Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 32
Filtrar
Mais filtros

Base de dados
País/Região como assunto
Tipo de documento
País de afiliação
Intervalo de ano de publicação
1.
Int J Mol Sci ; 25(7)2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38612518

RESUMO

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, with proto-oncogene, receptor tyrosine kinase (c-kit), or PDGFRα mutations detected in around 85% of cases. GISTs without c-kit or platelet-derived growth factor receptor alpha (PDGFRα) mutations are considered wild-type (WT), and their diverse molecular alterations and biological behaviors remain uncertain. They are usually not sensitive to tyrosine kinase inhibitors (TKIs). Recently, some molecular alterations, including neurotrophic tyrosine receptor kinase (NTRK) fusions, have been reported in very few cases of WT GISTs. This novel finding opens the window for the use of tropomyosin receptor kinase (TRK) inhibitor therapy in these subtypes of GIST. Herein, we report a new case of NTRK-fused WT high-risk GIST in a female patient with a large pelvic mass (large dimension of 20 cm). The tumor was removed, and the histopathology displayed spindle-predominant morphology with focal epithelioid areas, myxoid stromal tissue, and notable lymphoid infiltration with tertiary lymphoid structures. Ten mitoses were quantified in 50 high-power fields without nuclear pleomorphism. DOG1 showed strong and diffuse positivity, and CD117 showed moderate positivity. Succinate dehydrogenase subunit B (SDHB) was retained, Pan-TRK was focal positive (nuclear pattern), and the proliferation index Ki-67 was 7%. Next-generation sequencing (NGS) detected an ETV6::NTRK3 fusion, and this finding was confirmed by fluorescence in situ hybridization (FISH), which showed NTRK3 rearrangement. In addition, an RB1 mutation was found by NGS. The follow-up CT scan revealed peritoneal nodules suggestive of peritoneal dissemination, and Entrectinib (a TRK inhibitor) was administered. After 3 months of follow-up, a new CT scan showed a complete response. Based on our results and the cases from the literature, GISTs with NTRK fusions are very uncommon so far; hence, further screening studies, including more WT GIST cases, may increase the possibility of finding additional cases. The present case may offer new insights into the potential introduction of TRK inhibitors as treatments for GISTs with NTRK fusions. Additionally, the presence of abundant lymphoid infiltration in the present case may prompt further research into immunotherapy as a possible additional therapeutic option.


Assuntos
Tumores do Estroma Gastrointestinal , Estruturas Linfoides Terciárias , Feminino , Humanos , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Hibridização in Situ Fluorescente , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Imunoterapia , Proteínas Proto-Oncogênicas c-kit , Receptores Proteína Tirosina Quinases
2.
Br J Cancer ; 126(6): 874-880, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34937947

RESUMO

BACKGROUND: Aflibercept is an antiangiogenic drug against metastatic colorectal cancer (mCRC) combined with 5-fluorouracil/leucovorin/irinotecan (FOLFIRI); however, no antiangiogenic biomarker has yet been validated. We assessed aflibercept plus FOLFIRI, investigating the biomarker role of baseline vascular endothelial growth factor A (VEGF-A) and angiotensin-converting enzyme (ACE). METHODS: Phase II trial in oxaliplatin-treated mCRC patients who received aflibercept plus FOLFIRI. The reported 135 ng/mL ACE cut-off was used and ROC analysis was performed to assess the optimal VEGF-A cut-off for progression-free survival (PFS). Overall survival (OS), time to progression (TTP), time to treatment failure (TTF), overall response rate (ORR) and disease control rate (DCR) were also assessed. RESULTS: In total, 101 patients were followed for a median of 12 (6-17) months. The 1941 pg/mL VEGF-A was an optimal cut-off, with a longer median PFS when VEGF-A was <1941 versus ≥1941 pg/mL (9 versus 4 months). Patients with VEGF-A < 1941 pg/mL showed longer median OS (19 versus 8 months), TTP (9 versus 4 months) and TTF (8 versus 4 months), along with higher ORR (26% versus 9%) and DCR (81% versus 55%). No differences were identified according to ACE levels. CONCLUSIONS: This study supports aflibercept plus FOLFIRI benefits, suggesting VEGF-A as a potential biomarker to predict better outcomes.


