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1.
Oncologist ; 29(9): e1149-e1158, 2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39235326

RESUMO

INTRODUCTION: Predictive markers of LV5FU2 maintenance benefit after first-line induction with FOLFIRINOX in patients with metastatic pancreatic cancer are necessary to select patients who will not be harmed by this strategy. PATIENTS AND METHODS: We focused on patients who received 12 cycles of FOLFIRINOX (arm A, N = 88) or 8 cycles of FOLFIRINOX followed by LV5FU2 maintenance in controlled patients (arm B, N = 91) from the PRODIGE-35 trial. Prognostic factors and predictors of efficiency were identified by using Cox regression. Median progression-free survival (PFS), overall survival (OS), and time to deterioration of quality of life (TTD-QoL) were evaluated. RESULTS: Poor independent prognostic factors were primary tumor in place, age <65 years and the presence of liver metastases for PFS, a baseline neutrophil/lymphocyte ratio (NLR) ≥5 and CA19.9 ≥500 UI/L for OS, independent of the treatment arm. Patients with one metastatic site had a longer PFS in arm A, whereas patients with ≥2 metastatic sites had a longer PFS in arm B. We also identified predictors of OS and TTD-QoL in arm B but these differences were not statistically significant. CONCLUSION: Except for patients with one metastatic site who benefited more from 12 cycles of FOLFIRINOX, a maintenance strategy with LV5FU2 should be widely offered to mPC patients whose survival and QoL are preserved after 4 months of FOLFIRINOX. (ClinicalTrials.gov: NCT02352337).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Fluoruracila , Irinotecano , Leucovorina , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Leucovorina/uso terapêutico , Leucovorina/administração & dosagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Irinotecano/uso terapêutico , Irinotecano/administração & dosagem , Prognóstico , Qualidade de Vida , Oxaliplatina/uso terapêutico , Oxaliplatina/administração & dosagem , Adulto , Metástase Neoplásica
2.
Pain Pract ; 24(3): 567-572, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38050874

RESUMO

BACKGROUND: Post herpetic neuralgia (PHN) is a chronic neuropathic pain syndrome which presents after an episode of herpes zoster caused by the reactivation of varicella zoster virus. Conservative treatment starts with pharmacological measures using Anti-epileptics and Antidepressants. Some patients also respond well to epidural steroid injections too, but the effect is usually short lasting. Dorsal Root Ganglion Stimulator (DRG-S) has recently been suggested as a new treatment modality for PHN due to its selective targeting of the pathophysiologic focus. CASE SERIES: We are reporting three cases, who were suffering from neuropathic pain after an episode of herpes zoster. Pain and pain related suffering scores were high, even with multiple antiepileptics and opioid medications. They underwent DRG-S implant and appreciated more than 50% reduction of their pain score, meaningful reduction in the dose of medications along with significant improvement of their general well being measured using Generalized Anxiety Disorder Questionnaire (GAD-7), pain disability index (PDI), and 9 Question Patient Health Questionnaire (PHQ-9). To our knowledge this is the first report on DRG stimulator from the Middle East Region. CONCLUSION: DRG-S has potential to be a preferable treatment option in patients with refractory PHN and acts as a specific targeted therapy in the treatment of these patients.


Assuntos
Herpes Zoster , Neuralgia Pós-Herpética , Neuralgia , Humanos , Neuralgia Pós-Herpética/tratamento farmacológico , Gânglios Espinais , Neuralgia/etiologia , Herpes Zoster/complicações , Anticonvulsivantes
3.
Br J Cancer ; 126(9): 1264-1270, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-34992255

RESUMO

BACKGROUND: Colorectal cancer (CRC) patients have a better prognosis if metastases are resectable. Initially, unresectable liver-only metastases can be converted to resectable with chemotherapy plus a targeted therapy. We assessed which of chemotherapy doublet (2-CTx) or triplet (3-CTx), combined with targeted therapy by RAS status, would be better in this setting. METHODS: PRODIGE 14 was an open-label, multicenter, randomised Phase 2 trial. CRC patients with initially defined unresectable liver-only metastases received either, 2-CTx (FOLFOX or FOLFIRI) or 3-CTx (FOLFIRINOX), plus bevacizumab/cetuximab by RAS status. The primary endpoint was to increase the R0/R1 liver-resection rate from 50 to 70% with the 3-CTx. RESULTS: Patients (n = 256) were mainly men with an ECOG PS of 0, and a median age of 60 years. In total, 109 patients (42.6%) had RAS-mutated tumours. After a median follow-up of 45.6 months, the R0/R1 liver-resection rate was 56.9% (95% CI: 48-66) with the 3-CTx versus 48.4% (95% CI: 39-57) with the 2-CTx (P = 0.17). Median overall survival was 43.4 months with 3-CTx versus 40 months with 2-CTx. CONCLUSION: We failed to increase from 50 to 70% the R0/R1 liver-resection rate with the use of 3-CTx combined with bevacizumab or cetuximab by RAS status in CRC patients with initially unresectable liver metastases.


