable information on solid tumors that is traditionally achieved through more invasive approaches. METHODS: We isolated ctDNAs from plasma of patients of 103 lung cancer and 74 other solid tumors of different tissue origins. Deep sequencing using the Guardant360 test was performed to identify mutations in 73 clinically actionable genes, and the results were associated with clinical characteristics of the patient. The mutation profiles of 37 lung cancer cases with paired ctDNA and tumor genomic DNA sequencing were used to evaluate clonal representation of tumor in circulation. Five lung cancer cases with longitudinal ctDNA sampling were monitored for cancer progression or response to treatments. RESULTS: Mutations in TP53, EGFR, and KRAS genes are most prevalent in our cohort. Mutation rates of ctDNA are similar in early (I and II) and late stage (III and IV) cancers. Mutation in DNA repair genes BRCA1, BRCA2, and ATM are found in 18.1% (32/177) of cases. Patients with higher mutation rates had significantly higher mortality rates. Lung cancer of never smokers exhibited significantly higher ctDNA mutation rates as well as higher EGFR and ERBB2 mutations than ever smokers. Comparative analysis of ctDNA and tumor DNA mutation data from the same patients showed that key driver mutations could be detected in plasma even when they were present at a minor clonal population in the tumor. Mutations of key genes found in the tumor tissue could remain in circulation even after frontline radiotherapy and chemotherapy suggesting these mutations represented resistance mechanisms. Longitudinal sampling of five lung cancer cases showed distinct changes in ctDNA mutation portraits that are consistent with cancer progression or response to EGFR drug treatment. CONCLUSIONS: This study demonstrates that ctDNA mutation rates in the key tumor-associated genes are clinical parameters relevant to smoking status and mortality. Mutations in ctDNA may serve as an early detection tool for cancer. This study quantitatively confirms the hypothesis that ctDNAs in circulation is the result of dissemination of aggressive tumor clones and survival of resistant clones. This study supports the use of ctDNA profiling as a less-invasive approach to monitor cancer progression and selection of appropriate drugs during cancer evolution.


Asunto(s)
ADN de Neoplasias/genética , Mutación , Invasividad Neoplásica/genética , Neoplasias/genética , Células Neoplásicas Circulantes , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Quimioradioterapia , Células Clonales , Progresión de la Enfermedad , Receptores ErbB/antagonistas & inhibidores , Clorhidrato de Erlotinib/uso terapéutico , Femenino , Perfilación de la Expresión Génica , Genes Relacionados con las Neoplasias , Genes erbB-1 , Genes p53 , Genes ras , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Neoplasias/mortalidad , Neoplasias/patología , Células Madre Neoplásicas , Inhibidores de Proteínas Quinasas/uso terapéutico , Estudios Retrospectivos , Análisis de Secuencia de ADN , Fumar/genética
11.
Oncotarget ; 7(46): 75407-75424, 2016 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-27705910

RESUMEN

Indoleamine 2,3-dioxygenase (IDO) has been implicated in immune evasion by tumors. Upregulation of this tryptophan (Trp)-catabolizing enzyme, in tumor cells and myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment (TME), leads to Trp depletion that impairs cytotoxic T cell responses and survival; however, exact mechanisms remain incompletely understood. We previously reported that a combination therapy of gemcitabine and a superoxide dismutase mimetic promotes anti-tumor immunity in a mouse model of lung cancer by inhibiting MDSCs, enhancing polyfunctional response of CD8+ memory T cells, and extending survival. Here, we show that combination therapy targets IDO signaling, specifically in MDSCs, tumor cells, and CD8+ T cells infiltrating the TME. Deficiency of IDO caused significant reduction in tumor burden, tumor-infiltrating MDSCs, GM-CSF, MDSC survival and infiltration of programmed death receptor-1 (PD-1)-expressing CD8+ T cells compared to controls. IDO-/- MDSCs downregulated nutrient-sensing AMP-activated protein kinase (AMPK) activity, but IDO-/- CD8+ T cells showed AMPK activation associated with enhanced effector function. Our studies provide proof-of-concept for the efficacy of this combination therapy in inhibiting IDO and T cell exhaustion in a syngeneic model of lung cancer and provide mechanistic insights for IDO-dependent metabolic reprogramming of MDSCs that reduces T cell exhaustion and regulates anti-tumor immunity.


