RESUMEN
PURPOSE: This phase II study investigated daily or weekly sapanisertib (a selective dual inhibitor of mTOR complexes 1 and 2) in combination with fulvestrant. PATIENTS AND METHODS: Postmenopausal women with estrogen receptor-positive (ER+)/HER2-negative (HER2-) advanced or metastatic breast cancer following progression during/after aromatase inhibitor treatment were randomized to receive fulvestrant 500 mg (28-day treatment cycles), fulvestrant plus sapanisertib 4 mg daily, or fulvestrant plus sapanisertib 30 mg weekly, until progressive disease, unacceptable toxicity, consent withdrawal, or study completion. RESULTS: Among 141 enrolled patients, baseline characteristics were balanced among treatment arms, including prior cyclin-dependent kinase-4/6 (CDK4/6) inhibitor treatment in 33% to 35% of patients. Median progression-free survival (PFS; primary endpoint) was 3.5 months in the single-agent fulvestrant arm, compared with 7.2 months for fulvestrant plus sapanisertib daily [HR, 0.77; 95% confidence interval (CI), 0.47-1.26] and 5.6 months for fulvestrant plus sapanisertib weekly (HR, 0.88; 95% CI, 0.53-1.45). The greatest PFS benefits were seen in patients who had previously received CDK4/6 inhibitors. The most common adverse events were nausea, vomiting, and hyperglycemia, all occurring more frequently in the combination therapy arms. Treatment discontinuation due to adverse events occurred more frequently in the two combination therapy arms than with single-agent fulvestrant (32% and 36% vs. 4%, respectively). CONCLUSIONS: Fulvestrant plus sapanisertib daily/weekly resulted in numerically longer PFS in patients with ER+/HER2- advanced or metastatic breast cancer, compared with single-agent fulvestrant. The combination was associated with increased toxicity. Further development of sapanisertib using these dosing schedules in this setting is not supported by these data.
Asunto(s)
Inhibidores de la Aromatasa , Neoplasias de la Mama , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/patología , Femenino , Fulvestrant , Humanos , Posmenopausia , Pirazoles , Pirimidinas , Receptor ErbB-2/uso terapéutico , Receptores de EstrógenosRESUMEN
PURPOSE: Well-differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcoma are characterized by co-amplification of the murine double minute-2 (MDM2) and cyclin-dependent kinase-4 (CDK4) oncogenes. Siremadlin, a p53-MDM2 inhibitor, was combined with ribociclib, a CDK4/6 inhibitor, in patients with locally advanced/metastatic WDLPS or DDLPS who had radiologically progressed on, or despite, prior systemic therapy. PATIENTS AND METHODS: In this proof-of-concept, phase Ib, dose-escalation study, patients received siremadlin and ribociclib across different regimens until unacceptable toxicity, disease progression, and/or treatment discontinuation: Regimen A [4-week cycle: siremadlin once daily (QD) and ribociclib QD (2 weeks on, 2 weeks off)], Regimen B [3-week cycle: siremadlin once every 3 weeks; ribociclib QD (2 weeks on, 1 week off)], and Regimen C [4-week cycle: siremadlin once every 4 weeks; ribociclib QD (2 weeks on, 2 weeks off)]. The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of siremadlin plus ribociclib in one or more regimens. RESULTS: As of October 16, 2019 (last patient last visit), 74 patients had enrolled. Median duration of exposure was 13 (range, 1-174) weeks. Dose-limiting toxicities occurred in 10 patients, most of which were Grade 3/4 hematologic events. The RDE was siremadlin 120 mg every 3 weeks plus ribociclib 200 mg QD (Regimen B). Three patients achieved a partial response, and 38 achieved stable disease. One patient (Regimen C) died as a result of treatment-related hematotoxicity. CONCLUSIONS: Siremadlin plus ribociclib demonstrated manageable toxicity and early signs of antitumor activity in patients with advanced WDLPS or DDLPS.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Liposarcoma , Aminopiridinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quinasa 4 Dependiente de la Ciclina/genética , Humanos , Imidazoles/uso terapéutico , Liposarcoma/tratamiento farmacológico , Liposarcoma/genética , Liposarcoma/patología , Proteínas Proto-Oncogénicas c-mdm2/genética , Purinas/uso terapéutico , Pirimidinas/uso terapéutico , Pirroles/uso terapéuticoRESUMEN
BACKGROUND: Alveolar soft-part sarcoma (ASPS) is a rare soft-tissue sarcoma that is unresponsive to chemotherapy. Cediranib, a tyrosine-kinase inhibitor, has shown substantial activity in ASPS in non-randomised studies. The Cediranib in Alveolar Soft Part Sarcoma (CASPS) study was designed to discriminate the effect of cediranib from the intrinsically indolent nature of ASPS. METHODS: In this double-blind, placebo-controlled, randomised, phase 2 trial, we recruited participants from 12 hospitals in the UK (n=7), Spain (n=3), and Australia (n=2). Patients were eligible if they were aged 16 years or older; metastatic ASPS that had progressed in the previous 6 months; had an ECOG performance status of 0-1; life expectancy of more than 12 weeks; and adequate bone marrow, hepatic, and renal function. Participants had to have no anti-cancer treatment within 4 weeks before trial entry, with exception of palliative radiotherapy. Participants were randomly assigned (2:1), with