Assuntos
Neoplasias Colorretais , Neoplasias Hepáticas , Neoplasias Pancreáticas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Camptotecina/uso terapêutico , Cetuximab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/tratamento farmacológico
4.
Lancet Oncol ; 22(5): 702-715, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33862000

RESUMO

BACKGROUND: Treatment of locally advanced rectal cancer with chemoradiotherapy, surgery, and adjuvant chemotherapy controls local disease, but distant metastases remain common. We aimed to assess whether administering neoadjuvant chemotherapy before preoperative chemoradiotherapy could reduce the risk of distant recurrences. METHODS: We did a phase 3, open-label, multicentre, randomised trial at 35 hospitals in France. Eligible patients were adults aged 18-75 years and had newly diagnosed, biopsy-proven, rectal adenocarcinoma staged cT3 or cT4 M0, with a WHO performance status of 0-1. Patients were randomly assigned (1:1) to either the neoadjuvant chemotherapy group or standard-of-care group, using an independent web-based system by minimisation method stratified by centre, extramural extension of the tumour into perirectal fat according to MRI, tumour location, and stage. Investigators and participants were not masked to treatment allocation. The neoadjuvant chemotherapy group received neoadjuvant chemotherapy with FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 intravenously every 14 days for 6 cycles), chemoradiotherapy (50 Gy during 5 weeks and 800 mg/m2 concurrent oral capecitabine twice daily for 5 days per week), total mesorectal excision, and adjuvant chemotherapy (3 months of modified FOLFOX6 [intravenous oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2, followed by intravenous 400 mg/m2 fluorouracil bolus and then continuous infusion at a dose of 2400 mg/m2 over 46 h every 14 days for six cycles] or capecitabine [1250 mg/m2 orally twice daily on days 1-14 every 21 days]). The standard-of-care group received chemoradiotherapy, total mesorectal excision, and adjuvant chemotherapy (for 6 months). The primary endpoint was disease-free survival assessed in the intention-to-treat population at 3 years. Safety analyses were done on treated patients. This trial was registered with EudraCT (2011-004406-25) and ClinicalTrials.gov (NCT01804790) and is now complete. FINDINGS: Between June 5, 2012, and June 26, 2017, 461 patients were randomly assigned to either the neoadjuvant chemotherapy group (n=231) or the standard-of-care group (n=230). At a median follow-up of 46·5 months (IQR 35·4-61·6), 3-year disease-free survival rates were 76% (95% CI 69-81) in the neoadjuvant chemotherapy group and 69% (62-74) in the standard-of-care group (stratified hazard ratio 0·69, 95% CI 0·49-0·97; p=0·034). During neoadjuvant chemotherapy, the most common grade 3-4 adverse events were neutropenia (38 [17%] of 225 patients) and diarrhoea (25 [11%] of 226). During chemoradiotherapy, the most common grade 3-4 adverse event was lymphopenia (59 [28%] of 212 in the neoadjuvant chemotherapy group vs 67 [30%] of 226 patients in the standard-of-care group). During adjuvant chemotherapy, the most common grade 3-4 adverse events were lymphopenia (18 [11%] of 161 in the neoadjuvant chemotherapy group vs 42 [27%] of 155 in the standard-of-care group), neutropenia (nine [6%] of 161 vs 28 [18%] of 155), and peripheral sensory neuropathy (19 [12%] of 162 vs 32 [21%] of 155). Serious adverse events occurred in 63 (27%) of 231 participants in the neoadjuvant chemotherapy group and 50 (22%) of 230 patients in the standard-of-care group (p=0·167), during the whole treatment period. During adjuvant therapy, serious adverse events occurred in 18 (11%) of 163 participants in the neoadjuvant chemotherapy group and 36 (23%) of 158 patients in the standard-of-care group (p=0·0049). Treatment-related deaths occurred in one (<1%) of 226 patients in the neoadjuvant chemotherapy group (sudden death) and two (1%) of 227 patients in the standard-of-care group (one sudden death and one myocardial infarction). INTERPRETATION: Intensification of chemotherapy using FOLFIRINOX before preoperative chemoradiotherapy significantly improved outcomes compared with preoperative chemoradiotherapy in patients with cT3 or cT4 M0 rectal cancer. The significantly improved disease-free survival in the neoadjuvant chemotherapy group and the decreased neurotoxicity indicates that the perioperative approach is more efficient and better tolerated than adjuvant chemotherapy. Therefore, the PRODIGE 23 results might change clinical practice. FUNDING: Institut National du Cancer, Ligue Nationale Contre le Cancer, and R&D Unicancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , Neoplasias Retais/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Irinotecano/efeitos adversos , Irinotecano/uso terapêutico , Leucovorina/efeitos adversos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Oxaliplatina/efeitos adversos , Oxaliplatina/uso terapêutico , Qualidade de Vida , Neoplasias Retais/mortalidade , Neoplasias Retais/psicologia
5.
Br J Cancer ; 124(12): 1941-1948, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33772154

RESUMO

BACKGROUND: FOLFIRINOX has shown promising results in locally advanced (LAPA) or borderline resectable (BRPA) pancreatic adenocarcinoma. We report here a cohort of patients treated with this regimen from the AGEO group. METHODS: This is a retrospective multicentre study. We included all consecutive patients with non-pre-treated LAPA or BRPA treated with FOLFIRINOX. RESULTS: We included 330 patients (57.9% male, 65.4% <65 years, 96.4% PS <2). Disease was classified as BRPA in 31.1% or LAPA in 68.9%. Objective response rate with FOLFIRINOX was 29.5% and stable disease 51%. Subsequent CRT was performed in 46.4% of patients and 23.9% had curative intent surgery. Resection rates were 42.1% for BRPA and 15.5% for LAPA. Main G3/4 toxicities were fatigue (15%), neutropenia (12%) and neuropathy (G2/3 35%). After a median follow-up of 26.7 months, median OS (mOS) and PFS were 21.4 and 12.4 months, respectively. For patients treated by FOLFIRINOX alone, or FOLFIRINOX followed by CRT, or FOLFIRINOX + /- CRT + surgery, mOS was 16.8 months, 21.8 months and not reached, respectively (p < 0.0001). CONCLUSIONS: FOLFIRINOX for LAPA and BRPA seems to be effective with a manageable toxicity profile. These promising results in "real-life" patients now have to be confirmed in a Phase 3 randomised trial.


