RESUMEN
PURPOSE: To assess whether panitumumab is active in patients with cetuximab-refractory metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Eligible patients had pretreated RAS (renin-angiotensin system) wild-type mCRC that progressed after cetuximab treatment, after having shown either objective response or stable disease. A minimax two-stage design was applied, with progression-free rate at 2 months as the primary end point. At least 12 of 28 and 21 of 41 successes at the first and second stage, respectively, were required for a positive result. Panitumumab 6 mg/kg was provided every 2 weeks, until progression or unacceptable toxicity. RESULTS: Overall, 52 patients with KRAS (Kirsten rat sarcoma viral oncogene) wild-type disease were enrolled, but 11 were found to have mutated disease after all-RAS retesting. Among 41 eligible patients, median time since diagnosis was 38 months, and 71% experienced an objective response to previous cetuximab. First stage was passed with 12 of 28 patients alive without progression at 2 months. At the second stage, 17 of 41 patients were alive without progression at 2 months. At a median follow-up of 21.8 months, 35 patients experienced disease progression, and 26 died. Median progression-free survival was 2.1 months (95% confidence interval, 1.8-3.6) and median overall survival 6.8 months (95% confidence interval, 4.6-16.6). Most of the patients experienced no adverse reactions; 25% of patients had grade 3 rash. CONCLUSION: According to our study design, panitumumab was not effective in patients with cetuximab-refractory RAS wild-type mCRC.
Asunto(s)
Cetuximab/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Panitumumab/administración & dosificación , Anciano , Cetuximab/uso terapéutico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Panitumumab/efectos adversos , Supervivencia sin Progresión , Estudios Prospectivos , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
BACKGROUND: The present study investigated the efficacy and safety of nivolumab in pre-treated patients with advanced NSCLC harbouring KRAS mutations. METHODS: Clinical data and KRAS mutational status were analysed in patients treated with nivolumab within the Italian Expanded Access Program. Objective response rate, progression-free survival and overall survival were evaluated. Patients were monitored for adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events. RESULTS: Among 530 patients evaluated for KRAS mutations, 206 (39%) were positive while 324 (61%) were KRAS wild-type mutations. KRAS status did not influence nivolumab efficacy in terms of ORR (20% vs 17%, P = 0.39) and DCR (47% vs 41%, P = 0.23). The median PFS and OS were 4 vs 3 months (P = 0.5) and 11.2 vs 10 months (P = 0.8) in the KRAS-positive vs the KRAS-negative group. The 3-months PFS rate was significantly higher in the KRAS-positive group as compared to the KRAS-negative group (53% vs 42%, P = 0.01). The percentage of any grade and grade 3-4 AEs were 45% vs 33% (P = 0.003) and 11% vs 6% (P = 0.03) in KRAS-positive and KRAS-negative groups, respectively. CONCLUSIONS: Nivolumab is an effective and safe treatment option for patients with previously treated, advanced non-squamous NSCLC regardless of KRAS mutations.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inmunoterapia , Nivolumab/administración & dosificación , Proteínas Proto-Oncogénicas p21(ras)/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Supervivencia sin ProgresiónRESUMEN
From the thymus to the peripheral lymph nodes, integrin-mediated interactions with neighbor cells and the extracellular matrix tune T cell behavior by organizing cytoskeletal remodeling and modulating receptor signaling. LFA-1 (αLß2 integrin) and VLA-4 (α4ß1 integrin) play a key role throughout the T cell lifecycle from thymocyte differentiation to lymphocyte extravasation and finally play a fundamental role in organizing immune synapse, providing an essential costimulatory signal for the T cell receptor. Apart from tuning T cell signaling, integrins also contribute to homing to specific target organs as exemplified by the importance of α4ß7 in maintaining the gut immune system. However, apart from those well-characterized examples, the physiological significance of the other integrin dimers expressed by T cells is far less understood. Thus, integrin-mediated cell-to-cell and cell-to-matrix interactions during the T cell lifespan still represent an open field of research.
