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1.
Clin Transl Oncol ; 22(4): 495-502, 2020 Apr.
Article in English | MEDLINE | ID: mdl-31280434

ABSTRACT

PURPOSE: Panitumumab is extensively used for RAS-WT metastatic colorectal cancer. This study assessed the efficacy and safety of panitumumab plus first-line chemotherapy [docetaxel (DOC) and cisplatin (CIS)] in treatment-naïve advanced gastric or gastro-oesophageal junction (GEJ) adenocarcinoma (ADC) patients. METHODS: Phase II, open-label, single-arm study includes treatment-naïve advanced gastric or GEJ-ADC patients from ten Spanish centres. Patients received panitumumab (6 mg/kg) plus DOC and CIS (50 mg/m2 both) every 2 weeks until disease progression, unacceptable toxicity, or patient withdrawal. Primary endpoint: objective response rate (ORR); main secondary endpoints: disease control rate (DCR), duration of response (DoR), time to progressive disease (TTP), progression-free-survival (PFS), overall survival (OS), and safety. RESULTS: Forty-four patients were included; median age: 67.8 (range 43.3-82.7) years, 68.2% male. The ORR was 27.3% (95% CI 15.0, 42.8); median PFS and OS: 5.0 (95% CI 3.6, 6.9) and 7.2 (5.5, 9.0) months, respectively. Median TTP, DCR and DoR: 5.3 (range 3.8-7.0) months, 70.5% (95% CI 54.8, 83.2%), and 4.8 (1.8, NE) months. Median panitumumab treatment duration: 11.9 (range 0.1-34.9) weeks; 25.0% patients had a dose reduction and 40.9% discontinued treatment. Grade 3-4 adverse events (AEs): 68.2%/22.2% patients. Most common AEs: asthenia (75.0%) and mucosal inflammation (54.5%). Serious AEs were experienced by 54.6% patients; 9.1%, 13.6%, and 15.9% related to panitumumab, DOC, and CIS, respectively. Three (6.8%) patients died due to AEs not related to study treatment. CONCLUSIONS: The addition of panitumumab to standard chemotherapy as the first-line treatment in advanced gastric or GEJ-ADC does not appear to improve the efficacy outcomes.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Esophagogastric Junction , Stomach Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Cisplatin/administration & dosage , Cisplatin/adverse effects , Docetaxel/administration & dosage , Docetaxel/adverse effects , Female , Humans , Male , Middle Aged , Panitumumab/administration & dosage , Panitumumab/adverse effects , Prospective Studies , Stomach Neoplasms/mortality
3.
Clin. transl. oncol. (Print) ; 20(5): 630-638, mayo 2018. ilus
Article in English | IBECS | ID: ibc-173540

ABSTRACT

Purpose. Management of metastatic disease in oncology includes monitoring of therapy response principally by imaging techniques like CT scan. In addition to some limitations, the irruption of liquid biopsy and its application in personalized medicine has encouraged the development of more efficient technologies for prognosis and follow-up of patients in advanced disease. Methods. PrediCTC constitutes a panel of genes for the assessment of circulating tumor cells (CTC) in metastatic colorectal cancer patients, with demonstrated improved efficiency compared to CT scan for the evaluation of early therapy response in a multicenter prospective study. In this work, we designed and developed a technology transfer strategy to define the market opportunity for an eventual implementation of PrediCTC in the clinical practice. Results. This included the definition of the regulatory framework, the analysis of the regulatory roadmap needed for CE mark, a benchmarking study, the design of a product development strategy, a revision of intellectual property, a cost-effectiveness study and an expert panel consultation. Conclusion. The definition and analysis of an appropriate technology transfer strategy and the correct balance among regulatory, financial and technical determinants are critical for the transformation of a promising technology into a viable technology, and for the decision of implementing liquid biopsy in the monitoring of therapy response in advanced disease


No disponible


Subject(s)
Humans , Biopsy , Medical Oncology/methods , Neoplastic Cells, Circulating/pathology , Precision Medicine/methods , Technology Transfer , Benchmarking , 50303
4.
Clin Transl Oncol ; 20(5): 630-638, 2018 May.
Article in English | MEDLINE | ID: mdl-29058262

