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1.
Acta Oncol ; 61(10): 1223-1229, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35866544

RESUMEN

BACKGROUND: While circulating tumour (ct)DNA is an indicator of minimal residual disease and negative prognostic factor in stage II-III colon cancer, no study has ever analysed the value of this biomarker in colon cancer patients treated with neoadjuvant chemotherapy. We sought to fill this gap by using prospectively collected plasma samples from 80 stage III colon cancer patients, receiving one cycle of neoadjuvant FOLFOX followed by surgery +/- adjuvant FOLFOX in the PePiTA trial. MATERIAL AND METHODS: Samples were collected at baseline, 2 weeks and surgery. NPY and WIF1 were selected as universal methylation markers for ctDNA, and analysed with ddPCR technology. ROC curves were applied for cut-off points, and outcome measures included 5-year disease-free survival (DFS) and 6-year overall survival (OS). RESULTS: After a median follow-up of 52.5 months, baseline circulating-free (cf) DNA was an independent prognostic factor for DFS (HR 3.35, 95% CI: 1.15-9.77, p = .03), and a trend towards a similar association was observed for relative cfDNA changes between baseline and surgery (HR 2.57, 95% CI: 0.94-7.05, p = .07). Among 60 ctDNA assessable patients, 25 (42%) had detectable ctDNA at baseline. While detection of ctDNA at any pre-operative timepoint was not associated with outcome, patients with ctDNA increase (change of the worst trending methylation marker ≥11%, or mean ctDNA change of NPY and WIF1 ≥ 0%) between baseline and surgery showed a trend towards worse 5-year DFS (HR 3.66, 95% CI: 0.81-16.44, p = .09). CONCLUSION: This is the first study of ctDNA in the neoadjuvant setting of early-stage colon cancer. Results are hypothesis-generating and should be confirmed in larger series.


Asunto(s)
Ácidos Nucleicos Libres de Células , ADN Tumoral Circulante , Neoplasias del Colon , Humanos , Terapia Neoadyuvante , Pronóstico , Biomarcadores de Tumor/genética , ADN Tumoral Circulante/genética , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Neoplasias del Colon/cirugía
2.
BMC Cancer ; 19(1): 134, 2019 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-30744591

RESUMEN

BACKGROUND: The prognostic value of body composition in cancer patients has been widely studied during the last decade. The main finding of these studies is that sarcopenia, or skeletal muscle depletion, assessed by CT imaging correlates with a reduced overall survival (OS). By contrast, the prognostic value of fat mass remains ill-defined. This study aims to analyze the influence of body composition including both muscle mass and adipose tissue on OS in a homogeneous population of advanced colorectal cancer (CRC) patients. METHODS: Among 235 patients with chemorefractory advanced CRC included in the SoMore and RegARd-C trials, body composition was assessed in 217 patients on baseline CT images. The relationship between body composition (sarcopenia, muscle density, subcutaneous and visceral fat index and density), body mass index (BMI) and OS were evaluated. RESULTS: Patients with a higher BMI had a better OS (≥30 versus < 30, HR: 0.50; 0.33-0.76). Those with low muscle index and muscle density had an increased mortality (HR: 2.06; 1.45-2.93 and HR: 1.54; 1.09-2.18, respectively). Likewise, low subcutaneous and visceral fat index were associated with an increased risk of dying (HR: 1.63; 1.23-2.17 and 1.48; 1.09-2.02 respectively), as were a high subcutaneous and visceral adipose tissue density (HR: 1.93; 1.44-2.57 and 2.40; 1.79-3.20 respectively). In multivariate analysis, a high visceral fat density was the main predictor of poor survival. CONCLUSIONS: Our results confirm the protective role of obesity in CRC patients at an advanced stage, as well as the negative prognostic impact of muscle depletion on survival. More importantly, our data show for the first time that visceral adipose tissue density is an important prognostic factor in metastatic CRC. TRIAL REGISTRATION: NCT01290926 , 07/02/2011 and NCT01929616 , 28/08/2013.