allocation by use of computer-generated random permuted blocks of six, to either cediranib (30 mg orally, once daily) or matching placebo tablets for 24 weeks. Treatment was supplied in number-coded bottles, masking participants and clinicians to assignment. Participants were unblinded at week 24 or sooner if they had progression defined by Response Evaluation Criteria in Solid Tumors (version 1.1); those on placebo crossed over to cediranib and all participants continued on treatment until progression or death. The primary endpoint was percentage change in sum of target marker lesion diameters between baseline and week 24 or progression if sooner, assessed in the evaluable population (all randomly assigned participants who had a scan at week 24 [or sooner if they progressed] with target marker lesions measured). Safety was assessed in all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01337401; the European Clinical Trials database, number EudraCT2010-021163-33; and the ISRCTN registry, number ISRCTN63733470 recruitment is complete and follow-up is ongoing. FINDINGS: Between July 15, 2011, and July 29, 2016, of 48 participants recruited, all were randomly assigned to cediranib (n=32) or placebo (n=16). 23 (48%) were female and the median age was 31 years (IQR 27-45). Median follow-up was 34·3 months (IQR 23·7-55·6) at the time of data cutoff for these analyses (April 11, 2018). Four participants in the cediranib group were not evaluable for the primary endpoint (one did not start treatment, and three did not have their scan at 24 weeks). Median percentage change in sum of target marker lesion diameters for the evaluable population was -8·3% (IQR -26·5 to 5·9) with cediranib versus 13·4% (IQR 1·1 to 21·3) with placebo (one-sided p=0·0010). The most common grade 3 adverse events on (blinded) cediranib were hypertension (six [19%] of 31) and diarrhoea (two [6%]). 15 serious adverse reactions in 12 patients were reported; 12 of these reactions occurred on open-label cediranib, and the most common symptoms were dehydration (n=2), vomiting (n=2), and proteinuria (n=2). One probable treatment-related death (intracranial haemorrhage) occurred 41 days after starting open-label cediranib in a patient who was assigned to placebo in the masked phase. INTERPRETATION: Given the high incidence of metastatic disease and poor long-term prognosis of ASPS, together with the lack of efficacy of conventional chemotherapy, our finding of significant clinical activity with cediranib in this disease is an important step towards the goal of long-term disease control for these young patients. Future clinical trials in ASPS are also likely to involve immune checkpoint inhibitors. FUNDING: Cancer Research UK and AstraZeneca.
Asunto(s)
Antineoplásicos/uso terapéutico , Quinazolinas/uso terapéutico , Sarcoma de Parte Blanda Alveolar/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Adulto , Anciano , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Reference centers (RCs) are a key point for improving the survival of patients with soft-tissue sarcomas (STS). The aim of this study was to evaluate selected items in the management of patients with STS, comparing results between RC and local hospitals (LHs). MATERIALS AND METHODS: Diagnostic and therapeutic data from patients diagnosed between January 2004 and December 2011 were collected. Correlation with outcome was performed. RESULTS: A total of 622 sarcomas were analyzed, with a median follow-up of 40 months. Imaging of primary tumor preoperatively (yes vs. no) correlated with a higher probability of free surgical margins (77.4% versus 53.7%; p = .006). The provenance of the biopsy (RC vs. LH) significantly affected relapse-free survival (RFS; 3-year RFS 66% vs. 46%, respectively; p = .019). Likewise, 3-year RFS was significantly worse in cases with infiltrated (55.6%) or unknown (43.4%) microscopic surgical margins compared with free margins (63.6%; p < .001). Patients managed by RCs had a better 3-year overall survival compared with those managed by LHs (82% vs. 70.4%, respectively; p = .003). Perioperative chemotherapy in high-risk STS, more frequently administered in RCs than in LHs, resulted in significantly better 3-year RFS (66% vs. 44%; p = .011). In addition, patients with stage IV disease treated in RCs survived significantly longer compared with those in LHs (30.4 months vs. 18.5 months; p = .036). CONCLUSION: Our series indicate that selected quality-of-care items were accomplished better by RCs over LHs, all with significant prognostic value in patients with STS. Early referral to an RC should be mandatory if the aim is to improve the survival of patients with STS. IMPLICATIONS FOR PRACTICE: This prospective study in patients diagnosed with soft-tissue sarcoma shows the prognostic impact of reference centers in the management of these patients. The magnitude of this impact encompasses all steps of the process, from the initial management (performing diagnostic biopsy) to the advanced disease setting. This is the first prospective evidence showing improvement in outcomes of patients with metastatic disease when they are managed in centers with expertise. This study provides extra data supporting referral of patients with sarcoma to reference centers.