Asunto(s)
Integrinas/genética , Integrinas/metabolismo , Linfocitos T/fisiología , Animales , Antígenos/inmunología , Adhesión Celular , Diferenciación Celular/genética , Movimiento Celular/genética , Movimiento Celular/inmunología , Matriz Extracelular , Humanos , Sinapsis Inmunológicas/genética , Sinapsis Inmunológicas/inmunología , Sinapsis Inmunológicas/metabolismo , Activación de Linfocitos/inmunología , Transducción de Señal , Linfocitos T/citología , Timocitos/citología , Timocitos/metabolismoRESUMEN
BACKGROUND: The treatment of refractory metastatic colorectal cancer (rmCRC) and the lack of predictive variables are matters of debate. PATIENTS AND METHODS: We conducted a multicentre phase II trial assessing the disease control rate (DCR) of the combination of tegafur/uracil and mitomycin C in rmCRC. The number of previous lines of chemotherapy, carcinoembryonic antigen (CEA) levels, progression-free survival of the last chemotherapy regimen (PPFS), and the neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio at the time of study entry were evaluated as indicators of early progression. RESULTS: We enrolled 42 patients. The combination was well tolerated with a DCR of 26.2% and median overall survival of 6.9 months. Low CEA levels, PPFS >6 months and low NLR were significantly associated with better prognosis. CONCLUSION: The study failed its primary endpoint. However, some putative indicators of early progressive patients have been described.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Anciano , Biomarcadores de Tumor/análisis , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Mitomicina/administración & dosificación , Mitomicina/uso terapéutico , Tegafur/administración & dosificación , Resultado del Tratamiento , Uracilo/administración & dosificaciónRESUMEN
INTRODUCTION: Patients with cancer need stable venous access using central vascular devices like central venous ports and peripherally inserted central catheters that can be used for a wide range of indications. Numerous flushing protocols exist including different frequencies for catheter locking to maintain catheter patency. The aim of this retrospective study was to evaluate the incidence of lumen occlusion of central venous ports in a group of adult cancer patients, adopting a policy of locking with normal saline every three months. METHODS: This is a single-center retrospective observational study. During follow-up, we analyzed adult cancer patients who had undergone port insertion from January 1st, 2007 to August 31st, 2014. Flushing and locking were performed every three months with a syringe containing normal saline. RESULTS: We collected data from 381 patients with ports inserted in subclavian vein (379 patients) and in the right jugular vein (2 patients). Locking was performed during 3-monthly follow-up visits. Median follow-up was 810 days (90-2700 days). Among 381 ports, 59 were removed; the reasons for removal were: end of use (45 cases), catheter rupture (9 cases), dislocation (3 cases) and catheter-related bloodstream infection (2 cases). We had no reports of lumen occlusion. CONCLUSIONS: Our data suggest that locking ports with normal saline every three months is not associated with an increased risk of lumen occlusion.
Asunto(s)
Antineoplásicos/administración & dosificación , Infecciones Relacionadas con Catéteres/prevención & control , Cateterismo Venoso Central/instrumentación , Catéteres de Permanencia , Catéteres Venosos Centrales , Descontaminación/métodos , Oncología Médica/métodos , Cloruro de Sodio , Administración Intravenosa , Infecciones Relacionadas con Catéteres/microbiología , Cateterismo Venoso Central/efectos adversos , Catéteres de Permanencia/efectos adversos , Catéteres Venosos Centrales/efectos adversos , Remoción de Dispositivos , Diseño de Equipo , Falla de Equipo , Humanos , Italia , Datos Preliminares , Estudios Retrospectivos , Cloruro de Sodio/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
PURPOSE: Non-small cell lung cancer (NSCLC) is a condition with significant clinical burden for patients and relevant economic impact. Limited evidence exists on the management costs of NSCLC patients, especially in the late phases of the disease. The main objective of this analysis was to evaluate the economic impact of clinical management of NSCLC patients in the Italian population. METHODS: This evaluation was an economic analysis of the observational and multicentre study LIFE, which described the therapeutic approach in routine clinical practice for NSCLC patients, progressing after first-line treatment. This study evaluated resource consumption in different Italian hospitals, including specialist visits, hospitalizations, accesses to first aid, pharmacological treatment, laboratory tests and palliative care. The National Healthcare Service perspective was adopted. RESULTS: In this study, N = 191 patients enrolled in the LIFE study were included. Patients were aged 64.2 years and were predominantly males (66%). In the different line of treatments, monthly costs of patients ranged between 1471 (first line) and 1788 (third line). The overall healthcare cost over the average period of observation (16.4 months) was 25,859 per patient. Overall, oncology therapy was the cost driver, although the composition of medical costs changed across the different lines of treatment, with costs for concomitant medication and palliative care being predominant in late phase of the disease. CONCLUSIONS: The economic burden of NSCLC is extremely high during the overall period of treatment, and a significant level of care is required in each stage of the disease.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/economía , Costo de Enfermedad , Neoplasias Pulmonares/economía , Femenino , Costos de la Atención en Salud , Humanos , Italia , Masculino , Persona de Mediana EdadRESUMEN
