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1.
Eur J Cancer ; 130: 63-71, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32172199

RESUMO

BACKGROUND: The variability of definitions for time-to-event (TTE) end-points impacts the conclusions of randomised clinical trials (RCTs). The Definition for the Assessment of Time-to-event Endpoints in CANcer (DATECAN) initiative aims to provide consensus definitions for TTE end-points used in RCTs. Here, we formulate guidelines for adjuvant colon cancer RCTs. METHODS: We performed a literature review to identify TTE end-points and events included in their definition in RCT publications. Then, a consensus was reached among a panel of international experts, using a formal modified Delphi method, with 2 rounds of questionnaires and an in-person meeting. RESULTS: Twenty-four experts scored 72 events involved in 6 TTE end-points. Consensus was reached for 24%, 57% and 100% events after the first round, second round and in-person meeting. For RCTs not using overall survival as their primary end-point, the experts recommend using disease-free survival (DFS) rather than recurrence-free survival (RFS) or time to recurrence (TTR) as the primary end-point. The consensus definition of DFS includes all causes of death, second primary colorectal cancers (CRCs), anastomotic relapse and metastatic relapse as an event, but not second primary non-CRCs. Events included in the RFS definition are the same as for DFS with the exception of second primary CRCs. The consensus definition of TTR includes anastomotic or metastatic relapse, death with evidence of recurrence and death from CC cause. CONCLUSION: Standardised definitions of TTE end-points ensure the reproducibility of the end-points between RCTs and facilitate cross-trial comparisons. These definitions should be integrated in standard practice for the design, reporting and interpretation of adjuvant CC RCTs.

2.
J Natl Cancer Inst ; 2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32191317

RESUMO

BACKGROUND: Carcinoembryonic antigen (CEA) levels are used in conjunction with imaging to monitor response to systemic therapy in metastatic colorectal cancer (mCRC). We sought to identify a threshold for CEA change from baseline to predict progressive disease (PD) in mCRC patients receiving first-line therapy. METHODS: Patients from trials collected in the ARCAD database were included if baseline CEA was ≥10ng/mL and repeat CEA was available within 14 days of first restaging scan. Optimal cutoffs for CEA change were identified by ROC analysis. Prediction performance of cutoffs was evaluated by sensitivity, specificity, and negative predictive value (NPV). Analyses were conducted by treatment class: chemotherapy alone (chemo), chemotherapy with anti-VEGF antibody (anti-VEGF), and chemotherapy with anti-EGFR antibody (anti-EGFR). RESULTS: 2643 mCRC patients treated with systemic therapy were included. Median percent change of CEA from baseline to first restaging for patients with CR/PR/SD (non-PD) and PD was -53.1% and +23.6% for chemo (n=957), and -71.7% and -45.3% for anti-VEGF (n=1355). The optimal AUC cutoff for differentiating PD from non-PD on first restaging was -7.5% for chemo and -62.0% for anti-VEGF, chemo, ORadj=6.51 (95%CI 3.31-12.83, P < 0.001); anti-VEGF, ORadj=3.45 (95%CI 1.93-6.18, P < 0.001). A 99% NPV clinical cutoff for prediction of non-PD would avoid CT scan at first restaging in 21.0% of chemo and 16.2% of anti-VEGF treated patients. Among patients with SD on first restaging, those with CEA decrease from baseline had statistically significantly improved progression-free and overall survival. CONCLUSIONS: Change in CEA from baseline to first restaging can accurately predict non-progression and correlates with long-term outcomes in patients receiving systemic chemotherapy.