Asunto(s)
Instituciones Oncológicas/estadística & datos numéricos , Recurrencia Local de Neoplasia/epidemiología , Derivación y Consulta/estadística & datos numéricos , Sarcoma/cirugía , Biopsia/estadística & datos numéricos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Márgenes de Escisión , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/prevención & control , Pronóstico , Estudios Prospectivos , Sistema de Registros/estadística & datos numéricos , Sarcoma/diagnóstico , Sarcoma/mortalidad , Sarcoma/patología , España/epidemiología , Factores de TiempoRESUMEN
Background Sorafenib is a potent targeted-therapy that blockades angiogenesis and has demonstrated activity against some sarcoma subtypes. Preclinical studies suggested that treatment with sorafenib plus cytotoxic agents could result in additive efficacy. Methods Patients with advanced soft tissue sarcoma, with or without anthracycline pretreatment were included. Patients received oral sorafenib 400 mg twice daily starting on Day +2, ifosfamide 2.0 g/m2 iv infusion lasting 4 h on days 1, 2 and 3 with concurrent mesna 400 mg/m2 every three weeks until disease progression or unacceptable toxicity or up to a maximum of 6 cycles of ifosfamide (sorafenib could be continued until progressive disease or unacceptable toxicity). Primary objective was progression-free rate (PFR) at 3 and 6 months; secondary objectives were overall response rate (ORR), Progression-free survival (PFS), Overall survival (OS) and safety. This article reports the phase II part of a phase I/II clinical trial. Results Thirty-five patients were enrolled. PFR at 3 and 6 months was 66% (95% CI 48-81) and 37% (95% CI 22-55). Six patients (17%) achieved partial response and 17 (49%) stable disease. Median PFS was 4.8 months (CI 95% 1.94-6.36) and overall survival 16.2 months (95% CI 8.75-NA). Conclusion Treatment with sorafenib plus ifosfamide achieved a significant clinical benefit with an acceptable safety profile in patients with advanced soft tissue sarcoma resistant to anthracyclines, which warrants a more detailed study in randomized clinical trials.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ifosfamida/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Sarcoma/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Sorafenib/uso terapéutico , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Ifosfamida/efectos adversos , Análisis de Intención de Tratar , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Cooperación del Paciente , Inhibidores de Proteínas Quinasas/efectos adversos , Sarcoma/patología , Neoplasias de los Tejidos Blandos/patología , Sorafenib/efectos adversos , España , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Gemcitabine plus sirolimus enhances apoptosis in vitro and increases anti-tumor efficacy in vivo in soft-tissue sarcoma (STS) models. OBJECTIVE: The objective of this study was to evaluate the activity and toxicity of the combination of gemcitabine plus sirolimus in patients with STS after failure of standard chemotherapy. PATIENTS AND METHODS: Advanced STS patients, previously treated with doxorubicin and/or ifosfamide, were included in this single-arm phase II study. Patients received gemcitabine 800 mg/m2 intravenously (iv) at 10 mg/m2/min on days 1 and 8 every 3 weeks plus sirolimus 5 mg daily orally (po). After enrolment of the first 12 patients, the study protocol was amended due to toxicity and the starting dose of sirolimus was reduced to 3 mg daily po. Archival tumor samples were analyzed for extracellular signal-regulated kinase 1 and 2 (ERK1/2) expression and correlated with outcome. The primary endpoint was progression-free rate (PFR) at 3 months. RESULTS: From May 2012 to May 2013, 28 patients were enrolled at eight centers. PFR at 3 and 6 months was 44% and 20%, respectively, with 12 patients being free of progression at 3 months. Median progression-free survival (PFS) was 1.85 months (95% confidence interval [CI] 0.73-2.97) and median overall survival (OS) was 9.2 months (95% CI 5.8-12.5). No responses were observed. The most common grade 3-4 hematologic toxicities were neutropenia (48%) and leukopenia (41%) and the most frequent grade 3 non-hematologic toxicities were infection (18.5%), transaminitis (15%), fatigue (11%), and pneumonitis (11%). ERK1/2 expression was significantly correlated with PFS (p = 0.026). CONCLUSIONS: The combination of gemcitabine and sirolimus is an active treatment in STS. Further investigation is warranted. ClinicalTrials.gov identifier: NCT01684449.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Desoxicitidina/análogos & derivados , Sarcoma/tratamiento farmacológico , Sirolimus/uso terapéutico , Adulto , Anciano , Antimetabolitos Antineoplásicos/farmacología , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Femenino , Hispánicos o Latinos , Humanos , Masculino , Persona de Mediana Edad , Proyectos de Investigación , Sarcoma/patología , Sirolimus/farmacología , Adulto Joven , GemcitabinaRESUMEN