Assuntos
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , Neoplasias Pancreáticas/terapia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Quimiorradioterapia/métodos , Estudos de Coortes , Terapia Combinada , Progressão da Doença , Feminino , Fluoruracila/uso terapêutico , França/epidemiologia , Humanos , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Oxaliplatina/uso terapêutico , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
6.
N Engl J Med ; 379(25): 2395-2406, 2018 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-30575490

RESUMO

BACKGROUND: Among patients with metastatic pancreatic cancer, combination chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) leads to longer overall survival than gemcitabine therapy. We compared the efficacy and safety of a modified FOLFIRINOX regimen with gemcitabine as adjuvant therapy in patients with resected pancreatic cancer. METHODS: We randomly assigned 493 patients with resected pancreatic ductal adenocarcinoma to receive a modified FOLFIRINOX regimen (oxaliplatin [85 mg per square meter of body-surface area], irinotecan [180 mg per square meter, reduced to 150 mg per square meter after a protocol-specified safety analysis], leucovorin [400 mg per square meter], and fluorouracil [2400 mg per square meter] every 2 weeks) or gemcitabine (1000 mg per square meter on days 1, 8, and 15 every 4 weeks) for 24 weeks. The primary end point was disease-free survival. Secondary end points included overall survival and safety. RESULTS: At a median follow-up of 33.6 months, the median disease-free survival was 21.6 months in the modified-FOLFIRINOX group and 12.8 months in the gemcitabine group (stratified hazard ratio for cancer-related event, second cancer, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.73; P<0.001). The disease-free survival rate at 3 years was 39.7% in the modified-FOLFIRINOX group and 21.4% in the gemcitabine group. The median overall survival was 54.4 months in the modified-FOLFIRINOX group and 35.0 months in the gemcitabine group (stratified hazard ratio for death, 0.64; 95% CI, 0.48 to 0.86; P=0.003). The overall survival rate at 3 years was 63.4% in the modified-FOLFIRINOX group and 48.6% in the gemcitabine group. Adverse events of grade 3 or 4 occurred in 75.9% of the patients in the modified-FOLFIRINOX group and in 52.9% of those in the gemcitabine group. One patient in the gemcitabine group died from toxic effects (interstitial pneumonitis). CONCLUSIONS: Adjuvant therapy with a modified FOLFIRINOX regimen led to significantly longer survival than gemcitabine among patients with resected pancreatic cancer, at the expense of a higher incidence of toxic effects. (Funded by R&D Unicancer and others; ClinicalTrials.gov number, NCT01526135 ; EudraCT number, 2011-002026-52 .).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Fluoruracila/uso terapêutico , Leucovorina/uso terapêutico , Compostos Organometálicos/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Combinação de Medicamentos , Feminino , Fluoruracila/efeitos adversos , Humanos , Irinotecano , Leucovorina/efeitos adversos , Doenças Pulmonares Intersticiais/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Compostos Organometálicos/efeitos adversos , Oxaliplatina , Modelos de Riscos Proporcionais , Estudos Prospectivos , Gencitabina
7.
Br J Clin Pharmacol ; 87(3): 1120-1128, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32656857

RESUMO

AIMS: Poor efficacy has been reported for patients with BRAF mutations for metastatic colorectal cancer (mCRC). METHODS: EREBUS is a French cohort study of wild-type (wt) KRAS unresectable mCRC patients initiating a first-line treatment with cetuximab from 2009 to 2010, followed for two years (five years for vital status). Molecular genetics platforms have provided additional RAS and BRAF mutation testing results. Progression-free survival (PFS) and overall survival (OS) were assessed according to tumour mutation (mt) status: RASmt/BRAFany, RASwt/BRAFmt and RASwt/BRAFwt. Multivariate Cox analyses were used to evaluate association between mutation status and death or progression. RESULTS: A total of 389 patients were included in 65 centres and with a known tumour mutation status: 64 RASmt/BRAFany (21%), 33 RASwt/BRAFmt (13%) and 213 RASwt/BRAFwt (87%). Respective baseline characteristics were: median age 65, 64 and 63 years, male gender 63%, 64% and 69%, Eastern Cooperative Oncology Group performance status ≤ 1 75%, 76% and 79%, and liver-only metastases 39%, 33% and 40%. Median progression-free survival was 8.0 months [5.9-9.3] for patients with RASmt/BRAFany, 6.0 months [2.3-7.2] for patients with RASwt/BRAFmt, and 10.4 months [9.5-11.0] for patients with RASwt/BRAFwt. Respectively, median overall survival was 18.4 months [10.9-23.3], 9.7 months [6.9-16.6] and 29.3 months [26.3-36.1]. In multivariate analyses, progression (HR = 2.71 [1.79-4.10]) and death (HR = 2.79 [1.81-4.30]) were more likely for RASwt/BRAFmt vs RASwt/BRAFwt patients. CONCLUSIONS: BRAF mutations were associated with markedly poorer outcomes in initially unresectable RASwt mCRC patients treated by cetuximab in first-line treatment.


Assuntos
Neoplasias Colorretais , Proteínas Proto-Oncogênicas B-raf , Protocolos de Quimioterapia Combinada Antineoplásica , Cetuximab/uso terapêutico , Estudos de Coortes , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Humanos , Masculino , Mutação , Metástase Neoplásica , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)
8.
Gut ; 69(3): 531-539, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31101691