3.
JAMA Netw Open ; 2(9): e1911750, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31539075

RESUMO

Importance: Tumor measurements can be used to estimate time to nadir and depth of nadir as potential surrogates for overall survival (OS). Objective: To assess time to nadir and depth of nadir as surrogates for OS in metastatic colorectal cancer. Design, Setting, and Participants: Pooled analysis of 20 randomized clinical trials within the Aide et Recherche en Cancerologie Digestive database, which contains academic and industry-sponsored trials, was conducted. Three sets of comparisons were performed: chemotherapy alone, antiangiogenic agents, and anti-epidermal growth factor receptor agents in first-line treatment for patients with metastatic colorectal cancer. Main Outcomes and Measures: Surrogacy of time to nadir and depth of nadir was assessed at the trial level based on joint modeling of relative tumor-size change vs baseline and OS. Treatment effects on time to nadir and on depth of nadir were defined in terms of between-arm differences in time to nadir and in depth of nadir, and both were assessed in linear regressions for their correlation with treatment effects (hazard ratios) on OS within each set. The strengths of association were quantified using sample-size-weighted coefficients of determination (R2), with values closer to 1.00 indicating stronger association. At the patient level, the correlation was assessed between modeled relative tumor-size change and OS. Results: For 14 chemotherapy comparisons in 4289 patients, the R2 value was 0.63 (95% CI, 0.30-0.96) for the association between treatment effects on time to nadir and OS and 0.08 (95% CI, 0-0.37) for depth of nadir and OS. For 11 antiangiogenic agent comparisons (4854 patients), corresponding values of R2 were 0.25 (95% CI, 0-0.72) and 0.06 (95% CI, 0-0.35). For 8 anti-epidermal growth factor receptor comparisons (2684 patients), corresponding values of R2 were 0.24 (95% CI, 0-0.83) and 0.21 (95% CI, 0-0.78). Conclusions and Relevance: In contrast with early reports favoring depth of response as a surrogate, these results suggest that neither time to nadir nor depth of nadir is an acceptable surrogate for OS in the first-line treatment of metastatic colorectal cancer.

4.
Cancer Epidemiol Biomarkers Prev ; 28(7): 1153-1161, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31263053

RESUMO

BACKGROUND: We explored and validated the association of postoperative carcinoembryonic antigen (CEA) with disease-free survival (DFS) and overall survival (OS) in stage III colon cancer. METHODS: Patients with stage III colon cancer from the MOSAIC and PETACC-8 trials were enrolled. The relation between CEA and outcomes was continuously modeled with the restricted cubic splines (RCS) method. Association of CEA with outcomes was assessed by the Kaplan-Meier method, with two risk groups among patients with a CEA level ≤5 ng/mL. Multivariate Cox proportional hazard models were constructed. RESULTS: The CEA level was available in 1,292 (96%) and 2,477 (97%) patients in the discovery and validation cohorts. The RCS analysis confirmed that patients with a CEA level >5 ng/mL were at highest risk of recurrence or death and those with a CEA level ≤5 ng/mL presented a heterogeneous risk population. In the discovery cohort, the 3-year DFS rate was 75%, 65%, and 45% in a group of patients with CEA level of 0-1.30 ng/mL (n = 630), 1.30-5 ng/mL (n = 613), and >5 ng/mL (n = 49), respectively (P < 0.001). CEA was independently associated with endpoints. All findings were confirmed in the validation cohort. CONCLUSIONS: Postoperative CEA level was highly and independently associated with DFS and OS, especially in patients with a CEA level of ≤5 ng/mL, suggesting that this cutoff is not optimal. IMPACT: CEA levels should be applied more accurately in future trials and clinical practice.

5.
Br J Cancer ; 121(4): 312-317, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31296923

RESUMO

BACKGROUND: Adjuvant treatment for stage II colon cancer (CC) can be proposed to patients with high-risk disease. Recently, 2.35 ng/mL carcinoembryonic antigen (CEA) was identified as the best cut-off value. This post hoc analysis of the MOSAIC trial assessed post-operative CEA prognostic value for survival outcomes and predictive value for the addition of oxaliplatin to adjuvant treatment. METHODS: Prognostic and predictive values of post-operative CEA in patients with stage II CC were evaluated with Kaplan-Meier survival curves and Cox model with interaction terms. Disease-free survival (DFS) and overall survival (OS) were estimated. RESULTS: Among 899 stage II CC patients, post-operative CEA was available in 867 (96.4%); and 434 (48.65%) had a high-risk stage II disease. The 3-year DFS rate was 88.5% and 78.7% in the ≤ 2.35 ng/mL and > 2.35 ng/mL group, respectively (P = 0.006). Use of oxaliplatin showed survival benefit only in patients with high-risk stage II CC and post-operative CEA > 2.35 ng/ml (interaction term P = 0.09 and 0.03 for DFS and OS). CONCLUSION: CEA is a strong prognostic factor for DFS and OS in stage II CC. In the MOSAIC trial, only high-risk stage II CC patients with post-operative CEA > 2.35 ng/mL benefited from the addition of oxaliplatin to LV5FU2. TRIAL REGISTRATION: NCT00275210 (January 11, 2006).