Gastrointestinal stromal sarcomas (GISTs) are the most common mesenchymal tumours originating in the digestive tract. They have a characteristic morphology, are generally positive for CD117 (c-kit) and are primarily caused by activating mutations in the KIT or PDGFRA genes(1). On rare occasions, they occur in extravisceral locations such as the omentum, mesentery, pelvis and retroperitoneum. GISTs have become a model of multidisciplinary work in oncology: the participation of several specialties (oncologists, pathologists, surgeons, molecular biologists, radiologists ) has forested advances in the understanding of this tumour and the consolidation of a targeted therapy, imatinib, as the first effective molecular treatment in solid tumours. Following its introduction, median survival of patients with advanced or metastatic GIST increased from 18 to more than 60months. Sunitinib and Regorafenib are two targeted agents with worldwide approval for second- and third-line treatment, respectively, in metastatic GIST.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Gastrointestinales/terapia , Tumores del Estroma Gastrointestinal/terapia , Proteínas Proto-Oncogénicas c-kit/genética , Terapia Combinada , Neoplasias Gastrointestinales/diagnóstico , Neoplasias Gastrointestinales/patología , Neoplasias Gastrointestinales/cirugía , Tumores del Estroma Gastrointestinal/diagnóstico , Tumores del Estroma Gastrointestinal/secundario , Tumores del Estroma Gastrointestinal/cirugía , Humanos , Mesilato de Imatinib/uso terapéutico , Indoles/uso terapéutico , Terapia Molecular Dirigida , Compuestos de Fenilurea/uso terapéutico , Piridinas/uso terapéutico , Pirroles/uso terapéutico , SunitinibRESUMEN
PURPOSE: Doxorubicin and trabectedin are considered active drugs in soft tissue sarcoma (STS). The combination of both drugs was hypothesized to be advantageous and safe on the basis of preclinical evidence and a previous phase I trial, respectively. The aim of this study was to compare the clinical outcome of trabectedin plus doxorubicin with doxorubicin as first-line treatment of advanced STS patients. PATIENTS AND METHODS: In this open-label randomized phase II trial, the main end point was progression-free survival (PFS). Trabectedin 1.1 mg/m(2) in a 3-hour infusion plus doxorubicin 60 mg/m(2) as the experimental arm and doxorubicin 75 mg/m(2) as the control arm were administered for up to six cycles. Translational research was planned to correlate the expression of apoptotic and DNA repair genes with clinical outcome. RESULTS: In 115 randomly assigned patients, the median PFS was 5.5 months in the control arm and 5.7 months in the experimental arm (hazard ratio, 1.16; 95% CI, 0.79 to 1.71; P = .45) in the intent-to-treat analysis. The trial was stopped for futility after the interim analysis, because the results in the experimental arm showed the risk reduction for the main end point to be < 9.64%. The proportion of patients with grade 3 or 4 thrombocytopenia, asthenia, and liver toxicity was significantly higher in the experimental arm. FAS and p53 were shown to be prognostic factors for PFS (7.0 months if FAS+ and p53-; 3.4 months if FAS+/p53+ or FAS-/p53-; and 0.7 months if FAS- and p53+; P < .001) and for overall survival. CONCLUSION: Trabectedin plus doxorubicin did not show superiority over doxorubicin alone as first-line treatment of advanced STS. The prognostic role of apoptotic key genes, FAS and p53, was shown to be robust enough to continue this research line.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dioxoles/administración & dosificación , Doxorrubicina/uso terapéutico , Sarcoma/tratamiento farmacológico , Tetrahidroisoquinolinas/administración & dosificación , Adolescente , Adulto , Anciano , Reparación del ADN , Dioxoles/efectos adversos , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Sarcoma/mortalidad , Tetrahidroisoquinolinas/efectos adversos , Trabectedina , Proteína p53 Supresora de Tumor/análisis , Receptor fas/análisisRESUMEN
STUDY DESIGN: Case report. OBJECTIVE: We present a case of isolated primary epidural lumbar Ewing sarcoma and review the current literature on the standard management. We also propose laminoplasty as safe procedure in this patient population that can provide good stabilization in young people. SUMMARY OF BACKGROUND DATA: Primary epidural Ewing's sarcoma is a very rare entity. The best generally accepted treatment option in sarcomas is to achieve a gross total resection with safe margins followed by local radiotherapy and chemotherapy. A total resection with safe margins is a great challenge in neurosurgical patients. METHODS: We present a previously healthy 17-year-old girl who complained of right sciatica with an epidural lumbar mass at L3-L4. She underwent complete resection of the tumor and a laminoplasty, which, in our experience, is a good way to preserve stability. RESULTS: At surgery, an isolated and noninvasive lesion was identified. Histopathological confirmation of Ewing sarcoma was obtained by immunohistochemical study and EWSR1 gene rearrangement detection. Treatment with 6 months of chemotherapy resulted in no further identifiable lesions by PET and MRI imaging at 4 years postsurgery. The laminoplasty has remained stable. CONCLUSION: Primary epidural Ewing sarcoma is extremely rare. The detection of the EWSR1 gene rearrangement can help to diagnose these tumors. The decision on how to treat these patients is difficult and can hardly be based on data from the current literature because of the small number of patients. The laminoplasty procedure can be safely performed in the setting of sarcoma of the epidural space.