RESUMO

PURPOSE: The objective of this study was to build and validate a radiomic signature to predict early a poor outcome using baseline and 2-month evaluation CT and to compare it to the RECIST1·1 and morphological criteria defined by changes in homogeneity and borders. METHODS: This study is an ancillary study from the PRODIGE-9 multicentre prospective study for which 491 patients with metastatic colorectal cancer (mCRC) treated by 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) and bevacizumab had been analysed. In 230 patients, computed texture analysis was performed on the dominant liver lesion (DLL) at baseline and 2 months after chemotherapy. RECIST1·1 evaluation was performed at 6 months. A radiomic signature (Survival PrEdiction in patients treated by FOLFIRI and bevacizumab for mCRC using contrast-enhanced CT TextuRe Analysis (SPECTRA) Score) combining the significant predictive features was built using multivariable Cox analysis in 120 patients, then locked, and validated in 110 patients. Overall survival (OS) was estimated with the Kaplan-Meier method and compared between groups with the logrank test. An external validation was performed in another cohort of 40 patients from the PRODIGE 20 Trial. RESULTS: In the training cohort, the significant predictive features for OS were: decrease in sum of the target liver lesions (STL), (adjusted hasard-ratio(aHR)=13·7, p=1·93×10-7), decrease in kurtosis (ssf=4) (aHR=1·08, p=0·001) and high baseline density of DLL, (aHR=0·98, p<0·001). Patients with a SPECTRA Score >0·02 had a lower OS in the training cohort (p<0·0001), in the validation cohort (p<0·0008) and in the external validation cohort (p=0·0027). SPECTRA Score at 2 months had the same prognostic value as RECIST at 6 months, while non-response according to RECIST1·1 at 2 months was not associated with a lower OS in the validation cohort (p=0·238). Morphological response was not associated with OS (p=0·41). CONCLUSION: A radiomic signature (combining decrease in STL, density and computed texture analysis of the DLL) at baseline and 2-month CT was able to predict OS, and identify good responders better than RECIST1.1 criteria in patients with mCRC treated by FOLFIRI and bevacizumab as a first-line treatment. This tool should now be validated by further prospective studies. TRIAL REGISTRATION: Clinicaltrial.gov identifier of the PRODIGE 9 study: NCT00952029.Clinicaltrial.gov identifier of the PRODIGE 20 study: NCT01900717.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/patologia , Biologia Computacional , Feminino , Fluoruracila/administração & dosagem , Humanos , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Interpretação de Imagem Radiográfica Assistida por Computador , Critérios de Avaliação de Resposta em Tumores Sólidos , Taxa de Sobrevida
9.
Br J Cancer ; 122(7): 957-962, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32015513

RESUMO

BACKGROUND: Identifying patients with metastatic colorectal cancer who will have an early disease progression during induction chemotherapy (IC) and identifying patients who may have a chemotherapy-free interval (CFI) after IC are two major challenges. METHODS: A logistic model was used to identify factors associated with early progression during IC and with short duration of the first CFI in 488 patients enrolled in the PRODIGE 9 trial. Independent factors were defined with a threshold 0.10. RESULTS: In multivariate analysis, baseline leukocytes >10 × 109/L (OR = 1.98 [1.02-3.8], p = 0.04), and stable or increasing CEA at 2 months (OR = 3.61 [1.68-7.75], p = 0.01) were independent factors associated with progression during IC. Male gender (OR = 1.725 [0.92-3.325], p = 0.09) and no tumour response at first evaluation (OR = 1.90 [0.96-3.76], p = 0.07) were significantly associated with a short CFI. The presence of BRAF V600E mutation was also associated with short CFI (OR = 4.59 [0.95; 22.3], p = 0.058). CONCLUSION: High baseline leukocyte count and the lack of CEA decrease level at first evaluation were associated with early progression, and could be in favour of early chemotherapy intensification. Male gender, no tumour response at first evaluation and BRAF mutation are associated with a short CFI, and may be considered for maintenance chemotherapy after IC. CLINICAL TRIAL NUMBER: NCT00952029.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Quimioterapia de Indução/métodos , Idoso , Progressão da Doença , Feminino , Humanos , Masculino
10.
BMC Cancer ; 20(1): 436, 2020 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-32423482

RESUMO

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) status is an indicator of a marked risk for toxicity following fluoropyrimidine (FP)-based chemotherapy. This notion is well-established for low DPD status but little is known about the clinical impact of high DPD activity. This study examined the possible link between high intrinsic lymphocytic DPD activity and overall survival, progression free survival and response to FP-based treatment in patients treated in our institution. METHODS: Lymphocytic DPD activity was assessed in a group of 136 patients receiving FP-based chemotherapy from 2004 to 2016. There were 105 digestive (77.2%), 24 breast (17.6%) and 7 head and neck cancers (5.2%). Cox or logistic regression models were applied with adjustment on all confounding factors that could modify OS, PFS or response. All models were stratified on the three cancer locations. A cut-off for DPD activity was assessed graphically and analytically. RESULTS: An optimal cut-off for DPD activity at 0.30 nmol/min/mg protein was identified as the best value for discriminating survivals and response. In multivariate analysis, individual lymphocytic DPD activity was significantly related to overall survival (p = 0.013; HR: 3.35 CI95%[1.27-8.86]), progression-free survival (p < 0.001; HR: 3.15 CI95%[1.75-5.66]) and response rate (p = 0.033; HR: 0.33 CI95%[0.12-0.92]) with a marked detrimental effect associated with high DPD activity. CONCLUSIONS: DPD status screening should result in a two-pronged approach with FP dose reduction in case of low intrinsic DPD and, inversely, an increased FP dose for high intrinsic DPD. In a context of personalized FP-based treatment, this innovative strategy needs to be prospectively validated.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Di-Hidrouracila Desidrogenase (NADP)/metabolismo , Neoplasias/tratamento farmacológico , Idoso , Capecitabina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Neoplasias/enzimologia , Neoplasias/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
11.
BMC Cancer ; 20(1): 352, 2020 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-32334548

