RESUMEN
BACKGROUND: Masitinib is a highly selective tyrosine kinase inhibitor with activity against the main oncogenic drivers of gastrointestinal stromal tumor (GIST). Masitinib was evaluated in patients with advanced GIST after imatinib failure or intolerance. PATIENTS AND METHODS: Prospective, multicenter, randomized, open-label trial. Patients with inoperable, advanced imatinib-resistant GIST were randomized (1 : 1) to receive masitinib (12 mg/kg/day) or sunitinib (50 mg/day 4-weeks-on/2-weeks-off) until progression, intolerance, or refusal. Primary efficacy analysis was noncomparative, testing whether masitinib attained a median progression-free survival (PFS) (blind centrally reviewed RECIST) threshold of >3 months according to the lower bound of the 90% unilateral confidence interval (CI). Secondary analyses on overall survival (OS) and PFS were comparative with results presented according to a two-sided 95% CI. RESULTS: Forty-four patients were randomized to receive masitinib (n = 23) or sunitinib (n = 21). Median follow-up was 14 months. Patients receiving masitinib experienced less toxicity than those receiving sunitinib, with significantly lower occurrence of severe adverse events (52% versus 91%, respectively, P = 0.008). Median PFS (central RECIST) for the noncomparative primary analysis in the masitinib treatment arm was 3.71 months (90% CI 3.65). Secondary analyses showed that median OS was significantly longer for patients receiving masitinib followed by post-progression addition of sunitinib when compared against patients treated directly with sunitinib in second-line [hazard ratio (HR) = 0.27, 95% CI 0.09-0.85, P = 0.016]. This improvement was sustainable as evidenced by 26-month follow-up OS data (HR = 0.40, 95% CI 0.16-0.96, P = 0.033); an additional 12.4 months survival advantage being reported for the masitinib treatment arm. Risk of progression while under treatment with masitinib was in the same range as for sunitinib (HR = 1.1, 95% CI 0.6-2.2, P = 0.833). CONCLUSIONS: Primary efficacy analysis ensured the masitinib treatment arm could satisfy a prespecified PFS threshold. Secondary efficacy analysis showed that masitinib followed by the standard of care generated a statistically significant survival benefit over standard of care. Encouraging median OS and safety data from this well-controlled and appropriately designed randomized trial indicate a positive benefit-risk ratio. Further development of masitinib in imatinib-resistant/intolerant patients with advanced GIST is warranted.
Asunto(s)
Antineoplásicos/uso terapéutico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/mortalidad , Inhibidores de Proteínas Quinasas/uso terapéutico , Tiazoles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Benzamidas/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Humanos , Mesilato de Imatinib , Indoles/efectos adversos , Indoles/uso terapéutico , Masculino , Persona de Mediana Edad , Piperazinas/uso terapéutico , Piperidinas , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Proto-Oncogénicas c-kit/biosíntesis , Piridinas , Pirimidinas/uso terapéutico , Pirroles/efectos adversos , Pirroles/uso terapéutico , Sunitinib , Tiazoles/efectos adversos , Insuficiencia del TratamientoRESUMEN
BACKGROUND: Soft tissue sarcomas (STS) are rare tumours for which treatment options are limited in the advanced setting. Histone deacetylase inhibitors have shown activity in preclinical models of STS. METHODS: We conducted a single-arm, open-label, multicentre phase II study to assess the efficacy and tolerability of panobinostat given orally, 40 mg thrice weekly in patients with advanced pretreated STS. The primary endpoint was the 3-month progression-free rate. RESULTS: Forty-seven STS patients were enrolled between January 2010 and December 2010. Median age was 59 (range 21-79) years, 22 (47%) patients were males. Panobinostat dose was lowered to 20 mg thrice weekly after nine patients were enrolled, based on the recommendation of an independent safety committee. The most common grade 3/4 adverse events were thrombocytopenia, fatigue, lymphopenia and anaemia. Forty-five patients were evaluable for the primary endpoint. Among them, nine patients (20%, 95% CI (10-35%)) were progression-free at 3 months. No partial response was seen, but 17 patients (36%) had stable disease (SD) as their best response. Six patients were progression-free at 6 months. CONCLUSION: Panobinostat was poorly tolerated at 40 mg thrice a week. Efficacy in unselected advanced STS was limited, although some patients had prolonged SD.