ABSTRACT

PURPOSE: Management of metastatic disease in oncology includes monitoring of therapy response principally by imaging techniques like CT scan. In addition to some limitations, the irruption of liquid biopsy and its application in personalized medicine has encouraged the development of more efficient technologies for prognosis and follow-up of patients in advanced disease. METHODS: PrediCTC constitutes a panel of genes for the assessment of circulating tumor cells (CTC) in metastatic colorectal cancer patients, with demonstrated improved efficiency compared to CT scan for the evaluation of early therapy response in a multicenter prospective study. In this work, we designed and developed a technology transfer strategy to define the market opportunity for an eventual implementation of PrediCTC in the clinical practice. RESULTS: This included the definition of the regulatory framework, the analysis of the regulatory roadmap needed for CE mark, a benchmarking study, the design of a product development strategy, a revision of intellectual property, a cost-effectiveness study and an expert panel consultation. CONCLUSION: The definition and analysis of an appropriate technology transfer strategy and the correct balance among regulatory, financial and technical determinants are critical for the transformation of a promising technology into a viable technology, and for the decision of implementing liquid biopsy in the monitoring of therapy response in advanced disease.


Subject(s)
Colorectal Neoplasms/pathology , Medical Oncology/methods , Neoplastic Cells, Circulating/pathology , Precision Medicine/methods , Colorectal Neoplasms/blood , Humans , Liquid Biopsy , Spain , Technology Transfer
5.
Ann Oncol ; 28(6): 1325-1332, 2017 Jun 01.
Article in English | MEDLINE | ID: mdl-28419195

ABSTRACT

BACKGROUND: RAS assessment is mandatory for therapy decision in metastatic colorectal cancer (mCRC) patients. This determination is based on tumor tissue, however, genotyping of circulating tumor (ct)DNA offers clear advantages as a minimally invasive method that represents tumor heterogeneity. Our study aims to evaluate the use of ctDNA as an alternative for determining baseline RAS status and subsequent monitoring of RAS mutations during therapy as a component of routine clinical practice. PATIENTS AND METHODS: RAS mutational status in plasma was evaluated in mCRC patients by OncoBEAM™ RAS CRC assay. Concordance of results in plasma and tissue was retrospectively evaluated. RAS mutations were also prospectively monitored in longitudinal plasma samples from selected patients. RESULTS: Analysis of RAS in tissue and plasma samples from 115 mCRC patients showed a 93% overall agreement. Plasma/tissue RAS discrepancies were mainly explained by spatial and temporal tumor heterogeneity. Analysis of clinico-pathological features showed that the site of metastasis (i.e. peritoneal, lung), the histology of the tumor (i.e. mucinous) and administration of treatment previous to blood collection negatively impacted the detection of RAS in ctDNA. In patients with baseline mutant RAS tumors treated with chemotherapy/antiangiogenic, longitudinal analysis of RAS ctDNA mirrored response to treatment, being an early predictor of response. In patients RAS wt, longitudinal monitoring of RAS ctDNA revealed that OncoBEAM was useful to detect emergence of RAS mutations during anti-EGFR treatment. CONCLUSION: The high overall agreement in RAS mutational assessment between plasma and tissue supports blood-based testing with OncoBEAM™ as a viable alternative for genotyping RAS of mCRC patients in routine clinical practice. Our study describes practical clinico-pathological specifications to optimize RAS ctDNA determination. Moreover, OncoBEAM™ is useful to monitor RAS in patients undergoing systemic therapy to detect resistance and evaluate the efficacy of particular treatments.


Subject(s)
Colorectal Neoplasms/diagnosis , DNA Mutational Analysis/methods , DNA, Neoplasm/blood , Genes, ras , Antineoplastic Agents/therapeutic use , Colorectal Neoplasms/blood , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , ErbB Receptors/antagonists & inhibitors , Humans , Monitoring, Physiologic/methods , Neoplasm Metastasis , Prospective Studies , Retrospective Studies
6.
Pharmacogenomics J ; 13(3): 209-17, 2013 Jun.
Article in English | MEDLINE | ID: mdl-22310351