Asunto(s)
Neoplasias Epidurales , Región Lumbosacra , Sarcoma de Ewing , Adolescente , Proteínas de Unión a Calmodulina/genética , Neoplasias Epidurales/diagnóstico por imagen , Neoplasias Epidurales/patología , Neoplasias Epidurales/cirugía , Femenino , Humanos , Laminoplastia , Región Lumbosacra/diagnóstico por imagen , Región Lumbosacra/patología , Región Lumbosacra/cirugía , Proteína EWS de Unión a ARN , Proteínas de Unión al ARN/genética , Sarcoma de Ewing/diagnóstico por imagen , Sarcoma de Ewing/patología , Sarcoma de Ewing/cirugíaRESUMEN
Soft tissue sarcomas (STS) constitute an uncommon and heterogeneous group of tumours, which require a complex and specialized multidisciplinary management. The diagnostic approach should include imaging studies and core needle biopsy performed prior to undertaking surgery. Wide excision is the mainstay of treatment for localized sarcoma, and associated preoperative or postoperative radiotherapy should be administered in high-risk patients. Adjuvant chemotherapy was associated with a modest improvement in survival in a meta-analysis and constitutes a standard option in selected patients with high-risk STS. In metastatic patients, surgery must be evaluated in selected cases. In the rest of patients, chemotherapy and, in some subtypes, targeted therapy often used in a sequential strategy constitutes the treatment of election. Despite important advances in the understanding of the pathophysiology of the disease, the advances achieved in therapeutic results may be deemed still insufficient. Moreover, due to the rarity and complexity of the disease, the results in clinical practice are not always optimal. For this reason, the Spanish Group for Research on Sarcoma (GEIS) has developed a multidisciplinary clinical practice guidelines document, with the aim of facilitating the diagnosis and treatment of these patients in Spain. In the document, each practical recommendation is accompanied by level of evidence and grade of recommendation on the basis of the available data.
Asunto(s)
Sarcoma/terapia , Neoplasias de los Tejidos Blandos/terapia , Antineoplásicos/uso terapéutico , Quimioterapia Adyuvante/métodos , Humanos , Sarcoma/diagnóstico , Sarcoma/patología , Neoplasias de los Tejidos Blandos/diagnóstico , Neoplasias de los Tejidos Blandos/patología , EspañaRESUMEN
Breast cancer patients suffer impairment in cardiorespiratory fitness after treatment for primary disease, affecting patients' health and survival. The aim of this study was to evaluate the ability of a pragmatic exercise intervention to improve cardiorespiratory fitness of breast cancer patients after primary treatment. Between February 2013 and December 2014, 94 women with early stage (I-III) breast cancer, 1-36 months post-chemotherapy, and radiotherapy were randomly assigned to an intervention program (EX) combining supervised aerobic and resistance exercise (n = 44) or usual care (CON) (n = 45) for 12 weeks. Primary study endpoint was VO2max. Secondary endpoints were muscle strength, shoulder range of motion, body composition, and quality of life (QoL). Assessments were undertaken at baseline, 12-week, and 6-month follow-ups. Eighty-nine patients aged 29-69 years were assessed at baseline and 12 weeks. The EX group showed significant improvements in VO2max, muscle strength, percent fat, and lean mass (p ≤ 0.001 in all cases) and QoL compared with usual care (CON). Apart from body composition, improvements were maintained for the EX at 6-month follow-up. There were no adverse events during the testing or exercise intervention program. A combined exercise intervention produced considerable improvement in cardiorespiratory fitness, physical function, and quality of life in breast cancer patients previously treated with chemotherapy and radiation therapy. Importantly, most of these benefits were maintained 6 months after ceasing the supervised exercise intervention.