RESUMO

BACKGROUND: Modified docetaxel, cisplatin, and 5-fluorouracil (mDCF) regimen has become a new standard for the treatment of metastatic or unresectable locally advanced recurrent squamous cell carcinoma of the anus (SCCA) after demonstrating improved efficacy (12-month PFS of 47%) in the Epitopes-HPV02 trial. Antibodies targeting the checkpoint inhibitor (CKI) programmed cell death protein-1 (PD1) have demonstrated the efficacy as monotherapies in second-line treatment of SCCA. The aim of this study is to evaluate the combination of atezolizumab and mDCF as first-line chemotherapy in a non-comparative multicentre randomized phase II study of advanced SCCA patients. METHODS: Patients with chemo-naive advanced histologically proven SCCA, metastatic or unresectable locally advanced recurrence, and Eastern Cooperative Oncology Group-performance status (ECOG-PS) < 2 will be eligible. The primary endpoint is a 12-month PFS rate. Using one-arm non-parametric survival with unilateral alpha type I error of 5% and a statistical power of 80%, the upper critical value for the 12-month PFS rate is 47% to reject H0. Assuming 5% lost to follow-up, 99 patients will be randomized on a 2:1 basis, 66 to the experimental arm (arm A, mDCF plus atezolizumab) and 33 to the standard arm (arm B, mDCF). In both arms, 8 cycles of mDCF will be administered. In arm A, patients receive mDCF with a fixed dose of atezolizumab (800 mg every 2 weeks) and are followed up to 1 year. Secondary endpoints are overall survival, PFS, response rate, safety, health-related quality of life, and an extensive biomarker programme and its correlation with the treatment efficacy. DISCUSSION: Although the Epitopes-HPV02 trial has changed long-lasting prognosis of patients with SCCA in advanced stage disease, more than 50% of patients will progress at 12 months. The purpose of the SCARCE trial to establish the addition of atezolizumab to mDCF as a new standard in this rare disease. Associated biomarker studies and the control arm could contribute to better understanding of the potential synergic and tumour resistance mechanisms in SCCA. TRIAL REGISTRATION: NCT03519295.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias do Ânus/patologia , Carcinoma de Células Escamosas/secundário , Cisplatino/administração & dosagem , Docetaxel/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Metástase Linfática , Masculino , Recidiva Local de Neoplasia/patologia , Prognóstico , Taxa de Sobrevida
12.
Gastric Cancer ; 23(1): 73-81, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31267360

RESUMO

BACKGROUND: The correlation between immune cells and the Lauren classification subtypes and their prognostic impact in advanced gastric cancer (AGC) are unknown. METHODS: Circulating natural killer (NK) cells, CD4+ and CD8+ T cells, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) were quantified in peripheral blood mononuclear cells (PBMCs) from 67 patients with untreated AGC enrolled in the PRODIGE 17-ACCORD 20 trial. CD56+ cells (NK), CD8+, and FoxP3+ (Treg) tumor-infiltrating lymphocytes (TILs) were assessed in tumor samples. RESULTS: Circulating NK and Treg proportions were significantly lower in patients with diffuse/mixed-type AGC (n = 27) than those with intestinal type (n = 40; median 6.3% vs 11.5%; p = 0.02 and median 3.3% vs 5.2%; p = 0.03, respectively). Proportions of circulating MDSC, CD4+ and CD8+ T cells were not associated with one pathological type. Among tumor-infiltrating cells, CD8+ T cells, but not NK or FoxP3+ cells, were significantly lower in diffuse/mixed-type AGC (median 21 vs 59 cells/field; p = 0.009). Patients with high circulating NK cell counts (> 17%) had a better overall survival than those with < 17% (HR 0.40; 95% CI [0.15-1.06]; p = 0.04). Patients with high CD8+ TIL counts (> 31 cells/field) had significantly longer overall survival (HR 0.44; 95% CI [0.21-0.92]; p = 0.02). The prognostic value of CD8+ TILs was maintained after adjustment for confounding factors, including the Lauren classification (HR = 0.42; 95% CI [0.18-0.96]; p = 0.039). CONCLUSION: Diffuse/mixed-type AGC has lower rates of CD8+ TILs and circulating NK cells and Tregs than the intestinal type. This "cold tumor" phenotype may be associated with a worse outcome.


Assuntos
Células Matadoras Naturais/imunologia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucócitos Mononucleares/patologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Gástricas/classificação , Neoplasias Gástricas/mortalidade
13.
Int J Mol Sci ; 21(18)2020 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-32957741

RESUMO

Docetaxel, cisplatin and 5-fluorouracil (DCF) chemotherapy regimen is highly effective in advanced anal squamous cell carcinoma (SCCA), as demonstrated by the Epitopes-HPV02 study results. Here, we analyzed the impact of DCF regimen and the prognostic value of adaptive immune responses and immunosuppressive cells in SCCA patients included in two prospective studies (Epitopes-HPV01 and HPV02). The presence of T-cell responses against Human papillomavirus (HPV)16-E6/E7 and anti-telomerase (hTERT)-antigens was measured by IFNᵧ-ELISpot. Here, we showed that HPV-adaptive immune responses are increased in SCCA patients. SCCA patients also displayed enhanced circulating TH1 T-cells restricted by hTERT. Exposition to DCF increased hTERT immunity but not HPV or common viruses immune responses. Notably, the correlation of hTERT immune responses with SCCA patients' clinical outcomes highlights that hTERT is a relevant antigen in this HPV-related disease. The influence of peripheral immunosuppressive cells was investigated by flow cytometry. While both regulatory T-cells and monocytic-myeloid-derived suppressive cells (M-MDSC) accumulated in the peripheral blood of SCCA patients, only high levels of M-MDSC were negatively correlated with hTERT adaptive immune responses and predicted poor prognosis. Altogether, our results reveal that hTERT is a relevant antigen in HPV-driven SCCA disease and that M-MDSC levels influence TH1-adaptive immune responses and patients' survival.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/tratamento farmacológico , Neoplasias do Ânus/imunologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/imunologia , Infecções por Papillomavirus/imunologia , Telomerase/imunologia , Imunidade Adaptativa , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Ânus/patologia , Neoplasias do Ânus/virologia , Linfócitos T CD4-Positivos , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/virologia , Cisplatino/uso terapêutico , Docetaxel/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Infecções por Papillomavirus/patologia , Prognóstico , Estudos Prospectivos , Células Th1/imunologia
14.
Oncologist ; 24(12): e1331-e1340, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31152084