ABSTRACT

The development of genotyping technologies has allowed for wider screening for inherited causes of variable outcomes following drug administration. We have performed a genome-wide association study (GWAS) on 221 colorectal cancer (CRC) patients that had been treated with 5-fluorouracil (5-FU), either alone or in combination with oxaliplatin (FOLFOX). A validation set of 791 patients was also studied. Seven SNPs (rs16857540, rs2465403, rs10876844, rs10784749, rs17626122, rs7325568 and rs4243761) showed evidence of association (pooled P-values 0.020, 9.426E-03, 0.010, 0.017, 0.042, 2.302E-04, 2.803E-03) with adverse drug reactions (ADRs). This is the first study to explore the genetic basis of inter-individual variation in toxicity responses to the administration of 5-FU or FOLFOX in CRC patients on a genome-wide scale.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Fluorouracil/administration & dosage , Adult , Aged , Aged, 80 and over , Biomarkers, Pharmacological , Clinical Trials, Phase II as Topic , Colorectal Neoplasms/pathology , Drug-Related Side Effects and Adverse Reactions/genetics , Female , Genome-Wide Association Study , Genotyping Techniques , Humans , Leucovorin/administration & dosage , Male , Middle Aged , Organoplatinum Compounds/administration & dosage , Pharmacogenetics , Polymorphism, Single Nucleotide/genetics , Treatment Outcome
7.
Cancer Chemother Pharmacol ; 69(6): 1591-9, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22535333

ABSTRACT

PURPOSE: We are trying to identify predictive factors of high risk of toxicity by analyzing candidate genes in the irinotecan pathways in order to identify useful tools to improve mCRC patient management under real practice conditions. METHODS: Genomic DNA was genotyped for UGT1A1 (*28, *60 and *93) from all 101 patients, and irinotecan dose was 180 mg/m(2) every second week. Clinical data were obtained by retrospective chart review. The primary endpoint is to find out whether the pharmacogenetic test in the clinical practice may predict toxicity. RESULTS: Grade 3/4 diarrhea occurred in twelve patients and required dose reduction in six patients, and neutropenia reached grade 3/4 in 19 patients (only one patient with *28/*28 genotype). The UGT1A1*93 seemed to relate with grade 3/4 neutropenia but only in the heterozygote state (G/A), p = 0.071, and UGT1A*60 showed no association with neutropenia. Twenty-eight percentage of patients required the use of G-CSF; 64.3% of them harbored *1/*28 or *28/*28 genotypes, p = 0.003. Thirty-seven (36.6%) patients required dose reduction of irinotecan and/or 5-FU owing to toxicity, mainly neutropenia and diarrhea. No significant association was detected between *28, *60 and *93 UGT1A variants and severe irinotecan-associated hematologic or GI toxicity. CONCLUSION: The impact of increased risk of toxicity attributed to the UGT1A variants may be offset by irinotecan in clinical practice by dose reduction or the use of colony-stimulating factor.


Subject(s)
Antineoplastic Agents, Phytogenic/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Camptothecin/analogs & derivatives , Colorectal Neoplasms/drug therapy , Glucuronosyltransferase/genetics , Polymorphism, Genetic , Adult , Aged , Aged, 80 and over , Camptothecin/administration & dosage , Camptothecin/adverse effects , Colorectal Neoplasms/genetics , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Female , Genotype , Granulocyte Colony-Stimulating Factor/therapeutic use , Humans , Irinotecan , Male , Middle Aged , Neoplasm Metastasis
8.
Clin. transl. oncol. (Print) ; 12(12): 843-848, dic. 2010.
Article in English | IBECS | ID: ibc-124384

ABSTRACT

OBJECTIVE: The aim of the project was to assess the effectiveness and safety of weekly epoetin-beta (EB) in patients with gastrointestinal cancer (GIC) subjected to concomitant chemoradiotherapy (CCTRT). METHODS: In this clinical prospective and multicentre cohort study EB was administered at a dose of 30,000 IU/ week, during CCTRT and in the four weeks thereafter, and suspended if haemoglobin (Hb) increased >2 g/dl or Hb >12-13 g/dl. Effectiveness was defi ned as Hb increase ≥1 g/dl vs. baseline. Time to response, treatment toxicity and transfusion requirements were also assessed. RESULTS: EB was effective in 75.8% of the evaluable population within a median of four weeks from EB initiation, without blood transfusions. Over 80% of all patients remained below the threshold (Hb ≤13 g/dl) and no study drug-related adverse reactions were recorded. CONCLUSION: Weekly EB proved to be effective and well tolerated by patients with GIC subjected to CCTRT (AU)