Asunto(s)
Antineoplásicos/uso terapéutico , Ácidos Hidroxámicos/uso terapéutico , Indoles/uso terapéutico , Sarcoma/tratamiento farmacológico , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Leiomiosarcoma/tratamiento farmacológico , Leiomiosarcoma/patología , Liposarcoma/tratamiento farmacológico , Liposarcoma/patología , Liposarcoma Mixoide/tratamiento farmacológico , Liposarcoma Mixoide/patología , Masculino , Persona de Mediana Edad , Neoplasias de la Vaina del Nervio/tratamiento farmacológico , Neoplasias de la Vaina del Nervio/patología , Panobinostat , Terapia Recuperativa/métodos , Sarcoma/patología , Sarcoma de Parte Blanda Alveolar/tratamiento farmacológico , Sarcoma de Parte Blanda Alveolar/patología , Sarcoma Estromático Endometrial/tratamiento farmacológico , Sarcoma Estromático Endometrial/patología , Sarcoma Sinovial/tratamiento farmacológico , Sarcoma Sinovial/patología , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: As most patients with retroperitoneal sarcomas (RPS) die of local recurrence, front-line aggressive surgery (FAS) has been developed, and it seems to achieve better local control. The aim of this study was to evaluate conformal postoperative radiotherapy (PORT) in patients who had enlarged surgery. PATIENTS AND METHODS: Between 1994 and 2008, 110 patients with primary RPS mainly operated by FAS were analysed. Sixty-two patients underwent surgery and no PORT (group S), and 48 received surgery and PORT (group S + R). The median age was 52. Most patients had 3D conformal PORT (81%) with a median dose of 50 Gy. RESULTS: Comparing results at 5 years in the S and the S + R group, the cumulative rate of local failure was, respectively, 36% and 22% (NS); relapse-free survival was 47% and 60% (P = 0.02), and overall survival was, respectively, 77% and 71% (NS). CONCLUSION: Even if patients with adjuvant PORT were at higher risk of recurrence, there was a trend for radiotherapy (RT) to decrease the local relapse rate and improve recurrence-free survival. This study confirms that adjuvant conformal RT should be evaluated in a randomized trial, the control arm being FAS. Adjuvant RT in the preoperative setting is being evaluated in an EORTC trial.
Asunto(s)
Recurrencia Local de Neoplasia/prevención & control , Neoplasias Retroperitoneales/radioterapia , Sarcoma/radioterapia , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Recurrencia Local de Neoplasia/diagnóstico por imagen , Recurrencia Local de Neoplasia/mortalidad , Modelos de Riesgos Proporcionales , Radiografía , Radioterapia Adyuvante , Neoplasias Retroperitoneales/mortalidad , Neoplasias Retroperitoneales/cirugía , Estudios Retrospectivos , Sarcoma/mortalidad , Sarcoma/cirugía , Adulto JovenRESUMEN
BACKGROUND: Pre-clinical data have suggested a therapeutic role of Hedgehog (Hh) pathway inhibitors in chondrosarcoma. METHODS: This phase II trial included patients with progressive advanced chondrosarcoma. They received GDC-0449 150 mg/day (days 1-28, 28-day cycle). The primary end point was the 6-month clinical benefit rate (CBR) defined as the proportion of patients with non-progressive disease at 6 months. A 6-month CBR of 40% was considered as a reasonable objective to claim drug efficacy. RESULTS: Between February 2011 and February 2012, 45 patients were included. Twenty had received prior chemotherapy. Thirty-nine were assessable for efficacy. The 6-month CBR was 25.6% (95% confidence interval 13.0-42.1). All stable patients had grade 1 or 2 conventional chondrosarcoma with documented progression within the 6 months before inclusion. All but one with available data also had overexpression of the Hh ligand. Median progression-free and overall survivals were 3.5 and 12.4 months, respectively. The most frequent adverse events were grade 1 or 2 myalgia, dysgeusia and alopecia. CONCLUSIONS: GDC-0449 did not meet the primary end point of this trial. Results suggest some activity in a subset of patients with progressive grade 1 or 2 conventional chondrosarcoma. Further studies assessing its role in combination with chemotherapy are warranted. CLINICALTRIALSGOV IDENTIFIER: NCT01267955.
Asunto(s)
Anilidas/administración & dosificación , Condrosarcoma/tratamiento farmacológico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Proteínas Hedgehog/biosíntesis , Piridinas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Condrosarcoma/genética , Condrosarcoma/patología , Supervivencia sin Enfermedad , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/clasificación , Femenino , Francia , Regulación Neoplásica de la Expresión Génica , Proteínas Hedgehog/genética , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: We previously demonstrated that interruption of imatinib mesylate (IM) in responding patients (pts) with advanced gastrointestinal stromal tumours (GISTs) results in rapid reprogression. The impact of interruption on residual tumour, quality of response and secondary resistance has not been fully investigated. PATIENTS AND METHODS: Within the BRF14 study, 71 non-progressing patients were randomly assigned in the interruption arms after 1, 3 or 5 years. IM was resumed in the case of progressive disease (PD). Tumour status at randomisation, relapse and after IM rechallenge, progression-free survival (PFS) and time to secondary resistance were analysed. RESULTS: At data cut-off, 51 of 71 patients had restarted IM following documented PD. Eighteen patients (35%) progressed on known lesions only, while 33 patients (65%) had new lesions, with concomitant progression of known lesions in 17 patients. Only 8 (42%) of complete remission (CR) patients and 12 (52%) of partial response (PR) patients at randomisation achieved a new CR and PR. Patients progressing rapidly after interruption had a poorer prognosis. Tumour status at randomisation influenced time to progression after rechallenge. CONCLUSION: In advanced GIST patients interrupting IM, quality of response upon reintroduction did not reach the tumour status observed at randomisation. Rapid progression after imatinib interruption is associated with poor PFS after reintroduction.
