RESUMO
BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers; â¼20% of patients have metastases at diagnosis, and 50%-60% subsequently develop metachronous metastases. Bone involvement, despite being rare, is usually associated with higher disease burden, worse prognosis, impaired quality of life, and significant health-related cost. In the last few years, following the positive results of the TRIBE and TRIBE2 trials, the association of FOLFOXIRI plus bevacizumab has become the new standard of care for metastatic CRC. Despite being highly efficacious in all subgroups, little is known about the activity of this regimen in patients with bone metastases. PATIENTS AND METHODS: We carried out a pooled analysis of TRIBE and TRIBE2 studies focusing on patients with skeletal deposits. RESULTS: Our analyses on the whole population showed that patients with baseline bone involvement reported shorter overall survival [OS; 14.0 versus 26.2 months; hazard ratio (HR) 2.04, 95% confidence interval (CI) 1.46-2.87; P < 0.001] and progression-free survival (PFS; 6.2 versus 11.1 months; HR 1.96, 95% CI 1.42-2.69; P < 0.001) compared with those without bone metastases; no significant interaction with the treatment was reported for PFS (P = 0.094) and OS (P = 0.38). Bone metastases had a negative prognostic implication in the multivariate analysis (HR 2.24, 95% CI 1.54-3.26; P < 0.001). Furthermore, patients with bone lesions at first radiological progression (including those with baseline bone metastases) had a shorter OS compared with those who progressed in other sites (10.4 versus 13.2 months; HR 1.48, 95% CI 1.15-1.91; P = 0.002). A trend toward inferior OS (7.5 versus 11 months, HR 1.50, 95% CI 0.92-2.45; P = 0.10) appeared in patients with basal skeletal deposits compared with those with bone involvement at first radiological progression. CONCLUSIONS: Our study confirmed the negative prognostic impact of bone metastases in CRC. Furthermore, we demonstrated for the first time that the survival advantage of triplet chemotherapy plus bevacizumab is maintained even in this prognostically unfavorable subgroup.
Assuntos
Neoplasias Ósseas , Neoplasias do Colo , Neoplasias Colorretais , Humanos , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Neoplasias Colorretais/patologia , Qualidade de Vida , Camptotecina/uso terapêutico , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Prognóstico , Neoplasias do Colo/tratamento farmacológico , Neoplasias Ósseas/tratamento farmacológicoRESUMO
BACKGROUND: The phase III TRIBE and TRIBE2 studies randomized metastatic colorectal cancer patients to first-line FOLFOXIRI/bevacizumab or a doublet (FOLFIRI or FOLFOX)/bevacizumab. The studies demonstrated a significant benefit from the triplet at the price of an increased incidence of chemotherapy-related adverse events (AEs). In both trials, males and females aged between 18 and 70 years with ECOG PS ≤2 and between 71 and 75 years with ECOG PS = 0 were eligible. We investigated the effect of FOLFOXIRI/bevacizumab versus doublets/bevacizumab according to age and gender. PATIENTS AND METHODS: Subgroup analyses according to age (<70 versus 70-75 years) and gender were carried out for overall response rate (ORR), progression-free survival (PFS), and AE rates. RESULTS: Of 1187 patients, 1005 (85%) were aged <70 years and 182 (15%) 70-75 years; 693 (58%) were males and 494 (42%) females. There was no evidence of interaction between age or gender and the benefit provided by the intensification of the upfront chemotherapy in terms of ORR and PFS, or the increased risk of experiencing G3/4 AEs. Elderly patients and females experienced higher rates of overall G3/4 AEs (73% versus 60%, P < 0.01 and 69% versus 57%, P < 0.01, respectively). Notably, in the FOLFOXIRI/bevacizumab subgroup, G3/4 diarrhea and febrile neutropenia occurred in 27% and 16% of elderly patients, respectively, while females reported high incidences of any grade nausea (67%) and vomiting (50%). CONCLUSIONS: The improvements in terms of ORR and PFS of FOLFOXIRI/bevacizumab versus doublets/bevacizumab are independent of gender and age, with a similar relative increase in AEs among elderly patients and females. Initial dose reductions and possibly primary G-CSF prophylaxis should be recommended for patients between 70 and 75 years old treated with FOLFOXIRI/bevacizumab, and a careful management of antiemetic prophylaxis should be considered among females.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/patologia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Náusea/patologia , Metástase Neoplásica , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Intervalo Livre de Progressão , Caracteres Sexuais , Resultado do Tratamento , Vômito/induzido quimicamente , Vômito/patologiaRESUMO
Background: Right-sided metastatic colorectal cancer (mCRC) patients have poor prognosis and achieve limited benefit from first-line doublets plus a targeted agent. In this unplanned analysis of the TRIBE study, we investigated the prognostic and predictive impact of primary tumor sidedness in mCRC patients and the differential impact of the intensification of the chemotherapy in subgroups defined according to both primary tumor sidedness and RAS and BRAF mutational status. Patients and methods: Patients were randomized to receive upfront 5-fluoruracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab or 5-fluoruracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab. Tumors were defined as right- or left-sided if they originated from the caecum to the transverse colon or within the splenic flexure and beyond, respectively. Patients with available information about both primary sidedness and RAS and BRAF status were included in the present analysis. Progression-free survival (PFS), overall survival (OS) and RECIST response rate were assessed according to tumor location and RAS and BRAF mutational status. Results: Information about primary sidedness and RAS and BRAF status was available for 358 (70.5%) out of 508 randomized patients. Patients with right-sided tumors (N = 173) presented shorter OS [23.7 versus 31.0 months, HR = 1.42 (95% CI 1.09-1.84), P = 0.010] and a trend toward shorter PFS [10.2 versus 11.5 months, HR = 1.24 (95% CI: 0.98-1.56), P = 0.083] than those with left-sided tumors (N = 185), but these associations were no longer evident when adjusting for RAS and BRAF status. Patients with right-sided tumors achieved more relative benefit from the intensification of the chemotherapy backbone in terms of both PFS (HR = 0.59 versus 0.89, P for interaction = 0.099) and OS (HR = 0.56 versus 0.99, P for interaction = 0.030) and this advantage was independent of their RAS and BRAF status. Conclusions: FOLFOXIRI plus bevacizumab may be regarded as a preferred first-line treatment option for clinically selected patients with right-sided metastatic colorectal cancer irrespective of their RAS and BRAF mutational status. Trial registration: clinicaltrials.gov identifier NCT00719797.