7.
Int J Oncol ; 54(4): 1433-1445, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30720091

RESUMO

Aflibercept in combination with 5­fluorouracil (5­FU)/irinotecan improves overall survival in the second­line therapy of patients with metastatic colorectal cancer (mCRC). In this study, we evaluated the effects of aflibercept in first­line therapy with FOLFOX followed by maintenance with fluoropyrimidine. VELVET was a prospective, single­arm multicenter phase II study (completed). Patients with previously untreated, unresectable, evaluable or measurable mCRC, with an age ≥18 years, and an ECOG performance status of 0­2 received 6 cycles of modified FOLFOX7 (5­FU/folinic acid and oxaliplatin) with aflibercept at 4 mg/kg every 2 weeks followed by maintenance therapy with fluoropyrimidine with aflibercept until disease progression or limiting toxicity. The reintroduction of oxaliplatin was performed at first progression. The primary endpoint was progression­free survival (PFS) at 6 months. From May, 2013 to May, 2014, 49 patients were included and 48 were evaluable for response. In total, 33 patients (67.4%) were alive without progression at 6 months. The Kaplan­Meier survival 6­month and 1­year PFS rates were 79.1 and 36.1%, respectively, and the median PFS was 9.3 months (95% CI, 8.3­12.5). The objective response rate was 59.2% (N=29/49). The most common (≥10%) grade 3­4 adverse events were hypertension (23%), fatigue (15%), neutropenia (12%), neuropathy (12%) and stomatitis (10%). Three (6%) treatment­related deaths occurred: One from stroke, one from pulmonary embolism and one from neutropenic sepsis. On the whole, this study demonstrates the efficacy of aflibercept in combination with an oxaliplatin­based regimen in the first­line therapy of patients with mCRC. A strict monitoring of blood pressure and immediate management of hypertension during therapy is mandatory.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/patologia , Esquema de Medicação , Feminino , Fluoruracila/efeitos adversos , Humanos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Estudos Prospectivos , Proteínas Recombinantes de Fusão/efeitos adversos , Análise de Sobrevida , Resultado do Tratamento
8.
Eur J Cancer ; 103: 205-213, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30268921

RESUMO

PURPOSE: Patients with left-sided colon tumours have better survival and respond differently to biologics compared with patients with right-sided tumours. Left-sided colon tumours and rectal cancers are often grouped together. Herein, we examined the clinicopathological differences and outcomes between left-sided colon and rectal cancers. PATIENTS AND METHODS: Data from 2879 metastatic colorectal cancer patients enrolled on six first-line clinical trials during 2004-2010 were pooled. Patients were included if the primary tumour origin was clearly defined. Progression-free survival (PFS) and overall survival (OS) were compared in the two groups after adjusting for patient and tumour characteristics, metastatic sites and the first-line regimen. RESULTS: In total, 1374 patients with metastatic left-sided colon cancer and 1505 patients with metastatic rectal cancers were evaluated. Left-sided colon cancer patients were more likely to be female (40.1% versus 32.6%; P < 0.0001) and older (31.0% ≥ 70 years versus 25.8%; P = 0.0033) compared with rectal cancers patients. Patients with left-sided colon cancer had higher rates of liver metastases (80.9% versus 72.3%, P < 0.0001) but lower rates of lung metastases (34.2% versus 53.8%, P < 0.0001). KRAS mutations were slightly less frequent among left-sided tumours (34.8% versus 40.5%; P = 0.0103). Patients with left-sided tumours had approximately similar PFS (median 7.4 versus 6.9 months; hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.87-1.03; P = 0.1998) and OS (median 17.4 versus 16.6 months; HR 0.99, 95% CI 0.91-1.07; P = 0.7597) compared with rectal cancer patients. CONCLUSION: The site of tumour origin within the left side was not prognostic of outcomes. Moreover, neither bevacizumab nor cetuximab impacted, differently, the findings of the comparisons in outcomes between patients with left-sided colon tumours or rectal cancers.