Asunto(s)
Benzamidas/administración & dosificación , Esquema de Medicación , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Piperazinas/administración & dosificación , Pirimidinas/administración & dosificación , Sarcoma/tratamiento farmacológico , Adulto , Anciano , Benzamidas/efectos adversos , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Tumores del Estroma Gastrointestinal/patología , Humanos , Mesilato de Imatinib , Masculino , Persona de Mediana Edad , Piperazinas/efectos adversos , Estudios Prospectivos , Pirimidinas/efectos adversos , Sarcoma/patología , Resultado del TratamientoRESUMEN
BACKGROUND: Decrease of circulating tumor cells (CTC) during treatment is an independent prognostic factor in metastatic breast cancer (MBC). We specifically evaluated the impact of CTC on brain metastasis outcome. METHODS: HER2-positive MBC with brain metastasis not previously treated with whole-brain radiotherapy received first-line combination of lapatinib and capecitabine in a phase II study. CTC were detected at baseline and day 21 (CellSearch). RESULTS: Median follow-up of the 44 analyzed patients was 21.2 months. The central nervous system objective response (CNS-OR) rate was 66%. At baseline, 20 of 41 assessable patients for CTC (49%) had ≥1 CTC (range 1-301, median 3) and 9 (22%) had ≥5 CTC. At day 21, 7 of 38 patients (18%) had ≥1 CTC (P = 0.006, versus baseline), and CTC had disappeared in 11 patients. CNS-OR rate was significantly higher in patients with no CTC at day 21 [25 of 31 (80%) versus 2 of 7 (29%), P = 0.01]. The 1-year overall survival rate was 83.9% in patients with no CTC at day 21 versus 42.9% in patients with ≥1 CTC (P = 0.02). CONCLUSIONS: This is the first report showing a correlation between CNS metastasis response, outcome and early CTC clearance under targeted treatment of HER2+ MBC. CLINICAL TRIALS NUMBER: NCT00967031.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias de la Mama/tratamiento farmacológico , Receptor ErbB-2/metabolismo , Adulto , Anciano , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/secundario , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Capecitabina , Quimioradioterapia , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Estimación de Kaplan-Meier , Lapatinib , Persona de Mediana Edad , Células Neoplásicas Circulantes/metabolismo , Pronóstico , Quinazolinas/administración & dosificación , Resultado del TratamientoRESUMEN
Aggressive fibromatosis (AF) is a monoclonal proliferative disease but does not metastasize and does not dedifferentiate to a high-grade malignancy in case of recurrence. Biopsy is usually necessary to confirm the diagnosis. A hallmark is its apparent unpredictable clinical course producing a large heterogeneity even with an indistinguishable morphology. Additional studies of the molecular determinants of desmoid behavior are needed to guide selection of the various therapeutic modalities. During the last 10 years, the treatment of AF has evolved and the role of routine, aggressive first-line treatment (radiotherapy and surgery) is now debated. If a wait-and-see policy is used at initial presentation, it is observed that >50% of patients will have relatively indolent disease. Aggressive treatments that take their indications from retrospective studies should be re-evaluated in the light of new data. The objective of this article is to propose an algorithm that commences with more conservative approaches before treatments that have associated long-term morbidity, the more aggressive therapies being reserved only for those who really need it.
Asunto(s)
Fibromatosis Agresiva/terapia , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteína de la Poliposis Adenomatosa del Colon/genética , Biopsia , Terapia Combinada , Fibromatosis Agresiva/genética , Fibromatosis Agresiva/patología , Mutación de Línea Germinal , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/radioterapia , Radioterapia Adyuvante , Estudios RetrospectivosRESUMEN
BACKGROUND: Fibromatosis comprises distinct clinical entities, including sporadic extra-abdominal fibromatosis, which have a high tendency for recurrence, even after adequate resection. There are no known molecular biomarkers of local recurrence. We searched for beta-catenin mutations in a European multicentre series of fibromatosis tumours to relate beta-catenin mutational status to disease outcome. METHODS: Direct sequencing of exon 3 beta-catenin gene was performed for 155 frozen fibromatosis tissues from all topographies. Correlation of outcome with mutation rate and type was performed on the extra-abdominal fibromatosis group (101 patients). RESULTS: Mutations of beta-catenin were detected in 83% of all cases. Among 101 extra-abdominal fibromatosis, similar mutation rates (87%) were observed, namely T41A (39.5%), S45P (9%), S45F (36.5%), and deletion (2%). None of the clinico-pathological parameters were found to be significantly associated with beta-catenin mutational status. With a median follow-up of 62 months, 51 patients relapsed. Five-year recurrence-free survival was significantly worse in beta-catenin-mutated tumours regardless of a specific genotype, compared with wild-type tumours (49 vs 75%, respectively, P=0.02). CONCLUSION: A high frequency (87%) of beta-catenin mutation hallmarks extra-abdominal fibromatosis from a large multicentric retrospective study. Moreover, wild-type beta-catenin seems to be an interesting prognostic marker that might be useful in the therapeutic management of extra-abdominal fibromatosis.