Asunto(s)
Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/terapia , Terapia por Ejercicio , Consumo de Oxígeno , Calidad de Vida , Adulto , Biomarcadores de Tumor , Composición Corporal , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Terapia Combinada , Ejercicio Físico , Terapia por Ejercicio/métodos , Femenino , Humanos , Persona de Mediana Edad , Fuerza Muscular , Estadificación de Neoplasias , Cooperación del Paciente , Rango del Movimiento Articular , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal soft tissue sarcoma of the gastrointestinal tract. Correct diagnosis with thorough use of pathologic and molecular tools of GIST mutations has been of the foremost importance. GIST are usually (95 %) KIT positive and harbor frequent KIT or platelet-derived growth factor receptor α-activating mutations. This deep molecular understanding has allowed the correct classification into risk groups with implications regarding prognosis, essential use in the development of targeted therapies and even response prediction to this drugs. Treatment has been evolving and an update to include lessons learned from recent trials in advanced disease as well as controversies in the adjuvant setting that are changing daily practice, is reviewed here. An effort from the Spanish Group for Sarcoma Research with investigators from the group has been undertaken to launch this third version of the GIST guidelines and provide a practical means for the different disciplines that treat this complex disease.
Asunto(s)
Neoplasias Gastrointestinales/diagnóstico , Tumores del Estroma Gastrointestinal/diagnóstico , Guías de Práctica Clínica como Asunto , Sarcoma/diagnóstico , Supervivencia sin Enfermedad , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/genética , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/genética , Humanos , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Sarcoma/tratamiento farmacológico , Sarcoma/genéticaRESUMEN
BACKGROUND: Physical activity has been demonstrated to increase survival in breast cancer patients, but few breast cancer patients meet the general recommendations for physical activity. The aim of this pilot study was to investigate if a supervised integrated counseling and group-based exercise program could increase leisure-time activity in women with breast cancer. METHODS: This pilot project, designed as a single-arm study with pre-post testing, consisted of 24 classes of combined aerobic and strength exercise training as well as classes on dietary and health behavior. A total of 48 women with breast cancer who were undergoing or had recently completed anticancer treatment completed the study. Leisure-time physical activity, grip strength, functional capacity, quality of life (QoL), and depression were assessed at baseline, after intervention, and at the 12-week follow-up after intervention. RESULTS: The breast cancer patients increased their leisure-time physical activity (P = .004), global strength (P = .004), functional capacity (P = .001), and QoL (P = .009), and their depression score (P = .004) significantly decreased. These improvements were independent of whether the patients were in ongoing therapy or had completed their treatment. CONCLUSION: This integrated intervention may produce lifestyle changes in breast cancer patients and survivors using the teachable moment to increase their leisure-time physical activity and, thereby, their QoL.
Asunto(s)
Neoplasias de la Mama/terapia , Terapia por Ejercicio/métodos , Actividades Recreativas , Estilo de Vida , Adulto , Neoplasias de la Mama/patología , Consejo/métodos , Depresión/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Actividad Motora/fisiología , Fuerza Muscular/fisiología , Proyectos Piloto , Calidad de Vida , Entrenamiento de Fuerza/métodosRESUMEN
Patients with localized high-risk soft tissue sarcomas (STS) of the limbs and trunk wall still have a considerable metastatic recurrence rate of more than 50%, in spite of adjuvant chemotherapy. This drug-ceiling effect of chemotherapy in sarcoma setting could be explained, at least partially, by multidrug resistance (MDR) mechanisms. The aim of this study was to ascertain whether mRNA and protein expression of ABCB1 (P-glycoprotein), ABCC1 (MRP1), and GSTA1 (glutathione S-transferase pi) was prognostic in localized high-risk STS. Immunohistochemistry and reverse transcriptase-PCR studies were performed from biopsies at the time of diagnosis. Patients of this series were prospectively enrolled into a phase III trial that compared three versus five cycles of epirubicin plus ifosfamide. The series of 102 patients found 41 events of recurrence and 37 of death with a median follow-up of 68 months. In univariate analysis, variables with a statistically significant relationship with relapse-free survival (RFS) were: MRP1 expression (5-year RFS rate of 23% in positive cases and 63% in negative cases, P = 0.029), histology (5-year RFS rate of 74% in undifferentiated pleomorphic sarcoma and 43% in synovial sarcoma, P = 0.028), and ABCC1 expression (5-year RFS rate of 33% in overexpression and 65% in downregulation, P = 0.012). Combined ABCC1/MRP1 was the only independent prognostic factor for both RFS (HR = 2.704, P = 0.005) and overall survival (HR = 2.208, P = 0.029). ABCC1/MRP1 expression shows robust prognostic relevance in patients with localized high-risk STS treated with anthracycline-based chemotherapy, which is the standard front line treatment in STS. This finding deserves attention as it points to a new targetable protein in STS.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/biosíntesis , Glutatión Transferasa/biosíntesis , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/biosíntesis , Recurrencia Local de Neoplasia/genética , Sarcoma/genética , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Anciano , Antraciclinas/administración & dosificación , Supervivencia sin Enfermedad , Resistencia a Múltiples Medicamentos/genética , Extremidades/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Glutatión Transferasa/genética , Humanos , Masculino , Persona de Mediana Edad , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Pronóstico , Sarcoma/tratamiento farmacológico , Sarcoma/mortalidad , Sarcoma/patologíaAsunto(s)
Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/cirugía , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/cirugía , Recurrencia Local de Neoplasia/prevención & control , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Benzamidas , Quimioterapia Adyuvante , Neoplasias Gastrointestinales/genética , Neoplasias Gastrointestinales/patología , Tumores del Estroma Gastrointestinal/genética , Tumores del Estroma Gastrointestinal/patología , Humanos , Mesilato de Imatinib , Complicaciones Intraoperatorias , Índice Mitótico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Piperazinas/administración & dosificación , Piperazinas/uso terapéutico , Pirimidinas/administración & dosificación , Pirimidinas/uso terapéutico , Riesgo , Rotura EspontáneaRESUMEN
The association between cancer and thrombosis is well established. Venous thromboembolism (VTE) is considered a main cause of mortality and morbidity in cancer patients and is commonly underestimated by oncologists. In recent years the incidence rates of VTE have notably increased. Several studies have clearly shown that cancer patients who are diagnosed with VTE present a poorer prognosis. The Spanish Society of Medical Oncology (SEOM) presents the guidelines for thrombosis and cancer in order to improve the prevention and management of VTE.
Asunto(s)
Oncología Médica/métodos , Neoplasias/terapia , Trombosis/terapia , Anticoagulantes/uso terapéutico , Cateterismo Venoso Central , Humanos , Neoplasias/complicaciones , Recurrencia , Factores de Riesgo , Sociedades Médicas , Trombosis/complicaciones , Trombosis/diagnóstico , Factores de Tiempo , Resultado del TratamientoRESUMEN
PURPOSE: To assess the activity and toxicity of the combination of gemcitabine plus dacarbazine (DTIC) in patients with advanced soft tissue sarcoma (STS) in a randomized, multicenter, phase II study using DTIC alone as a control arm. PATIENTS AND METHODS: Patients with previously treated advanced STS were randomly assigned to receive either fixed-dose rate gemcitabine (10 mg/m2/min) at 1800 mg/m2 followed by DTIC at 500 mg/m2 every 2 weeks, or DTIC alone at 1200 mg/m2 every 3 weeks. The primary end point of the study was progression-free rate (PFR) at 3 months. RESULTS: From November 2005 to September 2008, 113 patients were included. PFR at 3 months was 56% for gemcitabine plus DTIC versus 37% for DTIC alone (P = .001). Median progression-free survival was 4.2 months versus 2 months (hazard ratio [HR], 0.58; 95% CI, 0.39 to 0.86; P = .005), and median overall survival was 16.8 months versus 8.2 months (HR, 0.56; 95% CI, 0.36 to 0.90; P = .014); both favored the arm of gemcitabine plus DTIC. Gemcitabine plus DTIC was also associated with a higher objective response or higher stable disease rate than was DTIC alone (49% v 25%; P = .009). Severe toxicities were uncommon, and treatment discontinuation for toxicity was rare. Granulocytopenia was the more common serious adverse event, but febrile neutropenia was uncommon. Asthenia, emesis, and stomatitis were the most frequent nonhematologic effects. CONCLUSION: The combination of gemcitabine and DTIC is active and well tolerated in patients with STS, providing in this phase II randomized trial superior progression-free survival and overall survival than DTIC alone. This regimen constitutes a valuable therapeutic alternative for these patients.