Asunto(s)
Tejido Adiposo/patología , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Músculo Esquelético/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Composición Corporal , Índice de Masa Corporal , Ensayos Clínicos Fase II como Asunto , Neoplasias Colorrectales/diagnóstico por imagen , Neoplasias Colorrectales/terapia , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Pronóstico , Modelos de Riesgos Proporcionales , Tomografía Computarizada por Rayos X
3.
Eur J Nucl Med Mol Imaging ; 43(10): 1792-801, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-27072811

RESUMEN

INTRODUCTION: The introduction of targeted drugs has had a significant impact on the approach to assessing tumour response. These drugs often induce a rapid cytostatic effect associated with a less pronounced and slower tumoural volume reduction, thereby impairing the correlation between the absence of tumour shrinkage and the patient's unlikelihood of benefit. The aim of the study was to assess the predictive value of early metabolic response (mR) evaluation after one cycle, and its interlesional heterogeneity to a later metabolic and morphological response assessment performed after three cycles in metastatic colorectal cancer (mCRC) patients treated with combined sorafenib and capecitabine. METHODS: This substudy was performed within the framework of a wider prospective multicenter study on the predictive value of early FDG PET-CT response assessment (SoMore study). A lesion-based response analysis was performed, including all measurable lesions identified on the baseline PET. On a per-patient basis, a descriptive 4-class response categorization was applied based upon the presence and proportion of non-responding lesions. For dichotomic response comparison, all patients with at least one resistant lesion were classified as non-responding. RESULTS: On baseline FDG PET-CT, 124 measurable "target" lesions were identified in 38 patients. Early mR assessments showed 18 patients (47 %) without treatment resistant lesions and 12 patients (32 %) with interlesional response heterogeneity. The NPV and PPV of early mR were 85 % (35/41) and 84 % (70/83), respectively, on a per-lesion basis and 95 % (19/20) and 72 % (13/18), respectively, on a dichotomized per-patient basis. CONCLUSIONS: Early mR assessment performed after one cycle of sorafenib-capecitabine in mCRC is highly predictive of non-response at a standard response assessment time. The high NPV (95 %) of early mR could be useful as the basis for early treatment discontinuation or adaptation to spare patients from exposure to non-effective drugs.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/secundario , Monitoreo de Drogas/métodos , Fluorodesoxiglucosa F18/farmacocinética , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Adulto , Anciano , Capecitabina/administración & dosificación , Neoplasias Colorrectales/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida/métodos , Niacinamida/administración & dosificación , Niacinamida/análogos & derivados , Compuestos de Fenilurea/administración & dosificación , Radiofármacos/farmacocinética , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Sorafenib , Resultado del Tratamiento
4.
Cancers (Basel) ; 14(5)2022 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-35267491

RESUMEN

Retrospective studies reported that preoperative oxaliplatin-based chemotherapy increased pathological response (PR) in patients resected for colorectal liver metastases (CRLM). This multicenter prospective randomized (1/1) phase II trial evaluated PR on resected CRLM after preoperative mFOLFOX6 (arm A) or FOLFIRI (arm B) + bevacizumab. The primary endpoint was the major pathological response rate (MPRR), defined as the percentage of patients presenting CRLMs with mean tumor regression grade (TRG) < 3. Secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). Out of 65 patients, 57 patients (28 and 29 in arm A/B) were resected for CRLM (one patient with lung metastases). Clinical and treatment characteristics were similar in both arms. One-month postoperative complications were 39.3%/31.0% in arm A/B (p = 0.585). MPRR and complete PR were 32.1%/20.7% (p = 0.379) and 14.3%/0.0% (p = 0.052) in arm A/B, respectively. PFS and OS were not different. Patients with PR among all CRLMs (max TRG ≤ 3; 43.8% of patients) had a lower risk of relapse (PFS: HR = 0.41, 95%CI = 0.204−0.840, p = 0.015) and a tendency towards better survival (OS: HR = 0.34, 95%CI = 0.104−1.114, p = 0.075). The homogeneity of PR was associated with improved PFS/OS. This trial fails to demonstrate a significant increase in MPRR in patients treated with mFOLFOX6-bevacizumab but confirms PR as an important prognostic factor.