Assuntos
Neoplasias do Colo/terapia , Neoplasias Retais/terapia , Neoplasias do Colo/patologia , Feminino , Pool Gênico , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Retais/patologia
9.
World J Clin Oncol ; 9(5): 110-118, 2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30254966

RESUMO

AIM: To evaluate the efficacy and safety of the modified FOLFIRI3-aflibercept as second-line therapy in patients with metastatic colorectal cancer. METHODS: This is a retrospective multicenter cohort, evaluating the efficacy and safety of the association of aflibercept with FOLFIRI3 (day 1: aflibercept 4 mg/kg, folinic acid 400 mg/m2, irinotecan 90 mg/m2, 5-fluorouracil infusion 2400 mg/m2 per 46 h; day 3: irinotecan 90 mg/m2) in patients with previously treated metastatic colorectal cancer. The primary endpoint was overall response rate (ORR). Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Among 74 patients treated in four French centers, nine were excluded due to prior use of aflibercept (n = 3), more than one prior treatment line in irinotecan-naïve patients (n = 3), and inadequate liver function (n = 3). In the "irinotecan-naïve" patients (n = 30), ORR was 43.3% and DCR was 76.7%. Median PFS and OS were 11.3 mo (95%CI: 6.1-29.0) and 17.0 mo (95%CI: 13.0-17.3), respectively. The most common (> 5%) grade 3-4 adverse events were diarrhea (37.9%), neutropenia (14.3%), stomatitis and anemia (10.4%), and hypertension (6.7%). In the "pre-exposed irinotecan" patients (n = 35), 20 (57.1%) received ≥ 2 prior lines of treatment. ORR was 34.3% and DCR was 60.0%. Median PFS and OS were 5.7 mo (95%CI: 3.9-10.4) and 14.3 mo (95%CI: 12.8-19.5), respectively. CONCLUSION: Minimally modified FOLFIRI has improvement dramatically the FOLFIRI3-aflibercept efficacy, whatever prior use of irinotecan. A prospective randomized trial is warranted to compare FOLFIRI-aflibercept to FOLFIRI3-aflibercept.

10.
Eur J Cancer ; 100: 35-45, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29936065

RESUMO

BACKGROUND: Patient characteristics and stratification factors are key features influencing trial outcomes. However, there is substantial heterogeneity in reporting of patient characteristics and use of stratification factors in phase 3 trials investigating systemic treatment of metastatic colorectal cancer (mCRC). We aimed to develop a minimum set of essential baseline characteristics and stratification factors to include in such trials. METHODS: We performed a modified, two-round Delphi survey among international experts with wide experience in the conduct and methodology of phase 3 trials of systemic treatment of mCRC. RESULTS: Thirty mCRC experts from 15 different countries completed both consensus rounds. A total of 14 patient characteristics were included in the recommended set: age, performance status, primary tumour location, primary tumour resection, prior chemotherapy, number of metastatic sites, liver-only disease, liver involvement, surgical resection of metastases, synchronous versus metachronous metastases, (K)RAS and BRAF mutation status, microsatellite instability/mismatch repair status and number of prior treatment lines. A total of five patient characteristics were considered the most relevant stratification factors: RAS/BRAF mutation status, performance status, primary tumour sidedness and liver-only disease. CONCLUSIONS: This survey provides a minimum set of essential baseline patient characteristics and stratification factors to include in phase 3 trials of systemic treatment of mCRC. Inclusion of these patient characteristics and strata in study protocols and final study reports will improve interpretation of trial results and facilitate cross-study comparisons.


Assuntos
Ensaios Clínicos Fase III como Assunto/normas , Neoplasias Colorretais/terapia , Neoplasias Hepáticas/terapia , Seleção de Pacientes , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Consenso , Reparo de Erro de Pareamento de DNA , Técnica Delfos , Humanos , Avaliação de Estado de Karnofsky , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Instabilidade de Microssatélites , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Resultado do Tratamento
11.
Biomed Pharmacother ; 99: 543-551, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29902865

RESUMO

PURPOSE: Despite similarities with BRCA-mutated breast cancers, triple-negative breast cancers (TNBC) remain resistant to poly(ADP-ribose) polymerase (PARP) inhibitors as single agents. Histone deacetylase inhibitors (HDACi) can decrease expression of proteins involved in DNA repair. We thus hypothesized that a HDACi (suberoylanilide hydroxamic acid (SAHA) or belinostat) could sensitize TNBC to the PARP inhibitor olaparib. METHODS: Human TNBC cells were co-treated with olaparib and either SAHA or belinostat, and their effects on survival, proliferation, cell cycle, apoptosis and DNA repair pathways were evaluated. Subcutaneous xenografts were used to determine the effect of the combination treatment in vivo. RESULTS: HDACi and olaparib synergistically inhibited proliferation of a panel of 8 TNBC cell lines in vitro and in nude mice harboring TNBC xenografts in vivo. We noted a weaker synergism in PTEN-deficient TNBC cells and a stronger synergism in BRCA1-mutated TNBC cells. In the BRCA1-mutated cell line HCC-1937, we observed a drastic decrease in the expression of proteins involved in homologous recombination (HR), leading to a large imbalance of the ratio P-H2AX/RAD51. In BRCA1 wild type (wt) cell lines, effect of the combination treatment relied on DNA damage-induced cell cycle arrest followed by induction of apoptosis. CONCLUSION: In summary, these results provide a preclinical rationale to combine a HDACi with a PARP inhibitor to reduce HR efficiency in TNBC and sensitize these aggressive tumors to PARP inhibition.