Asunto(s)
Metabolismo Energético , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Microambiente Tumoral/inmunología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/genética , Línea Celular Tumoral , Modelos Animales de Enfermedad , Inmunomodulación/genética , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Ratones , Ratones Noqueados , Modelos Biológicos , Células Supresoras de Origen Mieloide/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Carga Tumoral
12.
Cancer Chemother Pharmacol ; 76(5): 949-55, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26395450

RESUMEN

PURPOSE: The sequence bendamustine (B) + Irinotecan (I) followed by etoposide (E) + carboplatin (C) was hypothesized to increase progression-free survival (PFS) and overall survival (OS) in untreated extensive-disease small cell lung cancer (EDSCLC) patients compared to historical controls by exploiting mitotic catastrophe. Absent expression of ERCC-1 and expression of topoisomerases were hypothesized to be predictive for PFS and OS. METHODS: This was a phase I/IIa trial in 30 patients to determine the maximum tolerated dose (MTD) of B + I and the PFS of B + I E + C with secondary end points including overall response rate (ORR) and OS. Biomarkers measured by immunohistochemistry (IHC) obtained from diagnostic specimens were correlated with outcome. RESULTS: The MTD of B + I was not reached. During treatment with B + I, there were two grade 5 toxicities from neutropenic sepsis and metabolic encephalopathy. Other toxicities included fatigue, nausea/vomiting, diarrhea, and weight loss. For the sequence, the PFS and OS were 6.0 months and 10 months, respectively. The ORR for B + I and the sequence were 82% and 83%, respectively. Topoisomerase-2 expression was predictive for TTP and OS, but absent ERCC-1 expression was not, contrary to our hypothesis. CONCLUSIONS: B + I is an active regimen in EDSCLC. Toxicities included two grade 5 events but were otherwise manageable. The novel sequence B + I E + C increased PFS and OS compared to historical controls. Correlative studies are conflicting regarding the mechanism of action of this novel sequence.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Clorhidrato de Bendamustina/administración & dosificación , Clorhidrato de Bendamustina/efectos adversos , Clorhidrato de Bendamustina/farmacología , Biomarcadores de Tumor/deficiencia , Biomarcadores de Tumor/genética , Encefalopatías Metabólicas/etiología , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/análogos & derivados , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Carcinoma de Células Pequeñas/genética , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Endonucleasas/deficiencia , Endonucleasas/genética , Etopósido/administración & dosificación , Etopósido/efectos adversos , Fatiga/inducido químicamente , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Hematológicas/inducido químicamente , Humanos , Irinotecán , Estimación de Kaplan-Meier , Neoplasias Pulmonares/genética , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Mitosis/efectos de los fármacos , Insuficiencia Multiorgánica/etiología , Neumonía/inducido químicamente , Resultado del Tratamiento , Pérdida de Peso/efectos de los fármacos
14.
Cancer Res ; 73(22): 6609-20, 2013 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-24085788

RESUMEN

Chemoresistance due to heterogeneity of the tumor microenvironment (TME) hampers the long-term efficacy of first-line therapies for lung cancer. Current combination therapies for lung cancer provide only modest improvement in survival, implicating necessity for novel approaches that suppress malignant growth and stimulate long-term antitumor immunity. Oxidative stress in the TME promotes immunosuppression by tumor-infiltrating myeloid-derived suppressor cells (MDSC), which inhibit host protective antitumor immunity. Using a murine model of lung cancer, we demonstrate that a combination treatment with gemcitabine and a superoxide dismutase mimetic targets immunosuppressive MDSC in the TME and enhances the quantity and quality of both effector and memory CD8(+) T-cell responses. At the effector cell function level, the unique combination therapy targeting MDSC and redox signaling greatly enhanced cytolytic CD8(+) T-cell response and further decreased regulatory T cell infiltration. For long-term antitumor effects, this therapy altered the metabolism of memory cells with self-renewing phenotype and provided a preferential advantage for survival of memory subsets with long-term efficacy and persistence. Adoptive transfer of memory cells from this combination therapy prolonged survival of tumor-bearing recipients. Furthermore, the adoptively transferred memory cells responded to tumor rechallenge exerting long-term persistence. This approach offers a new paradigm to inhibit immunosuppression by direct targeting of MDSC function, to generate effector and persistent memory cells for tumor eradication, and to prevent lung cancer relapse.


Asunto(s)
Carcinoma Pulmonar de Lewis/inmunología , Tolerancia Inmunológica/inmunología , Neoplasias Pulmonares/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Células Mieloides/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Carcinoma Pulmonar de Lewis/patología , Carcinoma Pulmonar de Lewis/terapia , Terapia Combinada , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Femenino , Inmunosupresores/uso terapéutico , Inmunoterapia Adoptiva , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Ratones , Ratones Endogámicos C57BL , Células Tumorales Cultivadas , Microambiente Tumoral/inmunología , Gemcitabina
15.
J Natl Compr Canc Netw ; 11(6): 645-53; quiz 653, 2013 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-23744864

RESUMEN

These NCCN Guidelines Insights focus on the diagnostic evaluation of suspected lung cancer. This topic was the subject of a major update in the 2013 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer. The NCCN Guidelines Insights focus on the major updates in the NCCN Guidelines and discuss the new updates in greater detail.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Humanos
16.
J Natl Compr Canc Netw ; 11(5): 562-76, 2013 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-23667206