RESUMO

BACKGROUND: BRAFV600E mutations occurring in about 10% of metastatic colorectal cancers (mCRCs) are usually associated with a poor outcome. However, their prognostic factors are unknown. MATERIALS AND METHODS: We built a multicenter clinico-biological database gathering data from patients with BRAFV600E -mutant mCRC treated in one of the 16 French centers from 2006 to 2017. The primary endpoint was to identify prognostic factors using a Cox model. RESULTS: We included 287 patients (median age, 67 years [28-95]; female, 57%). Their median overall survival was 20.8 months (95% confidence interval [CI], 17.97-27.04), and median progression-free survival in the first-line setting was 4.34 months (95% CI, 3.81-5.03). Chemotherapy regimen and biological agents (antiangiogenic or anti-epidermal growth factor receptor) were not associated with overall and progression-free survival. Stage IV disease (synchronous metastases) and absence of curative-intent surgery were statistically associated with poor overall survival. Among the 194 patients with mismatch repair (MMR) status available, overall survival was significantly longer in patients with deficient MMR tumors compared with those with proficient MMR tumors (adjusted hazard ratio = 0.56; p = .009). CONCLUSION: Despite that BRAFV600E -mutant mCRCs are associated with poor overall and progression-free-survival, patients with deficient MMR tumors and/or resectable disease experienced a longer survival. These results highlight the importance of MMR testing and resectability discussion in patients with BRAFV600E mCRC in day-to-day practice. IMPLICATIONS FOR PRACTICE: Mismatch repair (MMR) testing and resectability discussion in patients with BRAFV600E metastatic colorectal cancer (mCRC) should be performed in day-to-day practice to steer treatment decision making in patients with BRAFV600E -mutant mCRC.


Assuntos
Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica
15.
Lancet Oncol ; 19(8): 1094-1106, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30042063

RESUMO

BACKGROUND: The incidence of anal squamous cell carcinoma has been increasing markedly in the past few decades. Currently, there is no validated treatment for advanced-stage anal squamous cell carcinoma. Therefore, we aimed to validate the clinical activity and safety of docetaxel, cisplatin, and fluorouracil (DCF) chemotherapy in patients with metastatic or unresectable locally recurrent anal squamous cell carcinoma. METHODS: We did a multicentre, single-arm, phase 2 study. We recruited patients from 25 academic hospitals, cancer research centres, and community hospitals in France who were aged 18 years or older with histologically confirmed anal squamous cell carcinoma, with metastatic disease or with unresectable local recurrence; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and with at least one evaluable lesion according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Chemotherapy-naive patients received either six cycles of standard DCF (75 mg/m2 docetaxel and 75 mg/m2 cisplatin on day 1 and 750 mg/m2 per day of fluorouracil for 5 days, every 3 weeks) or eight cycles of modified DCF (40 mg/m2 docetaxel and 40 mg/m2 cisplatin on day 1 and 1200 mg/m2 per day of fluorouracil for 2 days, every 2 weeks), which were administered intravenously. The choice between the standard versus modified regimens was recommended based on, but not limited to, age (≤75 years vs >75 years) and ECOG performance status (0 vs 1). The primary endpoint was investigator-assessed progression-free survival at 12 months from the first DCF cycle; for the primary endpoint to be met, at least 11 (17%) of 66 enrolled patients had to be alive without disease progression at 12 months. Efficacy and safety analyses were done in a modified intention-to-treat population, defined as all patients who were evaluable for progression at 12 months who received at least one cycle of DCF. This trial is registered at ClinicalTrials.gov, number NCT02402842, and the final results are presented here. FINDINGS: Between Sept 17, 2014, and Dec 7, 2016, we enrolled 69 patients. Of these patients, three did not receive DCF. Of the 66 patients who received treatment, 36 received the standard DCF regimen and 30 received modified DCF. The primary endpoint was met: 31 (47%) of 66 patients were alive and progression free at 12 months. 22 (61%) of 36 patients who received the standard DCF regimen and 18 (60%) of 30 patients who received the modified DCF regimen had disease progression at data cutoff. 46 (70%) of 66 patients had at least one grade 3-4 adverse event (30 [83%] of 36 in the standard DCF regimen and 16 [53%] of 30 in the modified DCF regimen). The most common grade 3-4 adverse events were neutropenia (15 [23%]; eight [22%] for standard DCF vs seven [23%] for modified DCF), diarrhoea (12 [18%]; nine [25%] vs three [10%]), asthenia (ten [15%]; eight [22%] vs two [7%]), anaemia (ten [15%]; six [17%] vs four [13%]), lymphopenia (eight [12%]; three [8%] vs five [17%]), mucositis (seven [11%]; seven [19%] vs none), and vomiting (seven [11%]; five [14%] vs two [7%]). No grade 4 non-haematological adverse events and febrile neutropenia were observed with modified DCF, whereas three (8%) grade 4 non-haematological adverse events and five (14%) cases of febrile neutropenia were reported with standard DCF. 97 serious adverse events were reported (69 in patients who received the standard DCF regimen [61 drug-related] and 28 in those given the modified DCF regimen [14 drug-related]). No treatment-related deaths were recorded. INTERPRETATION: Compared with standard DCF, modified DCF provided long-lasting response with good tolerability in patients with metastatic or unresectable locally recurrent anal squamous cell carcinoma with ECOG performance status of 0-1 in the first-line setting, and therefore could be considered as a new standard of care for these patients. Regarding the elevated risk of high-grade and serious adverse events and febrile neutropenia, standard DCF cannot be recommended in this situation. FUNDING: Besançon University Hospital and Ligue contre le cancer Grand-Est.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Metástase Neoplásica/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Idoso , Neoplasias do Ânus/mortalidade , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/secundário , Cisplatino/administração & dosagem , Docetaxel/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão
16.
BMC Cancer ; 17(1): 574, 2017 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-28841909