Interleukin-6 (IL-6), a pro-inflammatory cytokine released by cancer-associated fibroblasts, has been linked to the invasive and metastatic behavior of ovarian cancer cells. Resveratrol is a naturally occurring polyphenol with the potential to inhibit cancer cell migration. Here we show that Resveratrol and IL-6 affect in an opposite manner the expression of RNA messengers and of microRNAs involved in cell locomotion and extracellular matrix remodeling associated with the invasive properties of ovarian cancer cells. Among the several potential candidates responsible for the anti-invasive effect promoted by Resveratrol, here we focused our attention on ARH-I (DIRAS3), that encodes a Ras homolog GTPase of 26-kDa. This protein is known to inhibit cell motility, and it has been shown to regulate autophagy by interacting with BECLIN 1. IL-6 down-regulated the expression of ARH-I and inhibited the formation of LC3-positive autophagic vacuoles, while promoting cell migration. On opposite, Resveratrol could counteract the IL-6 induction of cell migration in ovarian cancer cells through induction of autophagy in the cells at the migration front, which was paralleled by up-regulation of ARH-I and down-regulation of STAT3 expression. Spautin 1-mediated disruption of BECLIN 1-dependent autophagy abrogated the effects of Resveratrol, while promoting cell migration. The present data indicate that Resveratrol elicits its anti-tumor effect through epigenetic mechanisms and support its inclusion in the chemotherapy regimen for highly aggressive ovarian cancers. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Interleucina-6/genética , Interleucina-6/metabolismo , Neoplasias Ováricas/genética , Estilbenos/farmacología , Regulación hacia Arriba , Autofagia , Beclina-1/genética , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Resveratrol , Proteínas de Unión al GTP rho/genéticaRESUMEN
Cetuximab improves efficacy when added to chemotherapy for metastatic colorectal cancer (mCRC). Effective management of skin reactions from cetuximab improves quality of life (QoL), and treatment compliance in clinical trials. No data are available from real-world settings. The ObservEr observational, multicenter, prospective study evaluated QoL, the incidence of skin reactions, and management of chemotherapy plus cetuximab in first-line for mCRC. The primary endpoint was QoL measured with the Dermatology Life Quality Index (DLQI) and EORTC QLQ-C30. Secondary endpoints were the incidence of skin and serious adverse events, median overall and progression-free survival, tumor response, and resection rates. Between May 2011 and November 2012, 228 patients with KRASwt mCRC were enrolled at 28 Italian centers, 225 evaluable, median age 65 years. QoL did not change during treatment and was not affected by the choice of prophylactic or reactive skin management. The incidence of cetuximab-specific grade ≥3 skin reactions was 14%, with no grade 4/5 events. Skin reactions correlated with survival (P = 0.016), and their incidence was influenced by chemotherapy regimen (oxaliplatin vs. irinotecan-Incidence rate ratio [IRR] 1.72, P < 0.0001) and gender (male vs. female-IRR 1.38, P = 0.0008). Compliance at first postbaseline evaluation was 97.75%. Median overall survival was 23.6 months, median progression-free survival 8.3 months. Cetuximab plus chemotherapy did not compromise QoL in the routine clinical setting when patients receive close monitoring plus prophylactic or reactive management of skin reactions. We observed the same correlation between overall survival (OS) and skin reactions reported in controlled clinical trials, also in this setting.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Calidad de Vida , Proteínas ras/genética , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cetuximab/administración & dosificación , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