5.
Clin Ther ; 43(12): 2136-2145.e2, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34844770

RESUMEN

PURPOSE: Inoperable malignant intestinal obstruction (IMIO) is a severe complication in patients with cancer, usually gastrointestinal or gynecologic in origin. For patients with IMIO, there is a need to relieve symptoms and limit nasogastric tube (NGT) use. Previous studies have suggested the efficacy of somatostatin analogues in relieving obstruction-related symptoms, such as nausea, vomiting, and pain. The purpose of this study was to assess the efficacy of lanreotide autogel 120 mg (LAN 120 mg) in the management of symptoms resulting from IMIO in patients with advanced cancer. METHODS: This single-arm, multicenter study enrolled 52 patients mostly with advanced gastrointestinal or ovarian malignant tumors (35 patients with NGT and 17 patients without NGT). Patients received 1 deep subcutaneous injection of LAN 120 mg. Evaluations were performed on days 7, 14, and 28. The primary end point was the percentage of responding patients before or at day 7. Response was defined as ≤2 vomiting episodes per day (for patients without NGT at baseline) or no vomiting recurrence (after NGT removal) during at least 3 consecutive days at any time point between treatment and day 7. Responders at day 28 were offered a second LAN 120 mg injection and followed up until day 56. FINDINGS: The proportion of responders in the intention-to-treat population was 24 of 52 (46.2%), which was significantly greater than the reference proportion of 30% (P = 0.0055). Patients without NGT had a higher response (88.2%) than patients with NGT (25.7%) and had a steady trend for clinical improvement that led to sustainable responses. Median time to response was 9 days for the overall population, 3 days for patients without NGT, and 14 days for patients with NGT (P < 0.0001). IMPLICATIONS: Our study is the first to use long-acting LAN 120 mg in patients with IMIO and suggests an effect in controlling clinical symptoms in patients with and without NGT at baseline. The safety profile of LAN 120 mg was similar to that reported in other indications. ClinicalTrials.gov identifier: NCT02275338.


Asunto(s)
Obstrucción Intestinal , Péptidos Cíclicos , Somatostatina , Femenino , Humanos , Obstrucción Intestinal/tratamiento farmacológico , Obstrucción Intestinal/etiología , Péptidos Cíclicos/efectos adversos , Estudios Prospectivos , Somatostatina/efectos adversos
6.
Clin Colorectal Cancer ; 20(4): 326-333, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34404621

RESUMEN

BACKGROUND: Regorafenib is a standard treatment for refractory metastatic colorectal cancer (mCRC). In view of the toxicity burden, significant research efforts have been made to increase the therapeutic ratio of this multikinase inhibitor. Predictive factors for treatment-related adverse events (TRAEs), however, are still lacking. MATERIALS AND METHODS: We assessed the association between a number of baseline clinical, laboratory and imaging parameters and the occurrence of TRAEs in 136 patients who had received regorafenib (160 mg/day, 3-weeks-on/1-week-off) in a prospective phase II clinical trial. RESULTS: Grade ≥ 2 TRAEs during the first cycle of treatment (84% vs. 60%, P = .002) and grade ≥ 3 TRAEs throughout the whole treatment (71% vs. 53%, P = .035) occurred more frequently in females, with sex being the only independent predictive factor of early and any-time toxicity (OR 3.4; 95% CI: 1.2-11.1, P = .02 and OR 2.1; 95% CI: 1.0-4.4, P = .045, respectively). Fatigue, anorexia, hypertension, and rash were reported significantly more frequently by females than males (P < .04). Females were also more likely to suffer early (19% vs. 5%, P = .014) and any-time serious AEs (28% vs. 9%, P = .005), and to require early dose modifications (55% vs. 37%, P = .055). CONCLUSION: This is the first study showing an association between sex and TRAEs during regorafenib treatment for mCRC. If confirmed in larger, independent series, these results could pave the way for the implementation of personalized regorafenib dosing strategies with the potential to optimize oncological outcomes while reducing toxicity and preserving quality of life.


Asunto(s)
Neoplasias Colorrectales , Calidad de Vida , Neoplasias Colorrectales/tratamiento farmacológico , Femenino , Humanos , Masculino , Compuestos de Fenilurea/efectos adversos , Estudios Prospectivos , Piridinas
8.
Oncotarget ; 9(25): 17756-17769, 2018 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-29707145

RESUMEN

Predictive biomarkers are eagerly awaited in advanced colorectal cancer (aCRC). Targeted sequencing performed on tumor and baseline plasma samples in 20 patients with aCRC treated with regorafenib identified 89 tumor-specific mutations of which ≥50% are also present in baseline plasma. Droplet digital PCR (ddPCR) assays were optimized to monitor circulating tumor DNA (ctDNA) levels in plasmatic samples collected throughout the treatment course and showed the importance of using the absolute value for ctDNA rather than the mutant/wild type ratio in monitoring the therapy outcome. High baseline cell free DNA (cfDNA) levels are associated with shorter overall survival (OS) (HR 7.38, P=0.001). An early increase (D14) in mutated copies/mL is associated with a significantly worse PFS (HR 6.12, P=0.008) and OS (HR 8.02, P=0.004). These data suggest a high prognostic value for early ctDNA level changes and support the use of blood-born genomic markers as a tool for treatment.