Asunto(s)
Fibroma/diagnóstico , Fibroma/genética , Mutación Missense , beta Catenina/genética , Secuencia de Bases , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Análisis Mutacional de ADN , Femenino , Fibroma/terapia , Frecuencia de los Genes , Heterocigoto , Humanos , Masculino , Técnicas de Diagnóstico Molecular , Mutación Missense/fisiología , Evaluación de Resultado en la Atención de Salud , Pronóstico , Estudios Retrospectivos , beta Catenina/fisiologíaRESUMEN
BACKGROUND: The expression levels of excision repair cross-complementation group 1 (ERCC1), replication protein A (RPA) and xeroderma pigmentosum group F (XPF) nucleotide excision repair proteins may be important in the response to platin-based therapy in lung cancer patients. It is not known whether ERCC1, RPA and XPF expression levels differ between ever smokers (ES) and never smokers (NS). PATIENTS AND METHODS: ERCC1, RPA and XPF expression levels were immunohistochemically evaluated in 125 patients with resected lung adenocarcinoma (AC) and carefully reviewed smoking status. RESULTS: ERCC1 was correlated with XPF (P = 0.001), but not with RPA (P = 0.11). In the univariate analysis, ERCC1 and XPF levels were higher in NS compared with ES (P = 0.004 and P = 0.003, respectively). In the multivariate analysis, the smoking status was predictive of the ERCC1 level [odds ratio (OR) 2.5, 95% confidence interval (CI) 1.03-6.2] after adjustment for variables linked to the smoking status, including age and the presence of bronchioloalveolar (BAC) features. The smoking status was also predictive of both RPA (OR 6.7, 95% CI 1.5-33.3) and XPF levels (OR 12.5, 95% CI 2.9-50) after adjusting for age, sex and BAC features. CONCLUSION: In patients with resected lung AC, ERCC1, RPA and XPF expression levels are higher in NS compared with ES.
Asunto(s)
Adenocarcinoma/metabolismo , Neoplasias Pulmonares/metabolismo , Fumar/efectos adversos , Adenocarcinoma/patología , Anciano , Estudios de Cohortes , Proteínas de Unión al ADN/metabolismo , Endonucleasas/metabolismo , Femenino , Humanos , Inmunohistoquímica , Modelos Logísticos , Neoplasias Pulmonares/patología , Masculino , Análisis por Micromatrices , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Proteína de Replicación A/metabolismo , Distribución por Sexo , Fumar/metabolismoRESUMEN
PURPOSE: Radiation-induced sarcoma (RIS) is a rare but serious event. Its occurrence has been discussed during the implementation of new radiation techniques and justified appropriate radioprotection requirements. New approaches targeting intrinsic radio-sensitivity have been described, such as radiation-induced CD8 T-lymphocyte apoptosis (RILA) able to predict late radio-induced toxicities. We studied the role of RILA as a predisposing factor for RIS as a late adverse event following radiation therapy (RT). PATIENTS AND METHODS: In this prospective biological study, a total of 120 patients diagnosed with RIS were matched with 240 control patients with cancer other than sarcoma, for age, sex, primary tumor location and delay after radiation. RILA was prospectively assessed from blood samples using flow cytometry. RESULTS: Three hundred and forty-seven patients were analyzed (118 RIS patients and 229 matched control patients). A majority (74%) were initially treated by RT for breast cancer. The mean RT dose was comparable with a similar mean (± standard deviation) for RIS (53.7⯱â¯16.0â¯Gy) and control patients (57.1⯱â¯15.1â¯Gy) (p =â¯.053). Median RILA values were significantly lower in RIS than in control patients with respectively 18.5% [5.5-55.7] and 22.3% [3.8-52.2] (pâ¯=â¯.0008). Thus, patients with a RILA >21.3% are less likely to develop RIS (p <â¯.0001, OR: 0.358, 95%CI [0.221-0.599]. CONCLUSION: RILA is a promising indicator to predict an individual risk of developing RIS. Our results should be followed up and compared with molecular and genomic testing in order to better identify patients at risk. A dedicated strategy could be developed to define and inform high-risk patients who require a specific approach for primary tumor treatment and long term follow-up.