RESUMO
Background: Neutrophil/lymphocyte ratio (NLR), defined as absolute neutrophils count divided by absolute lymphocytes count, has been reported as poor prognostic factor in several neoplastic diseases but only a few data are available about unresectable metastatic colorectal cancer (mCRC) patients (pts). The aim of our study was to evaluate the prognostic and predictive role of NLR in the TRIBE trial. Patients and methods: Pts enrolled in TRIBE trial were included. TRIBE is a multicentre phase III trial randomizing unresectable and previously untreated mCRC pts to receive FOLFOXIRI or FOLFIRI plus bevacizumab. A cut-off value of 3 was adopted to discriminate pts with low (NLR < 3) versus high (NLR ≥ 3) NLR, as primary analysis. As secondary analysis, NLR was treated as an ordinal variable with three levels based on terciles distribution. Results: NLR at baseline was available for 413 patients. After multiple imputation at univariate analysis, patients with high NLR had significantly shorter progression-free survival (PFS) [hazard ratio (HR) 1.27 (95% CI 1.05-1.55), P = 0.017] and overall survival (OS) [HR 1.56 (95% CI 1.25-1.95), P < 0.001] than patients with low NLR. In the multivariable model, NLR retained a significant association with OS [HR 1.44 (95% CI 1.14-1.82), P = 0.014] but not with PFS [HR 1.18 (95% CI 0.95-1.46), P = 0.375]. No interaction effect between treatment arm and NLR was evident in terms of PFS (P for interaction = 0.536) or OS (P for interaction = 0.831). Patients with low [HR 0.84 (95% CI 0.64-1.08)] and high [HR 0.73 (95% CI 0.54-0.97)] NLR achieved similar PFS benefit from the triplet and consistent results were obtained in terms of OS [HR 0.83 (95% CI 0.62-1.12) for low NLR; HR 0.82 (95% CI 0.59-1.12) for high NLR]. Conclusion: This study confirmed the prognostic role of NLR in mCRC pts treated with bevacizumab plus chemotherapy in the first line, showing the worse prognosis of pts with high NLR. The advantage of the triplet is independent of NLR at baseline.