CONTEXT: Oxycodone and morphine are recommended as first-choice opioids for moderate/severe cancer pain, but evidence about their relative tolerability has significant methodological limitations. OBJECTIVES: This study was mainly aimed at comparing the risk of developing adverse events (AEs) with controlled-release oral morphine vs. oxycodone; secondary aims were comparing their analgesic efficacy and testing heterogeneity in tolerability across different age and renal function subgroups. METHODS: An open-label multicenter RCT (EudraCT number: 2006-003151-21) was carried out in patients with moderate/severe cancer pain. At baseline, 7 and 14 days, patients scored on 0-10 rating scales (0-10 numerical rating scale) the intensity of pain and of a list of common opioid side effects. The primary end point was the percentage of patients reporting an AE (a worsening ≥ 2 points on any of the listed side effects); tolerability by subgroups and average follow-up pain intensity were compared through regression models. RESULTS: One hundred eighty-seven patients were enrolled (47% of originally planned). Intention to treat (ITT) analysis (N = 185, morphine 94, oxycodone 91) did not show any difference in the risk of developing AEs (risk difference -0.6%, 95% CI -11.0% to 9.9%) nor in analgesia (0-10 numerical rating scale pain intensity difference -0.28, 95% CI -0.83 to 0.27). No evidence of heterogeneity of tolerability across age and renal function patient subgroups emerged. CONCLUSION: This trial failed to show any difference in tolerability and analgesic efficacy of morphine and oxycodone as first-line treatment for moderate/severe cancer pain but results interpretation is difficult due to lack of power, potential bias from open-label design, and concerns about assay sensitivity. These data, however, can significantly contribute to future meta-analyses comparing WHO Step-III opioids and are relevant in designing future randomized studies.
Asunto(s)
Analgésicos Opioides/administración & dosificación , Dolor en Cáncer/tratamiento farmacológico , Morfina/administración & dosificación , Oxicodona/administración & dosificación , Adulto , Anciano , Analgésicos Opioides/efectos adversos , Preparaciones de Acción Retardada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Morfina/efectos adversos , Oxicodona/efectos adversos , Dimensión del Dolor , Cuidados Paliativos , Riesgo , Resultado del TratamientoRESUMEN
Proliferating cancer cells oxidize glucose through the glycolytic pathway. Since this metabolism is less profitable in terms of ATP production, cancer cells consume large quantity of glucose, and those that experience insufficient blood supply become glucose-addicted. We have analyzed the response to glucose depletion in WRO and FTC133 follicular thyroid cancer cells, which differ in the expression of two key regulators of the glucose metabolism. WRO cells, which express wild type p53 and PTEN, showed a higher rate of cell proliferation and were much less sensitive to glucose-depletion than FTC133 cells, which are PTEN null and express mutant p53. Glucose depletion slowed-down the autophagy flux in FTC133 cells, not in WRO cells. In a wound-healing assay, WRO cells were shown to migrate faster than FTC133 cells. Glucose depletion slowed down the cell migration rate, and these effects were more evident in FTC133 cells. Genetic silencing of either wild-type PTEN or p53 in WRO cells resulted in increased uptake of glucose, whereas the ectopic expression of PTEN in FTC133 cells resulted in diminished glucose uptake. In conclusion, compared to WRO, FTC133 cells were higher glucose up-taker and consumer. These data do not support the general contention that cancer cells lacking PTEN or expressing the mutant p53R273H are more aggressive and prone to better face glucose depletion. We propose that concurrent PTEN deficiency and mutant p53 leads to a glucose-addiction state that renders the cancer cell more sensitive to glucose restriction. The present observation substantiates the view that glucose-restriction may be an adjuvant strategy to combat these tumours.
RESUMEN
Glucose represents an important source of energy for the cells. Proliferating cancer cells consume elevated quantity of glucose, which is converted into lactate regardless of the presence of oxygen. This phenomenon, known as the Warburg effect, has been proven to be useful for imaging metabolically active tumours in cancer patients by (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET). Glucose is internalised in the cells by glucose transporters (GLUTs) belonging to the GLUT family. GLUT1 (SLC2A1) is the most prevalent isoform in more aggressive and less differentiated thyroid cancer histotypes. In a previous work, we found that loss of expression of PTEN was associated with increased expression of GLUT1 on the plasma membrane (PM) and probability of detecting thyroid incidentalomas by FDG-PET. Herein, we investigated the molecular pathways that govern the expression of GLUT1 on the PM and the glucose uptake in WRO (expressing WT PTEN) and FTC133 (PTEN null) follicular thyroid cancer cells cultured under glucose-depleted conditions. The membrane expression of GLUT1 was enhanced in glucose-deprived cells. Through genetic manipulations of PTEN expression, we could demonstrate that the lack of this oncosuppressor has a dominant effect on the membrane expression of GLUT1 and glucose uptake. We conclude that loss of function of PTEN increases the probability of cancer detection by FDG-PET or other glucose-based imaging diagnosis.