9.
Clin Ther ; 38(8): 1902-1911.e2, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-27423779

RESUMEN

PURPOSE: Chronic idiopathic diarrhea is the passage of loose stools >3 times daily, or a stool weight >200 g/d, persisting for >4 weeks without clear clinical cause. Patients refractory to standard anti-diarrhetics have limited treatment options. Somatostatin analogues have the ability to reduce gastrointestinal secretions and motility. This study evaluated the efficacy and safety of lanreotide Autogel(*) 120 mg in chronic idiopathic diarrhea. METHODS: Other anti-diarrhetics were not allowed during the study and were stopped at screening. Patients received lanreotide Autogel 120 mg at baseline and day 28. Stool frequency and consistency (Bristol Stool Scale) were recorded; quality of life (QoL) was assessed using the 36-item Short Form Health Survey and irritable bowel syndrome QoL questionnaires; adverse events were monitored. The primary outcome was the proportion of patients with a reduction of ≥50% or normalization to a mean of ≤3 stools/d at day 28. FINDINGS: Thirty-three patients with >3 stools/d at baseline were included; mean (SD) age was 55.2 (16.4) years. Fourteen patients (42.4%) had a response to lanreotide Autogel at day 28 and 17 (51.5%) at day 56. Mean (SD) number of stools decreased significantly from 5.7 (2.2) at baseline to 3.7 (2.2) at day 56 overall (n = 32; P < 0.001). Significant and clinically meaningful improvements in disease-specific QoL were found in the overall populations. No new safety signals emerged. IMPLICATIONS: Lanreotide Autogel 120 mg decreased symptoms in these patients with chronic idiopathic refractory diarrhea, and meaningfully improved QoL. These finding have to be confirmed in further clinical trials. ClinicalTrials.gov IDENTIFICATION: NCT00891371; Eudract CT 2009-009356-20.


Asunto(s)
Diarrea/tratamiento farmacológico , Péptidos Cíclicos/administración & dosificación , Calidad de Vida , Somatostatina/análogos & derivados , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Somatostatina/administración & dosificación , Encuestas y Cuestionarios , Resultado del Tratamiento
10.
PLoS One ; 10(9): e0138341, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26421426

RESUMEN

BACKGROUND: Tumoral heterogeneity is a major determinant of resistance in solid tumors. FDG-PET/CT can identify early during chemotherapy non-responsive lesions within the whole body tumor load. This prospective multicentric proof-of-concept study explores intra-individual metabolic response (mR) heterogeneity as a treatment efficacy biomarker in chemorefractory metastatic colorectal cancer (mCRC). METHODS: Standardized FDG-PET/CT was performed at baseline and after the first cycle of combined sorafenib (600mg/day for 21 days, then 800mg/day) and capecitabine (1700 mg/m²/day administered D1-14 every 21 days). MR assessment was categorized according to the proportion of metabolically non-responding (non-mR) lesions (stable FDG uptake with SUVmax decrease <15%) among all measurable lesions. RESULTS: Ninety-two patients were included. The median overall survival (OS) and progression-free survival (PFS) were 8.2 months (95% CI: 6.8-10.5) and 4.2 months (95% CI: 3.4-4.8) respectively. In the 79 assessable patients, early PET-CT showed no metabolically refractory lesion in 47%, a heterogeneous mR with at least one non-mR lesion in 32%, and a consistent non-mR or early disease progression in 21%. On exploratory analysis, patients without any non-mR lesion showed a significantly longer PFS (HR 0.34; 95% CI: 0.21-0.56, P-value <0.001) and OS (HR 0.58; 95% CI: 0.36-0.92, P-value 0.02) compared to the other patients. The proportion of non-mR lesions within the tumor load did not impact PFS/OS. CONCLUSION: The presence of at least one metabolically refractory lesion is associated with a poorer outcome in advanced mCRC patients treated with combined sorafenib-capecitabine. Early detection of treatment-induced mR heterogeneity may represent an important predictive efficacy biomarker in mCRC. TRIAL REGISTRATION: ClinicalTrials.gov NCT01290926.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Colorrectales , Glucosa-6-Fosfato/análogos & derivados , Tomografía de Emisión de Positrones , Adulto , Anciano , Anciano de 80 o más Años , Capecitabina/administración & dosificación , Neoplasias Colorrectales/diagnóstico por imagen , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/mortalidad , Supervivencia sin Enfermedad , Femenino , Glucosa-6-Fosfato/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Niacinamida/administración & dosificación , Niacinamida/análogos & derivados , Compuestos de Fenilurea/administración & dosificación , Estudios Prospectivos , Radiografía , Sorafenib , Tasa de Supervivencia
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