RESUMO

BACKGROUND: The squamous cell carcinoma of the anus (SCCA) is a rare disease, but its incidence is markedly increasing. About 15% of patients are diagnosed at metastatic stage, and more than 20% with a localized disease treated by chemoradiotherapy (CRT) will recur. In advanced SCCA, cisplatin and 5-fluorouracil (CF) combination is the standard option but complete response is a rare event and the prognosis remains poor with most disease progression occurring within the first 12 months. We have previously published the potential role of the addition of docetaxel (D). Among 8 consecutive patients with advanced recurrent SCCA after CRT, the DCF regimen induced a complete response in 4 patients, including 3 pathological complete responses. Then, the Epitopes-HPV02 study was designed to confirm the interest of DCF regimen in SCCA patients. METHODS: This multicentre phase II trial assesses the DCF regimen in advanced SCCA patients. Main eligibility criteria are: histologically proven SCCA, unresectable locally advanced recurrent or metastatic disease, Eastern Cooperative Oncology Group-performance status (ECOG-PS) <2, and being eligible for DCF. Patients receive either 6 cycles of standard DCF or 8 cycles of modified DCF depending on age (> vs. ≤ 75 years-old) and ECOG-PS (0 vs. 1). The trial was set up based on a Simon's optimal two-stage design for phase II trials, allowing an early futility interim analysis. The primary endpoint is the observed progression-free survival (PFS) rate at 12 months from the first DCF cycle. A PFS rate below 10% is considered uninteresting, while a PFS rate above 25% is expected. With a unilateral alpha error of 5% and a statistical power of 90%, 66 evaluable patients should be included. Main secondary endpoints are overall survival, PFS, response rate, safety, health-related quality of life, and the correlation of biomarkers with treatment efficacy. DISCUSSION: Since the recommended CF regimen is based in a small retrospective analysis and generates a low rate of complete responses, the Epitopes-HPV02 study will establish a new standard in case of a positive result. Associated biomarker studies will contribute to understand the underlying mechanism of resistance and the role of immunity in SCCA. TRIAL REGISTRATION: NCT02402842 , EudraCT: 2014-001789-81.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/uso terapêutico , Fluoruracila/uso terapêutico , Recidiva Local de Neoplasia , Taxoides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Ânus/patologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/secundário , Docetaxel , França , Humanos , Pessoa de Meia-Idade , Prognóstico , Projetos de Pesquisa , Adulto Jovem
17.
Dis Colon Rectum ; 60(8): 785-791, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28682963

RESUMO

BACKGROUND: Because of the rarity of the condition, studies concerning the management of patients with squamous cell carcinoma of the anus with distant metastasis are scarce. The available studies indicate poor outcomes with exclusive chemotherapy. OBJECTIVE: Our aim was to evaluate the impact of multidisciplinary treatment on overall survival among patients presenting with metastatic squamous cell carcinoma of the anus. DESIGN: This was a retrospective study. SETTINGS: The study was conducted at a single French institution between 2000 and 2014. PATIENTS: Consecutive patients with histologically proven, newly diagnosed, or recurrent metastatic squamous cell carcinoma of the anus were included. INTERVENTIONS: Study interventions included multimodal therapy combining systemic chemotherapy and local ablative treatment to remove all metastases through surgery, radiofrequency ablation, or radiotherapy. MAIN OUTCOME MEASURES: The primary outcome measure was overall survival. RESULTS: Fifty patients (median age, 62 years; men/women: 8/42) fulfilled the inclusion criteria, and 39 were available for Response Evaluation Criteria in Solid Tumors. Forty had metastatic relapse after previous treatment of localized disease, and 10 presented with synchronous metastasis. P16 status was not available. Patients received at least 1 chemotherapy regimen, including 5-fluorouracil-mitomycin C (n = 22), cisplatin-5-fluorouracil (n = 20), or 5-fluorouracil alone (n = 3). Thirteen also had surgical metastasectomy, 11 had radiotherapy, and 6 had radiofrequency ablation. Median overall survival was 20.0 months (95% CI, 18.2-21.8 mo), and median time to failure of strategy was 6.0 months (95% CI, 2.9-9.1 mo). Overall response rate was 56% (95% CI, 40%-73%). Outcomes from the 5-fluorouracil-mitomycin C and cisplatin regimens did not statistically differ. Patients treated with multimodal therapy had a median overall survival of 22.0 months (95% CI, 15.3-28.6 mo) versus 13.0 months (95% CI, 9.5-16.5 mo; p = 0.002). Median time to failure of strategy was 10.0 months (95% CI, 4.2-15.7 mo) versus 5.0 months (95% CI, 2.8-7.2; p = 0.007). After 2 years, 40% of patients with multimodal treatment and 20% of those without ablative treatment were alive. LIMITATIONS: This study is limited by its retrospective design and modest sample size. CONCLUSIONS: Stage IV squamous cell carcinoma of the anus outcomes are poor, but first-line chemotherapy can enable good response rates. Other treatment modalities, including surgery, radiotherapy, and thermoablation, should be considered, because they may provide a survival advantage. See Video Abstract at http://links.lww.com/DCR/A336.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/terapia , Neoplasias Ósseas/terapia , Carcinoma de Células Escamosas/terapia , Neoplasias Hepáticas/terapia , Neoplasias Pulmonares/terapia , Metastasectomia , Radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Ânus/patologia , Neoplasias Ósseas/secundário , Carcinoma de Células Escamosas/secundário , Ablação por Cateter , Cisplatino/administração & dosagem , Estudos de Coortes , Terapia Combinada , Feminino , Fluoruracila/administração & dosagem , França , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
18.
Ther Drug Monit ; 39(3): 290-296, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28346313