Asunto(s)
Membrana Celular/metabolismo , Transportador de Glucosa de Tipo 1/metabolismo , Glucosa/metabolismo , Fosfohidrolasa PTEN/metabolismo , Neoplasias de la Tiroides/metabolismo , Línea Celular Tumoral , Expresión Génica , Humanos , Espacio Intracelular/metabolismo , Fosfohidrolasa PTEN/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Transporte de Proteínas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Neoplasias de la Tiroides/genéticaRESUMEN
Autophagy is dysregulated in cancer and might be involved in ovarian carcinogenesis. BECLIN-1, a protein that interacts with either BCL-2 or PI3k class III, plays a critical role in the regulation of both autophagy and cell death. Induction of autophagy is associated with the presence of vacuoles characteristically labelled with the protein LC3. We have studied the biological and clinical significance of BECLIN 1 and LC3 in ovary tumours of different histological types. The positive expression of BECLIN 1 was well correlated with the presence of LC3-positive autophagic vacuoles and was inversely correlated with the expression of BCL-2. The latter inhibits the autophagy function of BECLIN 1. We found that type I tumours, which are less aggressive than type II, were more frequently expressing high level of BECLIN 1. Of note, tumours of histologic grade III expressed low level of BECLIN 1. Consistently, high level of expression of BECLIN 1 and LC3 in tumours is well correlated with the overall survival of the patients. The present data are compatible with the hypotheses that a low level of autophagy favours cancer progression and that ovary cancer with upregulated autophagy has a less aggressive behaviour and is more responsive to chemotherapy.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/biosíntesis , Autofagia , Regulación Neoplásica de la Expresión Génica , Proteínas de la Membrana/biosíntesis , Proteínas Asociadas a Microtúbulos/biosíntesis , Proteínas de Neoplasias/biosíntesis , Neoplasias Ováricas , Beclina-1 , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Thyroid cancer is the most common cancer of the endocrine system and is responsible for the majority of deaths from endocrine malignancies. Although a large proportion of thyroid cancers belong to well differentiated histologic subtypes, which in general show a good prognosis after surgery and radioiodine ablation, the treatment of radio-resistant papillary-type, of undifferentiated anaplastic, and of medullary-type thyroid cancers remains unsatisfactory. Autophagy is a vesicular process for the lysosomal degradation of protein aggregates and of damaged or redundant organelles. Autophagy plays an important role in cell homeostasis, and there is evidence that this process is dysregulated in cancer cells. Recent in vitro preclinical studies have indicated that autophagy is involved in the cytotoxic response to chemotherapeutics in thyroid cancer cells. Indeed, several oncogenes and oncosuppressor genes implicated in thyroid carcinogenesis also play a role in the regulation of autophagy. In addition, some epigenetic modulators involved in thyroid carcinogenesis also influence autophagy. In this review, we highlight the genetic and epigenetic factors that mechanistically link thyroid carcinogenesis and autophagy, thus substantiating the rationale for an autophagy-targeted therapy of aggressive and radio-chemo-resistant thyroid cancers.