Assuntos
Proteína BRCA1/genética , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Mutação/genética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Camundongos Nus , Ftalazinas/farmacologia , Ftalazinas/uso terapêutico , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Neoplasias de Mama Triplo Negativas/patologia , Vorinostat , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Eur J Cancer ; 98: 1-9, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29807237

RESUMO

BACKGROUND: Previous studies showed that high and low body mass index (BMI) was associated with worse prognosis in early-stage colorectal cancer (CRC), and low BMI was associated with worse prognosis in metastatic CRC (mCRC). We aimed to assess efficacy outcomes according to BMI. PATIENTS AND METHODS: A pooled analysis of individual data from 2085 patients enrolled in eight FFCD first-line mCRC trials from 1991 to 2013 was performed. Comparisons were made according to the BMI cut-off: Obese (BMI ≥30), overweight patients (BMI ≥ 25), normal BMI patients (BMI: 18.5-24) and thin patients (BMI <18.5). Interaction tests were performed between BMI effect and sex, age and the addition of antiangiogenics to chemotherapy. RESULTS: The rate of BMI ≥25 patients was 41.5%, ranging from 37.6% (1991-1999 period) to 41.5% (2000-2006 period) and 44.8% (2007-2013 period). Comparison of overweight patients versus normal BMI range patients revealed a significant improvement of median overall survival (OS) (18.5 versus 16.3 months, HR = 0.88 [0.80-0.98] p = 0.02) and objective response rate (ORR) (42% versus 36% OR = 1.23 [1.01-1.50] p = 0.04) but a comparable median progression-free survival (PFS) (7.8 versus 7.2 months, HR = 0.96 [0.87-1.05] p = 0.35). Subgroup analyses revealed that overweight was significantly associated with better OS in men. OS and PFS were significantly shorter in thin patients. CONCLUSION: Overweight patients had a prolonged OS compared with normal weight patients with mCRC. The association of overweight with better OS was only observed in men. The pejorative prognosis of BMI <18.5 was confirmed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Índice de Massa Corporal , Neoplasias Colorretais/tratamento farmacológico , Sobrepeso/fisiopatologia , Idoso , Inibidores da Angiogênese/administração & dosagem , Ensaios Clínicos como Assunto , Neoplasias Colorretais/patologia , Neoplasias Colorretais/fisiopatologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Metástase Neoplásica , /estatística & dados numéricos , Prognóstico
13.
J Cancer Res Clin Oncol ; 144(6): 1197-1204, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29644408

RESUMO

PURPOSE: The old approach of one therapeutic for all patients with mCRC is evolving with a need to target specific molecular aberrations or cell-signalling pathways. Molecular screening approaches and new biomarkers are required to fully characterize tumours, identify patients most likely to benefit, and predict treatment response. METHODS: MODUL is a signal-seeking trial with a design that is highly adaptable, permitting modification of different treatment cohorts and inclusion of further additional cohorts based on novel evidence on new compounds/combinations that emerge during the study. RESULTS: MODUL is ongoing and its adaptable nature permits timely and efficient recruitment of patients into the most appropriate cohort. Recruitment will take place over approximately 5 years in Europe, Asia, Africa, and South America. The design of MODUL with ongoing parallel/sequential treatment cohorts means that the overall size and duration of the trial can be modified/prolonged based on accumulation of new data. CONCLUSIONS: The early success of the current trial suggests that the design may provide definitive leads in a patient-friendly and relatively economical trial structure. Along with other biomarker-driven trials that are currently underway, it is hoped that MODUL will contribute to the continuing evolution of clinical trial design and permit a more 'tailored' approach to the treatment of patients with mCRC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Estudos de Coortes , Neoplasias Colorretais/enzimologia , Determinação de Ponto Final , Humanos , Quimioterapia de Indução , Quimioterapia de Manutenção , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Receptor ErbB-2/metabolismo
14.
J Clin Oncol ; 36(15): 1469-1477, 2018 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-29620995