RESUMO

BACKGROUND: Gemcitabine remains a pillar in pancreatic cancer treatment. However, toxicities are frequently observed. Dose adjustment based on therapeutic drug monitoring might help decrease the occurrence of toxicities. In this context, this work aims at describing the pharmacokinetics (PK) of gemcitabine and its metabolite dFdU in pancreatic cancer patients and at identifying the main sources of their PK variability using a population PK approach, despite a sparse sampled-population and heterogeneous administration and sampling protocols. METHODS: Data from 38 patients were included in the analysis. The 3 optimal sampling times were determined using KineticPro and the population PK analysis was performed on Monolix. Available patient characteristics, including cytidine deaminase (CDA) status, were tested as covariates. Correlation between PK parameters and occurrence of severe hematological toxicities was also investigated. RESULTS: A two-compartment model best fitted the gemcitabine and dFdU PK data (volume of distribution and clearance for gemcitabine: V1 = 45 L and CL1 = 4.03 L/min; for dFdU: V2 = 36 L and CL2 = 0.226 L/min). Renal function was found to influence gemcitabine clearance, and body surface area to impact the volume of distribution of dFdU. However, neither CDA status nor the occurrence of toxicities was correlated to PK parameters. CONCLUSIONS: Despite sparse sampling and heterogeneous administration and sampling protocols, population and individual PK parameters of gemcitabine and dFdU were successfully estimated using Monolix population PK software. The estimated parameters were consistent with previously published results. Surprisingly, CDA activity did not influence gemcitabine PK, which was explained by the absence of CDA-deficient patients enrolled in the study. This work suggests that even sparse data are valuable to estimate population and individual PK parameters in patients, which will be usable to individualize the dose for an optimized benefit to risk ratio.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/uso terapêutico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Citidina Desaminase/metabolismo , Desoxicitidina/farmacocinética , Desoxicitidina/uso terapêutico , Monitoramento de Medicamentos/métodos , Humanos , Neoplasias Pancreáticas/metabolismo , Gencitabina
19.
Oncology ; 90(5): 261-6, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27097162

RESUMO

OBJECTIVE: Treating metastatic pancreatic cancer (MPC) remains a challenging issue. Maintenance therapy is a growing concept used in different types of cancer. Our retrospective analysis aims to evaluate the effectiveness and tolerability of early maintenance capecitabine administrated to patients with MPC treated with first-line FOLFIRINOX. METHODS: 103 patients treated for MPC between November 2009 and July 2014 were retrospectively identified in our institution. Among them, 30 patients initially treated with a minimum of 4 and no more than 8 cycles of FOLFIRINOX, without signs of progression (every 14 days), received maintenance therapy with capecitabine until progression. Upon first progression (first progression-free survival, PFS1), patients were retreated with FOLFIRINOX or another scheme until second progression (second progression-free survival, PFS2). RESULTS: Median OS was 17 months. Survival rates were 73% at 1 year (95% CI 0.59-0.91) and 25% at 2 years (95% CI 0.13-0.50). Median PFS1 was 5 months. Twenty-nine patients experienced disease progression during capecitabine treatment (96.7%). After disease progression, median PFS2 was 10 months. Considering the interval between the starting date of FOLFIRINOX treatment and second disease progression, the median time to treatment failure is 17 months. CONCLUSIONS: Maintenance with capecitabine seems effective without compromising FOLFIRINOX efficacy and allows obtaining very promising OS and PFS.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/administração & dosagem , Capecitabina/efeitos adversos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Irinotecano , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Resultado do Tratamento
20.
Oncology ; 90(2): 88-96, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26784946

RESUMO

OBJECTIVE: This study aimed to identify predictors of tumor control (TC) in metastatic esophageal squamous cell carcinoma patients receiving first-line chemotherapy. METHODS: A development cohort of 68 patients from a prospective multicenter trial (NCT01248299) was used to identify predictors of TC at first radiological tumor assessment and to generate a predictive score for TC. That score was applied in an independent retrospective single-center validation cohort of 60 consecutive patients. RESULTS: Multivariate analysis identified three predictors of TC: body mass index ≥18.5 (OR 4.5, 95% CI 0.91-22.5), absence of bone metastasis (OR 4.6, 95% CI 0.91-23.2) and albumin ≥35 g/l (OR 3.5, 95% CI 1.0-12.1). Based on the presence or absence of these three independent prognosticators, we built a predictive model using a score from 0 to 3. In the development cohort, the TC rates were 14.3 and 78.0% and in the validation cohort 12.5 and 44.2%, for scores of 0-1 and 2-3, respectively. With negative predictive values of 85 and 88% in the development and validation cohorts, respectively, we were able to identify patients with a very low probability of TC. CONCLUSION: We have developed and validated a score that can be easily determined at the bedside to predict TC in metastatic esophageal squamous cell carcinoma patients.


Assuntos
Neoplasias Ósseas/secundário , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Esofágicas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Área Sob a Curva , Índice de Massa Corporal , Carcinoma de Células Escamosas/secundário , Cisplatino , Neoplasias Esofágicas/patologia , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Compostos Organoplatínicos/administração & dosagem , Valor Preditivo dos Testes , Estudos Prospectivos , Curva ROC , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Albumina Sérica/metabolismo , Taxa de Sobrevida , Resultado do Tratamento , Vimblastina/administração & dosagem , Vimblastina/análogos & derivados , Vinorelbina
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