Assuntos
Neoplasias Colorretais , Fator A de Crescimento do Endotélio Vascular , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Camptotecina/uso terapêutico , Neoplasias Colorretais/patologia , Fluoruracila/uso terapêutico , Humanos , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/metabolismo
3.
BMC Cancer ; 20(1): 1164, 2020 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-33246428

RESUMO

BACKGROUND: Preoperative chemoradiotherapy with capecitabine is considered as a standard of care for locally advanced rectal cancer. The "Tratamiento de Tumores Digestivos" group (TTD) previously reported in a randomized Ph II study that the addition of Bevacizumab to capecitabine-RT conferred no differences in the pre-defined efficacy endpoint (pathological complete response). We present the follow-up results of progression-free survival, distant relapse-free survival, and overall survival data at 3 and 5 years. METHODS: Patients (pts) were randomized to receive 5 weeks of radiotherapy (45 Gy/25 fractions) with concurrent Capecitabine 825 mg/m2 twice daily, 5 days per week with (arm A) or without (arm b) bevacizumab (5 mg/kg once every 2 weeks). RESULTS: In our study, the addition of bevacizumab to capecitabine and radiotherapy in the neoadjuvant setting shows no differences in pathological complete response (15.9% vs 10.9%), distant relapse-free survival (81.0 vs 80.4 and 76.2% vs 78.2% at 3 and 5 years respectively), disease-free survival (75% vs 71.7 and 68.1% vs 69.57% at 3 and 5 years respectively) nor overall survival at 5-years of follow-up (81.8% vs 86.9%). CONCLUSIONS: the addition of bevacizumab to capecitabine plus radiotherapy does not confer statistically significant advantages neither in distant relapse-free survival nor in disease-free survival nor in Overall Survival in the short or long term. TRIAL REGISTRATION: EudraCT number: 2009-010192-24 . Clinicaltrials.gov number: NCT01043484 .


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/radioterapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/radioterapia , Adenocarcinoma/patologia , Bevacizumab/administração & dosagem , Capecitabina/administração & dosagem , Quimiorradioterapia , Feminino , Humanos , Masculino , Intervalo Livre de Progressão , Neoplasias Retais/patologia
4.
Br J Cancer ; 121(5): 378-383, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31363167

RESUMO

BACKGROUND: Targeted agents are standard treatment for RAS wild-type metastatic colorectal cancer in the first- and second-line settings. This phase 2 study determined the benefit of targeting the epidermal growth factor receptor (EGFR) with panitumumab plus irinotecan in irinotecan-refractory patients. METHODS: KRAS exon-2 wild-type patients failing prior irinotecan received panitumumab (6 mg/kg) and irinotecan (180 mg/m²) every 2 weeks. The primary endpoint was the overall response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). KRAS exon-2 status was evaluated centrally, along with NRAS, BRAF mutations, epiregulin, amphiregulin, PTEN and EGFR copy number status, and correlated with efficacy. RESULTS: Sixty-one patients were treated. Among the 46 wild-type RAS patients, the ORR was 15.2% (seven partial responses), with median PFS of 3.8 months (95% CI 2.7-4.3) and median OS of 12.5 months (95% CI 6.7-15.9). Wild-type BRAF patients showed a 13.0% response rate. No significant correlations between response and baseline biomarker expression were identified. Common grade 3-4 adverse events were diarrhoea and rash (18.0% each), hypomagnesaemia and asthenia (8.2% each). CONCLUSIONS: The addition of panitumumab to irinotecan as salvage therapy is feasible but has limited activity in irinotecan-refractory metastatic colorectal cancer. No biomarkers predictive of response were identified.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Terapia de Salvação , Adenocarcinoma/genética , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Anfirregulina/genética , Astenia/induzido quimicamente , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Diarreia/induzido quimicamente , Toxidermias , Epirregulina/genética , Receptores ErbB/genética , Feminino , GTP Fosfo-Hidrolases/genética , Humanos , Irinotecano/administração & dosagem , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Linfonodos/patologia , Magnésio/sangue , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/genética , Panitumumabe/administração & dosagem , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/secundário , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Taxa de Sobrevida , Resultado do Tratamento , Desequilíbrio Hidroeletrolítico/induzido quimicamente
5.
Oncologist ; 24(5): 680-687, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30126859