RESUMO

Purpose Reduction of adjuvant treatment duration may decrease toxicities without loss of efficacy in stage III colon cancer. This could offer clear advantages to patients and health care providers. Methods In International Duration Evaluation of Adjuvant Chemotherapy (IDEA) France, as part of the IDEA international collaboration, patient with colon cancer patients were randomly assigned to 3 and 6 months of modified FOLFOX6 (mFOLFOX6: infusional fluorouracil, leucovorin, and oxaliplatin) or capecitabine plus oxaliplatin (CAPOX) by physician choice. The primary end point was disease-free survival (DFS), and analyses were descriptive. Results A total of 2,010 eligible patients received either 3 or 6 months of chemotherapy (modified intention-to-treat population); 2,000 (99%) had stage III colon cancer (N1: 75%, N2: 25%); 1,809 (90%) received mFOLFOX6, and 201 (10%) received CAPOX. The median age was 64 years, and the median follow-up time was 4.3 years. Overall, 94% (3 months) and 78% (6 months) of patients completed treatment (fluoropyrimidines ± oxaliplatin). Maximal grade 2 and 3 neuropathy rates were 28% and 8% in the 3-month arm and 41% and 25% in the 6-month arm ( P < .001). Final rates of residual neuropathy greater than grade 1 were 3% in the 3-month arm and 7% in the 6-month arm ( P < .001). There were 578 DFS events: 314 and 264 in the 3- and 6-month arms, respectively. The 3-year DFS rates were 72% and 76% in the 3- and 6-month arms, respectively (hazard ratio [HR], 1.24; 95% CI, 1.05 to 1.46; P = .0112). In the 3 and 6-month arms, respectively, for patients who received mFOLFOX6, the 3-year DFS rates were 72% and 76% (HR, 1.27; 95% CI, 1.07 to 1.51); for the T4 and/or N2 population, they were 58% and 66% (HR, 1.44; 95% CI, 1.14 to 1.82); and for the T1-3N1 population, they were 81% and 83% (HR, 1.15; 95% CI, 0.89 to 1.49). Conclusion IDEA France, in which 90% of patients received mFOLFOX6, shows superiority of 6 months of adjuvant chemotherapy compared with 3 months, especially in the T4 and/or N2 subgroups. These results should be considered alongside the international IDEA collaboration data.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Oxaliplatina/administração & dosagem , Idoso , Quimioterapia Adjuvante , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Intervalo Livre de Doença , Feminino , Fluoruracila/uso terapêutico , França , Humanos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Compostos Organoplatínicos/uso terapêutico , Fatores de Tempo , Resultado do Tratamento
15.
Clin Cancer Res ; 24(11): 2548-2558, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29490990

RESUMO

Purpose: There is extensive cross-talk between VEGF- and EGFR-pathway signaling in colorectal cancer. However, combinations of VEGF- and EGFR-targeted monoclonal antibodies (mAb) show disappointing activity, in particular for patients with mutant RAS Previous results show that tyrosine kinase inhibitors (TKI) can be active in colorectal cancer models resistant to mAbs. This prompted us to examine whether the activity of bevacizumab can be increased by combination with erlotinib.Experimental Design: The antitumor activity of bevacizumab, erlotinib, and their combination was determined in colorectal cancer models with different RAS status and bevacizumab sensitivity. EGFR/VEGF pathway activation was characterized by immunohistochemistry, Western blot, and ELISA assays. The influence of cetuximab and erlotinib on EGF-mediated migration and the EGFR-EGF ligand feedback loop was established in colorectal cancer cell lines with different RAS status.Results: The addition of erlotinib increased bevacizumab activity in all models independent of RAS status. Bevacizumab exposure was accompanied by marked EGFR activation in tumor cells as well as in tumor-associated endothelial cells (TECs) and resulted in strong accumulation of intracellular EGFR, which could be attenuated by erlotinib. In cellular models, erlotinib was able to attenuate EGF-mediated functions in all cell lines independent of RAS status while cetuximab only showed activity in RAS wild-type cells.Conclusions: These results should provide a molecular framework to better understand the increased activity of the bevacizumab-erlotinib combination, compared with bevacizumab alone, in the GERCOR DREAM phase III clinical trial. Differential activity of mAbs and TKIs targeting the same signaling pathway is likely applicable for other tumor types. Clin Cancer Res; 24(11); 2548-58. ©2018 AACR.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Proteínas ras/genética , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Cloridrato de Erlotinib/administração & dosagem , Humanos , Camundongos , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Transdução de Sinais , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas ras/metabolismo
16.
Oncotarget ; 9(12): 10272-10283, 2018 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-29535805