Asunto(s)
Autofagia/genética , Carcinogénesis/genética , Carcinogénesis/patología , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Animales , Epigénesis Genética , Genes Supresores de Tumor , Humanos , Oncogenes , Transducción de Señal/genética , Transducción de Señal/inmunologíaRESUMEN
AIMS AND BACKGROUND: In recent years, the number of oral anticancer drugs used in clinical practice has rapidly increased. The Italian Society of Medical Oncology (AIOM) conducted a survey to describe the impact of the use of oral anticancer drugs on the daily activity of Italian oncology practices. METHODS AND STUDY DESIGN: A survey questionnaire was distributed to the coordinators of the regional sections of AIOM. A 6-month period was considered, from January 1, 2010 to June 30, 2010. The survey addressed (1) quantitative aspects of the use of oral anticancer drugs; (2) practical aspects in the management of patients treated with these drugs; (3) issues related to treatment costs and reimbursement procedures. RESULTS: Thirty-six questionnaires were received from institutions distributed throughout the Italian territory. Oral anticancer drugs (both chemotherapy and molecularly targeted agents) accounted for a significant proportion (17%) of prescribed treatments. Among the responding institutions, there were different dispensation procedures of oral drugs to patients: drugs were dispensed by the pharmacist (57%) or directly by the medical oncologist (23%) or nurse (20%). The medical oncologist played a major role in the communication with patients (73% alone and a further 24% in cooperation with other professional figures) and was the point of reference in the event of side effects in 97% of cases. In most cases, the reimbursement of drug costs was separated ("File F" procedure) from the flat fare received by the hospital for outpatient visits or day-hospital access. CONCLUSIONS: Optimal organization of oral anticancer treatment warrants the cooperation and integration of multiple professional figures. At least three figures are involved in patient management in the hospital: the medical oncologist, the nurse, and the hospital pharmacist. Oral anticancer treatments are associated with specific reimbursement issues: in the majority of cases, the cost of the drug is reimbursed separately from the cost of patient access.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/economía , Costos de la Atención en Salud/estadística & datos numéricos , Oncología Médica/economía , Pautas de la Práctica en Medicina/estadística & datos numéricos , Mecanismo de Reembolso/organización & administración , Administración Oral , Adulto , Anciano , Costos de los Medicamentos/estadística & datos numéricos , Femenino , Encuestas de Atención de la Salud , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida/economía , Enfermería Oncológica/economía , Farmacéuticos/economía , Médicos/economía , Pautas de la Práctica en Medicina/economía , Sociedades Médicas , Encuestas y Cuestionarios , Recursos HumanosRESUMEN
Mutation analysis of KRAS is needed before starting treatment with anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer (CRC). In most of the cases, testing is performed on primary tumors, assuming that KRAS mutation status does not change in metastasis although correlation studies gave conflicting results. We evaluated the KRAS status concordance rate between primary tumors and related metastasis using a highly sensitive molecular assay. Forty-five primary tumors and related metastases from patients with CRC (28/45 male-62.2% and 17/45 female-37.8%; mean age 66.4 years) were analyzed by using TheraScreen: KRAS mutational kit. Metastatic samples were collected from lymph nodes (8/45-17.8%) and visceral sites (37/45-82.2%); 23 were synchronous (49%) and 22 were metachronous (51%), obtained after a mean of 30.8 months after the first diagnosis of CRC. Twenty-eight patients had KRAS mutations in both primary CRC and related metastases (62.2%). No differences in type and frequency of mutations were identified, despite different metastatic sites and time of onset of metastatic disease. Our results indicate that the mutation status of KRAS is the same in primary CRC and metastasis, suggesting that in clinical practice, KRAS testing can be performed on both tumor tissues when using a highly sensitive molecular assay.
Asunto(s)
Neoplasias Colorrectales/genética , Neoplasias Colorrectales/secundario , Análisis Mutacional de ADN , Mutación , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Predisposición Genética a la Enfermedad , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Fenotipo , Pronóstico , Proteínas Proto-Oncogénicas p21(ras) , Factores de TiempoRESUMEN
Autophagy is a lysosomal-driven catabolic process that contributes to preserve cell and tissue homeostases through the regular elimination of damaged, aged and redundant self-constituents. In normal cells, autophagy protects from DNA mutation and carcinogenesis by preventive elimination of pro-oxidative mitochondria and protein aggregates. Mutations in oncogenes and oncosuppressor genes dysregulate autophagy. Up-regulated autophagy may confer chemo- and radio-resistance to cancer cells, and also a pro-survival advantage in cancer cells experiencing oxygen and nutrient shortage. This fact is the rationale for using autophagy inhibitors along with anti-neoplastic therapies. Yet, aberrant hyper-induction of autophagy can lead to cell death, and this phenomenon could also be exploited for cancer therapy. The actual level of autophagy in the cancer cell is greatly affected by vascularization, inflammation, and stromal cell infiltration. In addition, small non-coding microRNAs have recently emerged as important epigenetic modulators of autophagy. The present review focuses on the potential involvement of macroautophagy, and on its genetic and epigenetic regulation, in ovarian cancer pathogenesis and progression.