RESUMO

BACKGROUND: Oncogenic KIT/PDGFRA signaling inhibition with imatinib achieves disease control in most patients with advanced/metastatic gastrointestinal stromal tumor (GIST), but resistance eventually develops after 20-24 months. Notably, a small subset of these patients obtain durable benefit from imatinib therapy. METHODS: We analyzed clinical, pathological, and molecular characteristics and long-term outcomes in patients with metastatic GIST treated with continuous daily dosing of frontline imatinib in a cohort of patients benefiting for ≥5 years. A control group was obtained from the national Spanish Group for Sarcoma Research database and used as comparator. RESULTS: Sixty-four imatinib long-term responders (LTRs) and 70 control cases were identified. Compared with controls, LTRs at baseline had better performance status (PS) 0-1 (100% vs. 81%), lower mitotic count (median, 8 vs. 15), and tumor burden (number of metastases, 3 vs. 7). KIT exon 11 was the only region found mutated in LTRs. LTRs achieved 34% complete responses and a median progression-free survival of 11 years, compared with 4% and 2 years, respectively, in the control cohort. Prognostic factors that independently predicted long-term benefit with imatinib were PS, number of metastases prior to imatinib, and response to imatinib. Fifteen LTR patients developed new side effects attributable to imatinib after ≥5 years of continuous treatment. No resistance mutations were found in metastatic samples from three patients progressing on imatinib. CONCLUSION: GISTs in LTRs are a distinctive entity with less aggressive behavior and marked sensitivity to KIT inhibition. Patients reaching 5 or more years on imatinib have a higher chance of remaining progression free over time. IMPLICATIONS FOR PRACTICE: This work demonstrates that clinical and inherent tumor characteristics define a subset of patients with gastrointestinal stromal tumor (GIST) with increased likelihood to achieve durable response to first-line imatinib therapy. Patients reaching ≥5 years on imatinib have a greater chance of remaining progression free over time, although the disease is unlikely to be cured. Imatinib is well tolerated for >5 years, and emergent toxicities are overall manageable. Resistance to imatinib emerging in patients with GISTs after long-term imatinib treatment does not involve polyclonal expansion of KIT secondary mutations.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mesilato de Imatinib/uso terapêutico , Sarcoma/tratamento farmacológico , Adulto , Antineoplásicos/farmacologia , Estudos de Casos e Controles , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Neoplasias Gastrointestinais/mortalidade , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mesilato de Imatinib/farmacologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Intervalo Livre de Progressão , Sarcoma/mortalidade , Sarcoma/patologia , Fatores de Tempo
6.
BMC Cancer ; 15: 60, 2015 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-25886378

RESUMO

BACKGROUND: Perioperatory chemoradiotherapy (CRT) improves local control and survival in patients with locally advanced rectal cancer (LARC). The objective of the current study was to evaluate the addition of bevacizumab (BEV) to preoperative capecitabine (CAP)-based CRT in LARC, and to explore biomarkers for downstaging. METHODS: Patients (pts) were randomized to receive 5 weeks of radiotherapy 45 Gy/25 fractions with concurrent CAP 825 mg/m(2) twice daily 5 days per week and BEV 5 mg/kg once every 2 weeks (3 doses) (arm A), or the same schedule without BEV (arm B). The primary end point was pathologic complete response (ypCR: ypT0N0). RESULTS: Ninety pts were included in arm A (44) or arm B (46). Grade 3-4 treatment-related toxicity rates were 16% and 13%, respectively. All patients but one (arm A) proceeded to surgery. The ypCR rate was 16% in arm A and 11% in arm B (p =0.54). Fifty-nine percent vs 39% of pts achieved T-downstaging (arm A vs arm B; p =0.04). Serial samples for biomarker analyses were obtained for 50 out of 90 randomized pts (arm A/B: 22/28). Plasma angiopoietin-2 (Ang-2) levels decreased in arm A and increased in arm B (p <0.05 at all time points). Decrease in Ang-2 levels from baseline to day 57 was significantly associated with tumor downstaging (p =0.02). CONCLUSIONS: The addition of BEV to CAP-based preoperative CRT has shown to be feasible in LARC. The association between decreasing Ang-2 levels and tumor downstaging should be further validated in customized studies. TRIAL REGISTRY: Clinicaltrials.gov identifier NCT01043484. Trial registration date: 12/30/2009.


Assuntos
Bevacizumab/administração & dosagem , Capecitabina/administração & dosagem , Quimiorradioterapia Adjuvante/métodos , Neoplasias Retais/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Biomarcadores Tumorais/metabolismo , Capecitabina/efeitos adversos , Quimiorradioterapia Adjuvante/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Período Pré-Operatório , Dosagem Radioterapêutica , Resultado do Tratamento
7.
Oncologist ; 19(10): 1042-3, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25209376