RESUMO

Background: The aim of this meta-analysis was to evaluate efficacy and safety of first-line chemotherapy with or without a monoclonal antibody in elderly patients (≥ 70 years) with metastatic colorectal cancer (mCRC), since they are frequently underrepresented in clinical trials. Results: Individual data from 10 studies were included. From a total of 3271 patients, 604 patients (18%) were ≥ 70 years (median 73 years, range 70-88). Of these, 335 patients were treated with a bevacizumab-based first-line regimen and 265 were treated with chemotherapy only. The median PFS was 8.2 vs. 6.5 months and the median OS was 16.7 vs. 13.0 months in patients treated with and without bevacizumab, respectively. The safety profile of bevacizumab in combination with first-line chemotherapy did not differ from published clinical trials. Materials and Methods: PubMed and Cochrane Library searches were performed on 29 April 2013 and studies published to this date were included. Authors were contacted to request progression-free survival (PFS), overall survival (OS) data, patient data on treatment regimens, age, sex and potential signs of toxicity in patients ≥ 70 years of age. Conclusions: This meta-analysis suggests that the addition of bevacizumab to standard first-line chemotherapy improves clinical outcome in elderly patients with mCRC and is well tolerated.

17.
J Natl Cancer Inst ; 110(6): 638-648, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29267900

RESUMO

Background: Estimating prognosis on the basis of clinicopathologic factors can inform clinical practice and improve risk stratification for clinical trials. We constructed prognostic nomograms for one-year overall survival and six-month progression-free survival in metastatic colorectal carcinoma by using the ARCAD database. Methods: Data from 22 674 patients in 26 randomized phase III clinical trials since 1997 were used to construct and validate Cox models, stratified by treatment arm within each study. Candidate variables included baseline age, sex, body mass index, performance status, colon vs rectal cancer, prior chemotherapy, number and location of metastatic sites, tumor mutation status (BRAF, KRAS), bilirubin, albumin, white blood cell count, hemoglobin, platelets, absolute neutrophil count, and derived neutrophil-to-lymphocyte ratio. Missing data (<11%) were imputed, continuous variables modeled with splines, and clinically relevant pairwise interactions tested if P values were less than .001. Final models were internally validated via bootstrapping to obtain optimism-corrected calibration and discrimination C-indices, and externally validated on a 10% holdout sample from each trial (n = 2257). Results: In final models, all included variables were associated with overall survival except for lung metastases, and all but total white cell count associated with progression-free survival. No clinically relevant pairwise interactions were identified. Final nomogram calibration was good (C = 0.68 for overall and C = 0.62 for progression-free survival), as was external validity (concordance between predicted >50% vs < 50% probability) and actual (yes/no) survival (72.8% and 68.2% concordance, respectively, for one-year overall and six-month progression-free survival, between predicted [>50% vs < 50% probability] and actual [yes/no] overall and progression-free survival). Median survival predictions fell within the actual 95% Kaplan-Meier confidence intervals. Conclusions: The nomograms are well calibrated and internally and externally valid. They have the potential to aid prognostication and patient-physician communication and balance risk in colorectal cancer trials.


Assuntos
Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Nomogramas , Medicina de Precisão/métodos , Idoso , Neoplasias Colorretais/mortalidade , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Metástase Neoplásica , Prognóstico , Intervalo Livre de Progressão , Análise de Sobrevida
18.
Cancers (Basel) ; 9(6)2017 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-28587143

RESUMO

Colorectal cancer is one of the most commonly diagnosed cancers worldwide and nearly half of patients will develop metastatic disease at some point during the course of their disease. The goal of anticancer therapy in this context is to extend survival, while trying to maximise the patient's health-related quality of life. To this end, we need to understand how to incorporate patient-reported outcomes into clinical trials and routine practice to accurately assess if treatment strategies are providing clinical benefit for the patient. This review reflects the proceedings of a 2016 European Society of Digestive Oncology workshop, where the authors discussed the use of patient-reported outcomes to measure health-related quality of life when evaluating treatment during the management of colorectal cancer. A summary of the challenges associated with implementing patient-reported outcomes in clinical trials is provided, as well as a review of the current clinical evidence surrounding patient-reported outcomes in metastatic colorectal cancer.