Assuntos
Neoplasias Colorretais/sangue , Contagem de Linfócitos , Metástase Neoplásica , Neutrófilos/citologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND: FOLFOXIRI plus bevacizumab is a valid option as upfront treatment for metastatic colorectal cancer (mCRC) patients. While several trials investigated the effect of combining bevacizumab with different chemotherapy regimens, including fluoropyrimidines monotherapy and oxaliplatin- or irinotecan-containing doublets, no randomized comparison assessing the impact of the addition of bevacizumab to FOLFOXIRI is available. PATIENTS AND METHODS: A total of 122 mCRC patients received first-line FOLFOXIRI in the phase III trial by the GONO (FOLFOXIRI group) and 252 patients received first-line FOLFOXIRI plus bevacizumab in the TRIBE trial (FOLFOXIRI plus bevacizumab group). A propensity score-adjusted method was adopted to provide an estimation of the benefit from the addition of bevacizumab to FOLFOXIRI in terms of survival and activity parameters. RESULTS: Patients in the FOLFOXIRI group had more frequently Eastern Cooperative Oncology Group performance status of one or two, high Köhne score, metachronous and liver-limited disease, had previously received adjuvant treatments and had their primary tumors resected. The median progression-free survival (PFS) was 12.3 months in the FOLFOXIRI plus bevacizumab group compared with 10.0 months in the FOLFOXIRI group {propensity score-adjusted hazard ratio (HR) 0.74 [95% confidence interval (CI) 0.59-0.94], P = 0.013}. This association was significant also in the multivariable model (P = 0.024). The median OS was 29.8 months in the FOLFOXIRI plus bevacizumab group compared with 23.6 months in the FOLFOXIRI group [propensity score-adjusted HR: 0.72 (95% CI 0.56-0.93), P = 0.014]. At the multivariable model, the addition of bevacizumab was still associated with significantly longer OS (P = 0.030). No significant differences in RECIST response rate (RR) [65.1% versus 55.7%; propensity score-adjusted odds ratio (OR): 1.29 (95% CI 0.81-2.05), P = 0.280], early RR [62.7% versus 57.8%; OR: 1.14 (95% CI 0.68-1.93), P = 0.619] and median depth of response (42.2% versus 53.8%, P = 0.259) were reported. CONCLUSIONS: Though in the absence of a randomized comparison, the addition of bevacizumab to FOLFOXIRI provides significant benefit in PFS and OS, thus supporting the use of FOLFOXIRI plus bevacizumab as upfront treatment for mCRC patients. TRIALS' NUMBERS: NCT01219920 and NCT00719797.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Adulto , Idoso , Inibidores da Angiogênese/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Camptotecina/administração & dosagem , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos Organoplatínicos/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND: The combination of bevacizumab with fluorouracil-based chemotherapy is a standard first-line treatment option in metastatic colorectal cancer (mCRC). We studied the efficacy of continuing or reintroducing bevacizumab in combination with second-line chemotherapy after progression to bevacizumab-based first-line therapy. PATIENTS AND METHODS: In this phase III study, patients with mCRC treated with fluoropyrimidine-based first-line chemotherapy plus bevacizumab were randomized to receive in second-line mFOLFOX-6 or FOLFIRI (depending on first-line regimen) with or without bevacizumab. The primary end point was progression-free survival. To detect a hazard ratio (HR) for progression of 0.70 with an α and ß error of 0.05 and 0.20, respectively, 262 patients were required. RESULTS: In consideration of the results of the ML18147 trial, the study was prematurely stopped. Between April 2008 and May 2012, a total of 185 patients were randomized. Bevacizumab-free interval was longer than 3 months in 43% of patients in chemotherapy alone arm and in 50% of patients in the bevacizumab arm. At a median follow-up of 45.3 months, the median progression-free survival was 5.0 months in the chemotherapy group and 6.8 months in the bevacizumab group [adjusted HR = 0.70; 95% confidence interval (CI) 0.52-0.95; stratified log-rank P = 0.010]. Subgroup analyses showed a consistent benefit in all subgroups analyzed and in particular in patients who had continued or reintroduced bevacizumab. An improved overall survival was also observed in the bevacizumab arm (adjusted HR = 0.77; 95% CI 0.56-1.06; stratified log-rank P = 0.043). Responses (RECIST 1.0) were similar in the chemotherapy and bevacizumab groups (17% and 21%; P = 0.573). Toxicity profile was consistent with previously reported data. CONCLUSIONS: This study demonstrates that the continuation or the reintroduction of bevacizumab with second-line chemotherapy beyond first progression improves the outcome and supports the use of this strategy in the treatment of mCRC. ClinicalTrials.gov number: NCT00720512.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Adulto , Idoso , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Retratamento , Taxa de SobrevidaRESUMO
Metronomic chemotherapy refers to the administration of chemotherapy at low, nontoxic doses on a frequent schedule with no prolonged breaks. The aim of the study is to rationally develop a CPT-11 metronomic regimen in preclinical settings of colon cancer. In vitro cell proliferation, apoptosis and thrombospondin-1/vascular endothelial growth factor (TSP-1/VEGF) expression analyses were performed on endothelial (HUVEC, HMVEC-d) and colorectal cancer (HT-29, SW620) cells exposed for 144 h to metronomic concentrations of SN-38, the active metabolite of CPT-11. HT-29 human colorectal cancer xenograft model was used, and tumour growth, microvessel density and VEGF/TSP-1 quantification was performed in tumours. In vitro and in vivo combination studies with the tyrosine inhibitor semaxinib were also performed. SN-38 preferentially inhibited endothelial cell proliferation alone and interacted synergistically with semaxinib; it induced apoptosis and increased the expression and secretion of TSP-1. Metronomic CPT-11 alone and combined with semaxinib significantly inhibits tumour growth in the absence of toxicity, which was accompanied by decreases in microvessel density and increases in TSP-1 gene expression in tumour tissues. In vitro results show the antiangiogenic properties of low-concentration SN-38, suggesting a key role of TSP-1 in this effect. In vivo, the CPT-11 metronomic schedule is effective against tumour and microvessel growth without toxic effect on mice.
Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Camptotecina/análogos & derivados , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/tratamento farmacológico , Indóis/farmacologia , Pirróis/farmacologia , Inibidores da Angiogênese/administração & dosagem , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Apoptose/efeitos dos fármacos , Camptotecina/administração & dosagem , Camptotecina/farmacologia , Proliferação de Células/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HT29 , Humanos , Técnicas Imunoenzimáticas , Imuno-Histoquímica , Indóis/administração & dosagem , Irinotecano , Masculino , Camundongos , Camundongos Nus , Microcirculação/efeitos dos fármacos , Pirróis/administração & dosagem , Trombospondina 1/efeitos dos fármacos , Trombospondina 1/metabolismo , Transplante Heterólogo , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
The pharmacokinetics (PK) and pharmacodynamics (PD) of metronomic irinotecan have not been studied in cancer patients. The aim of the study is to investigate the PK/PD profile of irinotecan/SN-38 administered by metronomic schedule. Twenty chemotherapy-refractory or chemotherapy-resistant patients with metastatic colorectal carcinoma were enrolled. Irinotecan was infused continuously as follows: irinotecan 1.4 mg m(-2) day(-1) (n=7), 2.8 mg m(-2) day(-1) (n=5) and 4.2 mg m(-2) day(-1) (n=8). Drug levels were examined by HPLC, whereas ELISAs and real-time RT-PCR were used, respectively, for the measurement of plasma levels and gene expression in peripheral blood mononuclear cells of vascular endothelial growth factor/thrombospondin-1. Pharmacokinetic analysis demonstrated that the steady-state levels (C(ss)) of SN-38 were between 1 and 3.3 ng ml(-1). From a PD point of view, higher thrombospondin-1 (TSP-1) plasma levels (153.4+/-30.1 and 130.4+/-9.2% at day 49 vs pretreatment values at 1.4 and 2.8 mg m(-2) day(-1) dose levels, respectively) and increased gene expression in PBMC were found during the metronomic irinotecan infusion, especially at the lower doses. Four patients (20%) obtained a stable disease (median 3.9 months) despite progressing during previous standard irinotecan schedule. Toxicities >grade 1 were not observed. Metronomic irinotecan administration is very well tolerated and induces an increase of gene expression and plasma concentration of TSP-1 at low plasma SN-38 concentrations.
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Idoso , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/farmacocinética , Camptotecina/farmacologia , Neoplasias Colorretais/mortalidade , Feminino , Fator Estimulador de Colônias de Granulócitos/farmacologia , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Trombospondina 1/sangue , Trombospondina 1/genética , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
BACKGROUND: We conducted two phase II trials evaluating the combination of 5-fluorouracil/folinic acid, oxaliplatin and irinotecan (FOLFOXIRI) as first-line treatment in 74 metastatic colorectal cancer patients. Results were very promising with an overall response rate of 71% and 72%, a median PFS of 10.4 and 10.8 months and an overall survival of 26.5 and 28.4 months, respectively. A concern about the use of all three active agents up-front is the possibility that this might limit, after progression, disease control with second-line treatments. Therefore, we conducted the present analysis to evaluate the outcome of second-line treatments in these 74 patients. METHODS: Among the 71 patients so far progressed 54 (76%) received second line chemotherapy (23: FOLFIRI, 17: FOLFOXIRI, five: 5-FU protracted infusion, three: FOLFOX, three: 5-FU+MMC, two: CPT-11, one: CPT-11+LOHP, one: raltitrexed). Seventeen patients (24%) did not receive second line treatments: 10 because of deterioration of performance status (PS), four because of patient refusal and three because of death. Patients' characteristics at the time of second-line treatment were: M/F 36 of 18 patients, median age 64 yrs (range 44-75), ECOG PS>or=1 21 (39%) patients, multiple sites of disease 33 (61%) patients. RESULTS: A median of 4.1 months of second-line chemotherapy per patient were administered (range 1-8). Overall response rate (52 out of 54 evaluable patients) was 33% and stable disease were 19 (37%). Median duration of response was 8.1 months. At a median follow up of 15.1 months from the start of salvage chemotherapy median PFS and overall survival were respectively 6.7 and 15.2 months. CONCLUSIONS: First-line FOLFOXIRI does not impair the possibility to obtain objective responses and delay tumor progression with second line treatments containing the same agents used in first-line.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Irinotecano , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Oxaliplatina , Resultado do TratamentoRESUMO