Asunto(s)
Biomarcadores de Tumor/sangre , Neoplasias Inducidas por Radiación/patología , Sarcoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis , Área Bajo la Curva , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/metabolismo , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Inducidas por Radiación/inmunología , Estudios Prospectivos , Curva ROC , Sarcoma/inmunología , Adulto JovenRESUMEN
BACKGROUND: Few data are available from clinical trials for elderly patients receiving cetuximab. PATIENTS AND METHODS: The clinical data of consecutive patients aged > or =70 years given cetuximab for metastatic CRC were retrospectively captured from hospital pharmacy registries in seven centers. RESULTS: Fifty-six patients received cetuximab+/-with irinotecan. Median age was 76 years (70-84), 86% of patients were pretreated with fluoropyrimidines, irinotecan and oxaliplatin and 69.6% had documented resistance to irinotecan. Objective response rate was 21% (95% CI: 11-32%). The median progression-free survival was 4.4 months (95% CI: 3.0-5.7 months) and the median overall survival was 16.0 months (95% CI: 13.5-18.5 months). Skin rash occurred in 75% of the patients (11% grade 3) and diarrhea in 80% (20% grades 3-4). CONCLUSION: Tolerability of cetuximab was acceptable in elderly patients with pretreated metastatic CRC. Efficacy appeared similar to that observed in younger patients.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Camptotecina/análogos & derivados , Neoplasias Colorrectales/tratamiento farmacológico , Compuestos Organoplatinos/uso terapéutico , Pirimidinas/uso terapéutico , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Antineoplásicos/efectos adversos , Antineoplásicos Fitogénicos/uso terapéutico , Camptotecina/uso terapéutico , Cetuximab , Ensayos Clínicos como Asunto , Estudios de Cohortes , Neoplasias Colorrectales/patología , Esquema de Medicación , Quimioterapia Combinada , Receptores ErbB/metabolismo , Femenino , Humanos , Irinotecán , Masculino , Estudios Multicéntricos como Asunto , Metástasis de la Neoplasia/tratamiento farmacológico , Metástasis de la Neoplasia/patología , Metástasis de la Neoplasia/terapia , Oxaliplatino , Sistema de Registros , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: We hypothesized that, among molecular subclasses of breast cancer, p53 status may have a differential predictive value for the efficacy of anthracyclines/alkylating agents-based regimen. We analysed the efficacy of a preoperative combination between 5-fluorouracil, anthracyclines and cyclophosphamide according to both p53 status and molecular classification. PATIENTS AND METHODS: Oestrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) expression and p53 status were determined by immunohistochemistry in 293 samples from two different centres. A logistic regression model was used for multivariate analysis of predictors for pathological complete response (pCR). RESULTS: p53 immunostaining (54%) was associated with high grade (P = 0.002) and ER negativity (P = 0.04). p53 was detected in 59% of triple-negative tumours (ER-/PgR-/HER2-, n = 120 patients). In the overall population, pCR (9.6%) was independently predicted by high tumour grade (P = 0.002) and ER/PgR/HER2 triple negativity (P = 0.0004), but not by p53 status (P = 0.12). p53 immunostaining was associated with a trend for a higher rate of pCR in triple-negative tumours [relative risk (RR) = 2.5, 95% confidence interval (CI) = 0.8-7.5, P = 0.09], but not in non-triple-negative tumours (RR = 0.73, 95% CI = 0.16-3.3, P = 0.69). CONCLUSION: p53 status may have a different predictive value for efficacy of anthracycline/alkylating agents-based regimen in each molecular subclass, a result which may explain the different results reported in literature.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/clasificación , Neoplasias de la Mama/tratamiento farmacológico , Proteína p53 Supresora de Tumor/metabolismo , Adenocarcinoma/clasificación , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Antraciclinas/administración & dosificación , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Esquema de Medicación , Femenino , Humanos , Inmunohistoquímica , Modelos Logísticos , Persona de Mediana Edad , Análisis Multivariante , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Estudios Retrospectivos , Resultado del Tratamiento , Carga TumoralRESUMEN
PURPOSE: To analyse feasibility, prognostic factors and patterns of recurrence after concurrent reirradiation and bevacizumab for recurrent high-grade gliomas. PATIENTS AND METHODS: Between 2009 and 2015, 35 patients (median 57-year-old; 21 men, 14 women) with WHO grade III (n=11) or grade IV (n=24) gliomas were included in this retrospective and consecutive single-centre study. All patients received bevacizumab (median number of treatments: 12) concomitant with reirradiation (median dose: 45Gy, median number of fractions: 18) for recurrence with median 22 months (range: 5.6-123.7 months) from first irradiation (median dose: 60Gy). RESULTS: The median follow-up was 9.2 months from reirradiation. The median overall survival from reirradiation was 10.5 months (95% confidence interval [95% CI]: 4.9-16.1) and the progression-free survival from reirradiation was 6.7 months (95% CI: 2.9-10.5). The median overall survival from initial diagnosis was 44.6 months (95% CI: 32-57.1). No grade 3 toxicity or above was reported. Prognostic factors significantly correlated with better overall survival in univariate analysis were: age at least 55 (P=0.024), initial surgery (P=0.003), and 2Gy equivalent dose (EQD2) at least 50Gy at reirradiation (P=0.046). Twenty-two patients bevacizumab-naïve at time of reirradiation had a significantly increased overall survival from reirradiation compared to patients treated with reirradiation after bevacizumab failure (17.7 vs. 5.4 months, P<0.001) as well as overall survival from initial diagnosis (58.9 vs. 33.5 months, P=0.006). This outcome was similar in patients with initial glioblastomas (P=0.018) or anaplastic gliomas (P=0.021). There was no correlation between overall survival and gross tumour volume or planning target volume, frontal localization, or number of salvage therapies before reirradiation (P>0.05). CONCLUSIONS: Concomitant reirradiation with bevacizumab in high-grade recurrent gliomas shows encouraging results in terms of survival and toxicities. Our data suggest that reirradiation should be favoured at initiation of bevacizumab, with EQD2 at least 50Gy.
Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Bevacizumab/uso terapéutico , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/terapia , Quimioradioterapia , Glioma/mortalidad , Glioma/terapia , Reirradiación , Adulto , Factores de Edad , Anciano , Neoplasias Encefálicas/patología , Femenino , Glioma/patología , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Pronóstico , Dosificación Radioterapéutica , Estudios Retrospectivos , Adulto JovenRESUMEN
AIM: To report initial results of observation as well as surgery in patients with desmoid tumors (DTs) of the breast, a rare tumor for which data are scarce. PATIENTS AND METHODS: The initial approaches were categorized as either front-line loco-regional treatment [(surgery or radiotherapy group, SRG) n = 20] or initial observation [(no surgery/no radiotherapy group, NSRG) n = 11]. RESULTS: A total of 27 women and 4 men were assessed between 1992 and 2013 and included in this study. Patient characteristics were adequately balanced in the 2 groups. Fifteen patients (48.4%) had a past history of breast surgery in the previous 24 months. The median initial DT size on MRI was 50 mm. The median follow-up was 36 months. In the SRG, 8/20 patients (40%) experienced recurrence. The median time to recurrence was 29 months. During the study period, 6 patients in the SRG (30%) received a mastectomy at the time of diagnosis (n = 3) or at relapse (n = 3), 7 patients (35%) received a thoracic wall resection and 8 patients (40%) received radiotherapy at the time of diagnosis (n = 2) or at recurrence (n = 5). In the NSRG, the median tumor size change was -4 mm (range -13 to +20). Three patients changed treatment strategies during the observation period; one received surgery, and 2 were administered anti-hormonal treatment. CONCLUSIONS: Loco-regional treatments of breast DTs resulted in undesired disfigurement. Front-line observation yielded encouraging results and could enable the identification of patients who require loco-regional treatment. This strategy needs further evaluation.
Asunto(s)
Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/terapia , Fibromatosis Agresiva/diagnóstico , Fibromatosis Agresiva/terapia , Recurrencia Local de Neoplasia/cirugía , Espera Vigilante , Adolescente , Adulto , Anciano , Mama/cirugía , Neoplasias de la Mama/patología , Neoplasias de la Mama Masculina/diagnóstico , Neoplasias de la Mama Masculina/patología , Neoplasias de la Mama Masculina/terapia , Progresión de la Enfermedad , Femenino , Fibromatosis Agresiva/patología , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Mastectomía , Persona de Mediana Edad , Recurrencia Local de Neoplasia/radioterapia , Radioterapia , Carga Tumoral , Adulto JovenRESUMEN
BACKGROUND: To analyse the natural history of extra-abdominal wall desmoid-type fibromatosis (DF) and compare outcome in patients who underwent initial surgery with those who did not. PATIENTS AND METHODS: All consecutive patients affected by primary sporadic extra-abdominal wall DF observed between January 1992 and December 2012 were included. Patients were divided into surgical (SG) or non-surgical groups (NSG) according to initial treatment. Relapse free survival was calculated for SG, and crude cumulative incidence (CCI) of switching to surgery or other treatments for NSG. RESULTS: 216 patients were identified, 94 in SG (43%), 122 in NSG (57%). A shift towards a more systematic use of a conservative approach (78% of all comers) was observed in the latter years (2006-2012), although a small proportion of patients (28%) had been offered the conservative strategy even in the early period (1992-2005). Median follow-up (FU) was 49 mo. (interquartile (IQ), 20-89 mo.), 76 months for SG and 39 months for NSG. 5-year relapse-free survival (RFS) for SG was 80% (95% confidence interval (CI), 72-89%). For the NSG, 5-year CCI of switching to surgery was 5% (95% CI: 1.7%, 14%), and 51% to other treatments (95% CI: 41%, 65%). 27 (20%) NSG patients underwent spontaneous regression. CONCLUSION: A non-surgical approach to extra-abdominal wall DF allowed surgery to be avoided in the majority of patients. This approach can be safely proposed and surgery offered as an option in selected cases.