19.
J Clin Oncol ; 35(17): 1929-1937, 2017 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-28414610

RESUMO

Purpose Factors contributing to early mortality after initiation of treatment of metastatic colorectal cancer are poorly understood. Materials and Methods Data from 22,654 patients enrolled in 28 randomized phase III trials contained in the ARCAD (Aide et Recherche en Cancérologie Digestive) database were pooled. Multivariable logistic regression models for 30-, 60-, and 90-day mortality were constructed, including clinically and statistically significant patient and disease factors and interaction terms. A calculator (nomogram) for 90-day mortality was developed and validated internally using bootstrapping methods and externally using a 10% random holdout sample from each trial. The impact of early progression on the likelihood of survival to 90 days was examined with time-dependent Cox proportional hazards models. Results Mortality rates were 1.4% at 30 days, 3.4% at 60 days, and 5.5% at 90 days. Among baseline factors, advanced age, lower body mass index, poorer performance status, increased number of metastatic sites, BRAF mutant status, and several laboratory parameters were associated with increased likelihood of early mortality. A multivariable model for 90-day mortality showed strong internal discrimination (C-index, 0.77) and good calibration across risk groups as well as accurate predictions in the external validation set, both overall and within patient subgroups. Conclusion A validated clinical nomogram has been developed to quantify the risk of early death for individual patients during initial treatment of metastatic colorectal cancer. This tool may be used for patient eligibility assessment or risk stratification in future clinical trials and to identify patients requiring more or less aggressive therapy and additional supportive measures during and after treatment.


Assuntos
Ensaios Clínicos Fase III como Assunto/estatística & dados numéricos , Neoplasias Colorretais/mortalidade , Nomogramas , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Idoso , Progressão da Doença , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Reprodutibilidade dos Testes
20.
Curr Treat Options Oncol ; 18(2): 9, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28214977

RESUMO

OPINION STATEMENT: The BRAF activating mutation, harbored by approximately 10% of colorectal cancers (CRC), confers dramatic prognosis to advanced diseases. In early-stage setting, the identification of the BRAF mutation does not impact the therapeutic decision. Yet, the BRAF mutation could be considered as a stratification factor in adjuvant trials, because of its prognostic impact after relapse. Moreover, both BRAF mutation and mismatch repair (MMR) statuses should be determined in all CRC to help identify sporadic tumors versus Lynch syndrome-related tumors. Indeed, in patients with MMR-deficient (dMMR) tumors and MLH1 loss of expression, the BRAFV600E mutation indicates a sporadic origin. In advanced BRAF-mutated CRC, the standard of care remains fluoropyrimidine-based cytotoxic regimen in combination with bevacizumab. Although a recent meta-analysis showed that there was insufficient data to justify the exclusion of anti-EGFR monoclonal antibodies, antiangiogenic agents should be preferred in the first-line setting. Despite the lack of a randomized phase 3 study dedicated to BRAF-mutated CRC, chemotherapy intensification combining a quadruple association of 5-fluorouracil, oxaliplatin, irinotecan (FOLFOXIRI), and bevacizumab seems like a valid option. Although first results with BRAF inhibitors as single agents in BRAF-mutated CRC were disappointing, their association with therapies targeting the MAPK pathway seems to overcome the primary resistance to BRAF inhibition. In the field of sporadic CRC, the BRAF mutation is strongly associated with MMR deficiency. Considering breakthrough results of immune checkpoint inhibitors in dMMR repair tumors, determination of the MMR status appears to be mandatory. Given the dramatic prognosis conferred by the BRAF mutation, patients with BRAF-mutated advanced CRC need to be systematically identified and proposed for clinical trial enrolment in order to benefit from innovative therapies.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/terapia , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Substituição de Aminoácidos , Códon , Neoplasias Colorretais/diagnóstico , Terapia Combinada , Reparo de Erro de Pareamento de DNA/efeitos dos fármacos , Predisposição Genética para Doença , Humanos , Instabilidade de Microssatélites , Terapia de Alvo Molecular , Metástase Neoplásica , Estadiamento de Neoplasias , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores
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