Asunto(s)
Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dacarbazina/uso terapéutico , Sarcoma/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Adolescente , Adulto , Anciano , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Dacarbazina/administración & dosificación , Dacarbazina/efectos adversos , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Hematológicas/inducido químicamente , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Terapia Recuperativa , Sarcoma/patología , Neoplasias de los Tejidos Blandos/patología , España , Resultado del Tratamiento , Adulto Joven , GemcitabinaRESUMEN
Los sarcomas de partes blandas (SPB) son un grupo heterogéneo de tumores poco frecuentes constituidos por una amplia variedad de subtipos histológicos que requieren un tratamiento multidisciplinario, con frecuencia especializado y complejo. A pesar de los avances obtenidos en el conocimiento de la fisiopatologý´a de la enfermedad, en Espana no hay unas recomendaciones multidisciplinarias de consenso acerca del diagnóstico y el tratamiento de los SPB. El objetivo de estas guý´as es proporcionar unas recomendaciones terapéuticas prácticas que puedan contribuir a mejorar los resultados terapéuticos en esta enfermedad en nuestro medio. Con este propósito, el Grupo Español de Investigación de Sarcomas (GEIS) celebro una reunión con un grupo multidisciplinario de expertos en el estudio y el tratamiento de los sarcomas. El resultado de esta reunión se recoge en este documento, en el cual se incluyen recomendaciones acerca del diagnóstico, el tratamiento y el seguimiento de los sarcomas de partes blandas. En definitiva, lo que se pretende con estas guías es facilitar la identificacio´n y elmanejo terapéutico de SPB en la práctica clínica en España (AU)
Soft tissue sarcomas (STS) constitute a rare heterogeneous group of tumours that include a wide variety of histological subtypes, which require a multidisciplinary and, frequently specialized and complex management. Despite advances in our understanding of the pathophysiology of the disease, there are no consensus multidisciplinary recommendations about its diagnosis and treatment in our country. The objective of these guidelines is to provide practical therapeutic recommendations that may contribute to improve the therapeutic results of this disease in our environment. With this purpose, the Spanish Group for Research in Sarcomas (GEIS) held a meeting with a multidisciplinary group of experts for the study and management of sarcomas. The results of this meeting are compiled in this document, in which recommendations on diagnosis, treatment and monitoring of soft tissue sarcomas are included. In summary, these guidelines aim to facilitate the identification and management of STS for clinical practice in Spain (AU)
Asunto(s)
Humanos , Sarcoma/diagnóstico , Neoplasias de los Tejidos Blandos/diagnóstico , Guías como Asunto , Sarcoma/terapia , Neoplasias de los Tejidos Blandos/terapiaRESUMEN
Soft tissue sarcomas (STS) constitute a rare heterogeneous group of tumours that include a wide variety of histological subtypes, which require a multidisciplinary and, frequently specialized and complex management. Despite advances in our understanding of the pathophysiology of the disease, there are no consensus multidisciplinary recommendations about its diagnosis and treatment in our country. The objective of these guidelines is to provide practical therapeutic recommendations that may contribute to improve the therapeutic results of this disease in our environment. With this purpose, the Spanish Group for Research in Sarcomas (GEIS) held a meeting with a multidisciplinary group of experts for the study and management of sarcomas. The results of this meeting are compiled in this document, in which recommendations on diagnosis, treatment and monitoring of soft tissue sarcomas are included. In summary, these guidelines aim to facilitate the identification and management of STS for clinical practice in Spain.
Asunto(s)
Sarcoma/diagnóstico , Sarcoma/terapia , Neoplasias de los Tejidos Blandos/diagnóstico , Neoplasias de los Tejidos Blandos/terapia , Humanos , Sarcoma/secundarioRESUMEN
BACKGROUND: In KIT-expressing Ewing sarcoma cell lines, the addition of doxorubicin to imatinib increases apoptosis, compared with imatinib or doxorubicin alone. On the basis of these in vitro data, the authors conducted a phase 1-2 trial of doxorubicin with imatinib in patients with gastrointestinal sarcoma tumors refractory to high-dose imatinib therapy. METHODS: Patients with metastatic gastrointestinal sarcoma tumor resistant to imatinib at 400 mg by mouth (p.o.) twice a day were eligible for this multicenter study, and received imatinib (400 mg p.o. every day [q.d.]) concomitantly with doxorubicin 15-20 mg/m2/weekly for 4 cycles (monthly cycles), followed by imatinib (400 mg p.o. q.d.) maintenance in nonprogressive patients. Spiral computed tomography and positron emission tomography with F18-fluorodeoxyglucose were done basally and after 2 months of therapy to evaluate response. An in vitro study assessed the effect of combining imatinib and doxorubicin. RESULTS: Twenty-six patients with progressive gastrointestinal sarcoma tumor were entered in the study. Treatment was well tolerated. Three (14%) of 22 evaluable patients had partial responses per Response Evaluation Criteria in Solid Tumors, and 8 (36%) had clinical benefit (partial response or stable disease for >or=6 months). Median progression-free survival (PFS) was 100 days (95% confidence interval [CI], 62-138), and median survival was 390 days (95% CI, 264-516). Interestingly, PFS was 211 days (95% CI, 52-370) in patients with wild type (WT) KIT and 82 days (95% CI, 53-111) in non-WT patients (10 mutant, 6 not assessed). A synergistic effect on cell line proliferation and apoptosis was found with imatinib and doxorubicin combination. CONCLUSIONS: Low-dose chemobiotherapy combination showed promising activity in heavily pretreated gastrointestinal sarcoma tumor patients, especially in those with WT-KIT genotype.