RESUMO

BACKGROUND: The need for preoperative chemoradiation or short-course radiation in all T3 rectal tumors is a controversial issue. A multicenter phase II trial was undertaken to evaluate the efficacy and safety of neoadjuvant capecitabine and oxaliplatin combined with bevacizumab in patients with intermediate-risk rectal adenocarcinoma. METHODS: We recruited 46 patients with T3 rectal adenocarcinoma selected by magnetic resonance imaging (MRI) who were candidates for (R0) resection located in the middle third with clear mesorectal fascia and who were selected by pelvic MRI. Patients received four cycles of neoadjuvant capecitabine and oxaliplatin combined with bevacizumab (final cycle without bevacizumab) before total mesorectal excision (TME). In case of progression, preoperative chemoradiation was planned. The primary endpoint was overall response rate (ORR). RESULTS: On an intent-to-treat analysis, the ORR was 78% (n = 36; 95% confidence interval [CI]: 63%-89%) and no progression was detected. Pathologic complete response was observed in nine patients (20%; 95% CI: 9-33), and T downstaging was observed in 48%. Forty-four patients proceeded to TME, and all had R0 resection. During preoperative therapy, two deaths occurred as a result of pulmonary embolism and diarrhea, respectively, and one patient died after surgery as a result of peritonitis secondary to an anastomotic leak (AL). A 13% rate of AL was higher than expected. The 24-month disease-free survival rate was 75% (95% CI: 60%-85%), and the 2-year local relapse rate was 2% (95% CI: 0%-11%). CONCLUSION: In this selected population, initial chemotherapy results in promising activity, but the observed toxicity does not support further investigation of this specific regimen. Nevertheless, these early results warrant further testing of this strategy in an enriched population and in randomized trials.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Capecitabina/uso terapêutico , Imageamento por Ressonância Magnética , Compostos Organoplatínicos/uso terapêutico , Neoplasias Retais/tratamento farmacológico , Adenocarcinoma/diagnóstico , Adenocarcinoma/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Capecitabina/efeitos adversos , Humanos , Terapia Neoadjuvante , Compostos Organoplatínicos/efeitos adversos , Oxaliplatina , Neoplasias Retais/diagnóstico , Neoplasias Retais/cirurgia , Reto/cirurgia
8.
Clin Transl Oncol ; 26(4): 825-835, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37787973

RESUMO

Watch-and-wait has emerged as a new strategy for the management of rectal cancer when a complete clinical response is achieved after neoadjuvant therapy. In an attempt to standardize this new clinical approach, initiated by the Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD), and with the participation of the Spanish Association of Coloproctology (AECP), the Spanish Society of Pathology (SEAP), the Spanish Society of Gastrointestinal Endoscopy (SEED), the Spanish Society of Radiation Oncology (SEOR), and the Spanish Society of Medical Radiology (SERAM), we present herein a consensus on a watch-and-wait approach for the management of rectal cancer. We have focused on patient selection, the treatment schemes evaluated, the optimal timing for evaluating the clinical complete response, the oncologic outcomes after the implementation of this strategy, and a protocol for surveillance of these patients.


Assuntos
Neoplasias Retais , Conduta Expectante , Humanos , Consenso , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Retais/patologia , Terapia Neoadjuvante/métodos , Quimiorradioterapia/métodos , Resposta Patológica Completa , Resultado do Tratamento
9.
Clin Transl Oncol ; 26(10): 2640-2651, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38642257

RESUMO

PURPOSE: RAS (KRAS/NRAS) mutational status on a tumor biopsy is mandatory to guide the best treatment in metastatic colorectal cancer (mCRC). Determining the RAS mutational status by tumor-tissue biopsy is essential in guiding the optimal treatment decision for mCRC. RAS mutations are negative predictive factors for the use of EGFR monoclonal antibodies. Cell-free DNA (cfDNA) analysis enables minimally invasive monitoring of tumor evolution. METHODS/PATIENTS: PERSEIDA was an observational, prospective study assessing cfDNA RAS, BRAF and EGFR mutations (using Idylla™) in first-line mCRC, RAS wild-type (baseline tumor-tissue biopsy) patients (cohort 2). Plasma samples were collected before first-line treatment, after 20 ± 2 weeks, and at disease progression. RESULTS: 117 patients were included (103 received panitumumab + chemotherapy as first-line treatment). At baseline, 7 (6.8%) patients had RAS mutations, 4 (3.9%) BRAF mutations and no EGFR mutations were detected (cfDNA, panitumumab + chemotherapy subpopulation [panitumumab + Ch]). The baseline RAS mutational status concordance between tissue and liquid biopsies was 94.0% (93.2%, panitumumab + Ch). At 20 weeks, only one patient in the study (included in the panitumumab + Ch) had an emerging cfDNA RAS mutation. No emerging BRAF or EGFR mutations were reported. At disease progression, 6 patients had emergent mutations not present at baseline (RAS conversion rate: 13.3% [6/45]; 15.0% [6/40], panitumumab + Ch). CONCLUSIONS: The concordance rate between liquid and solid biopsies at baseline was very high, as previously reported, while our results suggest a considerable emergence of RAS mutations during disease progression. Thus, the dynamics of the genomic landscape in ctDNA may provide relevant information for the management of mCRC patients.