Asunto(s)
Fibromatosis Agresiva/patología , Fibromatosis Agresiva/cirugía , Adulto , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Evaluación de Resultado en la Atención de Salud/métodos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , PronósticoRESUMEN
AIM: To evaluate the indications and results of preoperative radiotherapy (RT) on a series of selected patients treated at our institution with curative intent for a limb sarcoma (STS). PATIENTS AND METHODS: From 05/1993 to 12/2011, 64 STS patients received preoperative RT. RESULTS: RT was delivered as a "limb salvage treatment" prior to surgery for the following reasons: as the preferential induction treatment in 53 patients (83%) or as a second intent (17%) after the failure of neoadjuvant systemic chemotherapy/isolated limb perfusion. Surgery was performed after RT in 54 (84%) patients and final limb salvage was performed in 98%. Musculo-cutaneous flap reconstruction was planned upfront in 44% patients, and 19% had a skin graft. Seven patients (13%) had a postoperative RT boost. Thirteen (20%) patients had grade (G) 3/4 adverse events, one after RT and 12 after surgery. At a median follow-up of 3.5 years, the 3-year actuarial overall survival (OS) and distant relapse (DR) rates were 83% and 31%, respectively. Two patients developed a local relapse and two a local progression (non-operated patients). In the multivariate analysis (MVA), histological subtype (leiomyosarcoma) and grade 3 were predictive of poorer survival. Patients with >3 month delay between the start of RT and surgery at our institution had an increased risk of DR in the MVA. CONCLUSION: Induction RT should be personalised according to histological subtype, tumour site and risks-benefit ratio of preoperative radiotherapy and is best managed by a multidisciplinary surgical and oncology team in a specialist sarcoma centre.
Asunto(s)
Extremidades , Recuperación del Miembro/métodos , Terapia Neoadyuvante/métodos , Sarcoma/radioterapia , Sarcoma/cirugía , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Selección de Paciente , Medicina de Precisión , Pronóstico , Dosificación Radioterapéutica , Radioterapia Adyuvante , Reoperación , Factores de Riesgo , Sarcoma/tratamiento farmacológico , Sarcoma/mortalidad , Sarcoma/patología , Adulto JovenRESUMEN
PURPOSE: To assess the acute toxicity of intensity modulated radiotherapy as post-operative adjuvant treatment for retroperitoneal sarcoma. PATIENTS AND METHODS: Patients who received adjuvant intensity modulated radiotherapy from January 2009 to September 2010 were retrospectively reviewed. RESULTS: Fourteen patients entered the study (seven primary tumours and seven relapses). All tumours were liposarcoma and had macroscopically complete resection, epiploplasty was systematically realized. Median tumour size was 21 cm (range: 15-45), median planning target volume was 580 cm(3) (range: 329-1172) and median prescribed dose was 50.4 Gy (range: 45-54). Median follow-up was 11.5 months (range: 2-21.4). Acute toxicity was mild: acute digestive toxicity grade 1-2 occurred in 12/14 patients (86%). However, there was no weight loss of more than 5% during radiotherapy and no treatment interruption was required. Two months after completion of radiotherapy, digestive toxicity grade 1 remained present in 1/14 patients (7%). One case of grade 3 toxicity occurred during follow-up (transient abdominal pain). Three relapses occurred: two were outside treaded volume and one was both in and outside treated volume. CONCLUSIONS: Intensity modulated radiotherapy in the postoperative setting of retroperitoneal sarcoma provides low acute toxicity. Longer follow-up is needed to assess late toxicity, especially for bowel, kidney and radio-induced malignancies.