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Aged, 80 and over , Anemia/etiology , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Erythropoietin/administration & dosage , Erythropoietin/therapeutic use , Gastrointestinal Neoplasms/complications , Gastrointestinal Neoplasms/therapy , Anemia/metabolism , Chemoradiotherapy/methods , Chemoradiotherapy , Cohort Studies , Hemoglobins , Prospective Studies , Recombinant Proteins/administration & dosage , Recombinant Proteins/therapeutic use , Treatment Outcome
9.
Br J Cancer ; 103(10): 1536-41, 2010 Nov 09.
Article in English | MEDLINE | ID: mdl-20940719

ABSTRACT

BACKGROUND: Combination of bevacizumab and FOLFIRI has currently become one of the standard therapeutic regimens. However, published information is still limited. The objective of the present retrospective observational study is to analyse the response and toxicity of first-line treatment with FOLFIRI+bevacizumab in patients with metastatic colorectal cancer (mCRC). METHODS: Data were collected from patients from nine Spanish sites diagnosed with mCRC, ECOG≤2, whose first treatment for advanced disease was at least three cycles of FOLFIRI+bevacizumab. RESULTS: A total of 95 patients were enrolled into the study: 64.2% males, median age of 59 years (53.2-67.1 years), ECOG=0-1 in 96.9% of patients. The main site of primary tumour was the colon (69.7%), and most metastases occurred in the liver (71.6%). Clinical benefit was detected in 67.4% (57.0-76.6; 95% confidence interval (CI)), with 8.4% of CR and 42.1% of PR. Median TTP was 10.6 months (10.0-11.3; 95% CI), PFS was 10.6 months (9.8-11.3; 95% CI), and OS was 20.7 months (17.1-24.2; 95% CI). Main grade I-II toxicities included haematological toxicity (35.8%), diarrhea (27.3%), mucositis (25.3%), asthenia (19.0%), haemorrhages (11.6%), and emesis (10.6%). Toxicities reaching grades III-IV were haematological toxicity (9.5%), diarrhea (8.5%), mucositis (5.3%), hepatic toxicity (2.1%), asthenia (2.1%), proteinuria (1.1%), emesis (1.1%), pain (1.1%), and colics (1.1%). CONCLUSION: Results of this study support the beneficial effect of adding bevacizumab to FOLFIRI regimen in terms of efficacy and show a favourable tolerability profile.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Aged , Antibodies, Monoclonal/toxicity , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab , Camptothecin/administration & dosage , Camptothecin/adverse effects , Camptothecin/analogs & derivatives , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Disease Progression , Drug Tolerance , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Humans , Leucovorin/administration & dosage , Leucovorin/adverse effects , Liver Neoplasms/secondary , Male , Middle Aged , Neoplasm Metastasis , Rectal Neoplasms/drug therapy , Rectal Neoplasms/pathology , Retrospective Studies , Safety , Spain , Treatment Outcome
10.
Eur J Cancer ; 37(11): 1381-4, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11435068

ABSTRACT

The aim of this study was to determine the clinical activity and toxicity of a novel chemotherapy regimen of weekly gemcitabine and vinorelbine in patients with advanced non-small cell lung cancer (NSCLC). 40 chemotherapy-naïve patients with stage IIIB/IV NSCLC were included. The doses of gemcitabine and vinorelbine were 1000 and 25 mg/m(2), respectively, given on days 1, 8 and 15, every 28 days. 38 patients were evaluable for response. One patient achieved a complete response (CR) and 10 attained a partial response (PR), for an overall response rate (ORR) of 29% (95% confidence interval (CI): 15-43%). 47% of patients experienced a clinical benefit. The main toxicity consisted of grade 3 anaemia and neutropenia in 5% of patients. Non-haematological toxicity was minimal. The dose-intensities were 744 mg/m(2)/week for gemcitabine and 15 mg/m(2)/week for vinorelbine. 40% of the patients survived for longer than 1 year. The median time to progression was 4 months and the median survival 8.5 months (95% CI: 3.1-13.8 months). The weekly administration of gemcitabine and vinorelbine is very well tolerated and results in an acceptable response rate for the treatment of NSCLC.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Aged , Carcinoma, Non-Small-Cell Lung/pathology , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Female , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Survival Analysis , Treatment Outcome , Vinblastine/administration & dosage , Vinblastine/adverse effects , Vinblastine/analogs & derivatives , Vinorelbine , Gemcitabine
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