Assuntos
Ácidos Nucleicos Livres , Neoplasias Colorretais , Mutação , Panitumumabe , Proteínas Proto-Oncogênicas B-raf , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/sangue , Feminino , Masculino , Estudos Prospectivos , Idoso , Pessoa de Meia-Idade , Ácidos Nucleicos Livres/genética , Ácidos Nucleicos Livres/sangue , Proteínas Proto-Oncogênicas B-raf/genética , Panitumumabe/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptores ErbB/genética , Adulto , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , GTP Fosfo-Hidrolases/genética , Progressão da Doença , Proteínas de Membrana/genética
10.
Clin Transl Oncol ; 24(4): 646-657, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35303269

RESUMO

The management of localized rectal cancer requires a multidisciplinary approach to optimize outcomes, reduce morbidity and prevent under or overtreatments. While early stages may obtain benefit of local resections without any additional therapies, locally advanced rectal cancer becomes a challenge defining the better sequential strategy of surgery, radiotherapy and chemotherapy. The latest results of international phase III studies have positioned the total neoadjuvant therapy as a potential new standard of care in high risk rectal cancers, however, the best schedule is still not well defined.


Assuntos
Segunda Neoplasia Primária , Neoplasias Retais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia/métodos , Humanos , Terapia Neoadjuvante/métodos , Estadiamento de Neoplasias , Neoplasias Retais/patologia , Reto/cirurgia
11.
Eur J Surg Oncol ; 48(5): 1123-1132, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-34872775

RESUMO

INTRODUCTION: Retrospective studies and meta-analyses suggest that upfront primary tumour resection (UPTR) confers a survival benefit in patients with asymptomatic unresectable metastatic colorectal cancer (mCRC) undergoing chemotherapy, however a consensus of its role in routine clinical practice in the current era of targeted therapies is lacking. This retrospective study aimed to analyse the survival benefit of UPTR in terms of tumour location and mutational status, in patients with synchronous mCRC receiving chemotherapy and targeted therapy. PATIENTS AND METHODS: Survival was analysed in a pooled cohort of synchronous mCRC patients treated with a first-line anti-VEGF or anti-EGFR inhibitor in seven trials of the Spanish TTD group, according to UPTR, tumour-sidedness and mutational profiling. RESULTS: Of 1334 eligible patients, 642 (48%) had undergone UPTR. UPTR was associated with significantly longer overall survival (OS; 25.0 vs 20.3 months; HR 1.30, 95%CI 1.15-1.48; p < 0.0001). UPTR was associated with significant OS benefit in both left-sided (HR 1.38, 95%CI 1.13-1.69; p = 0.002) and right-sided (HR 1.39, 95%CI 1.00-1.94; p = 0.049) tumours, RASwt (HR 1.29, 95%CI 1.05-1.60; p = 0.016) and BRAFwt (HR 1.49, 95%CI 1.21-1.84; p = 0.0002) tumours, and treatment with anti-EGFRs (HR 1.47, 95%CI 1.13-1.92; p = 0.004) and anti-VEGFs (HR 1.25, 95%CI 1.08-1.44; p = 0.003). Multivariate analysis identified number of metastatic sites, RAS status, primary tumour location and UPTR as independent prognostic factors for OS. CONCLUSION: Considering the selection bias inherent to this study, our results support UPTR before first-line anti-EGFR or anti-VEGF targeted therapy in right and left-sided asymptomatic unresectable synchronous mCRC patients. RAS/BRAF mutational status may also influence UPTR function.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/patologia , Humanos , Neoplasias Retais/tratamento farmacológico , Estudos Retrospectivos
12.
Cancers (Basel) ; 14(24)2022 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-36551560