Asunto(s)
Enfermedades Gastrointestinales/etiología , Liposarcoma/radioterapia , Complicaciones Posoperatorias/etiología , Traumatismos por Radiación/etiología , Radioterapia Adyuvante/efectos adversos , Radioterapia de Intensidad Modulada/efectos adversos , Neoplasias Retroperitoneales/radioterapia , Enfermedad Aguda , Adulto , Anciano , Colectomía , Terapia Combinada , Femenino , Enfermedades Gastrointestinales/epidemiología , Humanos , Intestinos/efectos de la radiación , Liposarcoma/secundario , Liposarcoma/cirugía , Hígado/efectos de la radiación , Masculino , Persona de Mediana Edad , Nefrectomía , Neuralgia/epidemiología , Neuralgia/etiología , Órganos en Riesgo , Traumatismos por Radiación/epidemiología , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador , Radioterapia Adyuvante/métodos , Neoplasias Retroperitoneales/cirugía , Estudios Retrospectivos , Estómago/efectos de la radiaciónRESUMEN
Since the discovery of the remarkable efficacy of imatinib in the metastatic GIST, several studies advanced our knowledge on the care of this pathology. In the localized GIST, the efficacy of the adjuvant treatment by imatinib was proved, but the duration, the indication and the management in case of relapse after imatinib are not still consensual. The imatinib is also used in neoadjuvant setting to optimize the quality of resection, the main treatment remaining the maximal tumor resection. In metastatic setting, imatinib remains the standard of care first-line treatment. It must be administered until progress or intolerance. Nevertheless, secondary resistance to imatinib is a substantial problem in routine clinical practice; in second line, sunitinib demonstrated its efficacy. Several inhibitors of tyrosine-kinases are ongoing evaluated in all the therapeutic lines. Clearly, a better knowledge of the molecular profile and the pharmacokinetics underlying the resistance to imatinib as well as the development of a new class of broad-spectrum tyrosine-kinase inhibitors may allow in the near future new individualized therapeutic strategies for GIST patients.
Asunto(s)
Antineoplásicos/uso terapéutico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Antineoplásicos/farmacocinética , Benzamidas , Bencenosulfonatos/uso terapéutico , Quimioterapia Adyuvante , Resistencia a Antineoplásicos , Tumores del Estroma Gastrointestinal/genética , Tumores del Estroma Gastrointestinal/patología , Tumores del Estroma Gastrointestinal/cirugía , Humanos , Mesilato de Imatinib , Indoles/uso terapéutico , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piperazinas/farmacocinética , Piperidinas , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Pirimidinas/farmacocinética , Pirroles/uso terapéutico , Sorafenib , Sunitinib , Tiazoles/uso terapéuticoRESUMEN
BACKGROUND: Recent studies suggested substantial differences between primary tumors and metastases for EGFR expression in colorectal cancer (CRC). The aim of the study was to correlate the expression of a panel of molecular markers between primary CRC samples and metastases. METHODS: Expressions of EGFR, pEGFR, VEGF, pVEGF, PTEN, pAKT and p21 were analyzed in 28 primary tumors and 32 liver metastases by immunohistochemistry performed on formalin-fixed, paraffin-embedded sections from 46 CRC patients. The molecular profiles were evaluated by tissue micro-array. The correlation between tumor and metastasis biomarker expressions was tested. RESULTS: Among 60 CRC samples, 25% were EGFR positive, 38% were pEGFR positive, 38% were VEGF positive, 48% were pVEGF positive, 70% were pAKT positive and 51% were p21 positive. PTEN was deleted in 39% of cases and absence of p21 expression was found in 49% of cases. A significant correlation was observed between primary tumors and metastases for pAKT (p = 0.037) and pEGFR (p = 0.0002) status. In patients treated with cetuximab-based therapy (n = 18), p21 appeared as a significant predictive factor of response (p = 0.036). CONCLUSION: Biomarkers status may change between primary and metastatic sites in CRC, with potential implications for the identification of patients who are likely to respond to anti-EGFR treatment.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/metabolismo , Proteínas de Neoplasias/metabolismo , Adulto , Anciano , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Antineoplásicos/uso terapéutico , Bevacizumab , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Cetuximab , Neoplasias Colorrectales/tratamiento farmacológico , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Receptores ErbB/metabolismo , Femenino , Humanos , Irinotecán , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Masculino , Persona de Mediana Edad , Fosfohidrolasa PTEN/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
This bibliographic review evaluated phase II clinical trials aimed at the identification of antitumor activity of single agents in soft tissue sarcoma (STS) after failure of standard- of-care therapy including anthracyclines and ifosfamide. A total of 63 articles (on anthracyclines, ifosfamide, trabectedin and 27 investigational agents) were included (data from 1979 to 2008).Trabectedin is the most extensively studied agent in patients with STS after failure of anthracyclines and ifosfamide (457 patients), followed by ifosfamide (412), cisplatin (144), temozolomide (137), docetaxel (114), gemcitabine (112), etoposide (95) and doxorubicin (59). Dacarbazine and the remaining investigational agents have usually been tested in 50 or fewer patients, with vastly negative results not warranting further investigation. Methodological limitations are identified in the majority of the reviewed phase II studies, including small sample size, single-institution studies, lack of independent review of the antitumor responses and inadequate description of previous therapies/agents. However, all trabectedin studies fulfilled these methodological characteristics relevant for a phase II trial. A phase II randomized trial confirmed the results of 3 prior nonrandomized studies and, therefore, trabectedin is currently considered an important new option to control advanced sarcomas in patients with STS following failure of all conventional treatments.