RESUMEN

Masses in the anterior mediastinum can be neoplasms (eg, thymomas, thymic carcinomas, or lung metastases) or non-neoplastic conditions (eg, intrathoracic goiter). Thymomas are the most common primary tumor in the anterior mediastinum, although they are rare. Thymic carcinomas are very rare. Thymomas and thymic carcinomas originate in the thymus. Although thymomas can spread locally, they are much less invasive than thymic carcinomas. Patients with thymomas have 5-year survival rates of approximately 78%. However, 5-year survival rates for thymic carcinomas are only approximately 40%. These guidelines outline the evaluation, treatment, and management of these mediastinal tumors.


Asunto(s)
Timoma/diagnóstico , Timoma/terapia , Neoplasias del Timo/diagnóstico , Neoplasias del Timo/terapia , Humanos
17.
J Clin Oncol ; 23(28): 6854-64, 2005 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-16192577

RESUMEN

PURPOSE: Bec2 is an anti-idiotypic antibody that mimics GD3, a ganglioside that is expressed on the surface of tumor cells and is of neuroectodermal origin. We assessed whether Bec2/bacille Calmette-Guerin (BCG) vaccination prolongs survival in patients with limited-disease small-cell lung cancer (SCLC) after a major response to chemotherapy and chest radiation. PATIENTS AND METHODS: Patients were randomly assigned to receive five vaccinations of Bec2 (2.5 mg)/BCG vaccine or follow-up. Vaccination was given over a 10-week period. The sample size was targeted to detect an increase in median survival of 40% after random assignment, and stratification was by performance status, response, and institution. Quality of life was assessed by using the European Organisation for Research and Treatment of Cancer instrument. Humoral response was assessed in patients who received vaccination. RESULTS: A total of 515 patients were randomly assigned. The primary toxicities of vaccination were transient skin ulcerations and mild flu-like symptoms. There was no improvement in survival, progression-free survival, or quality of life in the vaccination arm. Median survival from randomization was 16.4 and 14.3 months in the observation and vaccination arms (P = .28), respectively. Among vaccinated patients, a trend toward prolonged survival was observed in those (one third) who developed a humoral response (P = .085). Multivariate analysis showed a positive impact on survival by prior treatment with concomitant chemoradiotherapy, prophylactic cranial irradiation, female sex, low lactate dehydrogenase, and normal platelets. CONCLUSION: Vaccination with Bec2/BCG has no impact on outcome of patients with limited-disease SCLC responding to combined-modality treatment. Vaccination strategies in SCLC may still be warranted using vaccines that produce a better immunologic response.


Asunto(s)
Adyuvantes Inmunológicos/uso terapéutico , Vacuna BCG/uso terapéutico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas del Tejido Nervioso/inmunología , Canales de Potasio con Entrada de Voltaje/inmunología , Adyuvantes Inmunológicos/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Formación de Anticuerpos , Carcinoma de Células Pequeñas/cirugía , Supervivencia sin Enfermedad , Esquema de Medicación , Canales de Potasio Éter-A-Go-Go , Femenino , Humanos , Inmunoterapia , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Calidad de Vida
18.
Cancer Chemother Pharmacol ; 55(1): 33-8, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15309507

RESUMEN

PURPOSE: Epidemiologic studies suggest that consumption of green tea may have a protective effect against the development of several cancers. Preclinical studies of green tea and its polyphenolic components have demonstrated antimutagenic and anticarcinogenic activity, and inhibition of growth of tumor cell lines and animal tumor models, including lung cancer. Green tea may also have chemopreventive properties, and enhancement of cytotoxicity of chemotherapeutic agents has been demonstrated. This trial was designed to determine the maximum tolerated dose (MTD) of green tea extract (GTE) in patients with advanced lung cancer. METHODS: A total of 17 patients with advanced lung cancer were registered to receive once-daily oral dosing of GTE at a starting dose of 0.5 g/m2 per day, with an accelerated dose-escalation scheme. RESULTS: On this schedule, the MTD of GTE was 3 g/m2 per day, and at this dose, GTE was well tolerated with no grade 3 or 4 toxicity seen. Dose-limiting toxicities were diarrhea, nausea and hypertension. No objective responses were seen in this trial. Seven patients had stable disease ranging from 4 to 16 weeks; no patient remained on therapy longer than 16 weeks due to the development of progressive disease. CONCLUSIONS: This study suggests that while relatively nontoxic at a dose of 3 g/m2 per day, GTE likely has limited activity as a cytotoxic agent, and further study of GTE as a single-agent in established malignancies may not be warranted. Further studies should focus on the potential chemopreventive and chemotherapy-enhancing properties of GTE.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , , Administración Oral , Adulto , Anciano , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad
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