RESUMO

The serial analysis of cell-free DNA (cfDNA) enables minimally invasive monitoring of tumor evolution, providing continuous genetic information. PERSEIDA was an observational, prospective study assessing the cfDNA RAS (KRAS/NRAS) mutational status evolution in first-line, metastatic CRC, RAS wild-type (according to baseline tumor tissue biopsy) patients. Plasma samples were collected before first-line treatment, after 20 ± 2 weeks, and at disease progression. One hundred and nineteen patients were included (102 received panitumumab and chemotherapy as first-line treatment-panitumumab subpopulation). Fifteen (12.6%) patients presented baseline cfDNA RAS mutations (n = 14 [13.7%], panitumumab subpopulation) (mutant allele fraction ≥0.02 for all results). No patients presented emergent mutations (cfDNA RAS mutations not present at baseline) at 20 weeks. At disease progression, 11 patients (n = 9; panitumumab subpopulation) presented emergent mutations (RAS conversion rate: 19.0% [11/58]; 17.7% [9/51], panitumumab subpopulation). In contrast, three (5.2%) patients presenting baseline cfDNA RAS mutations were RAS wild-type at disease progression. No significant associations were observed between overall response rate or progression-free survival and cfDNA RAS mutational status in the total panitumumab subpopulation. Although, in patients with left-sided tumors, a significantly longer progression-free survival was observed in cfDNA RAS wild-type patients compared to those presenting cfDNA RAS mutations at any time. Continuous evaluation of RAS mutations may provide valuable insights on tumor molecular dynamics that can help clinical practice.

13.
Oncologist ; 16(5): 614-20, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21467148

RESUMO

BACKGROUND: Concomitant chemoradiotherapy followed by total mesorectal excision is standard treatment for locally advanced rectal cancer. This approach, however, focuses on local disease control and delays systemic treatment. Induction chemotherapy has the advantage of earlier administration of systemic therapy and may improve distant control. The objective of the current study was to assess the efficacy and toxicity of adding bevacizumab to induction chemotherapy followed by preoperative bevacizumab-based chemoradiotherapy in patients with locally advanced rectal cancer. PATIENTS AND METHODS: Eligible patients had high-risk rectal adenocarcinoma defined by magnetic resonance imaging criteria. Treatment consisted of four 21-day cycles of bevacizumab (7.5 mg/kg) and XELOX (capecitabine plus oxaliplatin), followed by concomitant radiotherapy (50.4 Gy) plus bevacizumab (5 mg/kg every 2 weeks) and capecitabine (825 mg/m2 twice daily on days 1-15). Surgery was scheduled for 6-8 weeks after chemoradiotherapy. The primary endpoint was pathologic complete response (pCR). RESULTS: Between July 2007 and July 2008, 47 patients were recruited. Among 45 patients who underwent surgery, pCR was achieved in 16 patients (36%; 95% confidence interval: 22.29%-51.27%), and an additional 17 patients (38%) had Dworak tumor regression grade 3. R0 resection was performed in 44 patients (98%). Most grade 3/4 adverse events occurred during the induction phase and included diarrhea (11%), asthenia (4%), neutropenia (6%), and thrombocytopenia (4%). Eleven patients (24%) required surgical reintervention. CONCLUSIONS: Addition of bevacizumab to induction chemotherapy and chemoradiotherapy is feasible, with impressive activity and manageable toxicity. However, caution is recommended regarding surgical complications.


Assuntos
Adenocarcinoma/terapia , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Neoplasias Retais/terapia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/radioterapia , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab , Capecitabina , Terapia Combinada , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Oxaloacetatos , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/radioterapia , Resultado do Tratamento
14.
Drugs Aging ; 38(3): 219-231, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33615402

RESUMO

BACKGROUND: Biologicals, in combination with chemotherapy, are recommended as first-line treatment of metastatic colorectal cancer (mCRC); however, evidence guiding the appropriate management of older patients with mCRC is limited. OBJECTIVE: This study was undertaken to compare the efficacy and safety outcomes in older versus younger patients with mCRC who received first-line biological therapy. METHODS: This retrospective analysis used pooled data from five trials undertaken by the Spanish Cooperative Group for the Treatment of Digestive Tumours. All were studies of adults with advanced CRC who received first-line treatment with chemotherapy plus bevacizumab, cetuximab or panitumumab, stratified by age (≥ 65 vs. < 65 years). Endpoints included progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and safety. RESULTS: In total, 999 patients from five studies were included in the analysis: 480 (48%) were aged ≥ 65 years, and 519 (52%) were aged < 65 years. Median PFS did not differ significantly between patients aged ≥ 65 and < 65 years (9.9 vs. 9.4 months; hazard ratio [HR] 1.01; 95% confidence interval [CI] 0.88-1.17). Median OS was significantly shorter in older than in younger patients (21.3 vs. 25.0 months; HR 1.21; 95% CI 1.04-1.41). There was no significant difference between older and younger patients in ORR (59 vs. 62%). Patients aged ≥ 65 years experienced significantly more treatment-related grade 3 or higher adverse events (61.67%) than did patients aged < 65 years (45.86%). CONCLUSIONS: Biologicals plus chemotherapy is an effective first-line treatment option for selected patients aged ≥ 65 years with mCRC and has a manageable safety profile and efficacy comparable to that observed in younger patients.