BACKGROUND: In a previous phase I-II study we demonstrated that the FOLFOXIRI regimen [irinotecan 125-175 mg/m2 day 1, oxaliplatin 100 mg/m2 day 1, l-leucovorin (l-LV) 200 mg/m2 day 1, 5-fluorouracil (5-FU) 3800 mg/m2 as a 48-h chronomodulated continuous infusion starting on day 1, repeated every 2 weeks] has promising activity and efficacy in metastatic colorectal cancer. However, this regimen required a chronomodulated infusion of 5-FU, and because neutropenia occurred in 32% of cycles, granulocyte colony-stimulating factor (G-CSF) was used and the delivered dose intensity was only approximately 78% of planned. Therefore, we conducted the present phase II study in order to develop a simplified FOLFOXIRI regimen that could be more easily administered in clinical practice as well as in multicenter settings. PATIENTS AND METHODS: A total of 32 patients with unresectable metastatic colorectal cancer received irinotecan 165 mg/m2 day 1, oxaliplatin 85 mg/m2 day 1, l-LV 200 mg/m2 day 1 and 5-FU 3200 mg/m2 as a 48-h continuous (not chronomodulated) infusion starting on day 1, repeated every 2 weeks. RESULTS: All 32 patients were evaluated for safety and the incidence of grade 3-4 toxic effects, and the use of G-CSF seemed to be lower than with the previous FOLFOXIRI regimen: grade 4 neutropenia (34%), grade 3 diarrhea (16%), grade 3 stomatitis (6%) and grade 2-3 peripheral neurotoxicity (37%) were reported, and G-CSF was used in 23% of cycles. Delivered dose intensity was 88% of that planned, and no toxic deaths occurred. The intention-to-treat analysis for activity showed four complete responses, 19 partial responses, seven stable disease and two progressive disease, for an overall response rate of 72% (95% confidence interval 53% to 86%). Eight (25%) patients with residual liver or lung metastases were radically resected after chemotherapy. After a median follow-up of 18.1 months, the median progression-free survival is 10.8 months and median survival is 28.4 months. CONCLUSIONS: This simplified FOLFOXIRI combination can be delivered easily in outpatient settings, with manageable toxic effects, and has very promising antitumor activity. While the safety profile seems to be improved in comparison with our previous FOLFOXIRI regimen, antitumor activity and efficacy appear to be maintained.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Humanos , Infusões Intravenosas , Irinotecano , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Resultado do TratamentoRESUMO
OBJECTIVE: To describe the altered pharmacokinetics of 5-fluorouracil (5-FU) and its major catabolite 5-fluoro-5,6-dihydrouracil (5-FDHU) in a 52-year-old woman affected by a severe 5-FU toxicity. METHODS: Toxicities were rated according to World Health Organization. 5-FU and 5-FDHU plasma concentrations and dihydropyrimidine dehydrogenase (DPD) activity of peripheral blood mononuclear cells (PBMC) were measured by HPLC analysis. RESULTS: After a single cycle of 5-FU therapy the patient developed grade 4 diarrhea and stomatitis, grade 3 vomiting, neutropenia, and dermatitis. Compared to a control population, 5-FU AUC, elimination half-life, and C(max) were markedly increased (24.75 vs. 9.25 +/- 0.63 h microg/ml, >5 vs. 0.36 +/- 0.05 h, and 58.54 vs. 37.2 +/- 4.03 microg/ml, respectively) whereas systemic clearance was decreased (12 vs. 51.29 +/- 2.97 l/h/m2); also 5-FDHU AUC (3.3 vs. 12.35 +/- 0.7 h microg/ml) and C(max) (3.4 vs. 4.56 +/- 0.15 microg/ml), which was reached with delay, were reduced. Surprisingly, the PBMC DPD activity (110.8 pmol/min/mg protein) and urinary uracil (68.32 micromol/g urinary creatinine) were within normal range. CONCLUSIONS: Our results show the altered 5-FU and 5-FDHU pharmacokinetics in a severe 5-FU toxicity case due to an impairment of the hepatic DPD activity and suggest the necessity of a pharmacological evaluation of 5-FU treated patients.
Assuntos
Fluoruracila/análogos & derivados , Fluoruracila/efeitos adversos , Alopecia/induzido quimicamente , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Área Sob a Curva , Diarreia/induzido quimicamente , Toxidermias/etiologia , Feminino , Febre/induzido quimicamente , Fluoruracila/sangue , Fluoruracila/farmacocinética , Humanos , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Estomatite/induzido quimicamente , Vômito/induzido quimicamenteRESUMO
BACKGROUND: Previous work demonstrated that 5-fluorouracil (5-FU) metabolism is a critical factor for treatment tolerability. In order to study the predictivity of pharmacokinetics with respect to the occurrence of 5-FU toxicity, this study investigates the relationship between the pharmacokinetics of 5-FU and its metabolite 5-fluoro-5,6-dihydrouracil (5-FDHU), dihydropyrimidine dehydrogenase (DPD) activity in peripheral blood mononuclear cells (PBMNC) and treatment tolerability. PATIENTS AND METHODS: Pharmacokinetics and metabolism of 5-FU and activity of DPD in PBMNC were examined in 110 colorectal cancer patients given adjuvant 5-FU 370 mg/m2 plus L-folinic acid 100 mg/m2 for five days every four weeks. Drug levels were examined by HPLC. while toxicities were graded according to WHO criteria. RESULTS: DPD activity in patients with mild toxicities (WHO grade < or = 1) was 197.22 < or = 11.34 pmol of 5-FDHU/min/ mg of protein, while in five patients with grade 3-4 gastrointestinal toxicity, DPD ranged from low to normal values (range 31.12-182.37 pmol/min/mg of protein). In these patients. 5-FU clearance (CL) was lower (range 14.12-25.17 l/h/m2), and the area under the curve (AUC) was higher (range 14.70-26.20 h x microg/ml) than those observed in 84 patients with mild toxicities (CL, 56.30 +/- 3.60 l/h/M2; AUC, 7.91 +/- 0.44 h x microg/ml). The severity of adverse events was associated with increased 5-FU/5-FDHU AUC ratio and reduced 5-FU CL, while 5-FU and 5-FDHU pharmacokinetics were not related to DPD activity. CONCLUSION: This study shows that DPD activity in PBMNC is unrelated to 5-FU/5-FDHU disposition and patients with severe toxicity display marked pharmacokinetic alterations while a reduction of DPD activity may not occur.
Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/efeitos adversos , Fluoruracila/farmacocinética , Oxirredutases/metabolismo , Adulto , Idoso , Antimetabólitos Antineoplásicos/metabolismo , Quimioterapia Adjuvante , Cromatografia Líquida de Alta Pressão , Di-Hidrouracila Desidrogenase (NADP) , Feminino , Fluoruracila/metabolismo , Humanos , Leucovorina/administração & dosagem , Leucócitos Mononucleares/enzimologia , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: To investigate the sequence effect of irinotecan and a 48-hour infusion of fluorouracil (5-FU) modulated by leucovorin (LV) on the plasma pharmacokinetics of irinotecan and its metabolites, the toxicity profile of this combination, and irinotecan's maximum-tolerated dose (MTD). PATIENTS AND METHODS: Thirty-three metastatic colorectal cancer patients were randomized to receive a 60-minute infusion of irinotecan before or after a 48-hour infusion of 5-FU modulated by LV. The reverse sequence was used after 21 days for the second cycle. 5-FU 3,500 mg/m2 was preceded by l-LV 250 mg/m2. Irinotecan 150 mg/m2 (starting dose) was administered to the first three patients. The dose was escalated by 50 mg/m2 in subsequent groups of three to six patients to determine the MTD for both sequences. Pharmacokinetic analysis of irinotecan and its metabolites was performed after each cycle. RESULTS: Toxicities were affected by the sequence of administration of irinotecan and 5-FU, with an improved tolerability for irinotecan followed by 5-FU. The irinotecan MTD was reached at 300 mg/m2 when irinotecan followed 5-FU and at 450 mg/m2 when it preceded 5-FU. In seven of 23 patients who received both sequences at identical irinotecan doses, the dose-limiting toxicity was observed only when irinotecan followed 5-FU. Pharmacokinetic analysis revealed that the administration sequence significantly affected the SN-38 area under the concentration-versus-time curve (AUC), which was 40.1% lower (P <.05) when irinotecan preceded 5-FU. CONCLUSION: The sequence of treatment with irinotecan and infusional 5-FU affects the tolerability of this combination. This can be explained in part by a reduced SN-38 AUC when irinotecan preceded infusional 5-FU. Well-defined 5-FU/irinotecan regimens are needed because the administration sequence or the interval between the agents might affect treatment tolerance and perhaps also activity.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Camptotecina/farmacocinética , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/farmacologia , Adenocarcinoma/metabolismo , Adulto , Idoso , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Neoplasias Colorretais/metabolismo , Esquema de Medicação , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Infusões Intravenosas , Irinotecano , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Metástase NeoplásicaRESUMO
OBJECTIVE: The primary objective of this trial was to determine the objective response of two regimens with CDDP administered every 2 weeks immediately before or after an 'optimal' 48-hour chronomodulated infusion of 5-fluorouracil (5-FU) modulated with leucovorin (LV) in metastatic colorectal cancer patients. Secondary endpoints were toxicity, 5-FU and its metabolites, plasma pharmacokinetics and progression-free and overall survival. METHODS: Metastatic colorectal cancer patients with measurable disease who were chemotherapy-naive or pretreated only with a 5-FU-bolus-based chemotherapy were eligible for this study. The study was designed as a randomized phase II clinical trial. RESULTS: Eighty-three patients were entered into the study. Forty-two were randomized to CDDP given before 5-FU and 41 to CDDP given after 5-FU. Patient characteristics were similar among the two groups. Toxicities were also similar among the two arms and the most frequent WHO grade III-IV toxicities were stomatitis (14%) and neutropenia (39-50%). Plasma pharmacokinetic profiles of 5-FU and 5-FUH2 were not significantly affected by the sequence of CDDP and 5-FU administration. Antitumor activity was similar in the two arms and was very promising both in pretreated patients (response rate 29%; 95% confidence interval 15-46%) and in chemotherapy-naive patients (response rate 56%, complete response 9%, 95% confidence interval 40-71%). Median survival of the patients with and without pretreatment was 12 and 16 months, respectively. CONCLUSIONS: These results do not suggest a sequence dependence of the synergism between CDDP and 5-FU. However, they challenge the need of oxaliplatin to improve 5-FU/LV activity in advanced colorectal cancer. In fact, our results with an 'optimal' 5-FU dose and scheduling are very similar to those obtained with oxaliplatin plus 5-FU/LV. However, only a randomized phase III study will be able to give an answer to the hypotheses raised by this study.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Análise Atuarial , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Cisplatino/administração & dosagem , Cisplatino/farmacocinética , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/farmacocinética , Humanos , Infusões Intravenosas , Leucovorina/administração & dosagem , Leucovorina/farmacocinética , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Resultado do TratamentoAssuntos