RESUMEN
BACKGROUND AND OBJECTIVE: First-line bevacizumab-based therapy has been shown to improve outcomes in patients with advanced non-squamous non-small-cell lung cancer (NSCLC). The recent international phase IV SAiL study (a Study of Avastin [bevacizumab] in combination with platinum-containing chemotherapy in patients with advanced or recurrent non-squamous cell Lung cancer) evaluated the safety and efficacy of bevacizumab combined with standard chemotherapy regimens in routine clinical practice. Here we report the results of a subanalysis of baseline characteristics and efficacy data for Italian patients enrolled in SAiL. METHODS: In the SAiL study, patients with untreated locally advanced, metastatic or recurrent non-squamous NSCLC received bevacizumab (7.5 or 15 mg/kg) every 3 weeks plus chemotherapy for up to six cycles, followed by single-agent bevacizumab until disease progression. Efficacy was assessed in terms of time to disease progression (TTP) and overall survival (OS). RESULTS: The Italian intent-to-treat population comprised 215 patients from a SAiL population of 2212 patients. At baseline, Italian patients tended to have less advanced disease than the overall population. Thus, the proportion of patients at enrollment with tumour stage IIIb and IV was 23.7 and 76.3 %, respectively, for the Italian population versus 19.7 and 80.3 % for the whole SAiL population. In addition, a higher proportion of Italian patients had an Eastern Cooperative Oncology Group performance status of 0 (72.6 vs. 37.2 %) and the prevalence of co-morbid conditions was lower in Italian patients (59.5 % of Italian patients reported a co-morbid condition and 60.0 % were receiving non-oncological treatment compared with 73.3 and 73.4 %, respectively, of SAiL patients overall). The mean exposures to bevacizumab and to chemotherapy were comparable between the Italian patient group and overall patient population, although cisplatin doublets were more commonly employed in Italian patients whereas carboplatin doublets were more commonly employed in the overall SAiL population. The median TTP and OS times for Italian and SAiL populations were comparable (TTP, 7.8 months vs. 7.8 months; OS, 14.8 months vs. 14.6 months). CONCLUSION: The results of this subanalysis of the SAiL study of bevacizumab treatment in routine clinical practice suggest that Italian oncologists tend to prescribe bevacizumab to a selected population of patients with less advanced disease than is the case in the overall population. Nevertheless, the first-line use of bevacizumab in combination with chemotherapy offers clinical benefits to Italian patients with advanced or recurrent non-squamous NSCLC.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab , Carboplatino/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/irrigación sanguínea , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/secundario , Cisplatino/administración & dosificación , Comorbilidad , Progresión de la Enfermedad , Femenino , Humanos , Análisis de Intención de Tratar , Italia , Estimación de Kaplan-Meier , Neoplasias Pulmonares/irrigación sanguínea , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pautas de la Práctica en Medicina/tendencias , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The role of surgery for lung metastases (LM) secondary to colorectal cancer (CRC) remains controversial. The bulk of evidence is derived from single surgical series, hampering any definitive conclusions. The aim of this study was to compare the outcomes of CRC patients with LM submitted to surgery with those who were not. PATIENTS AND METHODS: Data from 409 patients with LM as the first evidence of advanced disease were extracted from a database of 1,411 patients. Patients were divided into three groups: G1, comprised of 155 patients with pulmonary and extrapulmonary metastases; G2, comprised of 104 patients with LM only and no surgery; G3, comprised of 50 patients with LM only and submitted to surgery. RESULTS: No difference in response rates emerged between G1 and G2. Median progression-free survival (PFS) times were: 10.3 months, 10.5 months, and 26.2 months for G1, G2, and G3, respectively. No difference in PFS times was observed between G1 and G2, whereas there was a statistically significant difference between G2 and G3. Median overall survival times were 24.2 months, 31.5 months, and 72.4 months, respectively. Survival times were longer in resected patients: 17 survived >5 years and three survived >10 years. In patients with LM only and no surgery, four survived for 5 years and none survived >10 years. CONCLUSIONS: Even though patients with resectable LM are more likely to be those with a better outcome, our study provides evidence suggesting an active role of surgery in improving survival outcomes in this patient subset.