Assuntos
Fatores Biológicos , Neoplasias Colorretais , Idoso , Bevacizumab/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Humanos , Panitumumabe , Estudos Retrospectivos
15.
Cancers (Basel) ; 12(8)2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-32806731

RESUMO

Background: The prospective phase IV AVAMET study was undertaken to correlate response evaluation criteria in solid tumors (RECIST)-defined response rates with computed tomography-based morphological criteria (CTMC) and pathological response after liver resection of colorectal cancer metastases. Methods: Eligible patients were aged ≥18 years, with Eastern Cooperative Oncology Group (ECOG) performance status 0/1 and histologically-confirmed colon or rectal adenocarcinoma with measurable liver metastases. Preoperative treatment was bevacizumab (7.5 mg on day 1) + XELOX (oxaliplatin 130 mg/m2, capecitabine 1000 mg/m2 bid on days 1-14 q3w). After three cycles, response was evaluated by a multidisciplinary team. Patients who were progression-free and metastasectomy candidates received one cycle of XELOX before undergoing surgery 3-5 weeks later, followed by four cycles of bevacizumab + XELOX. Results: A total of 83 patients entered the study; 68 were eligible for RECIST, 67 for CTMC, and 51 for pathological response evaluation. Of these patients, 49% had a complete or partial RECIST response, 91% had an optimal or incomplete CTMC response, and 81% had a complete or major pathological response. CTMC response predicted 37 of 41 pathological responses versus 23 of 41 responses predicted using RECIST (p = 0.008). Kappa coefficients indicated a lack of correlation between the results of RECIST and morphological responses and between morphological and pathological response rates. Conclusion: CTMC may represent a better marker of pathological response to bevacizumab + XELOX than RECIST in patients with potentially-resectable CRC liver metastases.

16.
ESMO Open ; 5(6): e000944, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33148620

RESUMO

PURPOSE: 5-Fluorouracil/leucovorin, oxaliplatin, irinotecan (FOLFOXIRI) plus bevacizumab is more effective than doublets plus bevacizumab as first-line therapy for metastatic colorectal cancer, but is not widely used because of concerns about toxicity and lack of predictive biomarkers. This study was designed to explore the role of circulating tumour cell (CTC) count as a biomarker to select patients for therapy with FOLFOXIRI-bevacizumab. PATIENTS AND METHODS: VISNÚ-1 was a multicentre, open-label, randomised, phase III study in patients with previously untreated, unresectable, metastatic colorectal carcinoma and ≥3 CTC/7.5 mL blood. Patients received bevacizumab 5 mg/kg plus FOLFOXIRI (irinotecan 165 mg/m2, oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 and 5-fluorouracil 3200 mg/m2) or FOLFOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil 400 mg/m2 then 2400 mg/m2) by intravenous administration every 2 weeks. The primary outcome was progression-free survival (PFS). RESULTS: The intention-to-treat population comprised 349 patients (FOLFOXIRI-bevacizumab, n=172; FOLFOX-bevacizumab, n=177). Median PFS was 12.4 months (95% CI 11.2 to 14.0) with FOLFOXIRI bevacizumab and 9.3 months (95% CI 8.5 to 10.7) with FOLFOX-bevacizumab (stratified HR, 0.64; 95% CI 0.49 to 0.82; p=0.0006). Grade≥3 adverse events were more common with FOLFOXIRI-bevacizumab 85.3% vs 75.1% with FOLFOX-bevacizumab (p=0.0178). Treatment-related deaths occurred in 8 (4.7%) and 6 (3.4%) patients, respectively. CONCLUSIONS: First-line FOLFOXIRI-bevacizumab significantly improved PFS compared with FOLFOX-bevacizumab in patients with metastatic colorectal cancer and ≥3 CTCs at baseline, which indicate a poor prognosis. CTC count may be a useful non-invasive biomarker to assist with the selection of patients for intensive first-line therapy.


Assuntos
Neoplasias Colorretais , Células Neoplásicas Circulantes , Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab/efeitos adversos , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila , Humanos , Leucovorina/efeitos adversos , Compostos Organoplatínicos
17.
Lung Cancer ; 63(1): 83-7, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18555556