Antineoplásicos/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Antimetabólitos Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Quimioterapia Adjuvante , Fluoruracila/administração & dosagem , Humanos , Infusões Intravenosas , Injeções Intravenosas , Metotrexato/administração & dosagem , Análise de Sobrevida , Resultado do TratamentoRESUMO
Hepatocellular carcinoma (HCC) remains one of the most common neoplasms in the world. Doxifluridine is an oral fluoropyrimidine derivative activated to 5-fluorouracil by uridine phosphorylase which is more expressed in malignant cells. Therefore, we conducted a phase II study to evaluate the activity of oral doxifluridine in patients with advanced hepatocellular carcinoma. Twenty-five advanced hepatocellular carcinoma patients entered the study; doxifluridine was given orally at the initial daily total dose of 2,250 mg for 4 consecutive days every week. All patients are evaluable for toxicity: these included mainly grade 1-2 (WHO) diarrhea, stomatitis, nausea and vomiting; 4 patients (16%) experienced grade 3-4 diarrhea. Twenty-four patients are evaluable for response and 1 complete and 3 partial responses have been observed (response rat 17%, 95% confidence interval: 5-37). Oral doxifluridine at the dose and schedule we used, although having only modest activity in advanced HCC, may represent an alternative to other frequently used chemotherapeutic agents, because of its favorable toxicity profile and its simple route of administration.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Floxuridina/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Administração Oral , Idoso , Assistência Ambulatorial , Antimetabólitos Antineoplásicos/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Floxuridina/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Análise de SobrevidaRESUMO
The aim of this study was to investigate the clinical pharmacokinetics of 5-fluorouracil (5-FU) and its major metabolite 5-fluoro-5,6-dihydrouracil (5-FDHU) in 20 colorectal cancer patients given two dose levels of 5-FU, 250 and 370 mg/m2, administered by i.v. bolus. A reverse-phase high-performance liquid chromatographic method was used for the simultaneous assay of 5-FU and 5-FDHU in plasma samples obtained at baseline and at multiple time points from 5 min to 4 h after 5-FU bolus as well as to assess the activity of dihydropyrimidine dehydrogenase (DPD) in peripheral blood mononuclear cells (PBMCs) before 5-FU dosing. Plasma pharmacokinetic parameters of patients given 250 mg/m2 5-FU were significantly different from those receiving 370 mg/m2; main differences were observed in the trapezoidal areas under the plasma levels-versus-time curve from to to the last measurable concentration (area under the curve, 3.77+/-0.21 versus 13.61+/-2.3 h x microg/ml), peak plasma concentration (Cmax, 18.15+/-1.35 versus 48.41+/-7.69 microg/ml), and total body clearance (CL(TB), 54.64+/-3.54 versus 25.43+/-2.3 l/h/m2). Significant differences were also observed in the main pharmacokinetic parameters of 5-FDHU after 250 and 370 mg/m2 5-FU including the area under the curve from to to 4 h (5.39+/-0.32 versus 8.75+/-1.24 h x microg/ml), Cmax (3.60+/-0.16 versus 5.26+/-0.55 microg/ml) and time to Cmax (Tmax, 0.45+/-0.03 versus 0.69+/-0.06 h). The mean DPD activity in PBMCs in this group of patients was 205.7+/-36.4 pmol of 5-FDHU/min/mg of protein and was within the normal range; however, no significant correlations were found between 5-FU or 5-FDHU pharmacokinetic parameters at two dose levels and DPD activity of PBMCs. The results of the present study provide the first detailed comparison of the distribution of 5-FU and its major metabolite 5-FDHU at the therapeutic level as well as at reduced test dose levels to obtain pharmacokinetic data to be used as reference values for the identification of patients at risk of major 5-FU toxicity due to impaired metabolism to 5-FDHU.
Assuntos
Adenocarcinoma/metabolismo , Antimetabólitos Antineoplásicos/farmacocinética , Neoplasias Colorretais/metabolismo , Fluoruracila/análogos & derivados , Fluoruracila/farmacocinética , Adenocarcinoma/sangue , Adenocarcinoma/enzimologia , Adulto , Idoso , Antimetabólitos Antineoplásicos/sangue , Quimioterapia Adjuvante , Neoplasias Colorretais/sangue , Neoplasias Colorretais/enzimologia , Di-Hidrouracila Desidrogenase (NADP) , Relação Dose-Resposta a Droga , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/sangue , Humanos , Leucócitos Mononucleares/enzimologia , Masculino , Pessoa de Meia-Idade , Oxirredutases/sangueRESUMO
Preclinical and clinical studies have demonstrated that the circadian modulation of 5-FU delivery may reduce toxicities and improve antitumor activity. However, the relative importance of the timing of 5-FU delivery has not been clinically addressed. The aims of this study were to determine the toxicities, the maximum tolerable doses and the activity of a regimen with 5-fluorouracil (5-FU) and leucovorin (LV) administered as a 14-day continuous infusion according to a flat or three different chronomodulated rhythms in patients with metastatic gastrointestinal carcinomas. A total of 113 patients entered the study and their characteristics were comparable among the four groups. Toxicities included mainly stomatitis and diarrhea, and a reduced toxicity was observed in all the three chronogroups that allowed the delivery of higher dose intensities. Response rates were not significantly different among the four groups. These results suggest that a reduction in 5-FU+LV toxicity and an increase in 5-FU dose intensity can be obtained by a nonsinusoidally circadian modulated infusion. However, the reduction in toxicity observed seems to be dependent mainly on the quasi-intermittency and not on the timing of 5-FU+LV delivery.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cronoterapia , Neoplasias Gastrointestinais/tratamento farmacológico , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Infusões Intravenosas , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND: Suramin and epirubicin are both active agents in the treatment of patients with hormone-refractory advanced prostate carcinoma, with demonstrated antitumor synergism in vitro on human prostate carcinoma cells and different dose-limiting toxicities. The authors conducted this Phase II study to determine the feasibility, toxicity, and antitumor activity of suramin in combination with epirubicin. METHODS: Only patients with hormone-independent advanced prostate carcinoma who had progressive disease after the last therapeutic maneuver they had undergone, including antiandrogen withdrawal, entered the study. Suramin was administered initially as a 6-day continuous infusion for 10 consecutive weeks and then for 6 days every 28 days for a maximum of 6 months. Doses were determined by a computer-assisted dosing system that used Bayesian pharmacokinetics to maintain suramin plasma concentrations of 200-250 microg/mL. Cortisone acetate 25 mg, administered at 8 a.m. and 8 p.m. daily, was begun 4 weeks after the initiation of suramin therapy. Epirubicin 25 mg/m2 was given as a weekly intravenous bolus beginning on Day 1 and was continued for a maximum of 6 months. RESULTS: Twenty-six patients entered the study. Toxicities mainly included World Health Organization Grade 1-2 nausea, fatigue, anorexia, neutropenia, peripheral neuropathy, creatinine elevation, proteinuria, and prolonged prothrombin time, whereas Grade 3 toxicities were uncommon. Among 11 patients with measurable disease, 3 (27%) demonstrated an objective response. Among 24 patients evaluated for prostate specific antigen (PSA) response, 8 (33%; 95% confidence interval 16-55%) had a > or =50% decrease in PSA levels, which lasted a median of 32 (range, 8-52) weeks. Median progression free and overall survival were both 8 months. CONCLUSIONS: The combination of suramin and epirubicin used in the current study is feasible, is associated with moderate toxicities, and has antitumor activity in advanced hormone-refractory prostate carcinoma. However, the results obtained with this combination do not represent major improvements in the treatment of patients with this disease, compared with suramin or epirubicin alone or other available treatments.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Sob a Curva , Teorema de Bayes , Intervalo Livre de Doença , Esquema de Medicação , Epirubicina/administração & dosagem , Epirubicina/efeitos adversos , Epirubicina/farmacocinética , Estudos de Viabilidade , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Suramina/administração & dosagem , Suramina/efeitos adversos , Suramina/farmacocinéticaRESUMO
Continuous-infusion (c.i.) 5-fluorouracil (5-FU) can overcome resistance to bolus 5-FU, and leucovorin (LV) enhances the cytotoxic effects of 5-FU, mainly when the duration of exposure to the latter is prolonged. The main objective of this study was therefore to determine the activity of a prolonged infusion schedule of 5-FU + LV in patients with metastatic colorectal cancer resistant to a 5-FU bolus-based chemotherapy. Only patients with metastatic measurable disease in progression during or within 2 months of the end of a 5-FU bolus +/- LV-based chemotherapy were eligible for the study. 5-FU and l-LV were given as a 14-day c.i. every 28 days, the 5-FU dose being 200 mg/m2 per day and the l-LV dose being 5 mg/m2 per day. A total of 59 patients entered the study, of which 48 were resistant to 5-FU + LV and 11, to 5-FU + levamisole. Treatment was well tolerated, and WHO grade 3-4 toxicities were uncommon (11% of patients developed stomatitis and 7%, diarrhea). According to an intent-to-treat analysis, 10 of 59 patients obtained an objective response (1 complete response, 9 partial responses), for an objective response rate of 16% (95% confidence interval 8-25%). The median progression-free survival and overall survival were 4 and 9 months, respectively. The protracted 5-FU + LV c.i. schedule used in the present study is a well-tolerated and moderately active regimen in metastatic colorectal cancer patients resistant to 5-FU bolus +/- LV. Only randomized studies can determine whether this palliative treatment has advantages in comparison with other second-line therapies such as 5-FU c.i. without LV, irinotecan, or oxaliplatin.