RESUMO

A retrospective analysis based on the Spanish Lung Cancer Group (SLCG) clinical trial of high-dose epirubicin/cisplatin in patients with small-cell lung cancer (SCLC) was performed. Patients younger than 70 years vs. older than 70 years old were analyzed to evaluate the influence of age on response to treatment, toxicity, time to progression (TTP) and overall survival (OS) of the chemotherapy schedule. Three hundred and thirty eight patients <70 years and sixty-four >70 years, were analyzed. Objective responses were similar in both groups. In patients less than 70 years higher TTP (36 weeks vs. 32 weeks) and OS (47 weeks vs. 42 weeks) were seen, attributable to the improved results observed in the subgroup of patients with limited disease (LD). No significant differences were observed when toxicity profile of both groups was compared, except for a higher rate of febrile neutropenia observed in the elderly group with extensive disease (4.6% vs. 8.8%, p=0.01). In the subgroup of patients with LD, elderly patients received less total cisplatin dose (401 vs. 508 mg/m(2), p=0.01) although less treatment delays were reported (10 days vs. 15 days, p=0.05). Age was likely to be a negative prognostic factor for OS of elderly patients with LD. It also seemed to be related to a greater dose reduction, which may explain that toxic episodes and delays occurred more frequently in the younger patients receiving the full scheduled dose. However, the definitive reason to explain this could not be established due to the characteristics of our analysis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Adulto , Fatores Etários , Idoso , Progressão da Doença , Epirubicina/administração & dosagem , Etoposídeo/administração & dosagem , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
18.
ESMO Open ; 4(6): e000599, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31803504

RESUMO

Purpose: Metastatic colorectal cancer (mCRC) is a group of distinct diseases, with clinical and molecular differences between right-sided and left-sided tumours driving varying prognosis. Methods: Patients with KRAS/RAS-wild type (wt) mCRC treated in first line with epidermal growth factor receptor inhibitors (EGFR-Is) (cetuximab or panitumumab) plus oxaliplatin or irinotecan-based chemotherapy from two phase II randomised trials conducted by the Spanish Cooperative for the Treatment of Digestive Tumours group were included in this retrospective study. The main objective was to analyse the prognostic effect of primary tumour location on objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: Patients with KRAS-wt right-sided tumours (n=52) had significantly lower efficacy as compared with patients with KRAS-wt left-sided tumours (n=209); confirmed ORR (25% vs 47%, respectively; OR 0.4, 95% CI 0.2 to 0.8, p=0.004); and shorter median PFS (7.2 vs 9.9 months; HR 0.6, 95% CI 0.4 to 0.9, p=0.0157) and OS (13.6 vs 27.7 months; HR 0.5, 95% CI 0.3 to 0.7, p<0.0001). Similar results were observed in the RAS-wt populations. The further classification of left-sided tumours as colon or rectum delivered similar survival outcomes, as well as a tendency to diminished ORR in patients with rectum tumours. Conclusion: We observed significantly improved efficacy outcomes in patients with KRAS/RAS-wt mCRC treated with first-line EGFR-I plus chemotherapy in left-sided primary tumours as compared with right-sided primary tumours. Trial registration numbers: NCT01161316 and NCT00885885.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cetuximab/farmacologia , Cetuximab/uso terapêutico , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Progressão da Doença , Receptores ErbB/antagonistas & inibidores , Feminino , GTP Fosfo-Hidrolases/genética , Humanos , Irinotecano/farmacologia , Irinotecano/uso terapêutico , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Panitumumabe/farmacologia , Panitumumabe/uso terapêutico , Prognóstico , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas p21(ras)/genética , Estudos Retrospectivos , Fatores de Tempo
19.
Lung Cancer ; 61(1): 104-8, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18243403

RESUMO

It has been analyzed the frequency of p16 inactivation in 67 blood samples of patients diagnosed with advanced non-small cell lung cancer (NSCLC), to establish the relationship between p16 inactivation and time to progression (TTP) and overall survival (OS), and its relationship with various clinical parameters. This is a retrospective study of 67 patients diagnosed with advanced NSCLC between August 2000 and July 2003 in the Hospital General de Valencia analysing p16 inactivation by assessing in plasma either loss of heterozygosity (LOH) or p16 promoter methylation. The study shows p16 inactivation in 28.3% (either by LOH or by p16 methylation). No significant differences were found between the group with p16 inactivation and the group without p16 inactivation, either in patients' TTP (31 weeks vs. 24 weeks; p=0.7) or in OS (53 weeks vs. 43 weeks; p=0.48). No relationship was found between the state of p16 and the clinical parameters analyzed (stage, ECOG, histology). Despite the fact that p16 is important in NSCLC carcinogenesis, the data obtained in our study do not allow the prognostic impact of this biological marker to be established.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , Genes p16 , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Metilação de DNA , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Perda de Heterozigosidade , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Regiões Promotoras Genéticas , Estudos Retrospectivos , Proteína Supressora de Tumor p14ARF/sangue , Proteína Supressora de Tumor p14ARF/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA